• Any patient with advanced prostate cancer presented to us through Tele-consult during COVID-19 for a consult.
• Patients consented to be enrolled in the study

• Patients that refuse to be enrolled in the study

• 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.

• 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

• 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.

• 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. 

PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)

• Patients must have been diagnosed with CLL and have > 5000 B-cells per uL of peripheral blood at any point during the course of their disease.
• This blood submission is mandatory prior to registration/randomization to perform FISH centrally that will be used for stratification. It should be obtained as soon after preregistration as possible.

REGISTRATION ELIGIBILITY CRITERIA (STEP 1) 

• Patients must be diagnosed with CLL in accordance with 2018 IWCLL criteria [28] that includes all of the following:
  • ≥ 5 x10^9 B lymphocytes (5000/μL) in the peripheral blood measured by flow cytometry at any point in the course of the disease;
  • On local morphologic review, the leukemic cells must be small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes;
  • CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell population, which express the B cell surface markers of CD19 and CD20, as well as the T-cell antigen CD5. Patients with bright surface immunoglobulin expression or lack of CD23 expression in >10% of cells must lack t(11;14) translocation by interphase cytogenetics.
• Patients must be intermediate or high-risk Rai stage CLL.
  • Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus any of the following: enlarged lymph nodes, hepatomegaly, or splenomegaly'
  • High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to autoimmune hemolytic anemia or thrombocytopenia.
• Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines which includes at least one of the following criteria:
  • Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia);
  • Massive (≥ 6 cm below the costal margin), progressive or symptomatic splenomegaly;
  • Massive nodes (≥ 10 cm) or progressive or symptomatic lymphadenopathy;
  • Progressive lymphocytosis with a lymphocyte doubling time < 6 months or an increase of ≥ 50% over a 2 month period;
  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy;
  • Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine);
  • Constitutional symptoms, which include any of the following:
    • Unintentional weight loss of 10% or more within 6 months;
    • Significant fatigue;
    • Fevers >100.5 degrees F for 2 weeks or more without evidence of infection;
    • Night sweats ≥1 month without evidence of infection.
• Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids).
• Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment. Palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration.
• Age ≥ 65 years.
• ECOG performance status 0-2.
• Required initial laboratory values.
• Absolute Neutrophil Count (ANC) ≥ 1,000/mm^3 except if due to bone marrow involvement.
• Platelet Count (untransfused) ≥ 30,000/mm^3.
• Calc. Creatinine Clearance ≥ 40 mL/min (by Cockcroft-Gault).
• Bilirubin ≤ 1.5 x upper limit of normal (ULN) except if due to liver involvement, hemolysis, or Gilbert’s disease.
• AST / ALT ≤ 2.5 x upper limit of normal (ULN) except if due to liver involvement.
• Patients must not have any history of Richter’s transformation or prolymphocytic leukemia (prolymphocytes in blood > 55%).
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated.
  • Please note: IVIG can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician.
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load.
• Patients with Class III or Class IV heart failure by New York Heart Association, those with unstable angina, and those with uncontrolled arrhythmia are not eligible.
• Patients who have had a myocardial infarction, intracranial bleed, or stroke within the past 6 months are not eligible.
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients must not be receiving active systemic anticoagulation with heparin or warfarin. Patients on warfarin must discontinue the drug for at least 10 days prior to registration on the study.
• Chronic concomitant treatment with strong inhibitors of CYP3A4/5 is not allowed on this study. Patients on strong CYP3A inhibitors must discontinue the drug for 14 days prior to registration on the study. 
• Chronic concomitant treatment with strong CYP3A4/5 inducers is not allowed.
• Patients must discontinue the drug 14 days prior to registration on the study.
• Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily.
• Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics.
• Central FISH blood results are mandatory prior to registration/randomization for it will be used for stratification.
• Patients must be able to swallow capsules and not have the following conditions:  disease significantly affecting gastrointestinal absorption, resection of the stomach or small bowel, partial or complete bowel obstruction.
• Patients must not have a known allergy to mannitol.
• Patients must not have prior significant hypersensitivity to rituximab (not including infusion reactions).
• Patients may not have had major surgery within 10 days prior to registration, or minor surgery within 7 days prior to registration. Examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration for a joint. The decision about whether a surgery is major or minor can be made at the discretion of the treating physician.
• Patients must be able to receive either a xanthine oxidase inhibitor or rasburicase for prophylaxis/treatment of TLS.

RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)

• Completion of treatment through Cycle 14 Day 28, and remain on ibrutinib therapy.
• Receipt of central BM MRD results.
• Response assessment completed per Section 5.0 with CR determination.

Eligibility last updated 1/17/22. Questions regarding updates should be directed to the study team contact.

PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)

• Patients must have been diagnosed with CLL and have > 5000 B-cells per uL of peripheral blood at any point during the course of their disease.
• This blood submission is mandatory prior to registration/randomization to perform FISH centrally that will be used for stratification. It should be obtained as soon after preregistration as possible.

