• Pregnant females age 18-45 years and their infants.
• Willing and able to provide written informed consent.
• Pregnant and planning to deliver at Mayo Clinic.

• Positive for HIV, HBV or TB.
• Delivery not planned at Mayo Clinic.
   

• Age ≥ 50 years old OR primary healthcare professional (defined as having a job that has had direct patient contact during the COVID-19 pandemic) and ≥ 18 years old.
• No symptoms of COVID-19 (a fever of 100.0 degrees F or greater, OR a new cough, OR new shortness of breath, OR new sore throat, OR new diarrhea, OR new fast breathing (respiratory distress), OR new chills, OR new muscle aches (myalgias), OR new loss of smell, OR new change or loss of taste sensation) in the past 7 days.
• Have a negative Elecsys Anti-SARS-CoV-2 immunoassay antibody test at screening .
• Have not had close contact with a person with a LABORATORY CONFIRMED case of COVID-19 (Close contact is defined by CDC as:  being within approximately 6 feet of a COVID-19 patient for a prolonged period of time (more than 5 minutes) or having direct contact with infectious secretions of a COVID-19 patient (e.g., being coughed on)) in the last 14 days.
• Mayo Clinic patient who has a patient online account set up or is willing to set up an online account.
• Must have a valid email address and internet service

• History of positive or indeterminate COVID PCR test prior to screening or positive or indeterminate Elecsys Anti-SARS-CoV-2 immunoassay antibody test at screening.
• Active symptoms of COVID ((a fever of 100.0 degrees F or greater, OR a new cough, OR new shortness of breath, OR new sore throat, OR new diarrhea, OR new fast breathing (respiratory distress), OR new chills, OR new muscle aches (myalgias), OR new loss of smell, OR new change or loss of taste sensation)) in past 7 days.
• Known intolerance to Centrum multivitamins or Zinc supplement from prior exposure.
• Inability to complete follow-up questions or grant access to electronic health record for surveillance.
• Have had close contact with a person with a LABORATORY CONFIRMED case of COVID-19 in past 14 days.
• Current or former smoker less than 5 years ago.
• Pregnant or breastfeeding.
• Prisoner.
• Any subject with known immunosuppressed state, including:
  • A history of solid organ or bone marrow transplantation;
  • Subjects currently receiving chemotherapy;
  • Current rheumatologic or autoimmune illness requiring treatment with glucocorticoids, antimetabolite agents (methotrexate, azathioprine, mercaptopurine, fluorouracil, mycophenolate, leflunomide), IMIDs (lenalidomide, thalidomide, pomalidomide), calcineurin inhibitors (tacrolimus, cyclosporine), mTOR inhibitors (sirolimus, everolimus), or any monoclonal antibody drugs (including any drug given intravenously or subcutaneously) for the purpose of immunosuppression;
  • Subjects with HIV or primary immunodeficiency syndromes.

• Ability to converse in English.
• Legal adult 18 years of age or older who have the capacity to consent to participating in this study.
• To meet Aims 1 and 2 and to ensure balanced stakeholder perspectives are gathered, eligible participants will be screened to identify employees of Mayo Clinic (currently employed by Mayo Clinic or employed by Mayo Clinic within the last five years) and non-employee (currently not employed by Mayo Clinic or employed by Mayo Clinic in the last five years).
• To meet the aims of this study, equilibrium of the number of eligible participants in the groups of the subject populations identified is desirable thus selective sampling of the groups will be implemented during recruitment

• Unable to converse in English.
• Individuals less than 18 years of age or who do not have the capacity to consent to participating in this study.
• Legally authorized representatives of contributors to the biobank
• To meet Aims 1 and 2, eligible participants in subject population group 1 will be screened to identify current participation in the Mayo Clinic Center for Individualized Medicine Biobank.
• Individuals who have donated to the Mayo Clinic.
• Biobank will be excluded from this study to safeguard an unbiased data collection on biospecimen research and perceptions of consent and voluntariness during a pandemic.

• Males and females, at least 40 years of age, capable and willing to provide informed consent
• Patient must have received a diagnosis of COVID-19 infection within the last 24 hours
• Outpatient setting (not currently hospitalized or under immediate consideration for hospitalization)
• Patient must possess at least one of the following high-risk criteria:
  • 70 years or more of age, obesity (BMI ≥ 30 kg/m2)
  • Diabetes mellitus
  • Uncontrolled hypertension (systolic blood pressure ≥150 mm Hg)
  • Known respiratory disease (including asthma or chronic obstructive pulmonary disease)
  • Known heart failure
  • Known coronary disease
  • Fever of ≥38.4°C within the last 48 hours
  • Dyspnea at the time of presentation
  • Bicytopenia
  • Pancytopenia
  • The combination of high neutrophil count and low lymphocyte count
• Female patient is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile, or is of childbearing potential and practicing at least one method of contraception and preferably two complementary forms of contraception including a barrier method (e.g. male or female condoms, spermicides, sponges, foams, jellies, diaphragm, intrauterine device (IUD)) throughout the study and for 30 days after study completion
• Patient must be able and willing to comply with the requirements of this study protocol.

• Patient currently hospitalized or under immediate consideration for hospitalization
• Patient currently in shock or with hemodynamic instability
• Patient with inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic diarrhea or malabsorption
• Patient with pre-existent progressive neuromuscular disease
• Estimated Glomerular filtration rate (eGFR), using the MDRD equation for all subjects being considered for enrollment, with a cut-off of < 30 mL/m in/1.73m2
• Patient with a history of cirrhosis, chronic active hepatitis or severe hepatic disease
• Female patient who is pregnant, or breast-feeding or is considering becoming pregnant during the study or for 6 months after the last dose of study medication
• Patient currently taking colchicine for other indications (mainly chronic indications represented by Familial Mediterranean Fever or gout)
• Patient with a history of an allergic reaction or significant sensitivity to colchicine
• Patient undergoing chemotherapy for cancer
• Patient is considered by the investigator, for any reason, to be an unsuitable candidate for the study.

• 18 years of age or older at the time of consent.
• Frontline healthcare professional.
• Have access to an Apple or Android device.
• Not pregnant by subject self-report at time of consent.
• Have the ability to provide informed consent.
• Have no contraindicating comorbid health condition as determined by the clinical investigators.

• Currently (within the past 3 weeks) been practicing mindfulness training on a weekly/regular basis.
• Currently (within the past 3 weeks) been undergoing an additional program (e.g., CAM) to improve quality of life or sleep.
• Currently (within 3 weeks) been enrolled in another clinical or research program (e.g., CAM) which intervenes on the patients’ QOL, stress or sleep.
• An unstable medical or mental health condition as determined by the physician investigator.

• Be ≥ 18 years of age
• Have been admitted to hospital
• Have a signed informed consent by participant or surrogate/representative
• Have a local diagnosis (confirmed or suspected) of influenza, or of a targeted non-influenza viral respiratory infection*, resulting in (or extending a previous) hospitalization
  • A list of targeted non-influenza respiratory viruses is maintained on the INSIGHT website.

• Current imprisonment, or compulsory detention (involuntary incarceration) for treat of a psychiatric or physical illness.

• Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) positive as determined by Polymerase Chain Reaction (PCR) or other commercially available or public health assay (e.g., Nucleic Acid Amplification Test [NAAT] and antigen tests) in any respiratory specimen.
• Hospitalized for COVID-19.
• Age ≥ 12 years and weighing at least 40 kg.
• Oxygen (O2) saturation ≤ 94% on room air or requiring O2 supplement or Radiographic evidence of pulmonary infiltrates for COVID-19.
• Have either:
  • Severely reduced kidney function (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m^2 ), using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and revised Schwartz equations for adults and adolescents, respectively, including people with ESKD requiring chronic dialysis but not people requiring RRT for AKI;
  • Adults: eGFR (mL/min/1.73 m²) 141 × min(SCr/κ, 1)α × max(SCr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if African American]
  • κ = 0.7 for females; 0.9 for males α = -0.329 for females; -0.411 for males
  • Adolescents (age 12–17 years): eGFR (mL/min/1.73 m²) = (0.41 × Height in cm) / SCr
  • SCr in mg/dL, age in years;
  • Ongoing AKI: defined as a 50% increase in SCr within a 48-hour period that is sustained (ie, requires confirmatory SCr) for ≥ 6 hours despite supportive care.
• Willing and able to provide written informed consent, or with a legal representative who can provide informed consent, or enrolled under ICH E6(R2) 4.8.15 emergency use provisions as deemed necessary by the investigator (age ≥ 18) prior to performing study procedures.
• The interval between COVID-19 symptoms onset and randomization is no more than 10 days.
• Male participants and female participants of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception.

• Received any investigational drug, RDV, or other antiviral treatment for COVID-19.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times the upper limit of normal.
• Invasive mechanical ventilation, noninvasive mechanical ventilation, ECMO, or RRT for acute kidney injury (AKI).
• Positive serum pregnancy test at screening for women of childbearing potential or currently breastfeeding.
• Known hypersensitivity to the study drug, metabolites, or formulation sulfobutylether-beta-cyclodextrin (SBECD).

Eligibility last updated 11/9/21. Questions regarding updates should be directed to the study team contact.

• 18 years of age or older.
• Community members in the catchment area.

• Under the age of 18.

• Adult (≥ 18 years old)
• Diagnosis of diabetes mellitus using insulin pump and/or CGM technology
• No evidence of cognitive impairment
• English proficiency
• Has a contact telephone number listed in patient chart

• Pediatric patients (<18 years old)
• Not diagnosed with diabetes mellitus
• Evidence of cognitive impairment, or inability to give consent
• Limited English proficiency
• No telephone number listed in patient chart

• Adults, ≥ 18 years of age.
• Member of the community in a leadership or representative position.

• Individuals 18 years of age.

Patients must have any one of the following diagnosis:

• Monoclonal B-cell lymphocytosis.
• Chronic lymphocytic leukemia/small lymphocytic lymphoma.
• B-cell Non-Hodgkin’s lymphoma:
  • Follicular lymphoma;
  • Mantle cell lymphoma;
  • Diffuse large B-cell lymphoma;
  • Marginal zone lymphoma;
  • Burkitt lymphoma;
  • Double hit/triple hit lymphoma;
  • Lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia;
• Hodgkin lymphoma.
• Individuals who are a participant of the Mayo Clinic Biobank.

