• Adult patients, 18 years or older.
• Previous participation in an Astex-sponsored ASTX727 clinical trial (including, but not limited to studies ASTX727-01, ASTX727-02, and ASTX727-04) in which the subject was treated with ASTX727 and was still on active treatment with ASTX727 at the time of study completion as determined by Astex. 
• Subject is considered to be benefitting from ASTX727 treatment in the opinion of the treating investigator at the time of parent study completion (subjects must not be withdrawn from the parent study until eligibility for this study is confirmed). 
• Subject is able to understand and comply with the study procedures and understands the risks involved in the study. 
• Subject provides written informed consent before undergoing any study-specific procedure.
• Women of childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential must agree to practice 2 highly effective contraceptive methods of birth control and must agree not to become pregnant for 6 months after completing treatment; men with female partners of childbearing potential must agree to practice 2 highly effective contraceptive measures and must agree not to father a child while receiving ASTX727 and for at least 3 months after completing ASTX727 treatment.

• Any subject who, in the opinion of the investigator, may have other conditions, organ dysfunction, or for whom safety data from parent study participation suggests the risks of continuing treatment with ASTX727 may outweigh the benefits.

• 18 years of age or older.
• Able to read, write and understand English.
• Undergoing chemotherapy, radiation therapy, CAR-T, or bone marrow transplant for a cancer diagnosis within the previous 3 years or have metastatic cancer.
• A mean score of at least 1.1 on the Cancer and Treatment Distress (CTxD) or at least one item rated at a 3 (often true) or 4 (nearly all the time).
• A minimum score of 3 on the PC-PTSD-5.
• Denial of suicidal ideation or intent, with no evidence of psychotic behavior.
• Participants must be willing and able to travel to Mayo Clinic outside of normally scheduled visits to participate in the study.

• Individuals under 18 years of age.

• Age > 22 years (minimum age approved for use).
• Polypoid (0-Is) and non-polypoid (0-IIa, 0-IIb and 0-IIc) lateral spreading lesions according to Paris classification.
• Colorectal lesions situated between 5 and 15 cm from the dentate line.
• Colorectal mucosal lesions ranging from 1.5 to 7 cm in maximum diameter.
• Colorectal subepithelial lesions < 2 cm in size.
• Absence of uncorrectable bleeding disorder or coagulopathy (platelet count > 50,000 and INR < 1.5).
• Ability to give informed consent.

• Inability to receive general anesthesia.
• Presence of medical conditions for which a transanal approach is contraindicated (e.g., anal stricture, radiation proctopathy).
• Excavated (0-III) colorectal lesions according to Paris classification.
• Suboptimal colon preparation.
• Clinical discretion of the provider.

• Biopsy-proven histological diagnosis of localized prostate cancer (pT2 or specimen confined pT3).
• Having undergone radical prostatectomy (open or laparoscopic) with bilateral pelvic lymph node dissection.
• Negative surgical margins on final specimen.
• Men that decline adjuvant therapy.
• Detectable serum PSA of 0.1 ng/mL or >.
• 24 months or less since radical prostatectomy at time of study screening.

• Unable or unwilling to provide informed consent.
• Treated prior to surgery with any form of hormone, antiandrogen, or androgen deprivation therapy.
• Treated prior to surgery with any form of chemotherapy or radiotherapy.
• Medical conditions/history that precludes subjects from following a fasting regimen including, but not limited to:
  • Diabetes Mellitus.
• On hormone therapy (Casodex, GnRH agonist/antagonist).

• Age ≥ 18 years.
• Histological confirmation of adenocarcinoma of the pancreas (head, body, or tail of pancreas).
• Imaging consistent with T1-4, N0-2,  M0 pancreas cancer, including potentially resectable, borderline resectable, or unresectable disease as per NCCN classification. When CT of the chest, abdomen, and pelvis are performed, this must be with contast per pancreas protocol. Imaging with a PET/MRI alone is acceptable on study. If a PET/CT is performed, a separate pancreas protocol CT is required for inclusion.
  • *Note: Imaging must be done prior to initiation of radiotherapy and does not need to be completed at time of enrollment.
• Must have received neoadjuvant chemotherapy at the discretion of medical oncology.
• Medical oncology consultation to confirm that patient is an appropriate candidate for concurrent chemotherapy, and surgical oncology consultation for confirmation of resection status.
  • Note: Consultation must be completed prior to initiation of radiotherapy and does not need to be completed at time of enrollment.
• Patients who have received previous chemotherapy for pancreatic cancer are allowed to participate in this study, unless they experienced a previous allergic reaction to the drugs used in this study.
• Planned to receive CRT, consisting of PBT or IMRT (45 Gy/15 fractions) with concurrent chemotherapy with 5 FU or Capecitabine.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 or Karnofsky Performance Status 70-100. 
• Willing to sign consent onto the Mayo Clinic Radiotherapy Patient Outcomes Registry and Biobanking study, IRB 15-000136*.
  • *Patients do not need to agree to Biobank blood draw. 
• Able to complete standard of care clinical questionnaire(s) by themselves or with assistance.

• Presence of non-regional nodal involvement or distant metastatic disease (M1).
• Prior radiotherapy resulting in overlap of radiation treatment fields.
• History of prior malignancy < 2 years of enrollment, except non-melanotic skin cancer or carcinoma-in-situ of the cervix.
• Immunocompromised patients and patients known to be HIV positive and not currently receiving antiretroviral therapy. 
  • Note: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Receiving any investigational agent concurrent with CRT which would be considered as a treatment for the primary neoplasm.
• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception.
• Co-morbid systemic or psychiatric illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.        
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated.
• Laboratory values used to assess eligibility must be no older than 7 days at the start of therapy.
• Laboratory tests need not be repeated if therapy starts within 7 days of obtaining labs to assess eligibility.
• If a post-enrollment lab value is outside the limits of eligibility, or laboratory values are > 7 days old, then laboratory evaluations must be re-checked within 48 hours prior to initiating therapy. If the recheck is outside the limits of eligibility, the patient may not receive protocol therapy and will be considered off protocol therapy.
• A pre- and post-operative brain MRI with and without contrast, and a baseline spine MRI with contrast, must be obtained prior to enrollment. The requirement for post-operative MRI is waived for patients who undergo biopsy only.
• Patients must be ≥ 3 years and ≤ 21 years of age at the time of enrollment.
• Patients must have eligibility confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1:
  • Newly diagnosed high-grade glioma with BRAFV600-mutation;
  • Positive or negative results for H3 K27M by immunohistochemistry (IHC)
  • Histologically confirmed high-grade glioma (WHO Grade III or IV) including but not limited to: anaplastic astrocytoma (AA), anaplastic pleomorphic xanthoastrocytoma (aPXA), anaplastic gangliogliomas (aGG), glioblastoma (GB), and high-grade astrocytoma, NOS.
• Patients must have had histologic verification of a high-grade glioma diagnosis. CSF cytology by lumbar puncture must be done if clinically indicated and determined to be safe prior to study enrollment. If cytology proves positive, the patient would be considered to have metastatic disease and would, therefore, be ineligible.
• A pre- and post-operative brain MRI with and without contrast and a baseline spine MRI with contrast must be obtained prior to enrollment. The requirement for a post-operative MRI is waived for patients who undergo biopsy only. If the spine MRI is positive, the patient would be considered to have metastatic disease and would be ineligible.
• Patients must have a performance status corresponding to ECOG scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age. See https://www.cogmembers.org/site/pages/default.aspx?page=Prot_reference_materials under Standard Sections for Protocols.
• Adequate Bone Marrow Function defined as:
  • Peripheral absolute neutrophil count (ANC) ≥ 1000/µL;
  • Platelet count ≥ 100,000/µL (transfusion independent);
  • Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions).
• Adequate Renal Function defined as:
  • Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m^2; or
  • A serum creatinine based on age/gender as follows:
  • 3 to < 6 years | Male 0.8 | Female 0.8;
  • 6 to < 10 years | Male 1.0 | Female 1.0;
  • 10 to < 13 years | Male 1.2 | Female 1.2;
  • 13 to < 16 years | Male 1.5 | Female 1.4;
  • ≥ 16 years | Male 1.7 | Female 1.4.
  • The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR32 utilizing child length and stature data published by the CDC.
  • Adequate Liver Function defined as:
    • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age; and
    • SGPT (ALT) ≤ 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
• Central Nervous System Function defined as:
  • Patients with a seizure disorder may be enrolled if their seizures are well controlled while on non-enzyme inducing anticonvulsants permitted on this study.
• Patients must be enrolled and protocol therapy must be projected to begin no later than 31 days after definitive surgery (Day 0). If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery.

• Patients with intrinsic brainstem or primary spinal cord tumors will be excluded.
• Patients with metastatic disease (defined as neuraxis dissemination either by imaging or by cytology) will be excluded.
• Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant for the treatment of HGG other than surgical intervention and/or corticosteroids.
• Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK inhibitor, or an ERK inhibitor.
• Patients with a history of a malignancy with confirmed activating RAS mutation.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib, trametinib, and their excipients.
• Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease, or uncontrolled infection), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol.
• Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs.
• History of Hepatitis B Virus, or Hepatitis C Virus infection (patients with laboratory evidence of cleared Hepatitis B Virus and/or Hepatitis C Virus may be enrolled).
• History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following:
  • Recent myocardial infarction (within the last 6 months);
  • Uncontrolled congestive heart failure;
  • Unstable angina (within last 6 months);
  • Clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker) except sinus arrhythmia within the past 24 weeks prior to the first dose of study treatment;
  • Coronary angioplasty or stenting (within last 6 months);
  • Intra-cardiac defibrillators;
  • Abnormal cardiac valve morphology (≥ Grade 2) documented by echocardiogram.
• Patients with a history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR), or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension).
• Patients with presence of interstitial lung disease or pneumonitis.
• Female patients who are pregnant are ineligible since there is yet no available information regarding human fetal or teratogenic toxicities.
• Lactating females are not eligible unless they have agreed not to breastfeed their infants for the duration of the study and for 4 months following discontinuation of study therapy.
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential (male or female) are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 4 months following discontinuation of study therapy. Male patients (including those who have had a vasectomy) taking dabrafenib and trametinib combination therapy must use a condom during intercourse while on study and for 16 weeks after stopping treatment, and should not father a child during these periods. Women of childbearing potential should use. effective non-hormonal contraception during therapy and for 4 weeks following discontinuation of dabrafenib and at least 4 months following the last dose of trametinib in patients taking combination therapy.  Women should be advised that dabrafenib may decrease the efficacy of hormonal contraceptives and an alternate method of contraception, such as barrier methods, should be used.
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, FDA, and NCI requirements for human studies must be met.

Eligibility last updated 9/28/21. Questions regarding updates should be directed to the study team contact.

For Patients with CLL

• Confirmed diagnosis of chronic lymphocytic leukemia (CLL).
• Must have received at least two (2) prior therapy regimens.
• Patients with Richter's transformation should have failed standard therapy.

For Patients with NHL

• Histologically confirmed diagnosis of B- or T-cell non-Hodgkins lymphoma (NHL).
• Must have a site of disease amenable to biopsy, and be suitable and willing to undergo study required biopsies at screening and during therapy.
• The histologic subtypes of NHL that are permitted in the dose escalation part were specified.
• Must have received at least two (2) prior therapy regimens.
• Patients with indolent lymphoma must have received and failed standard-of-care therapy or be intolerant or ineligibile to approved therapies and must be in need of therapeutic intervention.
• Patients with prior CART T-cell therapy will be permitted on this trial 30 days after CART infusion and meet protocol defined inclusion/exclusion criteria.

Exclusion Criteria:

Applicable to both CLL and NHL

• History of anaphylactic or other severe hypersensitivity/infusion reactions to ADCs, monoclonal antibodies (mAbs) and/or their excipients such that the patient in unable to tolerate immunoglobulin/monoclonal antibody administration.
• Any prior history of treatment with maytansine (DM1 or DM4)-based ADC.
• Known intolerance to a maytansinoid.
• Patients with any active or chronic corneal disorders.
• Patients who have any other condition that precludes monitoring of the retina or fundus.
• Patients with active CNS involvement are excluded, except if the CNS involvement has been effectively treated and provided that local treatment was > 4 weeks before enrollment. Patients that have been effectively treated for CNS disease and are stable under systemic therapy may be enrolled provided all other inclusion and exclusion criteria are met.
• Impaired cardiac function or clinically significant cardiac disease.
• Known history of Human Immunodeficiency Virus (HIV) infection, Active Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection.

• Age ≥ 18 years on day of signing informed consent.
• Specific by tumor cohorts:
  • For the HCC cohort, confirmed diagnosis of inoperable HCC by histology or clinical/radiological criteria:
    • No prior therapy with a PD-(L)1 immune checkpoint inhibitor (prior sorafenib is permitted);
    • No or one prior line of systemic therapy only;
    • Child Pugh Score A or B7.
  • For the NSCLC cohort, histologically confirmed diagnosis of advanced and/or metastatic NSCLC in which radiological progression has been demonstrated during therapy with a PD(L)1 immune CPI and for which no existing options are felt to provide clinical benefit (only one line of PD-(L)1 therapy is permitted). Progression during or following 1 or more prior regimen(s) and no more than 3 prior therapeutic regimens for metastatic disease.
  • For the melanoma cohorts, histologically confirmed diagnosis of advanced and/or metastatic melanoma in which radiological progression has been demonstrated during therapy with a PD(L)1 immune CPI and for which no existing options are considered to provide clinical benefit (only one line of PD(L)1 therapy is permitted). Progression on ipilimumab is not required.
    • For the IT melanoma cohort:
      • At least one tumor lesion amenable to repeated IT injection via palpation or ultrasound. Injection of deep visceral lesions is not permitted;
      • Agrees to provide a newly obtained biopsy of injected and witness lesions prior to start of study treatment, and to repeat biopsies twice during study treatment, and to providing the acquired tissue for biomarker analysis. Tissue obtained for the biopsy must not be previously irradiated, but a new or progressing lesion in the radiation field is acceptable.
    • For the endometrial cancer cohort, histologically confirmed diagnosis of advanced and/or metastatic endometrioid endometrial adenocarcinoma. Eligible patients will not have had any prior systemic therapy in the metastatic setting.
• For patients treated with prior anti-PD-(L)1 therapy:
  • Last dose of anti-PD-(L)1 must be within 12 weeks of initiating study treatment.;
  • Patient must have received at least 4 doses on q2w, 3 doses on q3w or 2 doses on q4w schedule of the previous anti-PD-(L)1 therapy;
  • Progression on prior anti-PD-(L)1 therapy must be defined by:
    • Documented radiographic progression on a single radiographic scan, if treatment with anti-PD-(L)1 was ≥ 16 weeks;
    • Documented radiographic progression on two consecutive radiographic scans at least 4 weeks apart, if treatment with anti-PD-(L)1 therapy was between 8
      •16 weeks; if radiographic progression is accompanied with clinical progression, then a single scan assessment may be used;
    • If progression was only in lymph nodes, biopsy to provide histological confirmation of progression in the lymph node is required.
• Measurable disease based on RECIST 1.1.