REGISTRATION ELIGIBILITY CRITERIA (STEP 1) 

• Patients must be diagnosed with CLL in accordance with 2018 IWCLL criteria [28] that includes all of the following:
  • ≥ 5 x10^9 B lymphocytes (5000/μL) in the peripheral blood measured by flow cytometry at any point in the course of the disease;
  • On local morphologic review, the leukemic cells must be small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes;
  • CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell population, which express the B cell surface markers of CD19 and CD20, as well as the T-cell antigen CD5. Patients with bright surface immunoglobulin expression or lack of CD23 expression in >10% of cells must lack t(11;14) translocation by interphase cytogenetics.
• Patients must be intermediate or high-risk Rai stage CLL.
  • Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus any of the following: enlarged lymph nodes, hepatomegaly, or splenomegaly'
  • High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to autoimmune hemolytic anemia or thrombocytopenia.
• Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines which includes at least one of the following criteria:
  • Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia);
  • Massive (≥ 6 cm below the costal margin), progressive or symptomatic splenomegaly;
  • Massive nodes (≥ 10 cm) or progressive or symptomatic lymphadenopathy;
  • Progressive lymphocytosis with a lymphocyte doubling time < 6 months or an increase of ≥ 50% over a 2 month period;
  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy;
  • Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine);
  • Constitutional symptoms, which include any of the following:
    • Unintentional weight loss of 10% or more within 6 months;
    • Significant fatigue;
    • Fevers >100.5 degrees F for 2 weeks or more without evidence of infection;
    • Night sweats ≥1 month without evidence of infection.
• Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids).
• Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment. Palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration.
• Age ≥ 65 years.
• ECOG performance status 0-2.
• Required initial laboratory values.
• Absolute Neutrophil Count (ANC) ≥ 1,000/mm^3 except if due to bone marrow involvement.
• Platelet Count (untransfused) ≥ 30,000/mm^3.
• Calc. Creatinine Clearance ≥ 40 mL/min (by Cockcroft-Gault).
• Bilirubin ≤ 1.5 x upper limit of normal (ULN) except if due to liver involvement, hemolysis, or Gilbert’s disease.
• AST / ALT ≤ 2.5 x upper limit of normal (ULN) except if due to liver involvement.
• Patients must not have any history of Richter’s transformation or prolymphocytic leukemia (prolymphocytes in blood > 55%).
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated.
  • Please note: IVIG can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician.
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load.
• Patients with Class III or Class IV heart failure by New York Heart Association, those with unstable angina, and those with uncontrolled arrhythmia are not eligible.
• Patients who have had a myocardial infarction, intracranial bleed, or stroke within the past 6 months are not eligible.
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients must not be receiving active systemic anticoagulation with heparin or warfarin. Patients on warfarin must discontinue the drug for at least 10 days prior to registration on the study.
• Chronic concomitant treatment with strong inhibitors of CYP3A4/5 is not allowed on this study. Patients on strong CYP3A inhibitors must discontinue the drug for 14 days prior to registration on the study. 
• Chronic concomitant treatment with strong CYP3A4/5 inducers is not allowed.
• Patients must discontinue the drug 14 days prior to registration on the study.
• Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily.
• Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics.
• Central FISH blood results are mandatory prior to registration/randomization for it will be used for stratification.
• Patients must be able to swallow capsules and not have the following conditions:  disease significantly affecting gastrointestinal absorption, resection of the stomach or small bowel, partial or complete bowel obstruction.
• Patients must not have a known allergy to mannitol.
• Patients must not have prior significant hypersensitivity to rituximab (not including infusion reactions).
• Patients may not have had major surgery within 10 days prior to registration, or minor surgery within 7 days prior to registration. Examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration for a joint. The decision about whether a surgery is major or minor can be made at the discretion of the treating physician.
• Patients must be able to receive either a xanthine oxidase inhibitor or rasburicase for prophylaxis/treatment of TLS.

RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)

• Completion of treatment through Cycle 14 Day 28, and remain on ibrutinib therapy.
• Receipt of central BM MRD results.
• Response assessment completed per Section 5.0 with CR determination.

Eligibility last updated 1/17/22. Questions regarding updates should be directed to the study team contact.

PRE-REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS)

• Tissue available for biomarker testing (any brain metastasis tissue and extracranial site from any prior resection or biopsy).

REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS)