• Diagnosis of acute myeloid leukemia (AML) based on 2017 World Health Organization (WHO) criteria excluding acute promyelocytic leukemia with PML-RARA. 
• No activating mutation in the Fms-like tyrosine kinase-3 (FLT3) defined as a ratio of mutant to wild-type allele >= 0.05 by capillary electrophoresis or a variant allele fraction of >= 5% by next generation sequencing from either bone marrow or peripheral blood. 
• No evidence of CNS involvement of AML.
• No prior chemotherapy for myelodysplastic syndrome (MDS) or AML including hypomethylating agents (e.g., azacitidine and decitabine) or lenalidomide with the following exceptions: 
  • Emergency leukapheresis. 
  • Hydroxyurea.
  • Growth factor/cytokine support.
  • All-trans retinoic acid (ATRA). 
  • Single dose of intrathecal cytarabine and/or methotrexate for patients undergoing lumbar puncture to evaluate for CNS involvement.

• Patients with myeloid sarcoma without bone marrow involvement, acute leukemia of ambiguous lineage or blast transformation of chronic myelogenous leukemia (CML) are not eligible. 

• Participant has a localized invasive breast ductal adenocarcinoma, confirmed by the local pathologist, that includes either T1c-T2 (tumor size ≥ 2 cm), clinical node stage (cN)1-cN2, or T3-T4, cN0-cN2.
  • Note: Multifocal tumors defined as the presence of 2 or more foci of cancer within the same quadrant are allowed; at least 1 of the tumors needs to be ≥ 2 cm.
• ER+/HER2– status needs to be confirmed for each focus.
  • Note: Inflammatory breast cancer is allowed.
  • Note: Participants with node negative disease will be capped at 20% of the total population.
• Has centrally confirmed ER+/HER2–, Grade 3 breast cancer of ductal histology, according to the most recent American Society of Clinical Oncology/College of American Pathologist guidelines. Refer to Appendix 6 for country-specific requirements.
• Provides a new or recently obtained core needle biopsy, consisting of multiple cores, taken from the primary breast tumor(s) for central determination of HR status (ER and progesterone receptor), HER2, grade, and PD-L1 status.
  • Note: Adequacy of the biopsy specimen for the above analyses must be confirmed by the central laboratory. Submission of another tumor specimen may be required, if adequate tumor tissue was not provided the first time.
  • Note: Sponsor agreement is required for formalin-fixed paraffin-embedded (FFPE) tumor tissue sample or slides that were obtained greater than 60 days prior to the date that the informed consent was signed.
• Is a male or female ≥ 18 years of age on the day of signing informed consent.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 10 days prior to initiation of study treatment.
• A male participant must agree to use a contraception during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment and refrain from donating sperm during this period.
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
  • Not a woman of childbearing potential (WOCBP); OR
• A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment with pembrolizumab or placebo. 
• The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research.
• Has adequate organ function; all screening laboratory tests should be performed within 10 days prior to initiation of study treatment:
• Hematological
  • Absolute neutrophil count ≥ 1,500 cells/μL;
  • Platelets* ≥ 100,000 cells/μL;
  • Hemoglobin* ≥ 9 g/dL or ≥ 5.6 mmol/L.
• Renal
  • Creatinine ≤ 1.5 × ULN; OR
  • Measured or calculated** creatinine clearance (GFR can also be used instead of CrCl) ≥ 50 mL/min for participants with creatinine levels ≥ 1.5 × institutional ULN.
• Hepatic
  • Total bilirubin ≤ 1.5 × ULN; OR
  • Direct bilirubin ≤ ULN for participants with total bilirubin levels ≥ 1.5 × ULN;
  • AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN.
• Coagulation
  • INR or PT ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT/PTT is within therapeutic range of intended use of anticoagulants;
  • Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT).
• Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CrCl = creatinine clearance; GFR = glomerular filtration rate; INR = international normalized ratio; PT = prothrombin time; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of normal.
• *  Platelet and hemoglobin requirements cannot be met by use of recent transfusion or growth factor support (granulocyte colony stimulating factor [G-CSF], granulocyte-macrophage colony stimulating factor [GM-CSF], or erythropoietin) within 2 weeks prior to initiation of study treatment.
• ** Creatinine clearance should be calculated per institutional standard.

• Has a history of non-infectious pneumonitis that required treatment with steroids or has current pneumonitis.
• Has breast cancer with lobular histology.
• Has bilateral invasive breast cancer.
• Has metastatic (Stage IV) breast cancer.
• Has multi-centric breast cancer (presence of more than 1 tumor in different quadrants of the breast).
• Has any of the following clinical lymph node staging per current AJCC staging criteria for breast cancer staging based on radiological and/or clinical assessment:
  • cN3, cN3a, cN3b, or cN3c.
• Has ER–, progesterone receptor positive breast cancer.
• Participants who have undergone excisional biopsy of the primary tumor and/or axillary lymph nodes or have undergone sentinel lymph node biopsy prior to study treatment.
• Has a known additional, invasive, malignancy that is progressing or required active treatment in the last 5 years.
  • Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, breast ductal carcinoma in situ, or cervical carcinoma in situ that has undergone potentially curative therapy are not excluded.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
• Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
  • Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
• Has a known history of active tuberculosis (Bacillus tuberculosis).
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition (e.g., transfusion-dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that is specifically contraindicated per the current locally-approved labeling, that might confound the results of the study, interfere with the participant’s involvement for the full duration of the study, or is not in the best interest of the participant to be involved, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would may interfere with cooperation with the requirements of the study.
• Has left ventricular ejection fraction (LVEF) of < 50% or below the institution limit of normal, as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening.
• Has other significant cardiac disease, such as:
  • History of myocardial infarction, acute coronary syndrome, or coronary angioplasty/stenting/bypass within the last 6 months;
  • Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV.
• Has a known history of human immunodeficiency virus (HIV) infection.
  • Note: No HIV testing is required unless mandated by local health authority.
• Has a known history of hepatitis B (defined as hepatitis B surface antigen [HbsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
  • Note: No testing for hepatitis B or hepatitis C is required unless mandated by local health authority.
• A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of study treatment. If the urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

• Age ≥ 18 years.
• Ability to complete questionnaires by themselves or with assistance.
• Paclitaxel at a dose of 80 mg/m^2 given every week for a scheduled course of 12 weeks for treating breast cancer.
• Life expectancy ≥ 6 months.
• ECOG Performance Status (PS) 0, 1.
• Negative pregnancy test (serum or urine) done ≤ 14 days prior to registration, for persons of childbearing potential only.
• Provide written informed consent.

• Previous exposure to paclitaxel (please note that it is acceptable for patients to receive non-neurotoxic chemotherapy, like AC, before or after the weekly paclitaxel and/or to receive concurrent anti-her 2 therapy).
• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception.
• Previous diagnosis of diabetic or other peripheral neuropathy.
• Current or previous use of fingolimod.
• History of the following preexisting conditions: ischemic heart disease, cardiac arrest, cerebrovascular disease, uncontrolled hypertension, symptomatic bradycardia, macular edema, recurrent syncope, severe untreated sleep apnea, herpes zoster, chronic hepatitis, tuberculosis, systemic fungal infections, skin cancer, or insulin-dependent diabetes.
• Myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure < 6 months prior to registration.
• History or presence of Mobitz Type II second-degree or third-degree AV block or sick sinus syndrome, unless patient has a functioning pacemaker.
• History of a hypersensitivity reaction to fingolimod or any of the excipients including rash, urticarial, and angioedema upon treatment initiation.
• Baseline QTC interval ≥ 450 ms (on EKG).
• Concurrent use of a class Ia or III antiarrhythmic.
• Drugs with a KNOWN risk of torsades de pointes (Information regarding drug specific risk of QT prolongation can be found at www.crediblemeds.org).
• Concurrent use of beta blockers, calcium channel blockers or digoxin.
• Use of immunosuppressive, or immune-modulating therapies that may have immunosuppressive effects.
• Immunocompromised patients including patients known to be HIV positive.
• Uncontrolled intercurrent illness including, but not limited to:
  • ongoing or active infection;
  • unstable angina pectoris;
  • cardiac arrhythmia;
  • psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent.
• Family history of a genetic/familial neuropathy.
• Received a vaccine (inactivated) ≤ 14 days prior to registration.
• Positive varicella zoster IgM titer, consistent with recent exposure.

• Age ≥ 18 years old.
• Pain or symptoms of CIPN of ≥ 3 months duration, for which the patient wants intervention.
  • NOTE: Neurotoxic chemotherapy must have been completed ≥ 3 months (93 days) prior to registration and there must be no further planned neurotoxic chemotherapy for > 2 months after registration.
• Tingling, numbness or pain was at least a four out of ten problem during the week prior to registration, on a 0-10 scale where zero was no problem and ten was the worst possible problem (patient verbal report to clinician utilizing question in Appendix VI).
• ECOG Performance Status (PS) 0, 1 or 2.
• Negative pregnancy test done ≤ 14 days prior to registration, for persons of childbearing potential only.
• Provided written informed consent.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Life expectancy ≥ 6 months.

• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception.
• Previous diagnosis of diabetic or other peripheral neuropathy.
• Current or previous use of fingolimod.
• History of the following preexisting conditions: ischemic heart disease, cardiac arrest, cerebrovascular disease, uncontrolled hypertension, symptomatic bradycardia, macular edema, recurrent syncope, severe untreated sleep apnea, Herpes simplex virus (HSV) varicella zoster (VZV), chronic hepatitis, tuberculosis, fungal infections, skin cancer, or diabetes.
• Myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure < 6 months prior to registration.
• History or presence of Mobitz Type II second degree or third degree AV block or sick sinus syndrome, unless patient has a functioning pacemaker.
• History of hypersensitivity reaction to fingolimod or any of the excipients including rash, urticarial, and angioedema upon treatment initiation.
• Baseline QTc interval ≥ 450 ms (on patient EKG)
• Concurrent use of a class Ia or III antiarrhythmic drug
• Drugs with a known risk of torsades de pointes
• Concurrent use of beta blockers, calcium channel blockers, or digoxin
• Use of immunosuppressive or immune-modulating therapies that may have immunosuppressive effects
• Immunocompromised patients including patients known to be HIV positive.
• Uncontrolled intercurrent illness including, but not limited to:
  • ongoing or active infection;
  • unstable angina pectoris;
  • cardiac arrhythmia;
  • or psychiatric illness/social situations that would limit compliance with study requirements.
• Family history of genetic/familial neuropathy.
• Currently receiving another agent to treat CIPN, such as duloxetine, gabapentin or pregabalin, and not willing to be weaned off of these medications prior to therapy initiation.
• History of peripheral neuropathy prior to receiving neurotoxic chemotherapy.
• Received a vaccine (inactivated) ≤ 2 weeks prior to registration.
• Positive varicella zoster IgM titer, consistent with recent exposure.