Patients meeting any of the following exclusion criteria at Screening/Day-1 of first dosing will not be enrolled in the study.

• Availability of and patient acceptance of an alternative curative therapeutic option.
• Recent or ongoing serious infection, including any active Grade 3 or higher per the National Institute of Cancer Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE, v5.0) viral, bacterial, or fungal infection within 2 weeks of registration.
• Known seropositivity for and with active infection by the human immunodeficiency virus (HIV):
  • Patients who are seropositive for HIV but are receiving antiviral therapy and show non-detectable viral load and a normal CD4 T cell count for at least 6 months are eligible;
  • Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV);
  • Patients who are hepatitis B surface antigen (HBsAg) negative and HBV viral DNA negative are eligible;
  • Patients who had HBV but have received an antiviral treatment and show non-detectable viral DNA for 6 months are eligible;
  • Patients who are seropositive because of HBV vaccine are eligible.
• Seropositive for and with active viral infection with hepatitis C virus (HCV):
  • Patients who had HCV but have received an antiviral treatment and show no detectable HCV viral DNA for 6 months are eligible.
• Known history of active or latent TB (bacillus tuberculosis).
• Any concomitant serious health condition, which, in the opinion of the investigator, would place the patient at undue risk from the study, including uncontrolled hypertension and/or diabetes, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease requiring hospitalization within 3 months) or neurological disorder (e.g., seizure disorder active within 3 months).
• Prior therapy within the following timeframe before the planned start of study treatment as follows:
  • Small molecule inhibitors, and/or other investigational agent: ≤ 2 weeks or 5 half-lives, whichever is shorter;
  • Chemotherapy, other monoclonal antibodies, antibody-drug conjugates, or other similar experimental therapies:
    • ≤ 3 weeks or 5 half-lives, whichever is shorter;
    • Antibody drug conjugates and radioimmunoconjugates or other similar experimental therapies ≤ 6 weeks or 5 half-lives, whichever is shorter.
• New York Heart Association (NYHA) classification III or IV, known symptomatic coronary artery disease, or symptoms of coronary artery disease on systems review, or known cardiac arrhythmias (atrial fibrillation or supraventricular tachycardia).
• Any known or suspected active organ-threatening autoimmune disease, such as inflammatory bowel disease, autoimmune hepatitis, lupus, or pneumonitis, with the exception of hypothyroidism and type 1 diabetes that are controlled with treatment .
• Immunodeficiency or immunosuppression.
• History of Grade 3 or 4 immune-mediated adverse reaction to immune CPIs.
• Toxicities from previous therapies that have not resolved to a Grade 1 or less.
• History of non-infectious pneumonitis that required steroids, or current pneumonitis.

• Have a projected life expectancy of at least 12 weeks, as assessed by the Investigator.
• Have histological confirmation of AML by World Health Organization (WHO) 2016 criteria and are either:
  • refractory to intensive induction chemotherapy; OR
  • relapsed after intensive induction chemotherapy or stem cell transplant; OR
  • relapsed after or refractory to treatment with molecularly targeted and/or low-intensity chemotherapeutic regimens.
• Have an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2.
• Have adequate renal function as demonstrated by measured or calculated creatinine clearance ≥ 60 mL/min.
• Have adequate liver function as demonstrated by:
  • Aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN);
  • Alanine aminotransferase (ALT) ≤ 2.5 × ULN;
  • Bilirubin ≤ 1.5 × ULN
    •unless considered due to leukemic organ involvement.
• Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening.

• Poor medical risk in the investigator's opinion because of systemic diseases in addition to the cancer under study, for example, uncontrolled infections.
• Known clinically active central nervous system (CNS) leukemia.
• BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
• Diagnosis of acute promyelocytic leukemia (M3 AML or APML).
• Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy.
• Graft Versus Host Disease (GVHD), or any GVHD requiring treatment with immunosuppression. Any GVHD treatment (including calcineurin inhibitors) must be discontinued at least 28 days prior to Day 1 of study treatment.
• Presence of persistent toxicities of Grade > 1 from prior treatment including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, and surgery (except for alopecia).
• Hypersensitivity to decitabine, ASTX727, ASTX660, or any of their excipients.
• Liver cirrhosis, or chronic liver disease Child-Pugh Class B or C.
• Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator's opinion, could compromise participant safety, or the integrity of study outcomes, or interfere with the absorption or metabolism of ASTX660 or ASTX727.
• History of, or at risk for, cardiac disease.
• Known human immunodeficiency virus (HIV), active hepatitis B virus (HBV), or active hepatitis C virus (HCV) infection (participants with laboratory evidence of no active replication will be permitted).
• Known significant mental illness or other conditions, such as active alcohol or other substance abuse that, in the opinion of the investigator, predispose the participant to high risk of noncompliance with the protocol treatment or assessments.
• Treated with any investigational therapy within 2 weeks of the first dose of study treatment or treatment with a myelosuppressive therapy within 4 weeks of the first dose of study treatment.
• In Parts 1 and 2, prior treatment with decitabine for more than 2 cycles. In Part 3, any treatment with an HMA (azacitidine or decitabine, for more than one cycle).
• Inability to swallow oral medication or inability or unwillingness to comply with the administration requirements related to ASTX660-02.
  • Note: G-tube administration is not allowed.

• Adult females 13-45 years of age.
• Mild or moderate von Willebrand disease (VWF:RCo < 0.50 IU/ml, past bleeding.
• Menorrhagia and a PBAC > 100 in at least one of the last two menstrual cycles.
• Regular menses, at least every 21-35 days.
• Willingness to have blood drawn/
• No prior history of an allergic reaction or anaphylaxis to rVWF or TA.
• Willingness to avoid ASA and nonsteroidal anti-inflammatory agents (NSAIDS) during the study.
• Willingness to comply with randomization to rVWF or TA study arms.
• Willingness to keep a personal diary of menorrhagia bleeding frequency duration and severity by pictorial blood assessment chart, and any drugs or hemostatic agents taken.
• Willingness to make 4 visits, undergo blood sampling for coagulation studies, and accept randomization of two therapies for each of four consecutive menstrual cycles, including an end-of-study visit.
• Willingness to use “double-barrier” method of contraception during the study.

• Any bleeding disorder other than von Willebrand disease; or past thrombotic disease
• Pregnant or lactating, or use of hormones or oral contraceptives, and contraceptive implants in past 3 months.
• Platelet count < 100,000/ul.
• Use of immunomodulatory or experimental drugs.
• Surgery within the past 8 weeks.
• Concomitant use of antiplatelet drugs, anticoagulants, dextran, aspirin or NSAIDs.
• Treatment with DDAVP, cryoprecipitate, whole blood, plasma and plasma derivatives containing VWF within 5 days of study.
• Inability to comply with study requirements.
• Hypothyroidism as defined by elevated TSH.
• Iron deficiency as defined by low serum ferritin, unless iron replacement has been initiated.
• History of renal disease.

• Age ≥ 18 years.
• The following laboratory values obtained ≤ 14 days prior to registration:
  • Calculated creatinine clearance (using Cockcroft-Gault equation*) ≥ 30 mL/min.;
  • Absolute neutrophil count ≥ 1000/mL;
  • Untransfused platelet count ≥ 75000/mL;
  • Hemoglobin ≥ 8.0 g/dL;
  • Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN);
  • Aspartate aminotransferase (AST) ≤ 3 x ULN;
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x.
• *Cockcroft-Gault Equation:
• Creatinine clearance for males = (140
  •age)(actual body weight in kg) (72)(serum creatinine in mg/dL).
• Creatinine clearance for females = (140
  •age)(actual body weight in kg)(0.85)(72)(serum creatinine in mg/dL).
• Patients with relapsed multiple myeloma who have already received one or more standard treatment regimens.
• Measurable disease of multiple myeloma as defined by at least ONE of the following:
  • Serum monoclonal protein ≥ 1.0 g/dL;
  • ≥ 200 mg of monoclonal protein in the urine on 24 hour electrophoresis;
  • Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio.
  • For patients with EMD measurable disease by CT or MRI or the CT portion of the PET/CT: Must have at least one lesion that has a single diameter of ≥ 2 cm. Skin lesions can be used if the area is ≥ 2 cm in at least one diameter and measured with a ruler;
  • Plasma cell count ≥ 0.5 X 10^9/L or 5 percent of the peripheral blood white cells
  • Plasma cell count if determined by flow cytometry, ≥ 200/150,000 events.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2.
• Provide informed written consent.
• Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only.
• Willing to return to Mayo Clinic institution for follow-up during the Active Monitoring Phase of the study.
  • NOTE: during the Active Monitoring Phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up.

Arms A – D only:

• Patients should be proteasome inhibitor naïve (including bortezomib and carfilzomib) OR have received less than 6 cycles of therapy with a bortezomib or carfilzomib containing regimen and were not refractory to the bortezomib or carfilzomib based regimen (less than a PR or progression on or within 60 days of discontinuation).

Arm E only:

• Negative hepatitis B test (defined by a negative test for hepatitis B surface antigen [HBsAg], or antibodies to hepatitis B surface and/or core antigens [antiHBs or antiHBc).
  • NOTE:   Patients with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. Those who are PCR positive will be excluded.

• Recent prior chemotherapy.
• Alkylators (i.e., melphalan, cyclophosphamide) 14 days prior to registration.
• Anthracyclines ≤ 14 days prior to registration.
• High dose corticosteroids, immune modulatory drugs (thalidomide or lenalidomide) ≤ 7 days prior to registration.
• Prior therapy with any proteasome inhibitor other than bortezomib,  carfilzomib, or ixazomib,
• Concomitant high dose corticosteroids other than what is part of treatment protocol (concurrent use of corticosteroids). 
  • EXCEPTION:  Patients may be on chronic steroids (maximum dose 20 mg/day prednisone equivalent) if they are being given for disorders other than myeloma; i.e., adrenal insufficiency, rheumatoid arthritis, etc.
• Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease.  Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. 
• Any of the following:
  • Pregnant women or women of reproductive ability who are unwilling to use 2 effective methods of contraception from the time of signing the informed consent form through 90days after the last dose of study drug;
  • Nursing women;
  • Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 30 days after stopping treatment.
• Other co-morbidity which would interfere with patient's ability to participate in trial; e.g. uncontrolled infection, uncompensated heart or lung disease.
• Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational. 
  • NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment.
• Patient has ≥ Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.
• Major surgery within 14 days before study registration.
• Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort within 14 days before the first dose of study treatment.
• Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction within the past 6 months. 
  • NOTE:  Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
• Known human immunodeficiency virus (HIV) positive.
• Known hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection.
• Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
• Known allergy to any of the study medications, their analogues or excipients in the various formulations.
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing.
• Diarrhea > Grade 1, based on the NCI CTCAE grading, in the absence of antidiarrheals.

Arm E only: 

• Refractory to bortezomib, ixazomib or carfilzomib (less than a PR or progression on or within 60 days of discontinuation).
• Refractory to any combination of a proteasome inhibitor and Daratumumab.
• Known chronic obstructive pulmonary disease with a forced expiratory volume in 1second (FEV1) < 50% of predicted normal.
  • NOTE: that FEV1 testing is required for subjects suspected of having chronic obstructive pulmonary disease and subjects must be excluded if FEV1 < 50% of predicted normal.
• Known moderate or severe persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification (see Asthma Guidelines => https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf).

