• Patients must have a body surface area (BSA) of ≥ 0.5 m^2 at enrollment.
• Patients must have neurofibromatosis type 1 (NF1) based on clinical criteria and/or germline genetic testing.
• Patients must be newly diagnosed or have previously diagnosed NF-1 associated LGG that has not been treated with any modality other than surgery.
• For patients with optic pathway gliomas (OPGs): 
  • Newly-diagnosed patients with OPG are eligible if there are neurologic symptoms (including visual dysfunction, as defined below) or other exam findings associated with the tumor;
  • Previously-diagnosed patients with OPG are eligible if they have new or worsening neurologic symptoms (including visual dysfunction, as defined below) or have tumor growth;
  • For both newly-diagnosed and previously-diagnosed OPG, the patient may be eligible, irrespective of whether there has been tumor growth or other neurological symptoms or worsening, if they meet at least one of the following visual criteria: 
    • Visual worsening, defined as worsening of visual acuity (VA) or visual fields (VF) documented within the past year (by examination or history); OR
    • Significant visual dysfunction (defined as VA worse than normal for age by 0.6 logMAR [20/80, 6/24, or 2.5/10] or more in one or both eyes).
• For patients with LGG in other locations (i.e., not OPGs): 
  • Newly-diagnosed patients with LGG are eligible if there are neurologic symptoms or other exam findings associated with the tumor;
    • NOTE: Newly-diagnosed patients with LGG without associated neurologic symptoms or exam findings are not eligible.
  • Previously-diagnosed patients with LGG are eligible if they have new or worsening neurologic symptoms or have tumor growth.
• Although not required, if a biopsy/tumor resection is performed, eligible histologies will include all tumors considered LGG or low-grade astrocytoma (World Health Organization [WHO] grade I and II) by 5th edition WHO classification of central nervous system (CNS) tumors with the exception of subependymal giant cell astrocytoma.
• Patients must have two-dimensional measurable tumor ≥ 1 cm^2.
• Patients with metastatic disease or multiple independent primary LGGs are allowed on study.
• Creatinine clearance or radioisotope glomerular filtration Rate (GFR) ≥ 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender within 7 days prior to enrollment as follows: 
  • Age; maximum serum creatinine (mg/dL)
  • 2 to < 6 years; 0.8 (male) and 0.8 (female)
  • 6 to < 10 years; 1 (male) and 1 (female)
  • 10 to < 13 years; 1.2 (male) and 1.2 (female)
  • 13 to < 16 years; 1.5 (male) and 1.4 (female) 
  • ≥ 16 years; 1.7 (male) and 1.4 (female).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age within 7 days prior to enrollment (children with a diagnosis of Gilbert's syndrome will be allowed on study regardless of their total and indirect [unconjugated] bilirubin levels as long as their direct [conjugated] bilirubin is < 3.1 mg/dL).
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 3 x upper limit of normal (ULN) = 135 U/L within 7 days prior to enrollment. For the purpose of this study, the ULN for SGPT is 45 U/L.
• Albumin ≥ 2 g/dL within 7 days prior to enrollment.
• Left ventricular ejection fraction (LVEF) ≥ 53% (or institutional normal; if the LVEF result is given as a range of values, then the upper value of the range will be used) by echocardiogram within 7 days prior to enrollment.
• Corrected QT (QTc) interval ≤ 450 msec by electrocardiography (EKG) within 7 days prior to enrollment.
• Absolute neutrophil count ≥ 1,000/uL (unsupported) within 7 days prior to enrollment.
• Platelets ≥ 100,000/uL (unsupported) within 7 days prior to enrollment.
• Hemoglobin ≥ 8 g/dL (may be supported) within 7 days prior to enrollment.
• Patients with a known seizure disorder should be stable and should have not experienced a significant increase in seizure frequency within 2 weeks prior to enrollment.
• Patients 2-17 years of age must have a blood pressure that is ≤ 95th percentile for age, height, and gender at the time of enrollment.
• Patients ≥ 18 years of age must have a blood pressure ≤ 130/80 mmHg at the time of enrollment (with or without the use of antihypertensive medications). 
  • Note: Adequate blood pressure can be achieved using medication for the treatment of hypertension.
• All patients must have ophthalmology toxicity assessments performed within 4 weeks prior to enrollment.
• For all patients, an MRI of the brain (with orbital cuts for optic pathway tumors) and/or spine (depending on the site(s) of primary disease) with and without contrast must be performed within 4 weeks prior to enrollment.
• For patients who undergo a surgery on the target tumor (not required), a pre- and post-operative* MRI of the brain (with orbital cuts for optic pathway tumors) or spine (depending on the site(s) of primary disease) with and without contrast must also be performed within 4 weeks prior to enrollment.
  • The post-operative MRIs should be performed ideally within 48 hours after surgery if possible.
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2.  Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age.
• Patients must have the ability to swallow whole capsules. 
• Patients must have receptive and expressive language skills in English or Spanish to complete the quality of life (QOL) and neurocognitive assessments.
• All patients and/or their parents or legal guardians must sign a written informed consent. 
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

• Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior surgical intervention is permitted.
• Patients with a concurrent malignancy or history of treatment (other than surgery) for another tumor within the last year are ineligible.
• Patients may not be receiving any other investigational agents.
• Patients with any serious medical or psychiatric illness/ condition, including substance use disorders likely in the judgement of the investigator to interfere or limit compliance with study requirements/treatment are not eligible.
• Patients who, in the opinion of the investigator, are not able to comply with the study procedures are not eligible.
• Female patients who are pregnant are not eligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
• Lactating females who plan to breastfeed their infants are not eligible. 
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 12 weeks after stopping study therapy are not eligible.
  • Note: Women of child-bearing potential and males with sexual partners who are pregnant or who could become pregnant (i.e., women of child-bearing potential) should use effective methods of contraception for the duration of the study and for 12 weeks after stopping study therapy to avoid pregnancy and/or potential adverse effects on the developing embryo.
• Cardiac conditions: 
  • Known genetic disorder that increases risk for coronary artery disease;
    • Note: The presence of dyslipidemia in a family with a history of myocardial infarction is not in itself an exclusion unless there is a known genetic disorder documented.
  • Symptomatic heart failure;
  • New York Heart Association (NYHA) class II-IV prior or current cardiomyopathy;
  • Severe valvular heart disease;
  • History of atrial fibrillation.
• Ophthalmologic conditions: 
  • Current or past history of central serous retinopathy;
  • Current or past history of retinal vein occlusion or retinal detachment;
  • Patients with uncontrolled glaucoma;
  • If checking pressure is clinically indicated, patients with intraocular pressure (IOP) > 22 mmHg or ULN adjusted by age are not eligible;
  • Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or strabismus) or longstanding orbito-temporal plexiform neurofibroma (PN, such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study.
• Treatments and/or medications patient is receiving that would make her/him ineligible, such as: 
  • Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to study enrollment even if less than 100% of the daily recommended dosing for vitamin E;
  • Recent surgery within a minimum of 2 weeks prior to starting study enrollment, with the exception of surgical placement for vascular access or cerebrospinal fluid (CSF) diverting procedures such as endoscopic third ventriculostomy (ETV) and ventriculo-peritoneal (VP) shunt.; 
    • Note: Patients must have healed from any prior surgery prior to enrollment.
  • Patients who have an uncontrolled infection are not eligible.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 12/14/22. Questions regarding updates should be directed to the study team contact.

• 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.

Cases

• Women 14 years or older who are undergoing surgical evaluation for potential primary peritoneal, fallopian tube, or epithelial ovarian cancer  
• Women who have previously participated in the research study and are returning to MCR for secondary debulking surgery for these diseases will be re-consented for permission to use excess tissue from the second surgery.
• Women who are not considering surgery but who schedule consultations through medical oncology for ovarian, primary peritoneal, or fallopian tube cancer

Community Controls

• Women age 14 and older residing in the six state areas of MN, IA, WI, SD, ND and IL.
  • No prior bilateral oophorectomy
  • No prior diagnosis of ovarian, primary peritoneal, or fallopian tube cancer

ELIGIBILITY CRITERIA
•CASES 

• Diagnosis of primary cancer at age 21 or younger, irrespective of current age.
• No prior history of allogeneic (non-autologous) hematopoietic cell transplant.
• Development of one of the following key adverse events at any time following initiation of cancer therapy:
  • Cardiac dysfunction;
  • Ischemic stroke (IS);
  • Subsequent malignant neoplasm (SMN);
  • Avascular necrosis (AVN); please note: case enrollment has been closed due to achievement of target accrual. 
• Submission of a blood specimen (or in certain cases a buccal cell specimen) to the Clinical Pharmacokinetics Laboratory at St. Jude Children's Research Hospital as per the requirements.
  • Please note: if a patient is currently receiving active cancer treatment, it is preferable to obtain the blood sample at a time when the patient's white blood cell (WBC) is > 2,000.
• Written informed consent from the patient and/or the patient?s legally authorized guardian. 
• In active follow up by a COG institution; active follow up will be defined as date of last visit or contact by a COG institution within the past 24 months; any type of contact, including contact specifically for participation in ALTE03N1, qualifies as active follow-up; please note: treatment on a COG (or legacy group) therapeutic protocol for the primary cancer is NOT required. 

ELIGIBILITY CRITERIA
•CONTROLS:

• CONTROL
  •Diagnosis of primary cancer at age 21 or younger, irrespective of current age.
• CONTROL: No prior history of allogeneic (non-autologous) hematopoietic cell transplant. 
• CONTROL: No clinical evidence of any of the following key adverse events:
  • Cardiac dysfunction (CD); please note: if a patient is currently receiving active cancer treatment, it is preferable to obtain the blood sample at a time when the patient's WBC is > 2,000;
  • Myocardial infarction (MI);
  • Ischemic stroke (IS);
  • Avascular necrosis (AVN);
  • Subsequent malignant neoplasm (SMN). 
• CONTROL: Submission of a blood specimen (or in certain cases a buccal cell specimen) to the Clinical Pharmacokinetics Laboratory at St. Jude Children's Research Hospital as per the requirements. 
• CONTROL: Written informed consent from the patient and/or the patient?s legally authorized guardian. 
• CONTROL: In active follow up by a COG institution; active follow up will be defined as date of last visit or contact by a COG institution within the past 24 months; any type of contact, including contact specifically for participation in ALTE03N1, qualifies as active follow-up; please note: treatment on a COG (or legacy group) therapeutic protocol for the primary cancer is NOT required.

Pre-Registration

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 9/7/22. Questions regarding updates should be directed to the study team contact.