• Patients must have inflammatory breast cancer without distant metastases. All biomarker subtype groups (estrogen receptor [ER], progesterone receptor [PR], HER2) are eligible. Inflammatory disease will be defined per American Joint Committee on Cancer (AJCC) 8th edition with documentation by history/exam and pathology at the time of diagnosis. 
• All patients must have completed neoadjuvant chemotherapy prior to mastectomy. The chemotherapy regimen is at the discretion of the treating physician but it is recommended that it include at least 4 cycles of anthracycline and/or taxane-based therapy (plus targeted therapy for patients with HER2+ disease). Response to chemotherapy is not a criterion for eligibility (both complete responders and those with residual disease are eligible). Please note that although pathologic complete response (pCR) is not required or excluded, pCR status must be determined post-surgery prior to randomization.
• All patients must have undergone modified radical mastectomy (with negative margins on ink) with pathologic nodal evaluation (from level I and II axillary lymph node dissection) at least 3 weeks and no more than 12 weeks prior to randomization, unless they receive additional chemotherapy after mastectomy. Patients must not have gross residual tumor or positive microscopic margins after mastectomy. 
• Additional adjuvant chemotherapy after surgery is allowed at the discretion of the treating physician, either completed prior to randomization or planned for after completion of protocol treatment. If adjuvant chemotherapy is administered after mastectomy, the patient must be randomized at least 3 weeks but no more than 12 weeks after the last dose of adjuvant chemotherapy. 
• Patients must not have a history of radiation therapy to the ipsilateral chest wall and/or regional nodes. Prior radiation therapy to other body sites is allowed.
• Patients must not be planning to receive any other investigational agents during radiation therapy. Prior therapy, including prior treatment with olaparib or other PARP inhibitor, is allowed. 
• Patients must not have a known hypersensitivity to olaparib or any of the excipients of the product.
• Patients must not have unresolved or unstable grade 3 or greater toxicity from prior administration of another investigational drug and/or prior anti-cancer treatment. 
• Patients must not be planning to receive strong or moderate CYP3A inhibitors or inducers while on olaparib treatment. Patients receiving strong or moderate CYP3A inhibitors must agree to discontinue use at least 2 weeks prior to receiving olaparib. Patients receiving strong or moderate CYP3A inducers must agree to discontinue use at least 5 weeks prior to receiving olaparib. 
• Patients must not be planning to receive live virus or live bacterial vaccines while receiving olaparib and during the 30 day follow up period.
• Patients must not be planning to receive any additional anti-cancer therapy (chemotherapy, endocrine therapy, immunotherapy, biological therapy or other novel agent) while receiving radiotherapy with or without study medication. If a patient is receiving concurrent anti-HER2 targeted therapies, they must not take these medications during the period of radiotherapy (with or without study drug) while enrolled on the study. 
• Patients must be ≥ 18 years of age.
• Patients must have Zubrod performance status 0-2. 
• Patients must have adequate hematologic function as evidenced by all of the following within 28 days prior to registration:
  • Absolute neutrophil count (ANC) >= 1000/mm^3 (within 28 days prior to registration);
  • Platelet count >= 100,000/mm^3 (within 28 days prior to registration);
  • Hemoglobin >= 9.0 g/dL (after transfusion if required and within 28 days prior to registration).
• Patients must have adequate renal function as evidenced by calculated creatinine clearance >= 51 mL/min by Cockcroft-Gault equation, within 28 days prior to registration.
• Calculated creatinine clearance = [(140
  •age) x wt (kg) x 0.85 (if female)]/[72 x creatinine (mg/dl)].
• Patients must have adequate hepatic function as evidenced by all of the following within 28 days prior to registration:  
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 28 days prior to registration).
  • Patients with documented Gilbert's disease may have bilirubin up to 2.5 mg/dL.
  • Serum glutamic-oxaloacetic transaminase (SGOT) =< 2.5 x ULN (within 28 days prior to registration).
  • Serum glutamate pyruvate transaminase (SGPT) =< 2.5 x ULN (within 28 days prior to registration) .
  • Alkaline phosphatase =< 2.5 x ULN (within 28 days prior to registration). 
• Patients must not have a history of other prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years.
• Female patients must be postmenopausal or have a negative urine or serum pregnancy test within 28 days prior to registration. Female patients of childbearing potential and male patients with partners of childbearing potential, who are sexually active, must agree to the use of two highly effective forms of contraception. 
• Patients who are breastfeeding must agree to discontinue breastfeeding before receiving olaparib due to potential risk for adverse events in nursing infants secondary to treatment of the mother with olaparib. 
• Patients must not have active uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia. 
• Patients must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of the study medication. 
• Patients must not have a history of a resting electrocardiography (ECG) indicating uncontrolled, potentially reversible cardiac conditions (such as unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, Fridericia's formula corrected QT interval [QTcF] prolongation > 500 ms, electrolyte disturbances) or congenital long QCYP3T syndrome. 
• Patients must not have myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML. 
• Patient must not have had major surgery within 2 weeks of starting study treatments and patients must have recovered from any effects of any major surgery. 
• Patients must not have a history of uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan. 
• Patients must not have had previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT). 
• Patients must not have had whole blood transfusions in the last 120 days prior to randomization.

• Age ≥ 18 years
• Histological confirmation of non-small cell lung cancer (NSCLC) with advanced disease.
• Prior treatment required:
• Anti-PD1/PD-L1 agent in combination with platinum-based chemotherapy
• NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease; Disease that is measurable by physical examination only is not eligible.
•  
• ECOG Performance Status (PS) 0 or 1.
• The following laboratory values obtained ≤ 14 days prior to registration:
• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1500/mm^3
• Platelet count ≥ 100,000/mm^3
• Total bilirubin ≤ ULN
• Alanine aminotransferase (ALT/SGPT) and aspartate transaminase (AST/SGOT) ≤ 1.5 × ULN
• Alkaline phosphatase ≤ 2.5 × ULN
• PT/INR/aPTT ≤1.5 × ULN OR if patient is receiving anticoagulant therapy INR or aPTT is within target range of therapy
• •  
• Calculated creatinine clearance ≥ 30 ml/min using the Cockcroft-Gault formula.
• Negative pregnancy test done ≤7 days prior to registration, for persons of childbearing potential only.
• NOTE: If a urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Willing to use birth control as follows:
• If able to become pregnant: Willing to use birth control during treatment and for 6 months after last dose of docetaxel and/or bintrafusp alfa, whichever is later.
• If able to father a child: Willing to use birth control with partners able to become pregnant during treatment and for 3 months after last dose of docetaxel and/or bintrafusp alfa, whichever is later.
• Provide written informed consent.
• Willingness to provide mandatory blood specimens for correlative research.
• Willingness to provide mandatory tissue specimens for correlative research
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception.
• Any of the following prior therapies:
  • Surgery ≤ 4 weeks prior to registration;
  • Chemotherapy ≤ 4 weeks prior to registration;
  • Received single agent anti-PD1/PD-L1 as first line therapy for metastatic disease.
• 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.
• 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.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Other active malignancy ≤ 5 years prior to registration.
• EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.
• NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer.
•  
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases are excluded, with the following exceptions:
• • Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met:
  • Evaluable or measurable disease outside the CNS;
• • No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm);
  • No history of intracranial hemorrhage or spinal cord hemorrhage.
• No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted.
• No neurosurgical resection or brain biopsy ≤ 28 days prior to registration.
• Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following:
  • Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study;
  • No stereotactic radiation or whole-brain radiation ≤ 28 days prior to registration;
• • Screening CNS radiographic study ≥ 4 weeks from completion of radiotherapy and ≥ 2 weeks from discontinuation of corticosteroids.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• History or current evidence of bleeding disorder, including bleeding diathesis, i.e., any hemorrhage/bleeding event of CTCAE Grade ≥ 2 in ≤ 28 days prior to registration.
• Taking oral prednisone of ≥ 10 mg daily or equivalent.
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease.

Notes:

• Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible.
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
• History or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis.

Notes:

• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible.
• Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible.
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
  • Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations;
• • Rash must cover less than 10% of body surface area (BSA);
  • Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%);
  • No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids).
• Known active human immunodeficiency virus (HIV) infection (defined as patients who are not on anti-retroviral treatment and have detectable viral load and CD4+ < 500/ml).
  • Note: HIV-positive patients who are well controlled on anti-retroviral therapy are allowed to enroll.
• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
  • Note: History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Severe infections ≤ 4 weeks prior to registration, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
• History of peripheral neuropathy ≥ Grade 2.
• Known hypersensitivity to docetaxel or polysorbate 80.