Eligibility last updated 8/31/21. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria

• Documentation of Disease
  • Confirmation of GCT histology (both seminoma and nonseminoma) on pathologic review at the center of enrollment
  • Tumor may have originated in any primary site
    • In rare circumstances, patients will be allowed to enroll even if a pathologic diagnosis may not have been established
    • This would require a clinical situation consistent with the diagnosis of GCT (testicular, peritoneal, retroperitoneal or mediastinal mass, elevated tumor marker levels {HCG ≥ 500; AFP ≥ 500} and typical pattern of metastases)
• Evidence of Disease
  • Must have evidence of progressive or recurrent GCT (measurable or non-measurable) following one line of cisplatin-based chemotherapy, defined as meeting at least one of the following criteria
    • Tumor biopsy of new or growing or unresectable lesions demonstrating viable non-teratomatous GCT
      • Enrollment in this study for adjuvant treatment after macroscopically complete resection of viable GCT is not allowed
    • In the event of an incomplete gross resection where viable GCT is found, patients will be considered eligible for the study
    • Consecutive elevated serum tumor markers (HCG or AFP) that are increasing
      • Increase of an elevated LDH alone does not constitute progressive disease
    • Development of new or enlarging lesions in the setting of persistently elevated HCG or AFP, even if the HCG and AFP are not continuing to increase
• Prior Treatment
  • Must have received 3-6 cycles of cisplatin-based chemotherapy as part of first-line (initial) chemotherapy
    • Prior POMBACE, CBOP-BEP, or GAMEC are allowed
    • For patients requiring immediate treatment, 1 cycle of conventional-dose salvage chemotherapy is allowed
      • Therefore, these patients may have received 7 prior cycles of chemotherapy. 6 cycles as part of first-line chemotherapy and 1 cycle of salvage conventional chemotherapy
  • No more than one prior line of chemotherapy for GCT (other than the 1 cycle of salvage chemotherapy as defined in the protocol)
    • Definition of one line of chemotherapy: One line of therapy can in some cases consist of 2 different cisplatin-based treatment combinations, provided there is no disease progression between these two regimens
    • Prior treatment with carboplatin as adjuvant therapy is allowed, provided patients meet other eligibility criteria (e.g., the patient has also received 3-4 cycles of cisplatin-based chemotherapy)
    • Prior treatment with 1-2 cycles of BEP or EP as adjuvant chemotherapy for early stage GCT is allowed, provided the patient also received 3-4 cycles of BEP or EP again at relapse.
      • Patients treated with 3-4 cycles of VIP at relapse following 1-2 cycles of BEP/EP are not eligible as this would be considered more than 1 line of prior therapy
  • No prior treatment with high-dose chemotherapy (defined as treatment utilizing stem cell rescue)
  • No prior treatment with TIP with the exception when given as a bridge to treatment on protocol for patients with rapidly progressive disease who cannot wait to complete the eligibility screening process. Only one cycle is allowed.
  • No concurrent treatment with other cytotoxic drugs or targeted therapies
  • No radiation therapy (other than to the brain) within 14 days of day 1 of protocol chemotherapy except radiation to brain metastases, which must be completed 7 days prior to start of chemotherapy
  • No previous chemotherapy within 17 days prior to enrollment. A minimum of three weeks after the last day of the start of the previous chemotherapy regimen before the first day of chemotherapy on study protocol
  • Must have adequate recovery from prior surgery (eg, healed scar, resumption of diet)
• Age ≥ 14 years (≥ 18 years in Germany)
• ECOG performance status 0 to 2
• Male gender
• Required initial laboratory values
  • Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3
  • Platelet Count ≥ 100,000/mm^3
  • Calculated creatinine clearance ≥ 50 mL/min
  • Bilirubin ≤ 2.0 x upper limits of normal (ULN)
  • AST/ALT ≤ 2.5 x upper limits of normal (ULN)
• No concurrent malignancy other than non-melanoma skin cancer, superficial noninvasive (pTa or pTis) TCC of the bladder, contralateral GCT, or intratubular germ cell neoplasia
  • Patients with a prior malignancy, but at least 2 years since any evidence of disease are allowed
• Negative Serology (antibody test) for the following infectious diseases
  • Human Immunodeficiency Virus (HIV) type 1 and 2
  • Human T-cell Leukemia Virus (HTLV) type 1 and 2 (mandatory in US but optional in Canada and Europe)
  • Hepatitis B surface antigen
  • Hepatitis C antibody
• No late relapse with completely surgically resectable disease
• Patients with late relapses defined as relapse ≥ 2 years from the date of completion of the last chemotherapy regimen whose disease is completely surgically resectable are not eligible
  • Patients with late relapses who have unresectable disease are eligible.
• No large (≥ 2 cm) hemorrhagic or symptomatic brain metastases until local treatment has been administered (radiation therapy or surgery)
  • Treatment may begin ≥ 7 days after completion of local treatment
  • Patients with small (< 2 cm) and asymptomatic brain metastases are allowed and may be treated with radiation therapy and/or surgery concurrently with Arm A or cycles 1 and 2 of Arm B if deemed medically indicated
• Radiation therapy should not be given concurrently with high-dose carboplatin or etoposide
• No secondary somatic malignancy arising from teratoma (e.g., teratoma with malignant transformation) when it is actively part of the disease recurrence or progression

Eligibility Criteria
•Pre-Registration:

• Patients ≥ 18 years of age.
• Clinical stage T1-3 N1 M0 breast cancer at diagnosis (prior to the start of neoadjuvant chemotherapy) by American Joint Committee on Cancer (AJCC) staging 7th edition.
• No inflammatory breast cancer.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix
• All patients must have had an axillary ultrasound with fine needle aspiration (FNA) or core needle biopsy of axillary lymph nodes documenting axillary metastasis at the time of diagnosis, prior to or at most 14 days after starting neoadjuvant chemotherapy.
  • Note: Biopsy of intramammary nodes does not fulfill eligibility criteria.
• Patients must have completed all planned neoadjuvant chemotherapy prior to surgery. Planned sandwich chemotherapy is not allowed (i.e., anthracycline/Cytoxan or taxane chemotherapy planned to be given after surgery). Patients must have completed at least 4 cycles of neoadjuvant chemotherapy consisting of an anthracycline and/or taxane-based regimen without evidence of disease progression in the breast or the lymph nodes.
  • Note: Delays/dose modifications due to toxicities/adverse events are allowed as long as a minimum of 4 cycles of neoadjuvant chemotherapy is administered. More than 4 cycles of NAC may be administered at the discretion of the treating medical oncologist.
• Patients with HER-2 positive tumors must have received neoadjuvant trastuzumab or trastuzumab + pertuzumab or other approved anti-HER-2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen). Therapy must be Food and Drug Administration (FDA)-approved targeted anti-HER2 therapy, but additional therapies are allowed as are non-trastuzumab regimens if administered in the context of an Institutional Review Board (IRB)-approved clinical trial.  Completion of a course of trastuzumab, pertuzumab, TD-M1 and/or other anti-Her2 neu therapy after surgery is allowed.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • NOTE: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • Note: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• No more than 8 weeks of neoadjuvant endocrine therapy prior to the start of neoadjuvant chemotherapy.
• No neoadjuvant radiation therapy.
• No SLN surgery/excisional biopsy for pathological confirmation of axillary status prior to or during neoadjuvant chemotherapy.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No prior ipsilateral axillary surgery, such as excisional biopsy of lymph node(s) or treatment of hidradenitis.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed. Ipsilateral multifocal or multicentric disease is allowed.
• Patients must not be pregnant or nursing. A negative pregnancy test is required prior to registration for women of childbearing potential.
  • NOTE: Peri-menopausal women must be amenorrheic for > 12 months to be considered not of childbearing potential.
• Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1.

Eligibility Criteria
•Intra-Operative Registration/ Randomization:

• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• A minimum of 1 sentinel node and a maximum of 8 total nodes (sentinel + non-sentinel) are identified and excised during the sentinel lymph node surgery. More than 8 nodes identified by either surgeon or pathologist is NOT allowed. Note: Patients who do not have an identifiable sentinel lymph node will not proceed to Registration/Randomization.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on intra-operative pathologic assessment.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
  • NOTE: If on final pathology, more than 8 lymph nodes are seen pathologically, then the patient should discontinue study.
• ALND is not to be performed prior to Registration/Randomization.
  • NOTE: Patients for whom no positive lymph nodes (sentinel or non-sentinel) are found during sentinel lymph node surgery will not proceed to registration/ randomization and can be considered for discussion of the NRG NSABP B-51/RTOG 1304 study “A Randomized Phase III Clinical Trial Evaluating the Role of Post-mastectomy Chest Wall and Regional Nodal XRT and Post-lumpectomy Regional Nodal XRT in Patients with Documented Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy.”

Eligibility Criteria
•Post-Operative Registration/ Randomization:

• For cases where ALND has not been performed and one of the following is true:
  • intraoperative evaluation of sentinel lymph node could not be/was not performed and final pathology identified a positive lymph node (sentinel or non-sentinel) with metastasis greater than 0.2 mm; OR
  • lymph node (sentinel or non-sentinel) considered negative on intra-operative evaluation was found to be positive on final pathology (with metastasis greater than 0.2 mm).
• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• Negative margin (by either breast conservation or mastectomy) on final pathology where negative margin is defined as no tumor on ink. Patients may be registered and randomized with positive margins if there are plans to clear the margins prior to radiation therapy. Negative margins are required prior to initiation of radiation therapy, and if not achieved, the patient should discontinue participation in the study.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on final pathology (for cases where intra-operative evaluation was not performed, or was negative and completion dissection was not performed).
• At least one and no more than 8 lymph nodes (sentinel and non-sentinel) were found by the pathologists to have been actually excised during sentinel lymph node procedure.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
• For those patients who also undergo contralateral breast surgery, if invasive disease is found in the contralateral breast, the patient is not eligible for registration /randomization.

Eligibility last updated 11/12/21. Questions regarding updates should be directed to the study team contact.

Eligibility Criteria
•Pre-Registration:

• Patients ≥ 18 years of age.
• Clinical stage T1-3 N1 M0 breast cancer at diagnosis (prior to the start of neoadjuvant chemotherapy) by American Joint Committee on Cancer (AJCC) staging 7th edition.
• No inflammatory breast cancer.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix
• All patients must have had an axillary ultrasound with fine needle aspiration (FNA) or core needle biopsy of axillary lymph nodes documenting axillary metastasis at the time of diagnosis, prior to or at most 14 days after starting neoadjuvant chemotherapy.
  • Note: Biopsy of intramammary nodes does not fulfill eligibility criteria.
• Patients must have completed all planned neoadjuvant chemotherapy prior to surgery. Planned sandwich chemotherapy is not allowed (i.e., anthracycline/Cytoxan or taxane chemotherapy planned to be given after surgery). Patients must have completed at least 4 cycles of neoadjuvant chemotherapy consisting of an anthracycline and/or taxane-based regimen without evidence of disease progression in the breast or the lymph nodes.
  • Note: Delays/dose modifications due to toxicities/adverse events are allowed as long as a minimum of 4 cycles of neoadjuvant chemotherapy is administered. More than 4 cycles of NAC may be administered at the discretion of the treating medical oncologist.
• Patients with HER-2 positive tumors must have received neoadjuvant trastuzumab or trastuzumab + pertuzumab or other approved anti-HER-2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen). Therapy must be Food and Drug Administration (FDA)-approved targeted anti-HER2 therapy, but additional therapies are allowed as are non-trastuzumab regimens if administered in the context of an Institutional Review Board (IRB)-approved clinical trial.  Completion of a course of trastuzumab, pertuzumab, TD-M1 and/or other anti-Her2 neu therapy after surgery is allowed.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • NOTE: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • Note: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• No more than 8 weeks of neoadjuvant endocrine therapy prior to the start of neoadjuvant chemotherapy.
• No neoadjuvant radiation therapy.
• No SLN surgery/excisional biopsy for pathological confirmation of axillary status prior to or during neoadjuvant chemotherapy.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No prior ipsilateral axillary surgery, such as excisional biopsy of lymph node(s) or treatment of hidradenitis.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed. Ipsilateral multifocal or multicentric disease is allowed.
• Patients must not be pregnant or nursing. A negative pregnancy test is required prior to registration for women of childbearing potential.
  • NOTE: Peri-menopausal women must be amenorrheic for > 12 months to be considered not of childbearing potential.
• Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1.

Eligibility Criteria
•Intra-Operative Registration/ Randomization:

• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• A minimum of 1 sentinel node and a maximum of 8 total nodes (sentinel + non-sentinel) are identified and excised during the sentinel lymph node surgery. More than 8 nodes identified by either surgeon or pathologist is NOT allowed. Note: Patients who do not have an identifiable sentinel lymph node will not proceed to Registration/Randomization.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on intra-operative pathologic assessment.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
  • NOTE: If on final pathology, more than 8 lymph nodes are seen pathologically, then the patient should discontinue study.
• ALND is not to be performed prior to Registration/Randomization.
  • NOTE: Patients for whom no positive lymph nodes (sentinel or non-sentinel) are found during sentinel lymph node surgery will not proceed to registration/ randomization and can be considered for discussion of the NRG NSABP B-51/RTOG 1304 study “A Randomized Phase III Clinical Trial Evaluating the Role of Post-mastectomy Chest Wall and Regional Nodal XRT and Post-lumpectomy Regional Nodal XRT in Patients with Documented Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy.”

Eligibility Criteria
•Post-Operative Registration/ Randomization:

• For cases where ALND has not been performed and one of the following is true:
  • intraoperative evaluation of sentinel lymph node could not be/was not performed and final pathology identified a positive lymph node (sentinel or non-sentinel) with metastasis greater than 0.2 mm; OR
  • lymph node (sentinel or non-sentinel) considered negative on intra-operative evaluation was found to be positive on final pathology (with metastasis greater than 0.2 mm).
• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• Negative margin (by either breast conservation or mastectomy) on final pathology where negative margin is defined as no tumor on ink. Patients may be registered and randomized with positive margins if there are plans to clear the margins prior to radiation therapy. Negative margins are required prior to initiation of radiation therapy, and if not achieved, the patient should discontinue participation in the study.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on final pathology (for cases where intra-operative evaluation was not performed, or was negative and completion dissection was not performed).
• At least one and no more than 8 lymph nodes (sentinel and non-sentinel) were found by the pathologists to have been actually excised during sentinel lymph node procedure.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
• For those patients who also undergo contralateral breast surgery, if invasive disease is found in the contralateral breast, the patient is not eligible for registration /randomization.

Eligibility last updated 11/12/21. Questions regarding updates should be directed to the study team contact.

Eligibility Criteria
•Pre-Registration:

• Patients ≥ 18 years of age.
• Clinical stage T1-3 N1 M0 breast cancer at diagnosis (prior to the start of neoadjuvant chemotherapy) by American Joint Committee on Cancer (AJCC) staging 7th edition.
• No inflammatory breast cancer.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix
• All patients must have had an axillary ultrasound with fine needle aspiration (FNA) or core needle biopsy of axillary lymph nodes documenting axillary metastasis at the time of diagnosis, prior to or at most 14 days after starting neoadjuvant chemotherapy.
  • Note: Biopsy of intramammary nodes does not fulfill eligibility criteria.
• Patients must have completed all planned neoadjuvant chemotherapy prior to surgery. Planned sandwich chemotherapy is not allowed (i.e., anthracycline/Cytoxan or taxane chemotherapy planned to be given after surgery). Patients must have completed at least 4 cycles of neoadjuvant chemotherapy consisting of an anthracycline and/or taxane-based regimen without evidence of disease progression in the breast or the lymph nodes.
  • Note: Delays/dose modifications due to toxicities/adverse events are allowed as long as a minimum of 4 cycles of neoadjuvant chemotherapy is administered. More than 4 cycles of NAC may be administered at the discretion of the treating medical oncologist.
• Patients with HER-2 positive tumors must have received neoadjuvant trastuzumab or trastuzumab + pertuzumab or other approved anti-HER-2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen). Therapy must be Food and Drug Administration (FDA)-approved targeted anti-HER2 therapy, but additional therapies are allowed as are non-trastuzumab regimens if administered in the context of an Institutional Review Board (IRB)-approved clinical trial.  Completion of a course of trastuzumab, pertuzumab, TD-M1 and/or other anti-Her2 neu therapy after surgery is allowed.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • NOTE: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • Note: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• No more than 8 weeks of neoadjuvant endocrine therapy prior to the start of neoadjuvant chemotherapy.
• No neoadjuvant radiation therapy.
• No SLN surgery/excisional biopsy for pathological confirmation of axillary status prior to or during neoadjuvant chemotherapy.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No prior ipsilateral axillary surgery, such as excisional biopsy of lymph node(s) or treatment of hidradenitis.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed. Ipsilateral multifocal or multicentric disease is allowed.
• Patients must not be pregnant or nursing. A negative pregnancy test is required prior to registration for women of childbearing potential.
  • NOTE: Peri-menopausal women must be amenorrheic for > 12 months to be considered not of childbearing potential.
• Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1.