• Participants must have histologically confirmed metastatic disease to the brain from any solid tumor. Note: this includes patients that have controlled extracranial disease with progressive intracranial metastasis, as well as patients that have progressive intracranial and extracranial disease. 
• New or progressive brain metastases are defined as any one of the following: 
  • Untreated measurable lesions in patients who have received surgery and/or stereotactic radiosurgery (SRS) to one or more other lesions; 
  • Residual or progressive lesions after surgery if asymptomatic; 
  • Patients who have had prior whole-brain radiotherapy (WBRT) and/or SRS and then whose lesions have progressed by BM-RANO criteria or there are new lesions, are eligible. Lesions treated with SRS may be eligible if there is unequivocal evidence of progression;
  • Patients who have not previously been treated with cranial radiation (e.g., WBRT or SRS) are eligible, but such patients must be asymptomatic or neurologically stable from their CNS metastases. 
• Measurable CNS disease (> 10 mm). 
• Ability to obtain magnetic resonance imaging (MRI)s. 
• No surgery within 2 weeks prior to or after registration.
• No chemotherapy within 14 days prior to registration
  • Note: for abemaciclib arm, a 21-day chemotherapy washout is required).
  • For melanoma, patients must have progressed after prior immune checkpoint blockade or for BRAF positive melanoma, BRAF/MEK inhibitors.
  • For lung cancer, EGFR mutant patients must have failed EGFR therapies
  • For HER2-positive breast cancer patients, patients must have received at least one prior HER-2 directed therapy in the metastatic setting.
  • For triple negative breast cancer (TNBC), patients must have received at least one chemotherapy in the metastatic setting. 
  • For estrogen receptor (ER)/progesterone receptor (PR)+ breast cancer, patients must have received at least one endocrine therapy in the metastatic setting. 
  • Breast cancer patients who have received ribociclib or palbociclib are eligible as long as there is documentation of CDK4 pathway alteration on a biopsy at the point of progression post-ribociclib or palbociclib.
• Tissue available for sequencing (any brain metastasis tissue and extracranial site from any prior resection or biopsy that was resected as part of clinical care). If the patient does not have any evidence of extracranial disease, brain metastasis tissue is sufficient for eligibility.
• Presence of clinically actionable alteration in NTRK, ROS1, or CDK pathway or PI3K pathway in both a brain metastasis and extracranial site. 
• Not pregnant and not nursing, because this study involves investigational agents whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 14 days prior to registration is required.
  • Note: for abemaciclib arm, pregnancy test is required ≤ 7 days prior to registration.
  • No known leptomeningeal involvement. 
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Adequate organ function.
  •Absolute neutrophil count (ANC) ≥ 1,500/mm^3.
• Platelet count ≥ 100,000/mm^3. 
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except in patients with Gilbert's disease. 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN). 
• Creatinine ≤ 1.5 mg/dL OR calculated (Calc.) creatinine clearance > 45 mL/min. 
• No uncontrolled medical comorbidities per investigator discretion (e.g., interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
• Concurrent radiation to symptomatic non-target sites within neural axis is allowed (provided there is at least one untreated target lesion). 
• Concurrent systemic corticosteroids are allowed if stable dose of dexamethasone for 7 days prior to registration. Baseline doses and changes in steroid dosing will be captured. 
• No concurrent administration of anticancer therapies (except for endocrine therapy or continuation of hormonal therapy or trastuzumab in breast cancer patients). No chemotherapy, targeted therapy or immunotherapy within 14 days prior to entering the study
  •  Note: For abemaciclib arm, a 21-day chemotherapy washout is required. 
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug 14 days prior to registration on the study. 
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment.

ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR GDC-0084 ARM

• Urine protein to creatinine (UPC) ratio < 1 or urine protein ≤ 1. 
• Recent acute myocardial infarction in the last 6 months or current angina pectoris are excluded. Patients with symptomatic bradycardia should have an electrocardiogram at baseline. If QT interval > 470 msec, the patient is excluded. 
• Patients with uncontrolled type I or II diabetes mellitus should be excluded. Uncontrolled diabetes is defined as glycosylated hemoglobin (HbA1c) > 9% in addition to fasting glucose > 140 mg/dL on at least 2 occasions within 14 days prior to registration.

ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR ENTRECTINIB ARM

• Concurrent use of H2 receptor antagonists, receptor antagonists, proton pump inhibitors (PPIs), and/or antacids are prohibited.

ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR ABEMACICLIB ARM

• Hemoglobin ≥ g/dL. Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion. 
• Patients who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to randomization. A washout period of at least 21 days is required between last chemotherapy dose and registration (provided the patient did not receive radiotherapy). 
• Patients who received adjuvant radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and registration. 
• For females of childbearing potential: A female of childbearing potential, must have a negative serum pregnancy test within 7 days prior to registration and agree to use a highly effective contraception method during the treatment period and for 3 weeks following the last dose of abemaciclib. Contraceptive methods may include an intrauterine device [IUD] or barrier method. If condoms are used as a barrier method, a spermicidal agent should be added as a double barrier protection. Cases of pregnancy that occur during maternal exposures to abemaciclib should be reported. If a patient or spouse/partner is determined to be pregnant following abemaciclib initiation, she must discontinue treatment immediately. Data on fetal outcome and breast-feeding are to be collected for regulatory reporting and drug safety evaluation. 
• Patients with active bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive] are excluded. Screening is not required for enrollment.
• Patients with personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest, are excluded.

Eligibility Criteria: 