• Are ≥ 18 years of age at the time of signing the informed consent.
  • In Japan, if a patient is < 20 years, the written informed consent from his/her parent or guardian will be required in addition to the patient’s written consent.
• Participants must have measurable or non-measurable but evaluable disease assessed by the Investigator. Participants must have histologically documented NSCLC who present with Stage III locally advanced, unresectable disease (International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology], v8).
• 3. Availability of tumor material (< 6 months old) adequate for biomarker analysis is mandatory for all participants and central laboratory confirmation is required. For participants enrolled in the safety run-in, PD-L1 expression will be tested retrospectively by a central laboratory. For participants enrolled in the expansion part of the study, PD-L1 expression must be tested by the central laboratory and results available before randomization. Only results from the central laboratory testing will be used for randomization and if PD-L1 status is non-evaluable, the participant is not eligible for this study. Tumor samples obtained by endoscopic biopsies, core needle biopsies, excisional biopsies, punch biopsies, and surgical specimens that are < 6 months old and adequate for biomarker analysis are acceptable. Biopsies obtained by fine needle aspiration are not acceptable.
• Participants with tumor harboring an EGFR sensitizing (activating) mutation, ALK translocation, ROS-1 rearrangement are eligible. These tests are not required for enrollment in the study.
• Participants with ongoing post-obstructive pneumonia due to the tumor are eligible.
• If a pleural effusion is present, the following criteria must be met to exclude malignant involvement (incurable T4 disease):
  • When pleural fluid is visible on both the CT scan and on a chest x-ray, a thoracentesis is required to confirm that the pleural fluid is cytologically negative;
  • Participants with exudative pleural effusions are excluded, regardless of cytology;
  • Participants with effusions that are minimal; i.e., are too small to safely tap are eligible.
• Participants must be at least 3 weeks from prior thoracotomy (if performed).
• Participants must have adequate pulmonary function defined as a forced expiratory volume in 1 second (FEV1) ≥ 1.2 liters or ≥ 50% of predicted normal volume measured within 3 weeks prior to randomization. If participants do not meet the above criteria, treatment with inhaled steroids and bronchodilators can be initiated if clinically indicated and eligibility can be reassessed after 1-2 weeks.
• ECOG performance status of 0 to 1 at Screening and on the day of first dose.
• Life expectancy ≥ 12 weeks.
• Have adequate organ function as indicated by the following laboratory values:
  • Adequate hematological function defined by absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL;
  • Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × upper limit of normal (ULN), an aspartate aminotransferase (AST) level ≤ 3.0 × ULN, an alanine aminotransferase (ALT) level ≤3.0 × ULN and alkaline phosphatase ≤ 2.5 ULN;
  • Adequate renal function defined by creatine ≤ 1.5 × ULN or calculated creatinine clearance (CrCl) ≥ 50 mL/min for participant with Cr > 1.5 × ULN (GFR can also be used).
    • Note: CrCl  should be calculated per institutional standard. If no local guideline is available, CrCl should be calculated using the Cockcroft-Gault Method:
    • CrCl = ((140-age) * weight (kg) * (0.85 for females only)) / (72 * creatinine).
  • Adequate coagulation function defined as international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN unless the participant is receiving anticoagulant therapy and activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless the participant is receiving anticoagulant therapy.
• Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies.
  • Male Participants:
    • Contraceptive measures should be continued as per guidance specified in labeling document for approved chemotherapies. If not specified, continue measures similar to investigational agent i.e agree to the following during the study intervention period and for at least 6 months after the last dose of study intervention
    • Refrain from donating sperm; PLUS, either:
      • Abstain from intercourse with a WOCBP;
        • OR
      • Use a male condom: When having sexual intercourse with a WOCBP, who is not currently pregnant, and advise her to use a highly effective contraceptive method with a failure rate of < 1% per year, since a condom may break or leak.
  • Female Participants:
    • Are not pregnant or breastfeeding, and at least one of the following conditions applies:
      • Not a WOCBP.
        • OR
      • If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year), preferably with low user dependency, for the following time periods:
        • Before the first dose of the study intervention(s), if using hormonal contraception:
        • Has completed at least one 4-week cycle of an oral contraception pill and either had or has begun her menses; OR
        • Has used a depot contraceptive or extended-cycle oral contraceptive for least 28 days and has a documented negative pregnancy test using a highly sensitive assay.
        • During the intervention period.
      • Contraceptive measures should be continued as per guidance specified in labeling document for approved chemotherapies. If not specified, continue measures similar to investigational agent i.e., after the study intervention period (i.e., after the last dose of study intervention is administered) for at least 4 months after the last dose of study intervention and agree not to donate eggs (ova, oocytes) for reproduction during this period.
    • Have a negative pregnancy test, as required by local regulations, on W1D1 before the first dose of study intervention.
    • Additional requirements for pregnancy testing during and after study intervention are in SoA.
    • The Investigator reviews the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early undetected pregnancy.
• Can give signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and this protocol.

• Participants with mixed small cell with non-small cell lung cancer histology.
• Greater than minimal, exudative, or cytologically positive pleural effusions.
• Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) that would prevent administration of study drug.
• Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
• History of organ transplant that requires therapeutic immunosuppression.
• Significant acute or chronic infections including, among others:
  • Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (testing at Screening is not required). If an Investigator has a strong suspicion of HIV infection without known history for a participant in Screening, however participant refuses testing, discuss with Medical Monitor to assess eligibility. (Note: HIV testing is not mandated for study inclusion; however, if it is performed at any point in Screening or while on study, a site must consent the participant for HIV testing as per local standard guidance);
  • Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (HBV surface antigen positive and HBV core antibody positive with reflex to positive HBV DNA, or HBV core antibody positive alone with reflex to positive HBV DNA, or positive HCV antibody with reflex to positive HCV RNA) at Baseline. Discuss with the Medical Monitor if history of HBV or HCV  infection is known. If medically indicated, participants infected with HBV must be treated and on a stable dose of antivirals (e.g, entecavir, tenofovir, or lamivudine; adefovir or interferon are not allowed) at study entry and with planned monitoring and management according to appropriate labeling guidance. Participants on active HCV therapy at study entry must be on a stable dose without documented clinically significant impaired liver function test or hematologic abnormalities (must meet criteria above) and with planned monitoring and management according to appropriate labeling guidance. HBV and/or HCV viral titers must be monitored according to SoA in these participants.
  • Participants with active tuberculosis (history of exposure or history of positive tuberculosis test; plus presence of clinical symptoms, physical, or radiographic findings).
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, active uveitis or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent. Participants with history of bleeding diathesis or recent major bleeding events considered by the Investigator as high risk for investigational drug treatment are also excluded.
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization.
• Known clinical history of tuberculosis, lung sarcoidosis and Interstitial Lung Diseases.
• History of another primary malignancy within 3 years prior to starting study drug, except for adequately treated basal or squamous cell carcinoma of the skin, adequately treated carcinoma in situ, e.g., cancer of the cervix in situ, superficial bladder cancer. History of other localized malignancies treated with curative intent needs to be discussed with the Medical Monitor.
• Uncontrolled neuropathy Grade 2 or greater regardless of cause.
• Significant hearing loss and participants unwilling to accept potential for further hearing loss (Investigator should consider treating the participant with carboplatin/paclitaxel).
• Any prior systemic cytotoxic chemotherapy for their NSCLC or any antibody or drug targeting T-cell coregulatory proteins (immune checkpoints) such as anti-PD-(L)1, or anti-CTLA-4 antibody.
• Current or prior use of immunosuppressive medication within 28 days before the first dose of study drug, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Systemic steroid administration required to manage toxicities arising from radiation therapy delivered as part of the cCRT for locally advanced NSCLC is allowed.
• Active autoimmune disease that has required systemic treatment in past 1 year (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), OR is receiving systemic steroid therapy < 3 days prior to the first dose of study intervention or receiving any other form of immunosuppressive medication. Participants requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at low doses (typically ≤ 10 mg of prednisone or equivalent per day). Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy. Corticosteroid use on study as a premedication for IV contrast allergies/reactions (related to scans) is allowed and must be documented. This must be discussed with Medical Monitors for clinical indications in which participants may require a higher dose. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes Type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.  Consult Medical Monitor for other autoimmune diseases.
• Receipt of live attenuated vaccination within 30 days of receiving study drug.
• Use of a prohibited concomitant drug within 4 weeks randomization.
• Known severe hypersensitivity (Grade ≥ 3 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0) to study interventions or any components in their formulations, or uncontrolled asthma (i.e., 3 or more features of partially controlled asthma).
• Participation in another clinical study with an investigational product within the last 4 weeks.
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
• ≥ 10% weight loss within the past month.
• Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control.
• Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study drug or interpretation of participant safety or study results.

• Pre- or postmenopausal.  Postmenopausal women are defined as:
  • 60 years of age with no vaginal bleeding over the prior year; or
  • < 60 years with "premature menopause" or "premature ovarian failure” manifest itself with secondary amenorrhea for at least 1 year and follicle stimulating hormone (FSH) and estradiol levels in the postmenopausal range according to institutional standards; or
  • surgical menopause with bilateral oophorectomy.
    • Note: Premenopausal women who meet all of the other entry criteria must be maintained on ovarian suppression (such as Lupron) during the study and subjects counseled to use appropriate contraception to prevent pregnancy.
• If possible, a biopsy of metastatic breast cancer tissue will be obtained to provide histological or cytological confirmation of ER+ and HER2− disease as assessed by a local laboratory, according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, using slides, paraffin blocks, or paraffin samples. If a biopsy is not possible, the ER and HER2 status from the tissue obtained at the time of the original diagnosis must confirm that the subject’s cancer is ER+ and HER2−.
• Locally advanced or metastatic breast cancer with radiological or clinical evidence of progression while on an AI in combination with a CDK4/6 inhibitor for advanced breast cancer with demonstrated prior sensitivity to endocrine therapy (recurrence or progression after at least 12 months of treatment in the metastatic setting).
• Locally advanced or metastatic breast cancer with measurable (according to RECIST 1.1 and/or non-measurable lesions.
• At least one or more of the following ESR1 point mutations as assessed in cell-free circulating tumor DNA (ctDNA) obtained from a blood (plasma) or tissue sample: Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N.  The ctDNA sample collection must be obtained within 90 days prior to randomization to determine eligibility and baseline.
  • Note: a prior genomic test confirming that the subject has an ESR1 mutation can be used to determine eligibility; however, an ESR1 sample must also be collected within 30 days of randomization.
• Subjects who have not received cytotoxic chemotherapy or who have received one cytotoxic chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to entry into the trial; and/or no more than one chemotherapy regimen for metastatic breast cancer. Subjects must be free of all chemotherapy acute toxicity excluding alopecia and Grade II peripheral neuropathy before study entry.
• ECOG performance score of 0 or 1.
• Adequate organ function as shown by:
  • absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3;
  • platelet count ≥ 100,000 cells/mm^3;
  • hemoglobin ≥ 9.0 g/dl;
  • ALT and AST levels ≤ 2.5 upper limit of normal (ULN) or < 5 in the presence of visceral metastasis;
  • total serum bilirubin ≤ 0.5 x ULN (≤ 3.0 x ULN for subjects known to have Gilbert Syndrome);
  • alkaline phosphatase level < 2.5 x ULN;
  • creatinine clearance of 40 ml/min or greater as calculated by the Cockcroft-Gault formula;
  • international normalized ratio (INR) and activated partial thromboplastin (aPTT) < 2.0 x ULN.
• Able to swallow tablets.
• Able to understand and voluntarily sign a written informed consent before any screening procedures.