Eligibility Criteria
•Intra-Operative Registration/ Randomization:

• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• A minimum of 1 sentinel node and a maximum of 8 total nodes (sentinel + non-sentinel) are identified and excised during the sentinel lymph node surgery. More than 8 nodes identified by either surgeon or pathologist is NOT allowed. Note: Patients who do not have an identifiable sentinel lymph node will not proceed to Registration/Randomization.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on intra-operative pathologic assessment.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
  • NOTE: If on final pathology, more than 8 lymph nodes are seen pathologically, then the patient should discontinue study.
• ALND is not to be performed prior to Registration/Randomization.
  • NOTE: Patients for whom no positive lymph nodes (sentinel or non-sentinel) are found during sentinel lymph node surgery will not proceed to registration/ randomization and can be considered for discussion of the NRG NSABP B-51/RTOG 1304 study “A Randomized Phase III Clinical Trial Evaluating the Role of Post-mastectomy Chest Wall and Regional Nodal XRT and Post-lumpectomy Regional Nodal XRT in Patients with Documented Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy.”

Eligibility Criteria
•Post-Operative Registration/ Randomization:

• For cases where ALND has not been performed and one of the following is true:
  • intraoperative evaluation of sentinel lymph node could not be/was not performed and final pathology identified a positive lymph node (sentinel or non-sentinel) with metastasis greater than 0.2 mm; OR
  • lymph node (sentinel or non-sentinel) considered negative on intra-operative evaluation was found to be positive on final pathology (with metastasis greater than 0.2 mm).
• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• Negative margin (by either breast conservation or mastectomy) on final pathology where negative margin is defined as no tumor on ink. Patients may be registered and randomized with positive margins if there are plans to clear the margins prior to radiation therapy. Negative margins are required prior to initiation of radiation therapy, and if not achieved, the patient should discontinue participation in the study.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on final pathology (for cases where intra-operative evaluation was not performed, or was negative and completion dissection was not performed).
• At least one and no more than 8 lymph nodes (sentinel and non-sentinel) were found by the pathologists to have been actually excised during sentinel lymph node procedure.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
• For those patients who also undergo contralateral breast surgery, if invasive disease is found in the contralateral breast, the patient is not eligible for registration /randomization.

Eligibility last updated 11/12/21. Questions regarding updates should be directed to the study team contact.

PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)

• Patients must have paraffin tissue from the diagnostic or relapse biopsy available to be submitted for central pathology review.

ELIGIBILITY CRITERIA (STEP 1)

• Diagnosis of World Health Organization (WHO) diffuse large B-cell lymphoma, high grade B-cell lymphoma not otherwise specified, non-GCB by central review confirmation.
• Patient must be deemed eligible to proceed with high-dose chemotherapy and autologous stem cell transplantation by local transplant center.
• New York Heart Association class I or less; ordinary physical activity does not cause undue fatigue, palpitations, dyspnea, or angina pain; patients 60 years or older must have a left ventricular ejection fraction (LVEF) at rest ≥ 40% measured by echocardiogram or multi-gated acquisition (MUGA).
• Diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 40% of predicted (corrected for hemoglobin).
• Forced expiratory volume in 1 second (FEV1) ≥ 40% of predicted (corrected for hemoglobin).
• Forced vital capacity (FVC) ≥ 40% of predicted (corrected for hemoglobin).
• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN) unless isolated hyperbilirubinemia attributed to Gilbert's syndrome.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN).
• Creatinine ≤ 2.0 mg/dL OR creatinine clearance (calculated clearance permitted) ≥ 40 mL/min by Cockcroft-Gault formula.
• Prothrombin time (PT)/ international normalized ration (INR) < 1.5 x ULN and partial thromboplastin time (PTT) (activated [a]PTT) < 1.5 x ULN.
• Patient must have progressed or be refractory to prior anthracycline-containing chemotherapy (e.g., R-CHOP, DA-EPOCH-R, etc.).
• No more than 3 prior regimens for large cell component (e.g., one induction and two salvage therapies); monoclonal antibody alone or involved field/involved site radiotherapy do not count as lines of therapy.
• Prior use of ibrutinib is allowed unless patient has had disease progression while receiving ibrutinib.
• Patient must have chemosensitive disease as defined by at least a partial response to salvage therapy at their latest assessment.
• No major surgery ≤ 7 days prior to registration and no minor surgery ≤ 3 days prior to registration (with the exception of intravenous access placement; e.g., Hickman or peripherally inserted central catheter [PICC]).
• Not pregnant and not nursing; for women of childbearing potential only, a negative serum pregnancy test must be obtained within 14 days prior to registration.
  • Women of childbearing potential must use adequate contraception from study start to one month after the last dose of protocol therapy; adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence; men must practice complete abstinence or agree to use an adequate contraception method from study start to one month after the last dose of protocol therapy.
• Patients should not require chronic use of strong CYP3A inhibitors or strong CYP3A inducers.
• Patients should not require concurrent therapeutic doses of steroids (> 20 mg of prednisone/day or equivalent) unless they need them for the indications; steroids should be discontinued for 14 days before starting protocol treatment.
• Human immunodeficiency virus (HIV) infected patients are eligible provided they meet all other eligibility criteria, and:
  • There is no prior history of acquired immunodeficiency syndrome (AIDS) defining conditions other than historically low CD4+ T-cell count or B-cell lymphoma;
  • In the opinion of an expert in HIV disease, prospects for long-term survival are excellent were it not for the diagnosis of lymphoma;
  • Use of HIV protease inhibitors as part of the anti-HIV regimen OR as a pharmacologic booster is not allowed;
  • Zidovudine is not allowed;
  • Once daily combination pills for HIV containing a pharmacologic booster such as cobicistat are not allowed;
  • Patients with multi-drug resistant HIV are not eligible.
• Patients cannot have:
  • Active central nervous system or meningeal involvement by lymphoma; patients with a history of central nervous system (CNS) or meningeal involvement must be in a documented remission by cerebrospinal fluid (CSF) evaluation and contrast-enhanced magnetic resonance imaging (MRI) imaging for at least 91 days prior to registration;
  • Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy;
  • A known bleeding diathesis;
  • Requirement for warfarin or similar vitamin K antagonists; these drugs are prohibited 28 days prior to the first treatment and throughout the trial;
  • History of stroke or intracranial hemorrhage ≤ 6 months before treatment;
  • Currently active, clinically significant hepatic impairment (Child-Pugh class B or C according to the Child Pugh classification;
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or other agents used in study;
  • Serologic status reflecting active hepatitis B or C infection; patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment; (PCR positive patients will be excluded).
• Eastern Cooperative Oncology Group (ECOG) performance status must be ≤ 2

Patients who were pre-registered to NCI 9170 trial (Phase II Trial of Neoadjuvant MK-2206 in Combination with either Anastrozole if Postmenopausal or Anastrozole and Goserelin if Premenopausal in Women with Clinical Stage 2 or 3 PIK3CA Mutant Estrogen Receptor Positive and HER2 Negative Invasive Breast Cancer), started anastrozole (or anastrozole plus goserelin if premenopausal) < 6 weeks, and were found negative for PIK3CA hotspot mutations are eligible to be screened for the wild type cohort. In institutions without NCI9170 open, or after completion of enrollment to NCI9170 in institutions where it is open, patients will be pre-registered to this trial and those with PIK3CA mutations will be enrolled to the PIK3CA mutant cohort. Pre-registration is not required for patients to be enrolled in the endocrine resistant cohort, as PIK3CA mutation status will not be assessed.

Pre-Registration

• Clinical T2-T4c, any N, M0 invasive ER+ (Allred Score of 6-8) and HER2 negative (0 or 1+ by IHC or FISH negative for amplification) breast cancer, by AJCC 7th edition clinical staging, with the goal being surgery to completely excise the tumor in the breast and the lymph node.
  
  Note: Patients with invasive ER+ (Allred score of 6-8) HER2- breast cancer or DCIS in the contralateral breast the patient are eligible
   
• Female ≥18 years of age.
• ECOG performance status of 0, 1 or 2.
• Life expectancy > 4 months.
• If premenopausal, patient must be willing to comply with pregnancy requirements
• Adequate organ and marrow function as defined below:
  • leukocytes ≥ 3,000/mcL
  • absolute neutrophil count ≥ 1,500/mcL
  • platelets ≥ 100,000/mcL
  • total bilirubin ≤ upper normal institutional limits
  • AST(SGOT)/ and ALT(SGPT) ≤ 2.5 X institutional upper limit normal
  • Creatinine ≤ upper normal institutional limits
• Able to understand and willing to sign an IRB-approved written informed consent document.

Pre-Registration

• Prior treatment of this cancer including:
  • Surgery
  • Radiation therapy
  • Chemotherapy
  • Biotherapy
  • Hormonal therapy
  • Investigational agent prior to study entry.
• Receiving any other investigational agents.
• Prior therapy with any Cdk4 inhibitor.
• Any of the following in the previous 6 months:
  • myocardial infarction
  • severe/unstable angina
  • coronary/peripheral artery bypass graft
  • symptomatic congestive heart failure
  • cerebrovascular accident
  • transient ischemic attack
  • symptomatic pulmonary embolism.
• Uncontrolled intercurrent illness including, but not limited to:
  • ongoing or active infection
  • symptomatic congestive heart failure
  • unstable angina pectoris
  • uncontrolled symptomatic cardiac arrhythmia,
  • psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant/nursing.
• Unwilling to employ adequate contraception.
• Known HIV-positive on combination antiretroviral therapy.
  
  NOTE: HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with PD 0332991. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
   
• Evidence of inflammatory cancer (clinical presentation of skin erythema involving more than one third of the breast or pathological evidence of dermal lymphatic involvement)
• Known metastatic disease.
• Current use of anticoagulation therapy.
• Previous excisional biopsy of the breast cancer or sentinel lymph node biopsy.
• Any condition that impairs patient's ability to swallow PD 0332991 tablets (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption)
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to PD 0332991 or other agents used in the study.

Registration Inclusion Criteria

The criteria below must be met for registration onto the study in addition to the pre-registration criteria, except treatment with endocrine therapy for this cancer is allowed prior to registration.

• For the PIK3CA mutant cohort: tumor PIK3CA mutation present
• For the PIK3CA wild type cohort: tumor PIK3CA mutation absent.
  
  Note that if a patient did not have sufficient tissue for PIK3CA sequencing at pre-registration or if PIK3CA sequencing result is delayed, she could be registered and enrolled on this trial without assigning to a particular cohort at the time of enrollment. PIK3CA sequencing will be performed in the future on tumors collected at subsequent time points to assign the treatment cohort or when the PIK3CA sequencing data is available.
   
• In premenopausal women, serum estradiol level in postmenopausal range ≤ 7 days prior to registration.
• For the endocrine resistant cohort: Ki67 > 10% by central testing at Washington University AMP laboratory from a tumor biopsy performed after at least 2 weeks on neoadjuvant endocrine therapy.
  • Note that prior neoadjuvant endocrine therapy could include any endocrine therapy (including aromatase inhibitor, tamoxifen, fulvestrant) alone or in combination, or endocrine therapy in combination with any investigational agent that is not a Cdk 4/6 inhibitor.
  • Patients who had a Day 17 Ki67 > 10% from the NCI9170 trial are eligible for the endocrine resistant cohort.
  • Note that enrollment to the endocrine resistant cohort will depend on the funding availability. Please contact the study chair before enrolling patients to this cohort.

Registration Exclusion Criteria

The criteria below must be met for registration onto the study in addition to the pre-registration criteria.

• Current use or anticipated need for food or drugs that are known strong CYP3A4 inhibitors (i.e. grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, posaconazole, erythromycin, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, nefazodone, diltiazem, and delavirdine) or inducers (i.e. dexamethasone, glucocorticoids, progesterone, rifampin, phenobarbital, St. John's wort).

• Patients 0 to 70 years old
• Patients must have available both:
  • One or more potential related mismatched donors (biologic parent(s) or siblings (full or half) or children). At least low resolution DNA based HLA typing at HLA-A, -B, and -DRB1 for potential haploidentical sibling donors is required.
  • At least two potential umbilical cord blood units identified.
    • Each unit must have a minimum of 1.5 x 10^7/kg pre-cryopreserved total nucleated cell dose. For non-red blood cell depleted units, the minimum pre-cryopreserved total nucleated cell dose of each unit must be at least 2.0 x 10^7/kg.
    • Units must be HLA matched at a minimum of 4/6 to the recipient at HLA-A, HLA-B (at low resolution using DNA based typing) and HLA-DRB1 (at high resolution using DNA based typing). Confirmatory typing is not required for randomization.
• ALL in first complete remission (CR1) that is NOT considered favorable-risk as defined by the presence of at least one of the following:
  • Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), other MLL rearrangements;
  • White blood cell counts of greater than 30,000/mcL (B-ALL) or greater than 100,000/mcL (T-ALL)at diagnosis;
  • Recipient age older than 30 years at diagnosis
  • Time to CR greater than 4 weeks
• AML in CR1 that is NOT considered as favorable-risk. Favorable risk is defined as having one of the following:
  • t(8.21) without CKIT mutation,
  • inv(16) without CKIT mutation or t(16;16),
  • normal karyotype with mutated NPM1 and not FLT-IND, normal karyotype with double mutated CEBPA,
  • APL in first molecular remission at end of consolidation
• Acute Leukemias in 2nd or subsequent CR
• Biphenotypic/Undifferentiated/Prolymphocyctic Leukemias in first or subsequent CR, adult T-cell leukemia/lymphoma in first or subsequent CR
• Burkitt's lymphoma: second or subsequent CR
• Lymphoma fulfilling the following criteria: a) Chemotherapy-sensitive (complete or partial response; lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and are INELIGIBLE for an autologous transplant; b) Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at least at least two prior therapies (excluding single agent Rituxan).
• Performance status: Karnofsky score greater than or equal to 70%.