• The patient must be currently be enrolled or plan to be enrolled on a COG therapeutic study that aims to examine neuropsychological, social, emotional, and/or behavioral functioning
• The patient must have receptive and expressive English language skills

• Patients with a history of severe or profound mental retardation (i.e., intelligence quotient [IQ] ≤ 50) are not eligible for enrollment; PLEASE NOTE: Children with a prior history of attention deficit hyperactivity disorder (ADHD) or a specific learning disability (e.g., dyslexia) are eligible for this study

• All female patients, ages 18 to 100 years.
• Had a breast biopsy at Mayo Clinic between 1/1/67 and 3/31/2020 with benign findings.

• All male patients.
• Prior or concomitant diagnosis of breast cancer.
• Diagnosis of breast cancer within six months of benign breast disease.
• Denial of research authorization.
• Concurrent or post-biopsy prophylactic mastectomy.
• Women who had a tissue examined subsequent to reduction mammoplasty or implant related surgery

• Must be enrolled on a front line COG therapeutic trial for treatment of a primary malignancy OR must have been enrolled on a COG (or Legacy Group) therapeutic or non-therapeutic trial calling for long-term follow-up by ALTE05N1:
  • Hodgkin lymphoma
    • CCG-5942
    • POG-9425
    • POG-9426
    • COG-AHOD0031
    • COG
      •AHOD1331
    • SWOG
      •S1826
  • Brain tumor
    • CCG-A9961
  • Acute lymphoblastic leukemia
    • POG
      •9404
  • Osteosarcoma
    • POG
      •9754
  • Stem Cell Transplantation
    • ASCT0631D
  • Rhabdomyosarcoma
    • IRSG-III
      • CCSG631
      • IRS X8498
    • IRSG
      •IV
      • CCSG 671
      • CCG 6881
      • CCG 6901
      • CCG 6902
      • CCG 6903
      • POG 8788
      • POG 8889
      • POG 9150
      • POG 9151
      • POG 9152
      • IRS 8797
      • IRS 9198
• Must reside in the U.S. during trial enrollment

• 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.

Newly diagnosed aggressive lymphoma or CLL/small lymphocytic lymphoma (SLL) that meets disease specific criteria below:

• Study 1
  •Aggressive lymphoma
  • Newly diagnosed de-novo DLBCL or primary mediastinal B-cell lymphoma that will be treated with an anthracycline-containing regimen (rituximab-cyclophosphamide, doxorubicin hydrochloride, prednisone [R-CHOP] or equivalent); patients with composite lymphomas can also be enrolled as long as they have large cell component and will be treated with an anthracycline; in addition, patients with "B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma" or post-transplant DLBCL are also eligible as long as they meet other criteria; patients with typical Burkitt lymphoma are not eligible
    • NOTE: patients can be enrolled up through day 1 of cycle 3 of therapy; the patient is permitted to participate in any other therapeutic therapy for their disease as long as it does not concern vitamin D; patients can begin their chemotherapy while awaiting vitamin D results and treatment arm assignment or
  • Newly diagnosed untreated peripheral T-cell non-Hodgkin lymphoma (NHL) that will be treated with chemotherapy; NOTE: patients can be enrolled up through day 1 of cycle 3 of therapy; this includes the following disease types:
    • Peripheral T cell lymphoma, unspecified
    • Anaplastic large cell lymphoma (T and null cell type)
    • Extranodal NK/T-cell lymphoma, nasal type
    • Enteropathy-type T-cell lymphoma
    • Hepatosplenic T-cell lymphoma
    • Subcutaneous panniculitis-like T-cell lymphoma
    • Angioimmunoblastic T-cell lymphoma
    • Anaplastic large cell lymphoma
      •primary cutaneous type and
  • Willing to provide tissue for correlative research purposes
• Study 2
  •CLL/SLL
  • Newly diagnosed (< 12 months from pre-registration on this study) 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
    • Diagnosis of CLL according to NCI working group criteria as evidenced by all of the following:
      • Peripheral blood lymphocyte count of > 5,000/mm^3; if present, prolymphocytes should be < 55%
      • Immunophenotyping consistent with CLL defined as:
        • The predominant population of lymphocytes share both B-cell antigens (cluster of differentiation [CD]19, CD20, or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.)
        • Dim surface immunoglobulin expression
        • Restricted surface kappa or lambda light chain expression
      • Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by demonstrating a negative fluorescent in situ hybridization (FISH) analysis for t(11;14) (immunoglobulin H [IgH]/cyclin D 1 [CCND1]) on peripheral blood or tissue biopsy or negative immunohistochemical stains for cyclin D1 on involved tissue biopsy
  • Rai stage 0 or 1
  • Previously untreated
  • Asymptomatic with the plan for observation
  • Life expectancy of at least 24 months
  • Willing to provide tissue for correlative research purposes
  • Willing to be randomized to placebo for one year
• Both Studies:
  • Capable of swallowing intact study medication capsules
  • Serum calcium < 11 mg/dL; note: patients with hypercalcemia can be enrolled after the calcium is corrected with standard of care treatments
  • Willing to return to enrolling 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
  • Willing to provide blood samples for correlative research purposes
  • Vitamin D level (25 hydroxy D2 + hydroxyl D3) confirmed by central laboratory review