• Prior use of everolimus or other mammalian target of rapamycin (mTOR) inhibitor or phosphoinositide 3-kinase inhibitor (PI3K) inhibitors are excluded unless discontinued due to reasons other than disease progression.
• Presence of brain metastasis.
• Lymphangitic carcinomatosis involving the lung.
• Impending visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator. Radiotherapy within 30 days prior to randomization except in case of localized radiotherapy for analgesic purposes or for lytic lesions at risk of fracture, which can then be completed within 7 days prior to randomization. Subjects must have recovered from radiotherapy toxicities prior to randomization.
• History of long QTC syndrome or a QTC of > 480 msec.
• History of a pulmonary embolus (PE) or deep vein thrombosis (DVT) within the last 6 months or any known thrombophilia. Subjects stable on anti-coagulants for maintenance are eligible as long as the DVT and/or PE occurred > 6 months prior to enrollment and there is no evidence for active thrombosis. The use of low dose acetylsalicylic acid (ASA) is permitted.
• Any significant co-morbidity that would impact the study or the subject’s safety.
• History of a positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) at Screening. Subjects cured of hepatitis C (no viral load) are eligible.
• History of malignancy within the past 5 years (excluding breast cancer), except basal cell or squamous cell carcinoma of the skin curatively treated by surgery, or early stage cervical cancer.
• History of vaginal bleeding over the last year unless it is documented that the bleeding was due to non-uterine causes (e.g., vaginal atrophy).
• Uncontrolled hypertension defined as sitting systolic pressure >160 mm Hg or diastolic pressure > 100 mm Hg at Screening.
• History of non-compliance to medical regimens.
• Unwilling or unable to comply with the protocol.
• Current participation in any clinical research trial involving an investigational drug or device within the last 30 days.

Diagnosis of CLL according to the National Cancer Institute (NCI)/International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) criteria. This includes previous documentation of: 

• Biopsy-proven small lymphocytic lymphoma; OR 
• Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following: 
  • Peripheral blood lymphocyte count of greater than 5 x10^9/L;
  • Immunophenotype consistent with CLL defined as: 
    • The predominant population of lymphocytes share both B-cell antigens (CD19, CD20 [typically dim expression], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.);
    • Clonality as evidenced by kappa or lambda light chain restriction (typically dim immunoglobulin expression).
  • Negative fluorescent in situ hybridization (FISH) analysis for t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy (e.g., marrow aspirate) or negative immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g., marrow aspirate or lymph node biopsy.
• No prior chemotherapy, BTK inhibitor therapy, venetoclax, small molecule signaling inhibitor, or monoclonal anti-body therapy for treatment of CLL or SLL. 
• Has met at least one of the following indications for treatment: 
  • Evidence of progressive marrow failure as manifested by the development of worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets < 100 x 10^9/L);
  • Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly; 
  • One or more of the following disease-related symptoms: 
    • Weight loss >= 10% within the previous 6 months;
    • Grade 2 or 3 fatigue attributed to CLL;
    • Fevers > 100.5 degree Fahrenheit (F) for 2 weeks without evidence of infection;
    • Clinically significant night sweats without evidence of infection.
  • Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of > 50% over a two-month period or an anticipated doubling time of less than six months.
• Eastern Cooperative Oncology Group (ECOG) performance status between 0-2
  •Life expectancy of >= 12 months. 
• No deletion of 17p13 on cytogenetic analysis by FISH. 
• Glomerular filtration rate (GFR) > 40 mL/minute as calculated by the Cockcroft-Gault Formula (obtained =< 14 days prior to registration).
• Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's disease. For those with a total bilirubin > 1.5 x ULN, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed (obtained =< 14 days prior to registration).
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])/serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x the institutional ULN (obtained =< 14 days prior to registration).
• Prothrombin time (PT)/international normalized ratio (INR) < 1.5 ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN (obtained =< 14 days prior to registration). 
  • NOTE: If value is higher due to hepatic involvement by CLL, patient is eligible. 
• No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation.
• No current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted.
• No previous autoimmune complications (e.g. autoimmune hemolytic anemia or immune thrombocytopenia) that have developed since the initial diagnosis of CLL and have required treatment with high dose corticosteroids (e.g., equivalent of > 20 mg/day of prednisone), monoclonal antibody based therapy, or chemotherapy. Prior use of corticosteroids for reasons other than treatment of autoimmune complications is allowed.
• No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =< 2 years. 
  • NOTE: If there is a history of prior malignancy, the patient must not currently be receiving other specific treatment (other than hormonal therapy for their cancer). 
• Able to adhere to the study visit schedule and other protocol requirements.
• No major surgery within 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug. 
• No radiation therapy =< 4 weeks prior to registration. 
• Patients who are human immunodeficiency virus positive (HIV+) with undetectable HIV viral load are eligible provided they meet all other protocol criteria for participation and are not being treated with protease inhibitors or any non-nucleoside reverse transcriptase inhibitors (NNRTI) that are CYP3A4 inducers; if being treated for HIV, patients should be receiving an alternative antiretroviral therapy (ART) that is not a CYP3A inhibitor. 
• Patients must not have any of the following conditions: 
  • Congestive heart failure or New York Heart Association Functional Classification III or IV congestive heart failure; 
  • History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration;
  • Recent infections requiring systemic treatment; need to have completed anti-biotic therapy > 14 days before the first dose of study drug; 
  • Cerebral vascular accident or intracranial bleed within the last 6 months
    •Infection with known chronic, active hepatitis C; 
  • Serologic status reflecting active hepatitis B or C infection. Patients with hepatitis B or C infection may be eligible if viral loads are undetectable. Patients may be on suppressive therapy.
• Patients are not eligible if they require treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
• Patients may not have received the following within 7 days prior to the first dose of study drug: 
  • Steroid therapy for anti-neoplastic intent;
  • Strong and Moderate CYP3A inhibitors; 
  • Strong and Moderate CYP3A inducers.
• Patients may not be on any other investigational agents.
• Patients may not have received warfarin or another vitamin K antagonist in the preceding 30 days. 
• Women must not be pregnant or breast-feeding since this study involves investigational agents whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown. All females of childbearing potential must have a blood test 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: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (e.g., has had menses at any time in the preceding 24 consecutive months. 
• Women of childbearing potential and sexually active males must be strongly advised to use accepted and highly effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for: 
  • 18 months after the last dose of obinutuzumab; 
  • 90 days after the last dose of ibrutinib; and 
  • 30 days after the last dose of venetoclax Male subjects must also agree to refrain from sperm donation until 90 days after the last dose of protocol treatment.
• Patient must be able to swallow capsules and not have the following conditions: 
  • Disease significantly affecting gastrointestinal function;
  • Resection of the stomach or small bowel;
  • Symptomatic inflammatory bowel disease; 
  • Ulcerative colitis; 
  • Partial or complete bowel obstruction. 
• Patient must not be on any other systemic immunosuppressant therapy other than corticosteroids within 28 days of the first dose of study drug. 
• Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
• Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or hemophilia. 
• Patient must not have currently active, clinically significant hepatic impairment (>= moderate hepatic impairment according to the NCI/Child Pugh classification. 
• Patient must undergo assessment with Timed Up and Go (TUG) test. 
• Patient must be able to receive xanthine oxidase inhibitor or rasburicase for tumor lysis syndrome (TLS) prophylaxis.

Diagnosis of CLL according to the National Cancer Institute (NCI)/International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) criteria. This includes previous documentation of: 

• Biopsy-proven small lymphocytic lymphoma; OR 
• Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following: 
  • Peripheral blood lymphocyte count of greater than 5 x10^9/L;
  • Immunophenotype consistent with CLL defined as: 
    • The predominant population of lymphocytes share both B-cell antigens (CD19, CD20 [typically dim expression], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.);
    • Clonality as evidenced by kappa or lambda light chain restriction (typically dim immunoglobulin expression).
  • Negative fluorescent in situ hybridization (FISH) analysis for t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy (e.g., marrow aspirate) or negative immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g., marrow aspirate or lymph node biopsy.
• No prior chemotherapy, BTK inhibitor therapy, venetoclax, small molecule signaling inhibitor, or monoclonal anti-body therapy for treatment of CLL or SLL. 
• Has met at least one of the following indications for treatment: 
  • Evidence of progressive marrow failure as manifested by the development of worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets < 100 x 10^9/L);
  • Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly; 
  • One or more of the following disease-related symptoms: 
    • Weight loss >= 10% within the previous 6 months;
    • Grade 2 or 3 fatigue attributed to CLL;
    • Fevers > 100.5 degree Fahrenheit (F) for 2 weeks without evidence of infection;
    • Clinically significant night sweats without evidence of infection.
  • Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of > 50% over a two-month period or an anticipated doubling time of less than six months.
• Eastern Cooperative Oncology Group (ECOG) performance status between 0-2
  •Life expectancy of >= 12 months. 
• No deletion of 17p13 on cytogenetic analysis by FISH. 
• Glomerular filtration rate (GFR) > 40 mL/minute as calculated by the Cockcroft-Gault Formula (obtained =< 14 days prior to registration).
• Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's disease. For those with a total bilirubin > 1.5 x ULN, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed (obtained =< 14 days prior to registration).
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])/serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x the institutional ULN (obtained =< 14 days prior to registration).
• Prothrombin time (PT)/international normalized ratio (INR) < 1.5 ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN (obtained =< 14 days prior to registration). 
  • NOTE: If value is higher due to hepatic involvement by CLL, patient is eligible. 
• No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation.
• No current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted.
• No previous autoimmune complications (e.g. autoimmune hemolytic anemia or immune thrombocytopenia) that have developed since the initial diagnosis of CLL and have required treatment with high dose corticosteroids (e.g., equivalent of > 20 mg/day of prednisone), monoclonal antibody based therapy, or chemotherapy. Prior use of corticosteroids for reasons other than treatment of autoimmune complications is allowed.
• No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =< 2 years. 
  • NOTE: If there is a history of prior malignancy, the patient must not currently be receiving other specific treatment (other than hormonal therapy for their cancer). 
• Able to adhere to the study visit schedule and other protocol requirements.
• No major surgery within 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug. 
• No radiation therapy =< 4 weeks prior to registration. 
• Patients who are human immunodeficiency virus positive (HIV+) with undetectable HIV viral load are eligible provided they meet all other protocol criteria for participation and are not being treated with protease inhibitors or any non-nucleoside reverse transcriptase inhibitors (NNRTI) that are CYP3A4 inducers; if being treated for HIV, patients should be receiving an alternative antiretroviral therapy (ART) that is not a CYP3A inhibitor. 
• Patients must not have any of the following conditions: 
  • Congestive heart failure or New York Heart Association Functional Classification III or IV congestive heart failure; 
  • History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration;
  • Recent infections requiring systemic treatment; need to have completed anti-biotic therapy > 14 days before the first dose of study drug; 
  • Cerebral vascular accident or intracranial bleed within the last 6 months
    •Infection with known chronic, active hepatitis C; 
  • Serologic status reflecting active hepatitis B or C infection. Patients with hepatitis B or C infection may be eligible if viral loads are undetectable. Patients may be on suppressive therapy.
• Patients are not eligible if they require treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
• Patients may not have received the following within 7 days prior to the first dose of study drug: 
  • Steroid therapy for anti-neoplastic intent;
  • Strong and Moderate CYP3A inhibitors; 
  • Strong and Moderate CYP3A inducers.
• Patients may not be on any other investigational agents.
• Patients may not have received warfarin or another vitamin K antagonist in the preceding 30 days. 
• Women must not be pregnant or breast-feeding since this study involves investigational agents whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown. All females of childbearing potential must have a blood test 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: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (e.g., has had menses at any time in the preceding 24 consecutive months. 
• Women of childbearing potential and sexually active males must be strongly advised to use accepted and highly effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for: 
  • 18 months after the last dose of obinutuzumab; 
  • 90 days after the last dose of ibrutinib; and 
  • 30 days after the last dose of venetoclax Male subjects must also agree to refrain from sperm donation until 90 days after the last dose of protocol treatment.
• Patient must be able to swallow capsules and not have the following conditions: 
  • Disease significantly affecting gastrointestinal function;
  • Resection of the stomach or small bowel;
  • Symptomatic inflammatory bowel disease; 
  • Ulcerative colitis; 
  • Partial or complete bowel obstruction. 
• Patient must not be on any other systemic immunosuppressant therapy other than corticosteroids within 28 days of the first dose of study drug. 
• Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
• Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or hemophilia. 
• Patient must not have currently active, clinically significant hepatic impairment (>= moderate hepatic impairment according to the NCI/Child Pugh classification. 
• Patient must undergo assessment with Timed Up and Go (TUG) test. 
• Patient must be able to receive xanthine oxidase inhibitor or rasburicase for tumor lysis syndrome (TLS) prophylaxis.