Additional Patient Inclusion Criteria for Conditioning:

• Patients with Adequate Physical Function as Measured by:
  • Cardiac: Left ventricular ejection fraction at rest must be greater than or equal to 40%, or shortening fraction less than 25%;
  • Hepatic: Bilirubin less than or equal to 2.5 mg/dL, except for patients with Gilbert's syndrome or hemolysis. ALT, AST, and Alkaline Phosphatase less than 5 x ULN;
  • Renal: Serum creatinine within normal range, or if serum creatinine outside normal range, then renal function (measured or estimated creatinine clearance or GFR) greater than 40 mL/min/1.73m^; d. Pulmonary: DLCO (corrected for hemoglobin), FEV1, and FVC greater than 50% predicted;
• Additional Patient Inclusion Criteria for Patients Assigned to Haploidentical BM Arm:
  • Patients must be HLA typed at high resolution using DNA based typing at the following HLA-loci: HLA-A, -B, -C and DRB1 and have available a related haploidentical BM donor with 2, 3, or 4 HLA-mismatches. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must be HLA identical for at least one antigen (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype, and typing of additional family members is not required.
• Additional Patient Inclusion Criteria for Patients Assigned to Double Umbilical Cord Blood Arm:
  • Patients must have available two UCB units fulfilling the following criteria:
    • Each unit must have a minimum of 1.5 x 10^7/kg pre-cryopreserved total nucleated cell dose. For non-red blood cell depleted units, the minimum pre-cryopreserved total nucleated cell dose of each unit must be at least 2.0 x10^7/kg.
    • Units must be HLA matched at a minimum of 4/6 to the recipient at HLA -A, HLA-B (at low resolution using DNA based typing), and HLA -DRB1 (at high resolution using DNA based typing).
    • Additional graft selection criteria specified in section 2.5
  • Patients must have received at least one cycle of the cytotoxic chemotherapy regimens (or regimen of similar intensity) listed in Appendix D within 3 months of enrollment (measured from the start date of chemotherapy) OR have had an autologous transplant within 24 months of enrollment OR receive 300 cGy as part of the preparative regimen

• Patients with suitably matched related or unrelated donor, as defined per institutional practice.
• Recipients of prior autologous hematopoietic stem cell transplantation are ineligible if disease recurrence occurred less than 6 months from their autologous stem cell transplant.
• Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
• Prior allogeneic HCT.
• Patients with history of primary idiopathic myelofibrosis or any severe marrow fibrosis.
• Planned use of prophylactic donor lymphocyte infusion (DLI) therapy.
• Anti-donor HLA antibodies.

Additional exclusion criteria:

• Pregnancy or breast-feeding.
• Evidence of HIV infection or known HIV positive serology.

• Patients (men or women) must have histologically or cytologically confirmed invasive breast cancer, with metastatic disease. Patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis by physical exam or radiologic study.
• Invasive primary tumor or metastatic tissue confirmation of HER2-positive status, defined as presence of one or more of the following criteria:
  • Over-expression by immunohistochemistry (IHC) with score of 3+ (in > 30% of invasive tumor cells) AND/OR HER2 gene amplification (average of > 6 HER2 gene copies per nucleus or a FISH ratio [HER2 gene copies to chromosome 17 signals] of ≥ 2.0), according to guidelines and in keeping with past eligibility for ratio of ≥ 2.0 rather than the ratio of > 2.2 required by new guidelines:
    • http://www.asco.org/quality-guidelines/recommendations-human-epidermal-growth-factor-receptor-2-testing-breast-cancer
  • Note: Patients with a negative or equivocal overall result (FISH ratio of < 2.0 or ≤ 6.0 HER2 gene copies per nucleus) and IHC staining scores of 0, 1+, 2+ are not eligible for enrollment.
• No increase in corticosteroid dose in the week prior to baseline brain imaging.
• Age ≥ 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Patients must have normal organ and marrow function as described below:
  • Absolute neutrophil count > 1,000/uL;
  • Platelets > 100,000/uL;
  • Total bilirubin ≤ 1.5 X upper limit of normal (ULN) ;
  • AST(SGOT)/ALT(SGPT) ≤3 X institutional ULN without liver metastases, or ≤ 5X institutional ULN with liver metastases;
  • Creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 50 mL/min.
• Left ventricular ejection fraction ≥ 50%, as determined by RVG (MUGA) or echocardiogram within 60 days prior to initiation of protocol therapy.
• Prior therapy (see specifics by each cohort below):
  • Prior trastuzumab is allowed for all cohorts;
  • Prior capecitabine is NOT allowed for participants enrolled to Cohorts 3A/3B ONLY;
  • Prior lapatinib is allowed for Cohorts 1, 2, and 3B, but NOT Cohort 3A;
  • Prior T-DM1 is NOT allowed for Cohorts 4A and 4B but is required for Cohort 4C. Dose reductions on prior T-DM1 for Cohort 4C do not preclude enrollment on Cohort 4C. Patients on 4C may have progressed on prior T-DM1 in the CNS or non-CNS sites and had to have tolerated therapy without significant toxicity that would preclude retreatment;
  • No prior therapy with neratinib is allowed on any cohort;
  • There is no limit to the number of previous lines of therapy (including chemotherapy, trastuzumab, and endocrine therapies). At least 2 weeks washout period post chemotherapy, any prior protocol therapy, lapatinib, other targeted or biologic or immunotherapy, or radiation therapy is required prior to study entry;
  • No washout is required for hormonal therapy, but concurrent hormonal therapy is not allowed for patients on study. The only exception to this is longstanding ovarian suppression in pre-menopausal patients, if this has been started ≥ 6 months prior to study enrollment. Other hormonal therapies are not allowed while patients are on study.
• The effects of neratinib, capecitabine, and T-DM1 on the developing human fetus are not known. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• HIV-positive individuals on combination antiretroviral therapy are eligible for enrollment and will be monitored closely for potential pharmacokinetic interactions with neratinib.
• Concomitant medications listed in Appendix J should be avoided (when possible) while on study.
• Ability to understand and willingness to sign a written informed consent document.
• For Cohorts 1, 3A/3B, 4B and 4C patients must have new or progressive measurable CNS lesions, as assessed by the patient’s treating physician. This includes patients who have progressed after at least one line of standard local treatment for CNS disease (WBRT, SRS, or surgical resection as below).
• In Cohort 2, eligible patients will include those who have CNS disease that is amenable for surgery (typically < 3 brain metastases and with planned resection by neurosurgery). These patients may include those who have received or not received previous treatment(s) for their CNS.
• Further eligibility details for patients with progressive disease (Cohorts 1, 3A/3B, 4A, 4B, 4C):
  • Patients must have measurable CNS disease, defined as at least one parenchymal brain lesion that can be accurately measured in at least one dimension with longest dimension ≥10 mm by local radiology review. Note: measurable non-CNS disease is NOT required for study participation;
  • It is anticipated that some patients may have multiple progressive CNS lesions, one or several of which are treated with SRS or surgery with residual untreated lesions remaining. Such patients are eligible for enrollment on this study providing that at least one residual (i.e., non-SRS-treated or non-resected) lesion is measurable (≥10 mm). The location of the measurable lesion should be documented in the patient chart and case report form;
  • Patients who have had prior cranial surgery are eligible, provided that there is evidence of measurable residual or progressive lesions, and at least 2 weeks have passed since surgery. If a patient has surgical resection followed by WBRT, then there must be evidence of progressive CNS disease after the completion of WBRT;
  • Except for those in Cohort 4A where prior local CNS therapy is not allowed, patients who have had prior WBRT and/or SRS and then whose prior treated lesions have progressed thereafter are also eligible for all other cohorts. In this case, lesions which have been treated with SRS may be considered as target lesions if there is unequivocal evidence, in the opinion of the treating physician, of progression.
• Further eligibility details for patients with operable disease (Cohort 2):
  • It is anticipated that that patients who have intracranial disease amenable to surgery will have measurable CNS disease prior to study entry and to resection. However, this is not an eligibility requirement. Measurable disease is also not required to continue on protocol subsequent to surgical resection;
  • For patients who undergo surgery, postoperative whole brain radiation therapy will not be allowed while patients are on study (concurrent neratinib and radiation therapy has not been studied and toxicity of this is unknown). Patients will require discontinuation of neratinib if WBRT will be administered. However, if the treated provider feels that targeted radiosurgery (SRS, gamma knife, etc.) would be of benefit postoperatively, patients may proceed with this and then begin neratinib AFTER radiation completes.
• Further eligibility details for patients on Cohort 4A: All patients on Cohort 4A will not have received prior radiation or surgery to their brain. Prior systemic therapy aimed to treat disease in the brain is allowed (i.e., prior systemic standard therapy or protocol systemic therapy for brain mets).
  • Note: Laboratory tests required for eligibility must be completed within 4 weeks prior to study entry. Baseline measurements in the CNS must be documented from tests up to 21 days prior to planned start of protocol therapy unless not covered by insurance. If insurance coverage is an issue, a case by case approval of testing beyond this window may be approved by the overall study PI. Other non-laboratory tests must be performed as indicated.

• Participants who have had chemotherapy or radiotherapy (including investigational agents) within 2 weeks prior to entering the study or those who have not recovered adequately from adverse events due to agents administered more than 4 weeks earlier (excluding alopecia). Washout from trastuzumab or hormonal therapy is not required.
• Participants who are currently receiving any other investigational agents.
• History of severe allergic reactions or intolerability attributed to compounds of similar chemical or biologic composition to neratinib (all cohorts), capecitabine for Cohorts 3A/3B, and T-DM1 for Cohorts 4A-4C.
• Concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs), including phenytoin, carbamazepine, oxcarbazepine, fosphenytoin, phenobarbital, pentobarbital, or primidone.
• Patients who are receiving any cancer-directed concurrent therapy, such as concurrent chemotherapy, radiotherapy, or hormonal therapy while on study. Concurrent treatment with bisphosphonates and denosumab is allowed for bony metastases but should be started before the first dose of neratinib.
• Any prior treatment with capecitabine for patients enrolled to Cohorts 3A/3B, prior lapatinib for participants on Cohort 3A, and T-DM1 for Cohorts 4A-4B.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• For Cohorts 4A, 4B, and 4C: Patients with myocardial infarction or cardiomyopathy onset within the last 6 months are excluded.
• Active hepatitis B or hepatitis C with abnormal liver function tests (Cohorts 4A-4C):
  • Positive Hepatitis B (Hepatitis B surface antigen and antibody) and/or Hepatitis C (Hepatitis C antibody test) as indicated by serologies conducted ≤ 3 months prior to registration if liver function tests are outside of the normal institutional range.
  • Note: Patients with positive Hepatitis B or C serologies without known active disease are eligible if they meet all laboratory requirements.  Patients with laboratory evidence of vaccination to Hepatitis B (e.g., positive antibodies) are also eligible.
• Active liver disease from autoimmune disorders or sclerosing cholangitis.
• Lung disease from etiology other than metastatic breast cancer resulting in dyspnea at rest (4A-4C).
• More than two seizures over the last 4 weeks prior to study entry.
• Patients with known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign body. However, Head CT with contrast is allowed in place of MRI at baseline and throughout the study if MRI is contraindicated and a participant’s CNS lesions are clearly measurable on the head CT.
• Those with leptomeningeal metastases as the only site of CNS disease.
• Significant malabsorption syndrome or inability to tolerate oral medications.
• Any predisposing chronic condition resulting in baseline grade 2 or higher diarrhea.
• Inability to comply with study and/or follow-up procedures.
• Pregnant women are excluded from this study because neratinib (and other agents on study) is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with neratinib, breastfeeding should be discontinued if the mother is treated with neratinib. Negative urine pregnancy test is required for women of childbearing potential within 4 weeks of planned treatment start.
• Individuals with a history of a different active malignancy are ineligible.