• Age ≥ 18 years old.
• Must have:
  • Recurrent or progressive ovarian cancer, primary peritoneal cancer or fallopian tube cancer after prior treatment with platinum and taxanes
  • Histologic confirmation of the original primary tumor
  • Prior bilateral oophorectomy
• The following histologic epithelial cell types are eligible:
  • Serous adenocarcinoma;
  • Endometroid adenocarcinoma;
  • Mucinous adenocarcinoma;
  • Undifferentiated carcinoma;
  • Clear cell adenocarcinoma;
  • Mixed epithelial carcinoma;
  • Transitional cell carcinoma;
  • Malignant Brenner’s Tumor; or
  • Adenocarcinoma NOS.
• ECOG performance status (PS) of 0, 1, or 2.
• The following laboratory values obtained £7 days prior to registration:
  • ANC ≥ 1500/mL;
  • PLT ≥ 100,000/mL;
  • Total bilirubin ≤ upper normal limit;
  • AST ≤ 2 x ULN;
  • Creatinine ≤ 1.5 x ULN;
  • Hgb ≥ 9.0 g/dL.
• Normal cardiac function as defined by a normal ejection fraction by MUGA or echocardiogram.
• Provide informed written consent.
• Willing to return to Mayo Clinic Rochester for follow-up.
• Life expectancy ≥ 12 weeks.
• Willing to provide all biologic specimens as required by the protocol.
• Measurable disease by exam or CT scan, or for patients with CA-125 elevation or with microscopic residual but without measurable disease on imaging, willingness to undergo laparoscopy for evaluation of treatment effect if no radiographic progression after 6 treatment cycles.
• CD4 count count ≥ 200/mL or ≥ 15% of peripheral blood lymphocytes.

• Epithelial tumors of low malignant potential, stromal tumors, and germ cell tumors of the ovary.
• Known standard therapy for the patient's disease that is potentially curative or definitely capable of extending life expectancy; subjects will be excluded if this is their first relapse and they have recurred > 6 months from completion of primary (adjuvant) chemotherapy.
• Active infection ≤ 5 days prior to registration.
• History of tuberculosis or history of tuberculosis skin test (PPD) positivity.
• History of other malignancy ≤ 5 years prior to registration except for non-melanoma skin cancer, carcinoma in situ of the cervix, and ductal carcinoma in situ (DCIS).
• Any of the following prior therapies:
  • Chemotherapy ≤ 3 weeks prior to registration;
  • Immunotherapy ≤ 4 weeks prior to registration;
  • Biologic therapy ≤ 4 weeks prior to registration;
  • Extensive abdominal surgery if it includes enterotomy(ies) ≤ 3 weeks prior to registration; this criterion does not apply to placement of the peritoneal Port-A-Cath or lysis of adhesions at the time of registration;
  • Any viral or gene therapy prior to registration;
  • Radiation therapy to the abdomen or pelvis.
• New York Heart Association 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 [SVT]).
• Other cardiac or pulmonary disease that, at the investigators discretion, can impair treatment safety.
• Requiring blood product support.
• Central nervous system (CNS) metastases or seizure disorder.
• Human immunodeficiency virus (HIV)-positive test result or history of other immunodeficiency.
• History of organ transplantation.
• History of chronic hepatitis B or C.
• Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation).
• Intra-abdominal disease > 8 cm in diameter at the time of registration, intrahepatic disease, or disease beyond the abdominal cavity; patients with intra-abdominal lymph node involvement are eligible based on biodistribution data indicating viral dissemination to lymph nodes following intraperitoneal administration.
• Treatment with oral/systemic corticosteroids, with the exception of topical or inhaled steroids.
• Exposure to household contacts ≤ 15 months old or household contact with known immunodeficiency.
• Allergy to measles vaccine or history of severe reaction to prior measles vaccination.
• Allergy to iodine; this does not include reactions to intravenous contrast materials.
• Any other pathology or condition where the principle investigator may deem to negatively impact treatment safety.

• PATIENT PRE-REGISTRATION ELIGIBILITY CRITERIA:

• For pre-surgical patients

  • Suspected diagnosis of resectable non-small cell lung cancer
  • Suspected clinical stage of IIIA, II or large IB (defined as size ≥ 4cm)

• For post-surgical patients

  • Completely resected non-small cell lung cancer
  • Pathologic stage IIIA, II or IB (defined as size ≥ 4 cm)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• No patients who have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer
• No prior or concurrent malignancies within 5 years, except non-melanoma skin carcinoma or in situ carcinomas; a secondary primary lung cancer is considered a concurrent malignancy and would make a patient ineligible for A151216
• No prior treatment with agents targeting EGFR mutation or ALK rearrangement
• Non-lactating and no patients known to be pregnant
• Patients who have had local genotyping are eligible, regardless of the local result
• Note: Post-surgical patients should proceed to registration immediately following preregistration
• PATIENT REGISTRATION ELIGIBILITY CRITERIA:
• Completely resected non-squamous NSCLC; eligible histologic subtypes include adenocarcinoma, adenosquamous carcinoma, or large cell/poorly differentiated non-small cell lung cancer (NSCLC) as long as squamous carcinoma is not favored; patients with pure squamous carcinoma are not eligible
• Pathologic stage IIIA, II, or large IB (defined as size ≥ 4 cm)
• Adequate formalin-fixed, paraffin-embedded (FFPE) tissue available for central EGFR and ALK genotyping for all patients, including those already locally tested for EGFR and ALK

• In order to allow for time for central genotyping and eligibility for the ALCHEMIST treatment trial, patients must register within the following eligibility windows, depending on the adjuvant treatment approach:

  • If no adjuvant therapy, register patient within 75 days following surgery
  • If adjuvant chemotherapy only, register patient within 165 days following surgery
  • If adjuvant chemotherapy and radiation, register patient within 225 days following surgery

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

The patients on this protocol will have been evaluated and treated for their cancer using the standard of care as discussed by the treating physician.