nclusion Criteria: 

• The subject has a histologic or cytologic diagnosis of a variant histology renal cell carcinoma including papillary, chromophobe, Xp.11 translocation, undifferentiated, or unclassified which is treatment naïve or has previously been treated with one systemic treatment line not containing any vascular endothelial growth factor antibody or vascular endothelial growth factor receptor tyrosine kinase inhibitors. The patient may have received treatment with immune checkpoint therapy including nivolumab as a single agent or nivolumab plus ipilimumab in combination. Previous treatment with mammalian target of rapamycin agents such as temsirolimus or everolimus is acceptable.
• Measurable disease per RECIST v1.1 as determined by the investigator. 
• The subject has had an assessment of all known disease sites; e.g., by computerized tomography (CT) scan, magnetic resonance imaging (MRI), bone scan as appropriate, within 28 days before the first dose of cabozantinib or sunitinib. 
• The subject is ≥ 18 years old on the day of consent.
• The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
• Recovery to baseline or ≤ Grade 1 CTAE v.4.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy;
• The subject has organ and marrow function and laboratory values as follows within 4 days before the first dose of cabozantinib or sunitinib:
  • The ANC ≥ 1500/mm^3 without colony stimulating factor support;
  • White blood cell count ≥ 2500/mm^3 (≥ 2.5 GI/L);
  • Platelets ≥ 100,000/mm^3;
  • Hemoglobin ≥ 9 g/dL; 
  • Bilirubin ≤ 1.5 x the ULN.  For subjects with known Gilbert's disease, bilirubin ≤ 3.0 x ULN;
  • Serum albumin ≥ 2.8 g/dl;
  • Serum creatinine ≤ 2.0 X ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation:
  • Males: (140
    •age) x weight (kg)/(serum creatinine [mg/dL] × 72);
  • Females: [(140
    •age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85;
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 X upper limit of normal (ULN). ALP ≤ 5 X ULN with documented bone metastases;
  • Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol).
• The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.
• Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s).
• Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant; i.e., females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons.

• The subject has a variant histology that includes renal medullary carcinoma or collecting duct renal cell carcinoma. Any clear cell component in the tumor will lead to exclusion.
• Prior treatment with cabozantinib or sunitinib.
• Radiation therapy within 2 weeks. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• The subject has received any other type of investigational agent within 28 days before the first dose of study treatment.
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment.
• Concomitant anticoagulation with coumarin agents (e.g., warfarin).
• The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 2.0 × the laboratory ULN within 7 days before the first dose of study treatment.
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• Cardiovascular disorders:
  • Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias;
  • Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment;
  • Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose;
• Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
  • The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction;
  • Abdominal fistula, GI perforation, bowel obstruction, or intraabdominal abscess within 6 months before first dose.
    • Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose
• Clinically significant hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose.
• Other clinically significant disorders that would preclude safe study participation.
  • Serious non-healing wound/ulcer/bone fracture.
  • Uncompensated/symptomatic hypothyroidism.
  • Moderate- to- severe hepatic impairment (Child-Pugh B or C).
• Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 4 weeks before first dose of study treatment. Complete wound healing from major surgery must have occurred 2 month before first dose and from minor surgery (e.g., simple excision, tooth extraction) at least 10 days before first dose. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per electrocardiogram (ECG) within 28 days before first dose of study treatment [add reference for Fridericia formula]. For patients with a bundle branch block the QTcR will be calculated as based on study by Rataharju PM et al. Am J Cardiol 2004;93:1017-1021(see local site documents in ePRTCL). If QTcR is > 500 ms the patient will be eligible for the study.
  • Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility.
• Pregnant or lactating females.
• Inability to swallow tablets.
• Previously identified allergy or hypersensitivity to components of the study treatment formulations.
• Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy. Patients with Gleason 6 (3+3) prostate cancer with previous treatment or on active surveillance may also be allowed on protocol.
• The subject requires chronic concomitant treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort).

• Stratum 1 (IDH wild-type): Patients must be ≥ 3 years of age and ≤ 21 years of age at the time of enrollment.  Stratum 1 closed.
• Stratum 2 (IDH mutant): Patients must be ≥ 3 years of age and ≤ 25 years of age at the time of enrollment.
• Patients must have eligibility confirmed by rapid central pathology and central molecular screening reviews performed on APEC14B1:
  • Newly-diagnosed high-grade glioma such as anaplastic astrocytoma or glioblastoma;
  • Negative results for H3 K27M by immunohistochemistry (IHC);
  • Negative results for BRAFV600E mutation by next-generation sequencing (NGS).
• Patients must have histological verification of diagnosis.
• Patients with M+ disease (defined as evidence of neuraxis dissemination) are not eligible. Cerebrospinal fluid (CSF) cytology is not required but may be obtained if clinically indicated prior to study enrollment. If cytology is positive, the patient would be considered to have metastatic disease and would, therefore, be ineligible.
• Pre-operative and post-operative brain magnetic resonance imaging (MRI) with and without contrast must be obtained. The requirement for a post-operative MRI is waived for patients who undergo biopsy only. A spine MRI is not required, but may be obtained if clinically indicated. If the spine MRI is positive, the patient would be considered to have M+ disease (defined as neuraxis dissemination) and would be ineligible.
• Patients must have a performance status of ≥ 50 by Lansky or Karnofsky, 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 who are unable to walk because of paralysis, but are up in a wheelchair will be considered ambulatory for the purposes of assessing the performance score.
• Peripheral absolute neutrophil count (ANC) ≥ 1,000/uL.
• Platelet count ≥ 100,000/uL (transfusion independent). 
• Hemoglobin ≥ 8.0 gm/dL (can be transfused). 
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:
  • 3 to < 6 years: 0.8 (male and female) maximum serum creatinine (mg/dL);
  • 6 to < 10 years: 1 (male and female) maximum serum creatinine (mg/dL); 
  • 10 to < 13 years: 1.2 (male and female) maximum serum creatinine (mg/dL);
  • 13 to < 16 years: 1.5 (male), 1.4 (female) maximum serum creatinine (mg/dL);
  • ≥ 16 years: 1.7 (male), 1.4 (female) maximum serum creatinine (mg/dL).
• Adequate Liver Function defined as:
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age; and
  • SGPT (ALT) ≤ 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
• Central Nervous System Function defined as:
  • Patients with seizure disorder may be enrolled if seizures are wellcontrolled (i.e., patients must not have required rescue medications for uncontrolled seizures within 14 days prior to enrollment).
• Patients with seizure disorder may be enrolled if seizures are well-controlled (i.e., patients must not have required rescue medications for uncontrolled seizures within 14 days prior to enrollment).
• Patients must be enrolled and protocol therapy must be projected to begin no later than 31 days after definitive diagnostic surgery (Day 0). 
• 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 with the following histologies: 
  • Diffuse astrocytoma (grade 2);
  • Oligodendrogliomas (any grade);
  • Pleomorphic xanthoastrocytoma (PXA, any grade). 
• Patients with primary tumor location of brainstem or spinal cord.
• Patients with M+ disease (defined as neuraxis dissemination either by imaging or by cytology).
• Patients must not have received any prior tumor-directed therapy including radiation therapy, chemotherapy (tumor-directed therapy), molecularly targeted agents, or immunotherapy for the treatment of HGG other than surgical intervention.
• Lumbar CSF cytology is not required, but may be performed if clinically indicated prior to study enrollment. If lumbar CSF cytology is positive, the patient is considered to have M+ disease and is ineligible.
  • Note: False positive cytology can occur within 10 days of surgery.
• Patients with gliomatosis cerebri type 1 or 2. 
• Patients who are not able to receive protocol specified radiation therapy. 
• Patients must not be currently receiving other anti-cancer agents.
• Patients with known constitutional mismatch repair deficiency syndrome (CMMR-D)/biallelic mismatch repair deficiency (bMMRD). 
• Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies.
• Lactating females are not eligible unless they have agreed not to breastfeed their infants. 
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 4 months after the last dose of veliparib.