PHASE I (ARMS A, B, C, D, E, F, G, H, I, X, Y, Z):

• Age ≥ 18 years old.
• Patients must have pathologically confirmed relapsed or refractory lassical Hodgkin Lymphoma (cHL). A biopsy at any relapse is acceptable. Other histologies including lymphocyte predominant (LP) HL are not permitted.
• Patients must have relapsed after first line chemotherapy. May have relapsed after autologous or allogeneic stem cell transplant, or have primary refractory disease. No upper limit for number of prior therapies. If status post allogeneic stem cell transplant, no active  graft versus host disease.
• Patients may have received prior brentuximab vedotin, but must not have received brentuximab vedotin within 6 months prior to registration, and must not have relapsed within 6 months of receiving previous brentuximab vedotin. Patients may not have received prior nivolumab or PD1/PDL1 axis agents. Patients in the nivolumab/brentuximab cohorts ONLY (D, E, F, Y) may have received prior ipilimumab.
• Patients may have received other prior activating immunotherapies (i.e., checkpoint inhibitors), but must not have received them within 6 months prior to registration, and there must be no serious unresolved complication of therapy at the time of registration. For the  purposes of this study monoclonal antibodies and antibody drug conjugates are not considered to be activating immunotherapies and there are no additional time restrictions on prior exposure to these agents (except prior brentuximab vedotin).
• ECOG-ACRIN performance status between 0-2.
• Patients must have measurable disease as defined in Section 6. Baseline measurements and evaluations must be obtained within 4 weeks of registration to the study. Abnormal PET scans will not constitute evaluable disease unless verified by a diagnostic quality CT scan. Patients must use the same imaging modality (CT or PET/CT) throughout the study.
• Women must not be pregnant or breast-feeding due to risk of fetal harm by the chemotherapeutic agents prescribed in this protocol. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
  • has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  • Female of childbearing potential? ______ (Yes or No)
  • Date of blood or urine test: ___________
• Women of childbearing potential (WOCBP) and sexually active males must either abstain from sexual intercourse for the duration of their participation in the study or agree to use both single barrier contraception and birth control pills or implants for at least one week prior to the start of the study drug and continuing for 5 months after the last dose of study drug (for female patients) and for 7 months after the last dose of study drug (for male patients who are sexually active with WOCBP).  Should a woman become pregnant or  suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately.
• Patients must have no evidence of dyspnea at rest and a pulse oximetry > 92% while breathing room air.
• Patients must have FEV1/FVC > 60% by pulmonary function test (PFT), unless due to large mediastinal mass from HL. Carbon monoxide diffusion capacity (DLCO), FEV1, and FVC all >50% predicted value. All pulmonary function tests must be obtained within one month prior to registration.
• Hematologic parameters (unless due to documented marrow involvement) obtained within 2 weeks prior to registration)
  • ANC ≥ 1500/mcL (1.5 x 109/L)
  • Platelets ≥ 75,000/mcL (75 x 109/L)
  • Liver/Renal function, obtained within 2 weeks prior to registration
  • AST/ALT ≤ 2.5 x upper limit of normal (ULN)
  • Bilirubin ≤ 2 x upper limit of normal (ULN) (unless documented Gilbert’s Syndrome, for which Bilirubin ≤ 3 x upper limit of normal (ULN) is permitted)
  • Calculated creatinine clearance by Cockroft-Gault formula  ≥ 30 ml/min
• No evidence of prior malignancy except adequately treated nonmelanoma skin cancer, in situ cervical carcinoma or any surgically- or radiation-cured malignancy continuously disease free for  ≥ 5 years so as not to interfere with interpretation of radiographic response.
• Patient must have no current or prior history of CNS involvement.
• All prior therapy must have been completed at least 21 days prior to enrollment. No concomitant anti lymphoma therapy, including systemic corticosteroids for the purpose of treatment of lymphoma are allowed. Topical steroids are allowed.
• No history of Steven’s Johnson’s syndrome, TENs syndrome, or motor neuropathy.
• HIV positive patients are allowed on this study if they have a CD4 count > 400, and are on a stable antiviral regimen. Patients with poorly controlled HIV or other chronic active viral infections will be excluded.
• Patients must not have autoimmune disorders or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or ophthalmologic steroids. A history of occasional (but not continuous) use of steroid inhalers is allowed.
• Replacement doses of steroids for patients with adrenal insufficiency are allowed. Patients who discontinue use of these classes of medication for at least 2 weeks prior to initiation of study treatment are eligible if, in the judgment of the treating physician investigator, the patient is not likely to require resumption of treatment with these classes of drugs during the study. Exclusion from this study also includes patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis  scleroderma], systemic lupus erythematosus, Sjögren's syndrome, autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis); other CNS autoimmune disease (e.g., Multiple sclerosis). Patients with autoimmune hypothyroid disease or type I diabetes on replacement treatment are eligible.
  • Treatment with systemic corticosteroids (including oral steroids)?
    • Yes _____ No ______
  • Continuous use of topical steroid creams/ointments?
    • Yes _____ No ______
  • Continuous use of steroid containing inhalers?
    • Yes _____ No ______
  • Adrenal insufficiency?
    • Yes _____ No ______
  • Date of last dose of steroid containing medicines: _____________
• Patients must not have grade 2 or greater peripheral sensory neuropathy.
• Patients must not have NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia.
• Patients must not have previously existing hypersensitivity to brentuximab vedotin or ipilimumab.
• Patients must not have a serious medical or psychiatric illness likely to interfere with study participation.
• Patients must not be participating in any other clinical trial or taking any other experimental medications within 21 days prior to registration.
• Routine vaccinations, including seasonal influenza, should be given at least 2 weeks prior to study treatment. Vaccines are not prohibited on study, but must be given at least 6 weeks after cycle 1 and not within 7 days of treatment.
• Patients registering to Arms D, E, F, G, H, I, X, Y must not currently be smoking tobacco or other substances and must not have smoked within the past 6 months.

RANDOMIZED PHASE II (ARMS K AND L):

• Age ≥ 18 years old.
• Patients must have pathologically confirmed relapsed or refractory classical Hodgkin Lymphoma (cHL). A biopsy at any relapse is acceptable. Other histologies including lymphocyte predominant (LP) HL are not permitted.
• Patients must have relapsed after first line chemotherapy. May have relapsed after autologous stem cell transplant, or have primary refractory disease. No upper limit for number of prior therapies.  Patient must not have received a prior allogeneic stem cell transplant (out of risk of reactivation of pulmonary GVHD).
• Patients may have received prior brentuximab vedotin, but must not have received brentuximab vedotin within 6 months prior to registration, and must not have relapsed within 6 months of receiving previous brentuximab vedotin. Patients may not have received prior nivolumab or PD1/PDL1 axis agents. Patients may not have received prior ipilimumab.
• Patients may not have received other prior activating immunotherapies (i.e., checkpoint inhibitor therapies). For the purposes of this study monoclonal antibodies and antibody drug conjugates are not considered to be activating immunotherapies and there are no additional time restrictions on prior exposure to these agents (except prior brentuximab vedotin).
• ECOG-ACRIN performance status between 0-2.
• Patients must have measurable disease as defined in Section 6. Baseline measurements and evaluations must be obtained within 4 weeks of registration to the study. Abnormal PET scans will not constitute evaluable disease unless verified by a diagnostic quality CT scan. Patients must use the same imaging modality (CT or PET/CT) throughout the study.
• Women must not be pregnant or breast-feeding due to risk of fetal harm by the chemotherapeutic agents prescribed in this protocol. 
• All females of childbearing potential must have a blood test or urine study within 24 hours prior to enrollment to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  • Female of childbearing potential? ______ (Yes or No)
  • Date of blood or urine test: ___________
• Women of childbearing potential (WOCBP) and sexually active males must either abstain from sexual intercourse for the duration of their participation in the study or agree to use both double barrier contraception and birth control pills or implants for at least one week prior to the start of the study drug and continuing for 5 months after the last dose of study drug (for female patients) and for 7 months after the last dose of study drug (for male patients who are sexually active with WOCBP).  Should a woman become pregnant or  suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately.
• Patients must have no evidence of dyspnea at rest and a pulse oximetry > 92% while breathing room air.
• Patients must have FEV1/FVC > 60% by pulmonary function test (PFT), unless due to large mediastinal mass from HL. Carbon monoxide diffusion capacity (DLCO), FEV1, and FVC all >50% predicted value. All pulmonary function tests must be obtained within one month prior to registration.
• Hematologic parameters (unless due to documented marrow involvement) obtained within 2 weeks prior to registration)
• ANC  ≥ 1500/mcL (1.5 x 109/L)
• Platelets  ≥ 75,000/mcL (75 x 109/L)
• Liver/Renal function, obtained within 2 weeks prior to registration
• AST/ALT ≤  2.5 x upper limit of normal (ULN)
• Bilirubin ≤ 2 x upper limit of normal (ULN) (unless documented Gilbert’s Syndrome, for which Bilirubin ≤ 3 x upper limit of normal (ULN) is permitted)
• Calculated creatinine clearance by Cockroft-Gault formula  ≥ 30 ml/min
• No evidence of prior malignancy except adequately treated nonmelanoma skin cancer, in situ cervical carcinoma or any surgically- or radiation-cured malignancy continuously disease free for  ≥ 5 years so as not to interfere with interpretation of radiographic response.
• Patient must have no current or prior history of CNS involvement.
• All prior therapy must have been completed at least 21 days prior to enrollment (6 weeks for nitrosoureas or mitomycin C). No concomitant anti lymphoma therapy, including systemic corticosteroids for the purpose of treatment of lymphoma are allowed. Topical steroids are allowed.
• No history of Steven’s Johnson’s syndrome, TENs syndrome, or motor neuropathy.
• HIV positive patients are eligible provided they meet the other protocol criteria including the following:
  • Long term survival expected were it not for the cHL
  • HIV viral loads undetectable by standard clinical HIV testing
  • Willing to adhere to effective combination antiretroviral therapy
• Patients must not have autoimmune disorders or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or ophthalmologic steroids. A history of occasional (but not continuous) use of steroid inhalers is allowed.  Replacement doses of steroids for patients with adrenal insufficiency are allowed. Patients who discontinue use of steroid medication for at least 2 weeks prior to initiation of therapy are eligible if, in the judgment of the treating physician investigator, the patient is not likely to require resumption of treatment with these classes of drugs during the study.  Exclusion from this study also includes patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, Sjögren's syndrome, autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis); other CNS autoimmune disease (e.g., Multiple sclerosis). Patients with autoimmune hypothyroid disease or type I diabetes on replacement treatment are eligible.
  • Treatment with systemic corticosteroids (including oral steroids)?
    • Yes _____ No ______
  • Continuous use of topical steroid creams/ointments?
    • Yes _____ No ______
  • Continuous use of steroid containing inhalers?
    • Yes _____ No ______
  • Adrenal insufficiency?
    • Yes _____ No ______
  • Date of last dose of steroid containing medicines: _____________
• Patients must not have grade 2 or greater peripheral sensory neuropathy.
• Patients must not have NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia.
• Patients must not have previously existing hypersensitivity to brentuximab vedotin or ipilimumab.
• Patients must not have a serious medical or psychiatric illness likely to interfere with study participation.
• Patients must not be participating in any other clinical trial or taking any other experimental medications within 21 days prior to registration.
• Routine vaccinations, including seasonal influenza, should be given at least 2 weeks prior to study treatment. Vaccines are not prohibited on study, but must be given at least 6 weeks after cycle 1 and not within 7 days of treatment.
• Patients must not currently be smoking tobacco or other agents. Vaping is not allowed.
• Patients must not have a history of or evidence of cardiovascular risks including any of the following:
  • QT interval corrected for heart rate using the Bazett’s formula
  • QTcB ≥480 msec.at baseline.
  • History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to registration.
  • History prior to registration or evidence of current ≥ Class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system.
  • LVEF ≤ lower limit of normal on cardiac echo or MUGA.
  • Intra-cardiac defibrillator.
  • History of abnormal cardiac valve morphology (≥ grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study.
  • History or evidence of current clinically significant uncontrolled cardiac arrhythmias; Clarification: Subjects with atrial fibrillation controlled for >30 days prior to dosing are eligible.
  • Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy

• Newly diagnosed patients with histologically proven ALCL (International Classification of Diseases for Oncology [ICD-0] code: 9714/3)
• Disease must be cluster of differentiation (CD)30 positive
• Disease must be anaplastic lymphoma kinase (ALK) positive (defined by local institutional standards)
• Patients must have stage II, III, or IV disease
• Patients must have a life expectancy of >= 8 weeks
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x upper limit of normal (ULN) for age; for the purpose of this study, the ULN for ALT is 45 U/L
• If the lab abnormality is thought to be due to the lymphoma the patient is eligible and dose adjustments should be made
• Shortening fraction of >= 27% by echocardiogram, or
• Ejection fraction of >= 50% by radionuclide angiogram
• Patients with a history of pulmonary dysfunction must have no evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry > 92% while breathing room air unless current dysfunction is due to the lymphoma in which case the patient is eligible

• Patients with central nervous system (CNS) disease are not eligible
• Patients with disease limited to the skin are not eligible, regardless of how wide-spread
• Patients with stage I disease are not eligible
• Patients who have received any prior cytotoxic chemotherapy for the current diagnosis of ALCL or any cancer diagnosed previously are not eligible
• Previous steroid treatment and/or radiation treatment is not allowed unless it is for the emergent management of a mediastinal mass; emergent steroid treatment and/or radiation treatment should stop once protocol therapy is initiated
• Intrathecal chemotherapy prior to enrollment is allowed for the current diagnosis of ALCL as long as adequate cerebrospinal fluid (CSF) is obtained prior to administration of the intrathecal chemotherapy and subsequently demonstrated to be negative for ALCL
• Female patients who are pregnant are not eligible; pregnancy tests must be obtained in girls who are post menarchal
• Lactating females are not eligible unless they have agreed not to breastfeed their infants
• Sexually active patients of reproductive potential are not eligible unless they agree to use an effective contraceptive method for the duration of treatment and for 3 months after stopping treatment
• Patients with Down syndrome are not eligible
• Patients with an immunodeficiency that existed prior to diagnosis such as primary immunodeficiency syndromes or organ transplant recipients are not eligible
• Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) substrates with narrow therapeutic indices: Patients chronically receiving medications known to be metabolized by CYP3A4 and with narrow therapeutic indices including pimozide, aripiprazole, triazolam, ergotamine and halofantrine are not eligible; the topical use of these medications (if applicable) is allowed
• CYP3A4 inhibitors: patients chronically receiving drugs that are known potent CYP3A4 inhibitors within 7 days prior to study enrollment, including but not limited to ketoconazole, itraconazole, clarithromycin, erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, delavirdine, nefazodone, diltiazem, verapamil, and grapefruit juice are not eligible; the topical use of these medications (if applicable), e.g. 2% ketoconazole cream, is allowed
• CYP3A4 inducers: patients chronically receiving drugs that are known potent CYP3A4 inducers within 12 days prior to study enrollment, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, ritonavir, and St. John's wort are not eligible; the topical use of these medications (if applicable) is allowed
• Patients that are known to be positive for human immunodeficiency virus (HIV) are not eligible; note: inclusion of HIV positive patients will be considered at a later date
• Patients who weigh < 10 kg are not eligible

Inclusion Criteria

CLL/SLL patients only

• Diagnosis of CLL according to the National Cancer Institute (NCI) criteria or SLL according to the World Health Organization (WHO) criteria
• This includes previous documentation of biopsy-proven small lymphocytic lymphoma or
• Diagnosis of CLL according to NCI working group criteria as evidenced by all of the following:
  • Peripheral blood B cell count of > 5 x 10^9/L consisting of small to moderate size lymphocytes;
  • Immunophenotyping consistent with CLL defined as:
    • The predominant population of lymphocytes share both B-cell antigens;
    • Clonality as evidenced by kappa (κ) or lambda (λ) light chain expression  or other genetic method;
    • Splenomegaly, hepatomegaly, or lymphadenopathy are not required for the diagnosis of CLL;
    • Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by demonstrating a negative fluorescent in situ hybridization (FISH) analysis  on peripheral blood or tissue biopsy or negative immunohistochemical stains for cyclin D1 on involved tissue biopsy.
• Patients must be previously treated with at least one prior line of therapy.
• Prior chemotherapy or biologic novel therapy or anti-cancer monoclonal antibody based therapy for treatment of CLL will be considered prior therapy:
  • Nutraceutical treatments with no established benefit in CLL (such as epigallocatechin gallate or EGCG, found in green tea or other herbal treatments) will not be considered "prior treatment";
  • Prior oral corticosteroid therapy for an indication other than CLL will not be considered "prior treatment."
• Previous use of corticosteroids in the combination with other therapy for treatment of autoimmune complications of CLL does constitute prior therapy for CLL.
• Have progressive disease with any one of the following characteristics based on standard criteria for treatment as defined by the NCI-Working Group (WG) 1996.
• Symptomatic CLL characterized by any one of the following:
  • Weight loss ≥ 10% within the previous 6 months;
  • Extreme fatigue attributed to CLL;
  • Fevers ≥ 100.5*F for 2 weeks without evidence of infection;
  • Drenching night sweats without evidence of infection.
• Evidence of progressive bone marrow failure with hemoglobin ≤ 11 g/dL or platelet count ≤ 100 x 10^9/L.
• Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly:
  • Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease are not sufficient for protocol therapy.