Cohort 1: 

• Histologically confirmed primary cutaneous melanoma
• Patients with clinically stage I-II melanoma
• 18 years of age and older
• Breslow depth of invasion > 0.75 mm
• Patients who are undergoing a sentinel lymph node (SLN) biopsy as part of their surgical intervention as determined by their treating surgeon.
• Patients on the following immunosuppressive medications can be considered for accrual (but use of these medications will be documented by the study coordinator if used within 6 weeks of surgery)
  • Aspirin (daily)
  • Ibuprofen
  • NSAIDs
  • Low dose steroids
• Consent to pre-operative 10cc peripheral blood draw

Cohort 2:

• Women 18 years of age or older
• Patients who have chosen to undergo a prophylactic mastectomy.
• Patients on the following immunosuppressive medications can be considered for accrual (but use of these medications will be documented by the study coordinator if used within 6 weeks of surgery)
  • Aspirin (daily)
  • Ibuprofen
  • NSAIDs
  • Low dose steroids

Cohort 1:

• Biopsy proven regional lymph node involvement.
• Immunosuppressive medications within the past 6 weeks including:
  • High dose steroids
  • TNF-inhibitors
  • Methotrexate
  • IL-1Ra antagonist
• Women who are pregnant or nursing
• Elect not to provide peripheral blood draw

Cohort 2:

• History of ipsilateral breast cancer
• Contralateral inflammatory breast cancer
• Incidental invasive breast cancer identified in the ipsilateral breast during pathologic review of the mastectomy specimen.
• No lymph node identified in the ipsilateral breast during pathologic review of the mastectomy specimen
• Neoadjuvant chemotherapy within the past year
• Immunosuppressive mediations within the past 6 weeks including:
  • High dose steroids
  • TNF-inhibitors
  • Methotrexate
  • IL-1Ra antagonist
• Women who are pregnant or nursing

• Pathologically (histologically or cytologically) proven diagnosis of head and neck squamous cell carcinoma (HNSCC) involving the oral cavity (excluding lips), oropharynx (p16 negative), larynx, or hypopharynx within 63 days of registration
• Patients must have undergone gross total surgical resection of high-risk oral cavity, oropharynx (p16 negative), larynx, or hypopharynx within 63 days prior to registration
• Patients must have at least 1 of the following high-risk pathologic features: extracapsular nodal extension or invasive cancer at the primary tumor resection margin (tumor or ink)
• Pathologic stage III or IV head and neck squamous cell carcinoma (HNSCC), including no distant metastases, based upon the following minimum diagnostic workup:
  • General history and physical examination by a radiation oncologist and/or medical oncologist within 84 days prior to registration;
  • Examination by an ear nose throat (ENT) or head & neck surgeon prior to surgery; a laryngopharyngoscopy (mirror and/or fiber optic and/or direct procedure), if appropriate is recommended but not required. Intra-operative examination is acceptable documentation.
  • Pre-op Imaging: Either a computed tomography (CT) (with contrast) or CT/positron emission tomography (PET) (with contrast) and/or an magnetic resonance imaging (MRI) (T1 with gadolinium and T2) of the neck within 84 days prior to surgery; note: this imaging data (diagnostic pre-operative scan showing gross disease) is to be submitted in Digital Imaging and Communications in Medicine (DICOM) format via TRIAD; the report is to be uploaded into Rave
  • Chest CT scan (with or without contrast) or CT/PET that includes the chest (with or without contrast) either within 84 days prior to surgery or within 120 days prior to registration;
    • NOTE: If the CT/PET with or without contrast is done within 84 days prior to surgery, if fulfills the chest imaging requirement.
• Zubrod performance status of 0-1 within 14 days prior to registration
• Absolute granulocyte count (AGC) ≥ 1,500 cells/mm^3
• Platelets ≥ 100,000 cells/mm^3
• Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] ≥ 8.0 g/dl is acceptable)
• Total bilirubin < 2 x institutional upper limit of normal (ULN) within 14 days prior to registration
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x institutional ULN within 14 days prior to registration
• Serum creatinine institutional ULN within 14 days prior to registration or; creatinine clearance (CC) ≥ 50 ml/min within 14 days prior to registration determined by 24-hour collection or estimated by Cockcroft-Gault formula
• Negative serum or urine pregnancy test within 14 days prior to registration for women of childbearing potential
• The following assessments are required within 14 days prior to registration: sodium (Na), potassium (K), chloride (Cl), glucose, calcium (Ca), magnesium (Mg), and albumin;
  • Note: Patients with an initial magnesium < 0.5 mmol/L (1.2 mg/dl) may receive corrective magnesium supplementation but should continue to receive either prophylactic weekly infusion of magnesium and/or oral magnesium supplementation (eg, magnesium oxide) at the investigator's discretion
• Patients with feeding tubes are eligible for the study
• Women of childbearing potential and male participants who are sexually active must agree to use a medically effective means of birth control
• Patient must provide study specific informed consent prior to study entry, including consent for mandatory tissue submission for epidermal growth factor receptor (EGFR) analysis and for oropharyngeal cancer patients, human papilloma virus (HPV) analysis