• Metastatic disease defined as new or progressive lesions on cross-sectional imaging or bone scan. Patients must have at least:
  • One measurable site of disease as per RECIST v1.1;
  • One bone lesion on bone scan (tec99 or NaF PET/CT, CT or MRI) for the bone-only cohort;
• Histologically confirmed diagnosis of one of the following metastatic cohorts:
• Small cell/ neuroendocrine carcinoma of the bladder - All urothelial carcinomas with any amount of neuroendocrine differentiation (including small cell differentiation) will be included. If the tumor is purely neuroendocrine, metastasis from another site of origin should be clinically excluded;
• Adenocarcinoma of the bladder, or urachal adenocarcinoma, or bladder/urethra clear cell adenocarcinoma - must be pure (per WHO definition), (i.e. urothelial carcinoma with glandular differentiation is not considered a pure adenocarcinoma;
• Squamous cell carcinoma of the bladder
  •must be pure (i.e. urothelial carcinoma with squamous differentiation is not considered a pure squamous cell carcinoma);
• Plasmacytoid urothelial carcinoma - Tumor should show predominantly > or equal ~50% plasmacytoid histology (including all types of discohesive growth, such as tumors with signet-ring and/or rhabdoid features as well).
• Any penile cancer;
• Sarcomatoid renal cell carcinoma - Tumor should be predominantly sarcomatoid ~50% (including rhabdoid differentiation) is also unclassified RCCs: all (assuming they are high grade with metastasis) malignant angiomyolipomas are allowed;
• Sarcomatoid urothelial carcinoma - Tumor should show predominantly ~ 50% sarcomatoid differentiation;
• Renal medullary carcinoma - Per WHO definition, ideally confirmed with immunostains;
• Renal Collecting Duct Carcinoma
  •Per WHO definition (medullary involvement, predominant tubular morphology, desmoplastic stromal reaction, high grade cytology, infiltrative growth pattern, and absence of other renal cell carcinoma subtype or urothelial carcinoma);
• Bone only urothelial carcinoma or other non-prostate GU tumor;
• Urethra carcinoma- May be of any histology but if urothelial carcinoma then must be isolated to the urethra and not have metachronous or synchronous urothelial carcinoma of the bladder;
• Other miscellaneous histologic variants of the urothelial carcinoma, such as, but not limited to: micropapillary (Tumor should show predominantly > or equal 50% micropapillary architecture), giant cell, lipid-rich, clear cell and nested variants (Tumor should predominantly > or equal 50% show these features), large cell neuroendocrine carcinoma, lymphoepithelioma-like carcinoma and mixed patterns will be considered, as well as small cell neuroendocrine prostate cancer (Only treatment-naïve primary small cell of prostate with any amount of small cell component allowed. Post-treatment small cell prostatic carcinomas are not allowed), Malignant testicular Sertoli or Leydig cell tumors, and papillary and chromophobe RCC.Note: Translocation positive renal cell carcinoma patients are eligible. However, AREN1721 should be considered before this trial.
• H&E slides from diagnostic tumor tissue for retrospective central pathology review.
• Patients may have received up to 2 systemic anti-cancer treatments or be treatment naïve. Patients with small cell carcinoma should have received a platinum-based combination regimen either as neoadjuvant, adjuvant or first-line treatment). Patients in the bone-only cohort may be urothelial carcinoma histology but must receive standard cisplatin-based chemotherapy (if cisplatin- eligible).
• Age ≥ 18 years.
• Patients must be able to swallow oral formulation of the tablets.
• Karnofsky performance status ≥ 80%.
• Required Laboratory Values:
  • Absolute Neutrophil Count (ANC) ≥1,000/mcL;
  • Platelet Count ≥ 75,000/mcL;
  • Total Bilirubin ≤1.5 × ULN. For subjects with known Gilbert’s disease or similar syndrome with slow conjugation of bilirubin, total bilirubin ≤ 3.0 mg/dL AST/ALT ≤3.0 × institutional upper limit of normal (ULN) (or ≤5 x ULN for patients with liver metastases or Gilbert’s disease);
  • Creatinine ≤ 1.5 x upper limit of normal (ULN); OR
  • Creatinine clearance ≥ 40 mL/min/1.73 m2 (calculated using the CKD-EPI equation or Cockroft-Gault formula) for patients with creatinine levels above institutional normal hemoglobin ≥9 g/dL (transfusion of PRBCs allowed) serum albumin ≥3.2g/dL lipase and amylase ≤2.0 × ULN and no radiologic (on baseline anatomical imaging) or clinical evidence of pancreatitis.
• Prior treatment with MET or VEGFR inhibitors is allowed. However, prior cabozantinib will not be allowed. Also, patients that have received both prior MET or VEGF and prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are also not allowed.
• Prior treatment with any therapy on the PD-1/PD-L1 axis or anti- CTLA- 4/CTLA-4 inhibitors is allowed, either in the perioperative or in the metastatic setting. However, patients that have received both prior MET or VEGF and prior PD-1/PD- L1/CTLA-4 (sequentially or in combination) are not allowed.
• HIV-positive patients are eligible if on stable dose of highly active antiretroviral therapy (HAART) and no clinically significant drug-drug interactions are anticipated with the current HAART regimen, CD4 counts are greater than 350 and viral load is undetectable.
• Patients with rheumatoid arthritis and other rheumatologic arthropathies, Sjögren’s syndrome and psoriasis controlled with topical medication only and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies etc. are eligible but should be considered for rheumatologic evaluation for the presence of target organ involvement and potential need for systemic treatment.
• Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones or medications (eg thyrodidits managed with PTU or methamizole) including physiologic oral corticosteroids are eligible.
• Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess, and GI obstruction, within 12 months are not eligible.
• Women of childbearing potential must have a negative pregnancy test ≤ 7 days prior to registration.
• Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post menopause is defined as amenorrhea ≥12 consecutive months. Note: 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, ovarian suppression or any other reversible reason.
• Pregnant women may not participate in this study because with cabozantinib, nivolumab, and ipilimumab have potential for teratogenic or abortifacient effects.
• Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cabozantinib, nivolumab, and ipilimumab, breastfeeding should be discontinued if the mother is treated with these agents.
• The patient has received no cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 2 weeks before the first dose of study treatment.
• The patient has received no radiation therapy:
  • To the lungs and mediastinum or abdomen within 4 weeks before the first dose of study treatment, or has ongoing complications, or is healing from prior radiation therapy;
  • To brain metastasis within 3 weeks for WBXRT, and 2 weeks for SBRT before the first dose of study treatment;
  • To the abdomen within 4 weeks before the first dose of study treatment, or has ongoing complications, or is healing from prior radiation therapy;
  • To any other site(s) within 2 weeks before the first dose of study treatment.
• The patient has received no radionuclide treatment within 6 weeks of the first dose of study treatment.
• The patient has received no prior treatment with a small molecule kinase inhibitor within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment.
• The patient has received no prior treatment with hormonal therapy within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment. Subjects receiving Gonadotropin-releasing hormone (GnRH) agonists and antagonists are allowed to participate.
• The patient has not received any other type of investigational agent within 14 days before the first dose of study treatment.
• The patient must have recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia, neuropathy and other non-clinically significant AEs defined as lab elevation with no associated symptoms or sequelae.
• The patient may not have active brain metastases or epidural disease. Patients with brain metastases previously treated with whole brain radiation or radiosurgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility.
• No concomitant treatment with warfarin. Aspirin (up to 325 mg/day), thrombin or factor Xa inhibitors, low-dose warfarin (≤1 mg/day), prophylactic and therapeutic low molecular weight heparin (LMWH) are permitted.
• No chronic concomitant treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s Wort) or strong CYP3A4 inhibitors.
• Because the lists of these agents are constantly changing, it is important to regularly consult medical reference texts such as the Physicians’ Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• The patient has not experienced any of the following:
  • Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment;
  • Hemoptysis of ≥ 0.5 teaspoon (2.5 mL) of red blood per day within 1 months before the first dose of study treatment;
  • Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment.
• The patient has no tumor invading any major blood vessels.
• The patient has no evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib. Patients with rectal tumor masses are not eligible.
• The patient has no uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions.  Cardiovascular disorders including:
  • Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening;
  • Concurrent uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment;
  • The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms within 28 days before randomization.
  • Note: if initial QTcF is found to be > 500 ms, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is ≤500 ms, the subject meets eligibility in this regard.
  • Any history of congenital long QT syndrome.
• Any of the following within 6 months before registration of study treatment:
  • unstable angina pectoris;
  • clinically-significant cardiac arrhythmias (patients with atrial fibrillation are eligible);
  • stroke (including TIA, or other ischemic event)
  • myocardial infarction
  • cardiomyopathy.
• No significant gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:
  • Any of the following that have not resolved within 28 days before the first dose of study treatment:
  • Acute diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or malabsorption syndrome;
  • Active peptic ulcer disease;
  • None of the following within 2 years before the first dose of study treatment:
  • abdominal fistula or genitourinary fistula
  • gastrointestinal perforation
  • bowel obstruction or gastric outlet obstruction
  • intra-abdominal abscess.
    • Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 2 years before the first dose of study treatment.
• Disorders associated with a high risk of fistula formation including PEG tube placement are not eligible.
• No other clinically significant disorders such as:
  • severe active infection requiring IV systemic treatment within 14 days before the first dose of study treatment
  • serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
  • history of organ or allogeneic stem cell transplant
  • concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment (for asymptomatic patients with an elevated TSH, thyroid replacement may be initiated if clinically indicated without delaying the start of study treatment)
  • No history of major surgery as follows:
  • Major surgery within 3 months of the first dose of cabozantinib; however, if there were no wound healing complications, patients with rapidly growing aggressive cancers, may start as soon as 6 weeks if wound has completely healed post- surgery.
  • Minor surgery within 1 month of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications excluding core biopsies and mediport placement.
• Complete wound healing from prior surgery must be confirmed before the first dose of cabozantinib irrespective of the time from surgery.
• No history of severe hypersensitivity reaction to any monoclonal antibody.
• No evidence of active malignancy, requiring systemic treatment within 2 years of registration.
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib, nivolumab, ipilimumab or other agents used in study.
• No positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. If HBV sAG is positive, subsequent RNA PCR must be negative.
• No patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include, but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease.