Low Grade B-NHL patients only

• Histologically confirmed relapsed (response to last treatment ≥ 6 months duration) or refractory (no response to last treatment or response duration < 6 months) indolent/low grade B cell NHL:
  • If patient has received previous anti-PD-1 or anti-PDL-1 consult with study chair.
• Follicular lymphoma, grades 1, 2 and 3.
• Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type.
• Splenic and nodal marginal zone lymphoma.
• Lymphoplasmacytic lymphoma including Waldenstrom macroglobulinemia.
• Measurable disease (at least 1 lesion of ≥ 1.5 cm in diameter) as detected by computed tomography (CT) or the CT images of the positron emission tomography (PET)/CT:
  • Patients with Waldenstrom macroglobulinemia are not required to have measurable disease by CT or PET/CT if monoclonal protein is detectable by serum protein electrophoresis and/or immunoglobulin M (IgM) level is at least 2 times upper limit of normal.

All patients

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
• Creatinine ≤ 1.5 X upper limit of normal (ULN) OR creatinine clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN.
• Platelet count ≥ 25 x 10^9/L.
• Absolute neutrophil count ≥ 0.5 X 10^9/L.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) unless due to Gilbert's disease:
  • If total bilirubin is > 1.5 x ULN, a direct bilirubin should be performed and must be ≤ upper limit of normal.
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 X ULN.
• Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only.
• Provide informed written consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willing to provide bone marrow and blood samples for correlative research purposes.
• Must have failed or be unable to tolerate or refused other available Food and Drug Administration (FDA) approved effective therapies:
  • Patients should not have other treatment options considered curative.

• Currently participating in or has participated in a study of an investigational agent or using an investigational device ≤ 28 days prior to registration.
• Receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy ≤ 7 days prior to registration.  Exceptions:
  • Low doses of steroids (≤ 20 mg of prednisone or equivalent dose of other steroid/day) used for treatment of non-hematologic medical conditions;
  • Previous use of corticosteroids is allowed;
  • After initiation of MK-3475 therapy, steroid can be used for management of potential immune mediated adverse events  for less than 8 weeks of therapy;
  • Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption) are permitted.
• Prior anti-cancer monoclonal antibody < 28 days prior to registration or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Prior chemotherapy or radiation therapy ≤ 14 days prior to registration or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to a previously administered agent:
  • Subjects with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the study;
  • If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Known additional malignancy that is progressing or requires active treatment.  Exceptions:
  • Richter's transformation or Hodgkin's transformation of the CLL are permitted;
  • In situ cervical cancer that has undergone or will undergo potentially curative therapy;
  • Basal cell carcinoma, squamous cell carcinoma, melanoma of the skin that has undergone or will undergo potentially curative therapy.
• Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease/syndrome difficult to control in the past.  Exceptions:
  • Conditions not expected to recur in the absence of an external trigger are permitted to enroll;
  • Patients with psoriasis not requiring systemic treatment are permitted for participation;
  • Patients who have a positive Coombs test but no evidence of hemolysis are permitted for participation;
  • Subjects with hypothyroidism stable on hormone replacement, diabetes or Sjogren's syndrome are permitted for the study;
  • Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study;
  • Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule.
• Evidence of interstitial lung disease or active, non-infectious pneumonitis.
• Active infection requiring systemic therapy:
  • When the infection is controlled, patients are permitted for this study.
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Any of the following:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• Known to be human immunodeficiency virus (HIV) positive.
• Known active hepatitis B or hepatitis C:
  • Patients with a positive hepatitis B core antibody but with negative hepatitis B DNA may participate, but must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician;
  • Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, but should have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician.
• Received a live vaccine ≤ 30 days prior to registration.
• New York Heart Association classification III or IV cardiovascular disease or recent myocardial infarction or unstable angina pectoris or cardiac arrhythmia (< 30 days).
• Active central nervous system (CNS) lymphoma or cerebrospinal fluid involvement with malignant lymphoma cells that requires therapy.
• Has a clinically significant coagulopathy per investigator's assessment.
• Has received an allogeneic stem cell transplant.

Inclusion Criteria

• Phase I: Histological confirmation of expressing CD20 antigen as determined by pathology at the respective institution and central pathology review at Mayo Clinic Rochester. All types of B-cell lymphomas are allowed to participate. Patients with primary mediastinal large B-cell (PMLBCL) or transformed lymphoma are allowed to participate                                                                 
• Phase II: Histological confirmation of  DLBCL expressing CD20 antigen as determined by pathology at the respective institution and central pathology review at Mayo Clinic Rochester.  Only Diffuse large B cell lymphoma patients are allowed to participate in Phase II. Patients with primary mediastinal large B-cell (PMLBCL) lymphoma or transformed lymphoma are not allowed to participate
• Notes regarding slide submission
  • Central pathology review is mandatory but is retrospective in nature
  • Slides should be submitted within 30 days of enrollment
  • Patients can be enrolled prior to submission of slides
• Has measurable disease (at least 1 lesion ≥ 1.5 cm in diameter) as detected by PET/CT
• Only 1 line of previous anti-lymphoma therapy is allowed and not currently receiving any other agent that would be considered as a treatment for the lymphoma
• Patients must be ≥ 2 weeks from prior anti-lymphoma therapy
• The use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
• Absolute neutrophil count (ANC) ≥ 1500/mm^3
• Platelet count ≥ 75,000/mm^3
• Total bilirubin ≤ 2 × upper limit of normal (ULN) (unless related to lymphoma or Gilbert's disease) 
  • ≤ 5 × ULN for subjects with documented or suspected Gilbert's disease, or related to involvement of the liver by the lymphoma
• Aspartate transaminase (AST) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3 x ULN unless evidence of the direct liver and/or bone involvement by lymphoma, then ≤ 5 x ULN
• Phase I subjects must have calculated creatinine clearance ≥ 60 ml/min by Cockcroft-Gault formula
• Phase II subjects must have calculated creatinine clearance ≥ 30 ml/min by Cockcroft-Gault formula
• Negative pregnancy test done ≤10-14 days before registrationdays prior to registration, for women of childbearing potential only
• Provide informed written consent
• Willing to return to enrolling institution for follow-up during the active monitoring phase of the study, i.e. active treatment and observation
• Willing to provide blood samples for correlative research purposes
• Considered transplant-eligible, as determined by the opinion of the investigator at the participating institution
  • The participating institution does not need to be a transplant center but patients can be referred to a transplant center if needed
• Willing and able to register into and comply with the mandatory requirements of Celgene's REVLIMID (lenalidomide) Risk Evaluation and Mitigation Strategies (REMS™) program
• Females of reproductive potential are willing and able to adhere to the scheduled pregnancy testing as required by Celgene's REVLIMID REMS™ program
• Willing and able to take aspirin (81 mg) daily as prophylactic anticoagulation
  • Patients intolerant to acetylsalicylic acid [ASA] may use warfarin or low molecular weight heparin

Exclusion Criteria

• Pregnant women
• Nursing women
• Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Men must agree to use a latex condom during sexual contact with a female of child-bearing potential even if they have had a successful vasectomy
  • Women of child bearing potential must agree to use 2 methods of reliable contraception simultaneously
  • All patients must be counseled at a minimum of every 21 days about pregnancy precautions and risks of fetal exposure
• Has any co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens including, but not limited to
  • Ongoing or active infection
  • Symptomatic congestive heart failur
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness/social situations that would limit compliance with study requirements
• Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy
  • Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
  • Patients with HIV on antiretroviral therapy other than zidovudine (AZT) and/or stavudine and without prior acquired immunodeficiency syndrome (AIDS) defining conditions and adequate CD4 count > 400 are eligible
• History of myocardial infarction ≤ 180 days prior to registration
• Congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
  • Patients must be ≥ 2 weeks from prior anti-lymphoma therapy
  • The use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed
• Other active malignancy ≤ 3 years prior to registration, except for
  • Non-melanotic skin cancer
  • Carcinoma-in-situ of the cervix
  • Any cancer that, in the judgment of the investigator, has been treated with curative intent and will not interfere with the study treatment plan and response assessment
    • If there is a history of prior malignancy, they must not be receiving other specific treatment such as radiation, chemotherapy, or immunotherapy for their cancer
• Unable or unwilling to take any prophylaxis
  • Patients with history of or new/active deep vein thrombosis/embolism/thrombophilia are allowed to participate if they are on appropriate therapeutic anticoagulation during the treatment on the trial
  • These patients would not need the aspirin with the lenalidomide unless clinically indicated
  • Patients must be able and willing to receive anticoagulation prophylactically versus therapeutically as clinically indicated
• No history of radiation therapy to ≥ 25% of the bone marrow for other diseases
• Receiving erythroid stimulating agents (epoetin alfa [EPO]: Procrit, Aranesp)
• Has active or prior central nervous system (CNS) lymphoma or cerebrospinal fluid involvement with malignant lymphoma cells
  • These patients are usually treated with CNS directed therapy
  • Screening for cerebrospinal fluid CNS involvement is NOT required but can be performed per treating medical doctor  discretion
• Active hepatitis B as defined by seropositivity for hepatitis B surface antigen (HBsAg)
  • Subjects with positive hepatitis B core antibody titers and normal liver transaminases are allowed provided that antiviral prophylaxis is administered per institutional guidelines
  • Subjects with hepatitis C antibody will be eligible provided that they do not have elevated liver transaminases or other evidence of active hepatitis

• New diagnosis of de novo ALL, lymphomas (T or B cell), or mixed-phenotype acute leukemia.
• Planned 3-4 drug systemic induction chemotherapy with a corticosteroid, vincristine and a single dose or multiple doses of asparaginase, with or without daunorubicin.
• Functioning Central Venous Access Device.
• Must be able to tolerate oral medication or have it administered via an Nasogastric tube (NGT) or GT tube.
• Males and females, age 1 year(365 days) to < 18 (17 years and 364 days) years.

• Subjects scheduled to have > 3 Lumbar Punctures over the course of the study treatment period.
• Prior history of documented DVT or PE in the past 3 months.
• Known inherited bleeding disorder or coagulopathy.
• Major surgery [excluding Central Venous Access Device (CVAD) replacement and bone marrow aspiration and non-open biopsy] within the last 7 days prior to enrollment that may be associated with a risk of bleeding. Open biopsy is considered a major surgery.
• Uncontrolled severe hypertension at enrollment. Severe hypertension is defined as a systolic or diastolic blood pressure (BP) > 5 mm Hg above the 95th percentile as defined by the National High Blood Pressure Education Program Working Group (NHBPEP) established guidelines for the definition of normal and elevated blood pressure in children.
• Extreme hyperleukocytosis, white blood cell (WBC) counts over 200 x 10^9/L (200,000/microL) at the time of enrollment.
• Liver dysfunction manifested by SGTP (ALT) > 5 X Upper limit of normal (ULN) and/or Aspartate aminotransferase (AST) >5 X ULN and/or direct (conjugated) bilirubin > 2 X ULN.
• Renal function < 30% of normal for age and size as determined by the Schwartz formula
• International normalized ratio (INR) > 1.4 and activated partial thromboplastin time (aPTT) > 3 seconds above the upper limit of normal for age, within 1 week prior to enrollment.
• History of allergy to apixaban or Factor Xa inhibitors.
• History of significant adverse reaction or major bleeding related adverse reaction to other anticoagulant or antiplatelet agents.
• History of any significant drug allergy (such as anaphylaxis or hepatotoxicity
• Any investigational drug being administered during the study.