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 1095 days (3 years); noninvasive cancers (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) are permitted even if diagnosed and treated < 3 years ago
• Patients with simultaneous primaries or bilateral tumors are excluded, with the exception of patients with bilateral tonsil cancers or patients with T1-2, N0, M0 resected differentiated thyroid carcinoma, who are eligible
• Prior systemic chemotherapy or anti-epidermal growth factor (EGF) therapy for the study cancer; note that prior chemotherapy for a different cancer is allowable
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• Severe, active co-morbidity, defined as follows:
  • Unstable angina and/or congestive heart failure requiring hospitalization within 6 months prior to registration
  • Transmural myocardial infarction within 6 months prior to registration
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
  • Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen therapy or is thought to require oxygen therapy within 1 year prior to registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol
  • Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease and Control (CDC) definition; note: HIV testing is not required for entry into this protocol; the need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive; protocol-specific requirements may also exclude immuno-compromised patients
• Grade 3-4 electrolyte abnormalities (Common Terminology Criteria for Adverse Events [CTCAE], v. 4):
• Serum calcium (ionized or adjusted for albumin) < 7 mg/dl (1.75 mmol/L) or > 12.5 mg/dl (> 3.1 mmol/L) despite intervention to normalize levels
• Glucose < 40 mg/dl (< 2.2 mmol/L) or > 250 mg/dl (> 14mmol/L)
• Magnesium < 0.9 mg/dl (< 0.4 mmol/L) or > 3 mg/dl (> 1.23 mmol/L) despite intervention to normalize levels
• Potassium < 3.5 mmol/L or > 6 mmol/L despite intervention to normalize levels
• Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic
• Prior allergic reaction to cetuximab

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).

• Participants must have histologically proven primary (or locally recurrent after prior surgery) soft tissue sarcoma of the retroperitoneum. Patients in the Phase II portion of the trial will be primary soft tissue sarcomas only. Extraskeletal chondrosarcoma is allowed.  Pathology must be reviewed prior to study entry.

  • Note: For patients with retroperitoneal neoplasms that have ambiguous histological and/or immunohistochemical findings, the diagnoses of carcinoma, melanoma, and lymphoma should be excluded by immunohistochemical studies with antibodies to broad spectrum cytokeratin (AE1/AE3), S-100, CD45, or LCA (leucocyte common antigen), respectively. If these diagnoses are excluded by immunohistochemistry, then patients presenting with primary non-visceral retroperitoneal masses that are felt to be "consistent with sarcoma" shall be considered eligible for this trial.

• Participants must have histologically proven primary (or locally recurrent after prior surgery) soft tissue sarcoma of the retroperitoneum. Patients in the Phase II portion of the trial will be primary soft tissue sarcomas only. Extraskeletal chondrosarcoma is allowed.  Pathology must be reviewed at treating institution or DF/HCC affiliate  prior to study entry (for locally recurrent participants, biopsy and pathology review may be from time of original diagnosis). 
• Participants 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) as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan.
• No prior radiation therapy for retroperitoneal sarcoma is allowed.
• Age 18 years or older.  Children are excluded from this study but may be eligible for pediatric sarcoma trials of radiation therapy.
• Life expectancy of greater than 2 years.
• ECOG performance status <1.
• Participants must have normal organ and marrow function as defined below:
  • Leukocytes > 3,000/mcL;
  • Absolute neutrophil count > 1,500/mcL;
  • Platelets > 100,000/mcL;
  • Hemoglobin > 8.0g/dl;
    • Note: the use of transfusion or other intervention to achieve Hgb > 8.0 g/dl is acceptable.
  • Total bilirubin within normal institutional limits;
  • AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal;
  • For women of childbearing potential, negative urine or serum pregnancy test within 6 weeks prior to study entry.
• No distant metastases, based upon the following minimum diagnostic workup:
  • History and physical exam including a detailed description of the location, size and stage of the sarcoma, within 10 weeks prior to study entry;
  • CT or MRI with contrast of the abdomen and pelvis within 8 weeks prior to study entry; the maximal dimension of the primary tumor will be measured in CT and MRI images; and
  • CT scan of the chest within 8 weeks prior to study entry.
• The effects of radiation therapy on the developing human fetus have been known to be teratogenic.  Women of child-bearing potential and men must agree to use adequate contraception (i.e., hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• The ability to understand and the willingness to sign a written informed consent document.
• Participant must be evaluated by surgical oncologist and felt to have potentially resectable tumor and be medically fit for proposed surgery.

Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study:

• Participants who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to study entry or those with adverse events due to agents administered more than 4 weeks earlier that have not  resolved to < Grade 1 per CTCAE v. 4.
• Participants may not be receiving any other investigational agents.
• Participants with sarcoma of head and neck, lung, heart or extremity origin; or histopathology demonstrating rhabdomyosarcoma, extraosseous primitive neuroectodermal tumor (PNET) soft tissue Ewing’s sarcoma, osteosarcoma, Kaposi’s sarcoma, angiosarcoma, aggressive fibromatosis (desmoid tumor), or dermatofibrosarcoma protuberans or chondrosarcoma other than extraskeletal chondrosarcoma; or well differentiated liposarcoma where the target volume cannot be adequately distinguished from the normal retroperitoneal fat are excluded.
• Participants with multifocal disease, lymph node or distant metastases.
  • Note: multiple pulmonary nodules <8 mm without a histological diagnosis detected incidentally in a non-screening CT scan may not be a basis for study exclusion because of the sensitivity/specificity of the CT scans of the chest/abdomen/pelvis.
• History of sensitivity to, or history of conditions that are known to cause sensitivity to, radiation therapy.
• Participants for whom intraoperative or post-operative radiation therapy is planned as part of the overall primary tumor treatment.
• 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.
• Pregnant women are excluded from this study because radiation is known to have teratogenic effects.
• Individuals with a history of a different invasive malignancy are eligible per the discretion of the treating investigator and review by the principal investigator.
• HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for increased sensitivity to radiation therapy. (American Journal of Clinical Oncology: October 1998: 21(5), 479-81.