Please Note: While patients may meet eligibility criteria, treating physicians should use best judgement to assess if the patient is a good candidate for this therapy with three drug combination regimen.

• Patients must be women age 45 or older and under age 75 at the time of study entry.
• Women of childbearing potential must not be known to be pregnant or lactating.
• Patients must be scheduled for, or have intent to schedule, a screening mammogram.
• Patients must be able to tolerate digital breast tomosynthesis and full-field digital mammographic imaging required by protocol, to be performed at an American College of Radiology Imaging Network (ACRIN)-qualified facility.
• Patients must be willing and able to provide a written informed consent.
• Patients must not have new symptoms or signs of benign or malignant breast disease (e.g., bloody or clear nipple discharge, breast lump) based on physician physical exam or self breast exam that have not been previously worked up with imaging. Patients with physiologic nipple discharge or breast pain are eligible as long as other criteria are met.
• Patients must not have had a screening mammogram within the last 11 months prior to date of randomization.
• Patients must not have previous personal history of breast cancer including ductal carcinoma in situ.
• Patients must not have breast enhancements (e.g., implants or radiopaque injections).

ANNUAL SCREENING REGIMEN ELIGIBILITY CHECK 

To be eligible for inclusion in the annual screening regimen one of the following three conditions must be met in addition to the eligibility criteria above:

• Patients are pre-menopausal; or
• Post-menopausal aged 45-69 with any of the following four risks factors:
  • Dense Breasts (BIRADS density categories c-heterogeneously dense or d-extremely dense), or
  • At least one benign breast biopsy with a diagnosis of Lobular Carcinoma in Situ (LCIS) or atypia of any kind (atypical ductal hyperplasia, atypical lobular hyperplasia, atypical hyperplasia NOS, or intraductal papilloma with atypia), or
  • Family history of breast cancer (first degree relative with breast cancer) or family history of breast cancer is not known, or, participant positive genetic testing for any deleterious genes that indicate an increased risk for breast cancer, or
  • Currently on hormone therapy¹; or
• Post-menopausal ages 70-74 with either of the following three risk factors:
  • Dense Breasts (BIRADS density categories c-heterogeneously dense or d-extremely dense); or
  • At least one benign breast biopsy with a diagnosis of LCIS or atypia of any kind (atypical ductal hyperplasia, atypical lobular hyperplasia, atypical hyperplasia NOS, or intraductal papilloma with atypia); or
  • Currently on hormone therapy¹.
• Postmenopausal women are defined as those with their last menstrual period more than 12 months prior to study entry. For the purpose of defining menopausal status for women who have had surgical cessation of their periods, women who no longer have menses due to bilateral oophorectomy with either hysterectomy or endometrial ablation will be considered postmenopausal. Women who no longer have menses due to either hysterectomy or endometrial ablation, and who have at least one ovary will be considered premenopausal until age 52 and postmenopausal thereafter.
• All other postmenopausal women are eligible for inclusion in the biennial screening regimen.
• For those women who cannot be assigned to annual or biennial screening at the time of study entry and randomization because they are postmenopausal, have no family history or known deleterious breast cancer mutation, are not on hormone therapy1 AND for whom a prior mammogram interpretation is not available, breast density will be determined by the radiologist’s recording of it at the time of interpretation of the first study screening examination, either DM or TM. For those who are randomized to TM, radiologists will assign BI-RADS density through review of the DM or synthetic 2D portion of the TM examination. Such women cannot be part of the planned stratification by screening frequency and are expected to represent far less than 1% of the TMIST population.
• ¹ For this study we define hormone therapies as those that increase breast cancer risk, including: estrogen, progesterone, estrogen/progesterone analogs, or hormonal birth control prescribed by a doctor, and include hormones in oral contraceptives, patch, gel, etc. BUT, for this study, Soy use is not considered hormone therapy.
• Breast density will be determined by prior mammography reports, when available, or by radiologist review of prior imaging.
  • NOTE: If the latter method is used, a signed, dated attestation by the radiologist indicating the resulting determination must be kept as a record and made available for monitoring/auditing.
• All other risk factors used to determine patient eligibility for annual or biennial screening will be determined by subject self-report.

• There is no age limit for the low risk stratum (stage I ovarian immature teratoma and stage I non-seminoma or seminoma malignant GCT [all sites]).
• Standard risk 1: Patient must be < 11 years of age at enrollment.
• Standard risk 2: Patients must be ≥ 11 and < 25 years of age at enrollment.
• Patients enrolling on one of the low risk arms must be newly diagnosed with a stage I germ cell tumor; for the standard risk arms, patients must be newly diagnosed with metastatic germ cell tumor (stage II or higher); histologic confirmation of a primary extracranial germ cell tumor in any of the categories outlined below is required of all patients at enrollment except for those who were initially diagnosed with stage I non-seminoma malignant GCT and later recur during observation post surgery off study; for these patients, if elevated tumor markers rise to > 5 x upper limit of normal (ULN) on at least 2 measurements taken at least 1 week apart, a diagnostic biopsy is not required for enrollment
• Low risk stage I immature teratoma (IT); site: ovarian; stage: Children's Oncology Group (COG) stage I, Federation of Gynecology and Obstetrics (FIGO) stage IA and IB; grade: 2 or 3; histology: pure immature teratoma (may contain microscopic foci of yolk sac tumor), mixed immature and mature teratoma, (no pathological evidence of MGCT); tumor markers: alpha-FP ≤ 1,000 ng/mL, beta-HCG institutional normal; all ages.
• Low risk stage I non-seminoma MGCT; site: ovarian, testicular, or extragonadal; stage: COG stage I, FIGO stage IA and IB, American Joint Committee on Cancer (AJCC) testicular stage IA, IB and IS; histology: must contain at least one of the following: yolk sac tumor, embryonal carcinoma, or choriocarcinoma (pure or mixed); all ages.
• Low risk stage I seminoma-MGCT; site: testicular; stage: COG stage I; AJCC testicular stage IA IB, and IS; histology: must contain at least one of the following: may contain immature/mature teratoma; may NOT contain yolk sac tumor, embryonal carcinoma, or choriocarcinoma; all ages.
• Standard risk 1 (SR1); site: ovarian, testicular, or extragonadal; stage: COG stage II-IV, FIGO stage IC, FIGO stage II-IV (International Germ Cell Consensus Classification [IGCCC] criteria DO NOT apply); histology: must contain at least one of the following: yolk sac tumor, embryonal carcinoma, or choriocarcinoma; age (years) < 11.
• Standard risk 2 (SR2)
  • Site: ovarian; stage: COG stage II and III, FIGO stage IC, II and III; histology: must contain at least one of the following: yolk sac tumor, embryonal carcinoma, or choriocarcinoma; age (years) >= 11 and < 25;
  • Site: testicular; stage: COG stage II-IV, AJCC stage II, III, IGCCC good risk; histology: must contain at least one of the following: yolk sac tumor, embryonal carcinoma, or choriocarcinoma; tumor markers: must be IGCCC good risk; post op: alpha-FP < 1,000 ng/mL, beta-HCG < 5,000 IU/mL and lactate dehydrogenase (LDH) < 3.0 x normal; age (years) ≥ 11 and < 25;
  • Site: extragonadal; stage: COG stage II; histology: must contain at least one of the following: yolk sac tumor, embryonal carcinoma, or choriocarcinoma; age (years) ≥ 11 and < 25.
  • Notes:
    • IGCCC criteria only apply to SR2 patients with a testicular primary tumor;
    • Use post-op tumor marker levels to determine IGCCC risk group;
    • Stage 1 seminoma patients are not eligible for the standard risk arms of the study;
    • For the low risk stage I non-seminoma MGCT and the standard risk arms, components of yolk sac tumor, embryonal carcinoma, or choriocarcinoma can be mixed with other forms of GCT, such as seminoma or mature or immature teratoma; if yolk sac tumor is the only malignant component present, then it must be deemed by the pathologist to be greater than a "microscopic component" of yolk sac tumor.
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, 2 or 3; use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age.
• Organ function requirements apply ONLY to patients who will receive chemotherapy (SR1 and SR2 patients).
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m^2.
• A serum creatinine based on age/gender as follows: (mg/dL):
  • 1 month to < 6 months male: 0.4 female: 0.4;
  • 6 months to < 1 year male: 0.5 female: 0.5;
  • 1 to < 2 years male: 0.6 female: 0.6;
  • 2 to < 6 years male: 0.8 female: 0.8;
  • 6 to < 10 years male: 1 female: 1;
  • 10 to < 13 years male: 1.2 female: 1.2;
  • 13 to < 16 years: male: 1.5 female: 1.4;
  • ≥ 16 years male: 1.7 female: 1.4.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age.
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x upper limit of normal (ULN) for age (for the purpose of this study, the ULN for SGPT is 45 U/L).
• Peripheral absolute neutrophil count (ANC) ≥ 1,000/mm^3.
• Platelet count ≥ 100,000/mm^3.
• Patients enrolling on the standard risk arms must be medically fit to receive protocol treatment and with no contraindications to protocol treatment.
• Eligibility criteria to participate in the pilot study of the AYA-Hears instrument (patient reported outcomes [PROs] of ototoxicity).
  • Note: participants in group 1 will not receive AGCT1531 protocol-directed therapy; all other AYA-HEARS patients must be enrolled on the AGCT1531 SR2 arm in order to participate.
• ≥ 11 and < 25 years old at enrollment.
• Able to fluently speak and read English.
• Has received prior cisplatin- or carboplatin-based chemotherapy regimen for malignancy including diagnoses other than germ cell tumor.
• Followed for cancer or survivorship care at one of the following institutions:
  • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center;
  • Dana Farber/Harvard Cancer Center;
  • Hospital for Sick Children;
  • Children's Hospital of Eastern Ontario;
  • Oregon Health and Science University;
  • Seattle Children's Hospital;
  • Yale University.