Inclusion Criteria

• 18 years or older
• Eastern Cooperative Oncology Group (ECOG) performance status 0,1
• AJCC stage III or IV completely resectable melanoma identified before surgery
• Approximately 1 mg (1 cm3) of accessible and dispensable tumor that will not interfere with pathologic staging
• Clinically disease-free after surgery
• Completing SoC adjuvant therapy per NCCN guidelines to include chemotherapy, radiation therapy, and/or biologic therapy as clinically indicated (Consent #2 should be signed as close to completion of SoC as possible but may overlap completion by up to one month.)
• Vaccinations initiated between 3 weeks and 3 months from completion of SoC multi-modality cancer care
• Adequate organ function as determined by the following laboratory values
  • ANC ≥ 1,000/μL
  • Platelets ≥ 75,000/μL
  • Hgb ≥ 9 g/dL
  • Creatinine ≤ 1.5 x upper limit of normal (ULN) or Creatinine clearance ≥ 50%
  • Total bilirubin ≤ 1.5 ULN
  • ALT and AST ≤ 1.5 ULN
• For women of child-bearing potential, agreement to use adequate birth control (abstinence, hysterectomy, bilateral oophorectomy, bilateral tubal ligation, oral contraception, IUD, or use of condoms or diaphragms)
• Signed informed consent

Exclusion Criteria

• Evidence of residual disease after surgery and SoC adjuvant therapies
• Insufficient tumor available to produce vaccine
• ECOG >2 performance status
• Immune deficiency disease or known history of HIV, HBV, HCV
• Receiving immunosuppressive therapy including chronic steroids, methotrexate, or other known immunosuppressive agents
• Pregnancy (assessed by urine HCG)
• Breast feeding
• Active pulmonary disease requiring medication to include multiple inhalers (>2 inhalers and one containing steroids)
• Involved in other experimental protocols (except with permission of the other study PI)

• Histologically confirmed high grade serous or endometrioid ovarian, peritoneal or fallopian tube malignancy that is metastatic and for which curative measures do not exist.  The histology can be confirmed from tissue that was taken at the time of diagnosis. A biopsy at the time of recurrence prior to enrollment on study is not required.
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥ 2 cm) with conventional techniques or as ≥ 10 mm (≥ 1 cm) with spiral CT scan, MRI, or calipers by clinical exam. 
• Patients enrolled in the phase 2 portion of the study will be required to have archival tumor tissue available for analysis and be willing to have a tumor biopsy at baseline (after registration and prior to starting study treatment) and at Cycle 1 Day 2.
• Patients must have platinum sensitive disease and be in their first or second platinum sensitive recurrence. Platinum sensitive disease is defined as recurrence that occurred greater than six months after completion of their last line of platinum based therapy. No non-platinum regimens allowed. Prior therapy with PARP inhibitors as well as bevacizumab is allowed.
• No more than two prior platinum based regimens. One regimen is defined as the interval of treatment from start of platinum based doublet to finish of that treatment course for the initial therapy or for the recurrent disease episode. If the nonplatinum agent is altered due to any reason other than disease progression, it counts as one regimen. For example, if a patient started on carboplatin and paclitaxel but developed a taxol reaction and was switched to carboplatin and Abraxane, this counts as one prior regimen.
• Age ≥18 years.
• Because no dosing or adverse event data are currently available on the use of M6620 (VX-970) in combination with carboplatin and gemcitabine in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A).
• Life expectancy of greater than 6 months.
• Patients must have normal organ and marrow function as defined below:
  • Leukocytes ≥3,000/mcL
  • Absolute Neutrophil Count (ANC) ≥1,500/mcL
  • Platelets ≥100,000/mcL
  • Total Bilirubin Within normal institutional limits
  • AST(SGOT)/ALT(SGPT) ≤ 2 × institutional upper limit of normal (ULN)
  • Creatinine Within normal institutional limits OR
  • Creatinine Clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
• Negative serum pregnancy test result for females of child bearing potential
  • Note: The effects of M6620 (VX-970) on the developing human fetus are unknown. For this reason and because DNA-damage response (DDR) inhibitors as well as other therapeutic agents used in this trial may have teratogenic potential, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 6 months after completion of M6620 (VX-970) administration. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consentdocument.
• Of note, if appropriate per the FDA approved indications, patients may receive PARP inhibitor maintenance therapy after the primary endpoint has been reached, if desired. This therapy is not a part of the clinical trial and should be discussed and performed at the discretion of the patient and treating physician.

• Patients with platinum resistant disease or platinum sensitive disease that is past the first or second recurrence.
• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier, excluding alopecia. Patients with treatment related effects, such as peripheral neuropathy, that are grade 1 or less are eligible.
• Prior exposure to gemcitabine.
• Patients who are concurrently receiving any other investigational agents.
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to M6620 (VX-970), carboplatin, gemcitabine or to these specific compounds.
• M6620 (VX-970) is primarily metabolized by CYP3A4; therefore, concomitant administration with strong inhibitors or inducers of CYP3A4 should be avoided. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently- updated medical reference for a list of drugs to avoid or minimize use of. Appendix B (Patient Drug Information Handout and Wallet Card) should be provided to patients. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with studyrequirements.
• Pregnant women are excluded from this study because M6620 (VX-970) as a DNA-damage response (DDR) inhibitor may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M6620 (VX-970), breastfeeding should be discontinued if the mother is treated with M6620 (VX-970). These potential risks also apply to the other agents used in this study, such as carboplatin and gemcitabine.
• Patients with Li Fraumeni syndrome are excluded from the study as M6620 (VX-970) is a DDR inhibitor.
• Addition of bevacizumab to the treatment in this study is not allowed. If the treating physician feels that the addition of bevacizumab is in the best interest of the patient, the patient should be treated with the FDA approved carboplatin/gemcitabine/bevacizumab regimen outside of the present study.

• Histologically confirmed invasive carcinoma of the breast of any of the following histologies (ductal, lobular, mammary, medullary, or tubular). Patients with metaplastic breast cancer are not eligible.
• Patients will be staged according to the TNM staging system.
• For patients not receiving neoadjuvant chemotherapy, pathologic staging must be T0N1-2a, T1N1-2a, T2N1-2a, T3N0-2a, and all M0 status.
• For patients receiving neoadjuvant chemotherapy, clinical pre-chemo staging and post mastectomy pathological staging is required for all patients. Patients who have received neoadjuvant chemotherapy and are pathologically cT0-2 and N0 are only eligible if biopsy-proven clinically N1 or N2 disease is documented prior to the start of neoadjuvant chemotherapy. cT3N0 patients or ypT3N0 patients who receive neoadjuvant chemotherapy may be eligible based on clinical or pathological T stage, and do not require pathologically positive lymph nodes.
  • Note: Higher of the clinical or pathological T and N stage are used for final staging, if receiving neoadjuvant chemotherapy.
• All patients with clinical, radiographic or pathological T4, N3 or involved internal mammary disease (N1b, N1c, and N2b) are not eligible.
• No prior therapeutic radiation therapy to the chest, neck or axilla. Prior radioactive oral iodine is permitted.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed.
• No active collagen vascular diseases, such as: systemic lupus erythematous, scleroderma, or dermatomyositis.
• Negative inked histologic margins from mastectomy pathology (no invasive cells at margin).
• No significant post mastectomy complications in the ipsilateral or contralateral breast requiring an unplanned re-operation or admission for IV antibiotics. Re-operation for margins evaluation, nodal completion and routine reconstruction is acceptable.
• Radiation oncologist intends to treat all target volumes and respect all normal tissues in accordance with the dosimetric constraints described (simulation before registration recommended).
• Radiation oncologist is planning to treat regional lymph nodes including internal mammary nodes and meet acceptable protocol dosimetric requirements.
• Radiation oncologist is NOT planning to utilize a chest wall/scar boost.
• Patient must have undergone immediate reconstruction at the time of mastectomy or be planning to undergo reconstruction within 18 months after radiation.
• If a tissue expander is utilized it needs to be a fluid filled expander, NO air expander (unless completely deflated) during radiation therapy.
• For patients with diabetes, hemoglobin A1C test must have been performed ≤ 90 days prior to registration.
• No co-existing medical conditions with life expectancy < 5 years.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix.
• Negative serum or urine β-HCG in women of child-bearing potential ≤7 days prior to registration.
• A female of childbearing potential is a sexually mature female who has not undergone a hysterectomy or bilateral oophorectomy and has not been naturally postmenopausal for at least 12 consecutive months.
• Women of child-bearing potential must agree to utilize a form of birth control or agree to undergo sexual abstinence during radiation therapy.
• ECOG (Zubrod) Performance Status 0-1
• Patient ≥ 18 years of age
• Patients must be able to read and comprehend English, in order to be able to complete study questionnaires. However, patients participating through CCTG institutions who can read and comprehend French are eligible.

• None.

• Histologically confirmed invasive carcinoma of the breast of any of the following histologies (ductal, lobular, mammary, medullary, or tubular). Patients with metaplastic breast cancer are not eligible.
• Patients will be staged according to the TNM staging system.
• For patients not receiving neoadjuvant chemotherapy, pathologic staging must be T0N1-2a, T1N1-2a, T2N1-2a, T3N0-2a, and all M0 status.
• For patients receiving neoadjuvant chemotherapy, clinical pre-chemo staging and post mastectomy pathological staging is required for all patients. Patients who have received neoadjuvant chemotherapy and are pathologically cT0-2 and N0 are only eligible if biopsy-proven clinically N1 or N2 disease is documented prior to the start of neoadjuvant chemotherapy. cT3N0 patients or ypT3N0 patients who receive neoadjuvant chemotherapy may be eligible based on clinical or pathological T stage, and do not require pathologically positive lymph nodes.
  • Note: Higher of the clinical or pathological T and N stage are used for final staging, if receiving neoadjuvant chemotherapy.
• All patients with clinical, radiographic or pathological T4, N3 or involved internal mammary disease (N1b, N1c, and N2b) are not eligible.
• No prior therapeutic radiation therapy to the chest, neck or axilla. Prior radioactive oral iodine is permitted.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed.
• No active collagen vascular diseases, such as: systemic lupus erythematous, scleroderma, or dermatomyositis.
• Negative inked histologic margins from mastectomy pathology (no invasive cells at margin).
• No significant post mastectomy complications in the ipsilateral or contralateral breast requiring an unplanned re-operation or admission for IV antibiotics. Re-operation for margins evaluation, nodal completion and routine reconstruction is acceptable.
• Radiation oncologist intends to treat all target volumes and respect all normal tissues in accordance with the dosimetric constraints described (simulation before registration recommended).
• Radiation oncologist is planning to treat regional lymph nodes including internal mammary nodes and meet acceptable protocol dosimetric requirements.
• Radiation oncologist is NOT planning to utilize a chest wall/scar boost.
• Patient must have undergone immediate reconstruction at the time of mastectomy or be planning to undergo reconstruction within 18 months after radiation.
• If a tissue expander is utilized it needs to be a fluid filled expander, NO air expander (unless completely deflated) during radiation therapy.
• For patients with diabetes, hemoglobin A1C test must have been performed ≤ 90 days prior to registration.
• No co-existing medical conditions with life expectancy < 5 years.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix.
• Negative serum or urine β-HCG in women of child-bearing potential ≤7 days prior to registration.
• A female of childbearing potential is a sexually mature female who has not undergone a hysterectomy or bilateral oophorectomy and has not been naturally postmenopausal for at least 12 consecutive months.
• Women of child-bearing potential must agree to utilize a form of birth control or agree to undergo sexual abstinence during radiation therapy.
• ECOG (Zubrod) Performance Status 0-1
• Patient ≥ 18 years of age
• Patients must be able to read and comprehend English, in order to be able to complete study questionnaires. However, patients participating through CCTG institutions who can read and comprehend French are eligible.

• None.

• Histologically confirmed invasive carcinoma of the breast of any of the following histologies (ductal, lobular, mammary, medullary, or tubular). Patients with metaplastic breast cancer are not eligible.
• Patients will be staged according to the TNM staging system.
• For patients not receiving neoadjuvant chemotherapy, pathologic staging must be T0N1-2a, T1N1-2a, T2N1-2a, T3N0-2a, and all M0 status.
• For patients receiving neoadjuvant chemotherapy, clinical pre-chemo staging and post mastectomy pathological staging is required for all patients. Patients who have received neoadjuvant chemotherapy and are pathologically cT0-2 and N0 are only eligible if biopsy-proven clinically N1 or N2 disease is documented prior to the start of neoadjuvant chemotherapy. cT3N0 patients or ypT3N0 patients who receive neoadjuvant chemotherapy may be eligible based on clinical or pathological T stage, and do not require pathologically positive lymph nodes.
  • Note: Higher of the clinical or pathological T and N stage are used for final staging, if receiving neoadjuvant chemotherapy.
• All patients with clinical, radiographic or pathological T4, N3 or involved internal mammary disease (N1b, N1c, and N2b) are not eligible.
• No prior therapeutic radiation therapy to the chest, neck or axilla. Prior radioactive oral iodine is permitted.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed.
• No active collagen vascular diseases, such as: systemic lupus erythematous, scleroderma, or dermatomyositis.
• Negative inked histologic margins from mastectomy pathology (no invasive cells at margin).
• No significant post mastectomy complications in the ipsilateral or contralateral breast requiring an unplanned re-operation or admission for IV antibiotics. Re-operation for margins evaluation, nodal completion and routine reconstruction is acceptable.
• Radiation oncologist intends to treat all target volumes and respect all normal tissues in accordance with the dosimetric constraints described (simulation before registration recommended).
• Radiation oncologist is planning to treat regional lymph nodes including internal mammary nodes and meet acceptable protocol dosimetric requirements.
• Radiation oncologist is NOT planning to utilize a chest wall/scar boost.
• Patient must have undergone immediate reconstruction at the time of mastectomy or be planning to undergo reconstruction within 18 months after radiation.
• If a tissue expander is utilized it needs to be a fluid filled expander, NO air expander (unless completely deflated) during radiation therapy.
• For patients with diabetes, hemoglobin A1C test must have been performed ≤ 90 days prior to registration.
• No co-existing medical conditions with life expectancy < 5 years.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix.
• Negative serum or urine β-HCG in women of child-bearing potential ≤7 days prior to registration.
• A female of childbearing potential is a sexually mature female who has not undergone a hysterectomy or bilateral oophorectomy and has not been naturally postmenopausal for at least 12 consecutive months.
• Women of child-bearing potential must agree to utilize a form of birth control or agree to undergo sexual abstinence during radiation therapy.
• ECOG (Zubrod) Performance Status 0-1
• Patient ≥ 18 years of age
• Patients must be able to read and comprehend English, in order to be able to complete study questionnaires. However, patients participating through CCTG institutions who can read and comprehend French are eligible.

• None.