• 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.

Inclusion Criteria

• Pathologically confirmed MPNST, with or without underlying diagnosis of neurofibromatosis type 1 (diagnostic criteria for neurofibromatosis type 1)
• Measurable disease as defined by at least one tumor that is measurable in two dimensions on CT or magnetic resonance imaging (MRI) scan (minimum size 1.0 cm for at least one lesion)
• MPNST for which standard therapy is not curative, including patients with surgically unresectable lesions, progression (WHO criteria) or recurrence of an MPNST in a previously radiated field (if it has been at least 4 weeks prior to registration since the last dose of radiation)
• Has metastatic disease
• May have more than one site of recurrent or metastatic disease but only one lesion that is ≥ 1 cm in size will be injected (if in the lung, the lesion must be ≥ 2 cm and adjacent to the pleura in the lung)
• Absolute neutrophil count (ANC) ≥ 1500
• Platelet (PLT) ≥ 100,000
• Hemoglobin (HgB) ≥ 9.0 g/dL
• Total bilirubin ≤ institutional upper limit of normal (ULN)
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) ≤ 1.5 x upper limit of normal (ULN)
• Creatinine ≤ 1.0 mg/dL
• International normalized ratio (INR) ≤ 2.0
• Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
• Provide informed written consent
• Willing to return to Mayo Clinic Rochester for follow-up
• Willing to provide biologic samples for correlative research purposes
• Life expectancy ≥ 12 weeks
• Cluster of differentiation (CD)4 count ≥ 200/uL or ≥ 15% of peripheral blood lymphocytes
• Ability to complete questionnaire(s) by themselves or with assistance

Exclusion Criteria

• Any of the following
  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception during treatment and 8 weeks following the completion of treatment
• 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
• Receiving therapeutic anticoagulation (Coumadin or low molecular weight heparin, heparin, apixaban, dabigatran, rivaroxaban, warfarin)
• Active infection ≤ 5 days prior to registration
• History of tuberculosis or history of purified protein derivative (PPD) positivity
• Any of the following prior therapies
  • Chemotherapy ≤ 3 weeks prior to registration
  • Immunotherapy ≤ 4 weeks prior to registration
  • Biologic therapy ≤ 4 weeks prior to registration
  • Radiation therapy ≤ 3 weeks prior to registration
• Failure to fully recover from acute, reversible effects defined as ≤ grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.0 of prior chemotherapy regardless of interval since last treatment except alopecia and neuropathy
• Requiring blood product support
• Has central nervous system metastases or seizure disorder
• Human immunodeficiency virus (HIV)-positive test result or history of other immunodeficiency
• History of organ transplantation
• History of chronic hepatitis B or C
• Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation)
• Treatment with oral/systemic corticosteroids, with the exception of topical or inhaled steroids
• Current exposure to household contacts ≤ 15 months old or household contact with known immunodeficiency
  • Must avoid contact during documented viral shedding
  • If continuous viral shedding, will be given recommendations for restricted activities to avoid contact with immunocompromised persons
• Allergy to measles vaccine or history of severe reaction to prior measles vaccination
• Allergy to iodine
  • Does not include reactions to intravenous contrast materials
• Allergy to lidocaine, fentanyl, midazolam, or propofol (may be used during tumor biopsy or injection)

• 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

PRE-REGISTRATION INCLUSION CRITERIA:

• Ability to understand and the willingness to sign a written informed consent document.
• The effects of the candidate chemoprevention agents on the developing human fetus remain incompletely defined; however, study participants will be women who have gone through a bi-lateral oophorectomy procedure.
• Willingness to be evaluated for surgical placement of an intraperitoneal port and undergo biopsy if feasible for a research sample.

REGISTRATION/RANDOMIZATION INCLUSION CRITERIA:

• Age ≥ 18 years.
• Recurrent, persistent, or progressive epithelial ovarian, fallopian tube, or primary peritoneal cancer after treatment with bilateral oophorectomy and either cisplatin or carboplatin and either paclitaxel, albumin-bound paclitaxel, or docetaxel. Histologic confirmation of the primary tumor is required. Eligible histologies include serous, endometrioid, clear cell, mucinous, transitional cell, undifferentiated, or mixed carcinoma.
• Platinum-resistant or platinum-refractory disease, defined as either:
  • less than a complete response to the most recent carboplatin- or cisplatin-containing chemotherapy regimen;
  • serum CA-125 ≥2 x ULN within 180 days of last dose of carboplatin- or cisplatin-containing chemotherapy, confirmed by a second CA-125 (the second CA-125 does not have to be within 180 days of chemotherapy); or
  • CT or PET/CT evidence of cancer recurrence within 180 days of last dose of carboplatin- or cisplatin-containing chemotherapy.
• The following laboratory values obtained £7 days prior to registration:
  • ANC ≥ 1500/µL;
  • PLT ≥ 100,000/µL;
  • Total bilirubin ≤ ULN;
  • AST ≤ 2 x ULN;
  • Creatinine ≤ 1.5 x ULN;
  • Hgb ≥ 9.0 g/dL.
• Willingness to return to Mayo Clinic Rochester or another participating institution for follow-up. Patients who are randomized to Arm B (cytotoxic chemotherapy) may receive chemotherapy at any oncology clinic able to provide the protocol-directed therapy and willing to send laboratory data to the participating institution; however, patients must be willing to return to the participating institution every two months for evaluation. Patients who are randomized to Arm A must be willing to receive all treatment and follow-up at a participating institution.
• Life expectancy ≥ 12 weeks.
• Willingness to provide all biologic specimens as required by the protocol.
• Measurable disease by RECIST criteria, or evaluable disease by CA-125.
  • NOTE: CA-125-evaluable disease is defined as serum CA-125 ≥ 2 x ULN that is determined by the treating clinician to be due to recurrent ovarian, fallopian tube, or primary peritoneal cancer.
• Normal cardiac function, as determined by LVEF ≥ institutional lower limit of normal on echocardiogram or MUGA ≤ 1 month prior to registration.
• If DOXIL is selected as the investigator’s choice chemotherapy:
  • Lifetime exposure to doxorubicin ≤240 mg/m2 (or equivalent biologic dose if prior exposure to a different anthracycline).
• Candidate for surgical placement of an intraperitoneal port, as determined by a gynecologic oncology surgeon.
• Must have anti-measles immunity as demonstrated by serum IgG anti-measles antibody levels of ≥ 1.1 EU/ml as determined by BioPlex Measles IgG multiplex flow immunoassay.

REGISTRATION/RANDOMIZATION EXCLUSION CRITERIA:

• Epithelial tumors of low malignant potential, stromal tumors, and germ cell tumors of the ovary.
• Evidence of measurable disease (per RECIST 1.1)  outside of the peritoneal cavity (ex: mediastinal lymphadenopathy, parenchymal liver metastasis, or symptomatic pleural effusion proven or suspected to be due to cancer).
  • Note: Asymptomatic pleural effusion with or without minimal pleural involvement as long as there is no measurable disease outside the peritoneum/retroperitoneum is allowed.
• Bulky metastases, defined as any tumor nodule or lymph nodes >5 cm in greatest dimension on axial images on pre-treatment CT, PET/CT, or MRI.
  • Note: Patients with bulky (>5 cm) disease for whom gross total cytoreduction is deemed feasible by a surgeon (with confirmation by a second surgeon after radiologic review) are eligible for participation in the context of cytoreductive surgery.
• Resistant to all of the following:  DOXIL, GEM, TOPA, and weekly TAXOL.
  • NOTE: Resistance is defined as either less than a complete response to any chemotherapy regimen containing the agent in question (consider weekly TAXOL as a separate agent from every-three-week TAXOL), serum CA-125 ≥ 2 x ULN within 180 days of last dose of chemotherapy containing the agent in question, confirmed by a second CA-125 (the second CA-125 does not have to be within 180 days of chemotherapy), or CT or PET/CT evidence of cancer recurrence/progression within 180 days of last dose of chemotherapy containing the agent in question. (For example, if a patient previously received carboplatin and GEM, had a complete response, and had initial evidence of relapse >180 days after the last dose of GEM, that patient would not be considered resistant to GEM)).
• ECOG performance status (PS) of 3 or 4.
• History of other malignancy £5 years prior to registration except for non-melanoma skin cancer, carcinoma in situ of the cervix, and DCIS.
• Active infection ≤ 7 days prior to study entry.
• Any of the following prior therapies:
  • Chemotherapy ≤ 3 weeks prior to study entry;
  • Immunotherapy ≤ 4 weeks prior to study entry;
  • Biologic therapy ≤ 4 weeks prior to study entry;
  • Extensive abdominal surgery if it includes enterotomy(ies) ≤3 weeks prior to study entry.
    • NOTE: This criterion does not apply to placement of the peritoneal Port-A-Cath or lysis of adhesions at the time of study entry),
  • Any viral or gene therapy prior to study entry.
• Failure to recover to ≤Grade 1 from acute, reversible effects of prior chemotherapy, excluding alopecia regardless of interval since last treatment.
  • NOTE: Patients with residual peripheral neuropathy are allowed.
• New York Heart Association classification III or IV congestive heart failure, known symptomatic coronary artery disease, symptoms of coronary artery disease on systems review, or known cardiac arrhythmias (atrial fibrillation or SVT).
• Other cardiac or pulmonary disease that, at the investigator’s discretion, can impair treatment safety.
• CNS metastases or seizure disorder.
• HIV-positive test result, or history of other immunodeficiency.
• History of organ transplantation.
• History of chronic hepatitis B or C.
• Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-FDA-approved indication and in the context of a research investigation).
• Any concurrent medications which could interfere with the trial.
• History of tuberculosis or history of PPD positivity.
• Treatment with oral/systemic corticosteroids, with the exception of topical or inhaled steroids or steroids given for the purpose of adrenal replacement given at physiologic doses.
• Exposure to household contacts £15 months old or household contact with known immunodeficiency.
• Allergy to measles vaccine or history of severe reaction to prior measles vaccination.
• Allergy to iodine.
  • NOTE: This does not include reactions to intravenous contrast materials.
• Any other pathology or condition which the principal investigator may deem to negatively impact treatment safety.
• On anticoagulation and unable to discontinue temporarily for up to 7 days