• Patients with any diagnoses not listed including:

  • Stage I testicular cancer patients who have undergone primary RPLND (retroperitoneal lymph node dissection);
  • Pure dysgerminoma;
  • Pure mature teratoma;
  • Pure immature teratoma COG stage I, grade I;
  • Pure immature teratoma COG stage I, grade 2,3 with alpha-fetoprotein (AFP) ≥ 1000 ng/mL;
  • Pure immature teratoma COG stage II
    •IV or FIGO stage IC to IV;
  • "Poor risk" GCT (age ≥ 11 years old and COG stage IV ovarian, COG stage III or IV EG, or IGCCC intermediate or poor risk testicular); or
  • Primary central nervous system (CNS) germ cell tumor;
  • Germ cell tumor with somatic malignant transformation;
  • Spermatocytic seminoma.
• Patients must have had no prior systemic therapy for the current cancer diagnosis.
• Patients must have had no prior radiation therapy with the exception of CNS irradiation of brain metastases; (this exception only applies to SR1 patients; any patients over age 11 with distant metastases to brain [stage IV disease] would be considered poor risk and therefore not eligible for this trial).
• Patients with significant, pre-existing co-morbid respiratory disease that contraindicate the use of bleomycin, are ineligible for the standard risk arms of the trial.
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential; (this criteria applies ONLY to patients who will receive chemotherapy [SR1 and SR2 patients]).
• Lactating females who plan to breastfeed their infants; (this criteria applies ONLY to patients who will receive chemotherapy [SR1 and SR2 patients]).
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation; (this criteria applies ONLY to patients who will receive chemotherapy [SR1 and SR2 patients]).

Eligibility last updated 11/29/21. Questions regarding updates should be directed to the study team contact.

• Be willing and able to provide written informed consent/assent for the trial.
• Be ≥ 18 years of age on day of signing informed consent.
• Have received 1-5 prior chemotherapy lines for treating epithelial ROC (i.e., 2-6 total prior lines counting the front line).
• Have measurable disease based on RECIST 1.1.
  • Note: Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Have a performance status of 0 or 1 on the ECOG Performance Scale.
• Have histologically diagnosed recurrent epithelial ovarian, fallopian or primary peritoneal ovarian cancer.
• Have provided a tumor tissue sample from an archival tissue specimen collected from the primary ovarian tumor at the time of the initial debulking surgery. If primary ovarian cancer tissue is not available alternatively non lymph node tissue from a later biopsy may be used instead.
• Have received a tumor tissue test result of NanoString gene expression profiling that is indicative of the immunoreactive molecular subtype.
• Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 28 days of treatment initiation.
• Adequate Organ Function Laboratory Values:
• Hematological
  • Absolute neutrophil count (ANC) ≥ 1,500 /mcL;
  • Platelets ≥ 100,000 / mcL;
  • Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment).
• Renal
  • Serum creatinine OR Measured or calculated* creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤ 1.5 X upper limit of normal (ULN) OR ≥ 45 mL/min for subject with creatinine levels > 1.5 X institutional ULN.
• Hepatic
  • Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
  • AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
  • * Creatinine clearance should be calculated per institutional standard.
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Have received front line platinum-based chemotherapy (preoperative chemotherapy is allowed).
• Female subjects of childbearing potential must be willing to use an adequate method of contraception.  Contraception, for the course of the study through 120 days after the last dose of study medication.
  • Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 2 weeks of the first dose of treatment.
• Has had progression on or within 4 weeks of completing frontline platinum-based chemotherapy (primary platinum refractory).
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has a known history of active TB (Bacillus Tuberculosis).
• Hypersensitivity to pembrolizumab or any of its excipients.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
  • Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
  • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Has 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). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• 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.
• Has received a live vaccine or live-attenuated vaccine within 30 days of planned start of study therapy. Administration of killed vaccines is allowed.
  • Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

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

• 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.