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

• Histologically confirmed CD30-positive PTCL (most subtypes allowed) or TMF per the revised World Health Organization 2016 classification (Swerdlow, 2016).
  Note: Patients must wait for central results before first dose of study drug.
• Cohorts A and B (PTCL cohorts):
  • measurable by the modified Lugano Classification (Cheson, 2014);
  • measurable disease of ≥1.5 cm diameter by computed tomography (CT), assessed locally for eligibility.
    • Note: Confirmation by fluorodeoxyglucose (FDG) avid disease by positron emission tomography (PET) recommended, if possible.
• Cohort C (TMF cohort):
  • measurable by the Olsen Criteria (Olsen, 2011) including at least 1 cutaneous lymphoma lesion ≥2 cm in diameter, assessed locally for eligibility.

Patients must have relapsed or refractory disease AND the following: 

• Cohorts A and B (PTCL cohorts):
  • patients must have received at least 1 prior line of systemic therapy. For patients with systemic ALCL, patients must have failed or be intolerant to brentuximab vedotin [BV]; Adcetris®.
• Cohort C (TMF cohort):
  • patients must have received at least 1 prior line of systemic therapy; and have exhausted systemic therapies with full approval for their treatment of transformed mycosis fungoides 
• Completion of treatment with any radiotherapy, chemotherapy, antibody, immunoconjugates and/or another investigational drug ≥4 weeks (or 5 half-lives of the drug, whichever is shorter) prior to first dose of study drug.
  Note: patients may be enrolled after a minimum of 2 weeks of radiation if radiation was for palliative intent to a single cutaneous lesion or single nodal region after discussion with the sponsor.
• Completion of an autologous hematopoietic stem cell transplantation at least 3 months prior to first dose of study drug (if applicable). 
• Resolution of any clinically significant previous therapy-related toxicity to ≤Grade 1 or to baseline if pre-existing condition (exception: patients with all grade alopecia and ≤Grade 2 peripheral neuropathy.
• Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 (Appendix B).
• Life expectancy ≥12 weeks.
• Adequate laboratory functional values. Note: transfusions and growth factors allowed during screening; however, transfusion-dependency defined as requiring blood products ≥once per week is not allowed.

• Patients with the following subtypes of lymphoma:
  • T-cell prolymphocytic leukemia;
  • T-cell large granular lymphocytic leukemia;
  • Chronic lymphoproliferative disorder of NK cells;
  • Aggressive NK-cell leukemia;
  • Extranodal NK-/T-cell lymphoma;
  • Indolent T-cell lymphoproliferative disorder of the GI tract.
  • Adult T-cell leukemia/lymphoma (ATLL)
• Current evidence of central nervous system involvement.
• Has had an allogenic tissue hematopoietic cell/solid organ transplant within the last 3 years. Note: Patients who have had a transplant >3 years ago are eligible as long as there are no signs/symptoms of graft versus host disease (GvHD).
• Requirement for chronic systemic immunosuppressive therapy <12 weeks prior to the first dose of study drug for prophylaxis or management of conditions such as GvHD (e.g. mycophenolate, methotrexate, calcineurin inhibitor-based therapy, steroid doses that would require prolonged tapering for discontinuation).
• Major surgery ≤4 weeks prior to first dose of study drug.
• Any active, concurrent, significant illness or disease (other than T-cell lymphoma) or clinically significant findings including psychiatric and behavioral problems, medical history, and/or physical examination findings that would preclude the patient from participation in the study such as:
  • active infection requiring systemic therapy ≤10 days before the first dose of study drug
  • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to first study drug, uncontrolled cardiac arrhythmia e.g. atrial fibrillation/flutter, cerebrovascular accidents ≤6 months before first dose of study drug
  • any severe or uncontrolled other disease or condition which might increase the risk associated with study participation
  • active Hepatitis B or Hepatitis C. Antiviral prophylaxis for chronic Hepatitis B virus infection may be used at the discretion of the investigator.
• Diagnosis of Human Immunodeficiency Virus (HIV) i.e. presence of HIV 1/2 antibodies
• Diagnosis of immunodeficiency or requirement for systemic steroid therapy or any other form of immunosuppressive therapy (outside of samples already mentioned in Exclusion Criterion number 4) <7 days prior to the first dose study drug. Topical steroid creams for symptomatic relief for patients in Cohort C (TMF) are exceptions to this rule. Also, the use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor/Medical Monitor.
• Any other malignancy known to be active, with the exception of treated cervical intraepithelial neoplasia and non-melanoma skin cancer.
• General intolerance of any protocol medication or its excipients
• Patient´s inability to appreciate the nature, meaning and consequences of the trial and to formulate his/her own wishes correspondingly.
• Patient is unwilling to comply with the protocol; including the required biopsies and PK sampling.
• Prior treatment with AFM13.

• Age ≥ 18 years old.
• Histological confirmation of advanced biliary tract cancers including cancers originating in the gallbladder who have received at least one line of systemic anticancer therapy. Note: Patients who have either progressed on or are intolerant to the prior therapy can be included in this study.
• Measurable disease as defined by RECIST criteria.
  • NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease. Disease that is measurable by physical examination only is not eligible.
• ECOG Performance Status (PS) of 0 or 1).
• The following laboratory values obtained ≤ 21 days prior to registration.
  • Absolute neutrophil count (ANC) ≥ 1500/mm3;
  • Platelet count ≥ 100,000/mm3;
  • Total bilirubin ≤ 1.5 × upper limit of normal (ULN);
  • spartate transaminase (AST) or alanine transaminase (ALT) ≤ × ULN;
  • Creatinine ≤ 1.5 × ULN.
• Negative pregnancy test done ≤ days prior to registration, for persons of childbearing potential only.
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willingness to provide mandatory blood and tissue specimens for correlative research.

• Any of the following because this study involves an agent that has potential genotoxic, mutagenic and teratogenic effects:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception for at least 3 months after the last dose of the study drug.
• 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.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
  • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• 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.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm ≤ 21 days prior to registration.
• Receiving any anticancer therapy for biliary tract cancer ≤ 21 days prior to registration.
• Other active malignancy requiring treatment in ≤ 6 months prior to registration.
  • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.
    • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer.
• History of myocardial infarction ≤6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Previous treatment with irinotecan or irinotecan-based chemotherapy for biliary tract cancers.

• Patients must have histologically confirmed (biopsy-proven) diagnosis of mantle cell lymphoma (MCL), with documented cyclin D1 (BCL1) expression by immunohistochemical stains and/or t(11;14) by cytogenetics or FISH. 
• Patients must have measurable or evaluable disease as defined as a lymph node measuring >1.5 cm in any dimension or splenomegaly with spleen >15 cm in craniocaudal dimension. 
• Age ≥ 60 years. 
• No intention to undergo consolidation with high dose chemotherapy and autologous stem cell rescue (Autologous Stem Cell Transplant) in first remission
• ECOG performance status of 0-2. 
• Ability to understand and willingness to sign Institutional Review Board (IRB)-approved informed consent. 
• Willing to provide mandatory tissue samples (if sufficient tissue available), bone marrow and blood samples for research purposes. 
• Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks prior to registration: 
  • Absolute Neutrophil Count (ANC) ≥ 1000/mm³;
  • Hemoglobin ≥ 8 g/dL;
  • Platelets ˃75,000/mm³;
  • Creatinine clearance ≥ 40 mL/min, calculated with the use of 24-hour creatinine clearance or by Cockcroft-Gault formula;
  • Total Bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) or ≤ 3 x ULN for patients with documented Gilbert's syndrome;
  • Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤ 2.5 x ULN. 
• All females of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a blood test to rule out pregnancy within 2 weeks prior to registration. 
• Women must not be pregnant or breastfeeding. Females of childbearing potential who are sexually active with a non-sterilized male partner and sexually active men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) prior to study entry, for the duration of study participation, and for 12 months after last dose of therapy. Method of contraception must be documented. 
• Patients should not have prior chemotherapy, radiotherapy or immunotherapy for lymphoma.
• Corticosteroids used for other non-lymphomatous conditions will be allowed.
• Corticosteroids no greater than 1 mg/kg prednisone (or equivalent) given for ≤ 14 days will be allowed for treatment of lymphoma related symptoms.

• Patients should not have prior chemotherapy, radiotherapy or immunotherapy for lymphoma. 
• Patients must have no recent (< 1 year) history of malignancy except for the following:
  • adequately treated non-melanoma skin cancer;
  • adequately treated Stage I melanoma of the skin;
  • in situ cervical cancer;
  • low grade prostate adenocarcinoma (Gleason grade ≤ 6) managed with observation and stable for 6 months. 
• Patients should not have known evidence of central nervous system (CNS) lymphoma. 
• Patients must not have received a prior allogeneic stem cell transplant or solid organ transplant (except for cornea) for any indication. 
• Patients must have no active, uncontrolled infections. 
• Patients must not have active hepatitis B or be chronic carriers of hepatitis B. This is defined as patients with hepatitis B surface antigen (HBsAg) positive. Patients with prior exposure to hepatitis B (hepatitis B core antibody (anti-HBc) positive AND HBsAg negative) are allowed with a protective level hepatitis B surface antibody AND a negative hepatitis B viral load by polymerase-chain reaction (PCR). 
• Patients must not have active hepatitis C (HCV) as defined by a hepatitis C viral load detectable by PCR. Patients with a negative HCV antibody are assumed to have a negative HCV viral load. Patients with a positive HCV antibody must have a negative hepatitis C viral load by PCR. Prior treatment for an active HCV infection will be allowed as long as the hepatitis C viral load by PCR is negative.
• Patients must not have known active Human Immunodeficiency Virus (HIV). Testing not required in absence of clinical suspicion. 
• Patients must not have evidence of significant, uncontrolled concomitant diseases, including psychiatric diseases, that could affect compliance with the protocol or interpretation of results or that could increase risk to the patient.
• Patients must not have conditions that preclude oral administration or absorption of medications through the GI tract, including but not limited to the inability to swallow pills or malabsorption syndromes. 
• Patients must not have known allergies to both xanthine oxidase inhibitors and rasburicase. 
• Patients must not require the use of warfarin. Blood thinners of other classes are permitted.
• Patient may not receive the following agents within 7 days prior to the first dose of venetoclax: 
  • Strong and moderate CYP3A inhibitors
  • Strong and moderate CYP3A inducers
  • Strong and moderate P-gp inhibitors 
• Patients must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax.

• The subject must consent to take precautionary measures to prevent Newcastle Disease Virus (NDV) transmission to humans and birds.
• Subjects must have histologic documentation of advanced solid tumor and received and have progressed, are refractory, or are intolerant to standard therapy for the specific tumor type. All subjects are required to have had at least one prior line of treatment in the recurrent or metastatic setting.
• Subjects must have at least 1 measurable lesion.
• All subjects must consent to provide tumor tissue for correlative studies.
• ECOG performance status of 0 to 1.
• Adequate organ function.
• Use of highly effective contraception (females) or male condom plus spermicide (males).

• Rapidly progressing disease defined as a subject that cannot tolerate a break of at least 8 weeks from systemic anticancer therapy. 
• Primary central nervous system (CNS) disease is excluded.
• Subjects who have received prior immunotherapy will require varying washout times prior to the first dose of MEDI5395.
• Unresolved toxicities from prior anticancer therapy.
• History of severe allergic reactions to any of the study drug components.
• Infectious disease exclusions including tuberculosis, Human immunodeficiency virus (HIV), hepatitis A, B or C, active bacterial, fungal or viral infections plus receipt of live attenuated vaccine prior to first dose of MEDI5395.
• (NOTE: Subjects with hepatitis B/C with undetectable virus load and are on medications may be permitted). 
• Any conditions requiring use of any systemic immunosuppressant including systemic corticosteroids, methotrexate, azathioprine, tumor necrosis factor (TNF) inhibitor, and/or interleukin 6 (IL-6) blockers.
• Active autoimmune disease or chronic inflammatory condition (Exceptions include vitiligo, alopecia, hypothyroidism on stable treatment, diverticulosis, controlled celiac disease and chronic skin conditions not requiring systemic therapy).
• Active acquired immune-deficiency states.
• Subjects who are regularly exposed to poultry or birds.
• Current active hepatitis or biliary disease (except for Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease).
• Clinically significant pulmonary disease and cardiac disease.
• Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.

• Participant has documented NF1 mutation or a diagnosis of neurofibromatosis type 1 (NF1) using National Institute of Health (NIH) Consensus Conference criteria inclusive of the presence of a plexiform neurofibroma (PN). 
• Participant has a PN that is causing significant morbidity. 
• Participant has a PN that cannot be completely surgically removed.
• Participant has a target tumor that is amenable to volumetric MRI analysis. 
• Participant is willing to undergo a tumor biopsy pre- and end of treatment if ≥ 18 years of age. 
• Participant has adequate organ and bone marrow function.
• Participant can swallow capsules whole if the capsule dosage form is being utilized. This criterion does not apply if participant is utilizing the dispersible tablet dosage form of study treatment;

• Participant has abnormal liver function or history of liver disease.
• Participant has lymphoma, leukemia or any malignancy within the past 5 years (except for resected basal/squamous skin carcinomas without metastases within 3 years). 
• Participant has breast cancer within 10 years.
• Participant has active optic glioma or other low-grade glioma requiring treatment. 
• Participant has abnormal QT interval corrected or other heart disease within 6 months.
• Participant has a history of retinal pathology, risk factors for retinal vein occlusion or has a history of glaucoma. 
• Participant has known malabsorption syndrome or gastrointestinal conditions that would impair absorption of PD-0325901. 
• Participant has received NF1 PN-targeted therapy within 45 days. 
• Participant has received radiation therapy within 6 months or has received radiation to the orbit at any time. 
• Participant is unable to undergo or tolerate MRI.
• Participant has active bacterial, fungal or viral infection.
• Participant has experienced other severe acute or chronic medical or psychiatric conditions within 1 year.

• Male and/or female.
• Age ≥ 18 years at the time of screening. For patients aged < 20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.
• Confirmed HCC (by imaging or histopathologically from biopsy specimen).
• No evidence of extrahepatic disease on any available imaging.
• Disease not amenable to curative surgery or transplantation or curative ablation.
• Disease must be amenable to TACE and anticipated to require no more than 4 TACE treatments to treat sites of disease within a ≤ 16-week period (Permitted modalities are DEB-TACE or cTACE (using an emulsion of Lipiodol® and a permitted chemotherapeutic agent as per institutional practice, followed by embolizing agents).
• Child-Pugh score class A to B7.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment 10. Patients with HBV infection, which is characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥ 10 IU/ml or above the limit of detection per local lab standard), must be treated with antiviral therapy, as per institutional practice. HBV antiviral therapy must be initiated prior to randomization and patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication. Patients must show evidence HBV stabilization or signs of viral response (e.g., reduction HBV DNA levels) prior to starting IP. Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (< 10 IU/ml or under the limit of detection per local lab standard) do not require antiviral therapy prior to randomization. These subjects will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥ 10 IU/ml or above the limit of detection per local lab standard). HBV DNA detectable subjects must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication.
• Patients with HCV infection must have management of this disease per local institutional practice throughout the study. HCV diagnosis is characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody upon enrollment.
• At least 1 measurable intrahepatic lesion suitable for repeat assessments according to the following mRECIST criteria:
  • Liver lesions that show typical features of HCC on IV contrast-enhanced CT or MRI scans; i.e., hypervascularity in the arterial phase with washout in the portal or the late venous phase;
  • Viable, non-necrotic portion (arterial phase IV contrast-enhancing) that can be accurately measured at baseline as ≥ 10 mm in the longest diameter.
• Adequate organ and marrow function as defined below. Criteria “a,” “b,” “c,” and “f” may not be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose:
  • Hemoglobin ≥ 9.0 g/dL;
  • Absolute neutrophil count ≥1000/µL;
  • Platelet count ≥ 75000/µL;
  • Total bilirubin ≤ 2.0 × the upper limit of normal (ULN);
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 × ULN;
  • Albumin ≥2.8 g/dL;
  • International normalized ratio ≤1.6;
  • 2+ proteinuria or less urine dipstick reading;
  • Calculated creatinine clearance (CL) ≥ 30 mL/min as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine CL.
  • Males: Creatinine CL = Weight (kg) × (140
    •Age) (mL/min) 72 × serum creatinine (mg/dL);
  • Females: Creatinine CL = Weight (kg) × (140
    •Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL). 
• Must have a life expectancy of at least 12 weeks.
• Upper Endoscopy to evaluate varices and risk of bleeding is required within 6 months of randomization.
• Body weight >30 kg

• Any history of nephrotic or nephritic syndrome.
• Clinically significant (e.g., active) cardiovascular disease, including:
  • Unstable angina within ≤ 6 months of randomization;
  • New York Heart Association Grade ≥ 2 congestive heart failure;
  • Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG.
• Peripheral vascular disease Grade ≥ 3 (e.g., symptomatic and interfering with activities of daily living requiring repair or revision).
• Significant traumatic injury during 4 weeks prior to randomization.
• Known hereditary predisposition to bleeding or thrombosis; any prior or current evidence of bleeding diathesis.
• Systemic anticoagulation allowed, excluding Vitamin K antagonists.
• History of arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization 
• Non-healing wound, active ulcer, or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require wound examinations every 3 weeks.
• History of abdominal fistula or GI perforation, nonhealed gastric ulcer that is refractory to treatment, or active GI bleeding within 6 months prior to enrollment.
• Patients who have had any kind of surgery in the past 28 days (biopsy from any type of surgery within 28 days is not an exclusion criteria. Nor are procedures to treat varices.) 
• Uncontrolled hypertension defined by a systolic pressure > 150 mmHg or diastolic pressure > 90 mmHg, with or without antihypertensive medication. Patients with initial blood pressure (BP) elevations are eligible if initiation or adjustment of antihypertensive medication lowers pressure to meet entry criteria.
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• History of hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy (no lactulose, rifaximin, etc, if used for purposes of hepatic encephalopathy).
• Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose:
  • Patients with ascites that has required pharmacologic intervention (e.g., diuretics) and who have been on stable doses of diuretics for ascites for ≥ 2 months are eligible;
  • Major portal vein thrombosis visible on baseline/eligibility imaging, patients with Vp3 and Vp4 are excluded.
• Patients with infiltrative-type HCC.
• History of allogeneic organ transplantation.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [eg, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, and uveitis]). The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia;
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement;
  • Any chronic skin condition that does not require systemic therapy;
  • Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician;
  • Patients with celiac disease controlled by diet alone.
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection (except for noted HBV or HCV as detailed above), symptomatic congestive heart failure, poorly controlled diabetes mellitus, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• History of another primary malignancy except for:
  • Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of IP and of low potential risk for recurrence;
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
  • Adequately treated carcinoma in situ without evidence of disease.
• History of leptomeningeal carcinomatosis.
• History of active primary immunodeficiency.
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice) or human immunodeficiency virus (positive HIV 1/2 antibodies).
• Patients co-infected with HBV and hepatitis D virus (HDV). (HBV infection is indicated by the presence of HBsAg and/or anti-HBcAb with detectable HBV DNA ≥ 10 IU/mL or above the limit of detection per local lab standard ; HDV positive infection is indicated by the presence of anti-HDV antibodies.)
• Any unresolved toxicity National Cancer Institute (NCI) CTCAE v 5.0 Grade ≥ 2 from previous anticancer therapy, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• History of allogeneic bone marrow transplant and active chronic graft versus host disease.
• Receipt of anti-PD-1, anti-PD-L1, or anti-CTLA-4 prior to the first dose of IP.
• Receipt of prior TACE, prior bland embolization, or prior radioembolization. Use of TACE or TAE as part of a curative therapy (e.g., in conjuntion with ablation or surgery) can be acceptable if it is used in the lesions where curative therapy was attempted. However, TACE or TAE cannot have been used as sole modalities in prior curative therapy.
• Receipt of prior systemic anticancer therapies for HCC.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
  • Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 90 days after the last dose of IP.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of IP. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection);
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent;
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study.
• Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment group assignment.
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 6 months after the last dose of IP. Not engaging in sexual activity, as per the patient’s preferred and usual lifestyle, for the total duration of the treatment and 6 months after the last dose of study treatment is an acceptable practice.
• Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).