• Subject must be ≥ 18 years of age.
• Three or more prior lines of therapy with exposure to a PI, an IMiD, and an anti-CD38 antibody (e.g., daratumumab). In order to be eligible for this study subjects must not be candidates for treatment regimens known to provide clinical benefit in MM.
• Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.
• Subject is capable of understanding and complying with parameters as outlined in the protocol and able to sign informed consent.
• Subject must have adequate bone marrow function, defined as:
  • absolute neutrophil count (ANC) ≥ 1000/mm^3;
  • platelets ≥ 50,000/mm^3;
  • hemoglobin ≥ 8.0 g/dL;
  • Transfusion and / or growth factor support is permitted prior to assessment, but neutrophils, platelets, and hemoglobin must be stable for at least 72 hours after transfusion and / or growth factor administration prior to Screening for the subject to be eligible.
• Subject must have an eGFR ≥ 30 mL/min as estimated by the MDRD formula.
• Subject must have total bilirubin ≤ 1.5 × upper limit of normal (ULN; except if the subject has a known diagnosis of Gilbert’s syndrome, in which case bilirubin must be < 3 x ULN).
• Serum calcium (corrected for albumin) at or below the ULN range (subject may enroll in the setting of hypercalcemia at Screening IF hypercalcemia resolves with standard treatment by Cycle 1 Day 1) prior to study therapy initiation.
• Measurable Disease: Subject has a diagnosis of MM and documented prior treatment with a PI, an IMiD, and an anti-CD38 mAb (ie, daratumumab) as part of 3 or more lines of therapy. In order to be eligible for this study subjects must not be candidates for treatment regimens known to provide clinical benefit in MM. There is no maximum number of prior regimens and prior bone marrow transplant is acceptable if subject is > 12 weeks (autologous) or > 1 year (allogeneic) status-post transplantation.
• Measurable disease is defined as at least 1 of the following:
• • Serum M-protein ≥ 0.5 g/dL (≥ 5 g/L);
  • Urine M-protein ≥ 200 mg / 24h;
  • Serum free light chain (FLC) assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/L) and an abnormal serum FLC ratio (< 0.26 or > 1.65).
• Subject has confirmed evidence of relapse / progression from the immediately prior MM therapy, or subject is relapsed / refractory to the immediately prior MM therapy. (‘Refractory’ is defined as subjects with either progressive disease or best response of stable disease to the last therapy; ‘Relapsed / refractory’ is defined as subjects with a history of minimal response [MR] or better response to prior therapy, now with disease progression within 60 days of the last therapy. ‘Relapse’ is defined as previously treated myeloma that progresses and requires initiation of salvage therapy, without meeting IMWG uniform response criteria for relapsed / refractory).
• Subject has adequate archival tumor bone marrow tissue if available or consents to a fresh pre- treatment bone marrow tumor biopsy.

• Subject has been diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of basal cell or squamous cell carcinoma of the skin, in situ malignancy, low-risk prostate carcinoma after curative therapy, or complete resection / curative therapy of an advanced malignancy.
• Subject has a history of central nervous system (CNS) involvement by their myeloma.
• Subject has a history of Grade ≥ 3 peripheral neuropathy.
• Subject has a history of plasma cell leukemia, POEMS syndrome, or amyloidosis.
• Subject has received another investigational drug within 21 days of enrollment.
• Subject has ever received BCMA-targeted therapy. Subjects who have received targeted therapy against non-BCMA targets will not be excluded.
• Subject has received a peripheral autologous stem cell transplant within 12 weeks or an allogeneic stem cell transplant within 1 year of the first dose of study drug treatment.
• Subject has any medical or psychiatric condition which in the opinion of the investigator or Study Medical Monitor places the subject at an unacceptably high risk for toxicities, could interfere with successful or safe delivery of therapy, or could interfere with evaluation of the investigational product or interpretation of subject safety or study results. Examples include history of significant mucosal / internal bleeding, major psychiatric illness, drug abuse (including active alcoholism), or known allergy or hypersensitivity to components of the study drug formulation.
• Subject has received any therapy to treat cancer (including radiation, chemotherapy, biologics, cellular therapies and / or steroids at doses > 20 mg dexamethasone or equivalent) or undergone a major surgical procedure within 21 days, or within 5 half-lives of an anti-cancer drug, prior to the first dose of study treatment, whichever is shorter.
• Subject has known infection Grade ≥ 2 requiring anti-infective treatment. Upon completion of antibiotics and resolution to Grade ≤ 1, the subject is considered eligible for the study from an infection standpoint.
• Confirmed positive test results for human immunodeficiency virus (HIV), or subjects with chronic or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Subjects who have a history of HBV or HCV who have documented cures (HBV: hepatitis B surface antigen [HBsAg] negative; HCV: undetectable HCV RNA 24 weeks after the end of treatment) may be enrolled.
• Major cardiac abnormalities such as but not limited to the following: uncontrolled angina or unstable life-threatening arrhythmias, history of myocardial infarction ≤ 12 weeks before Screening, Class ≥ 3 New York Heart Association congestive heart failure, severe cardiac insufficiency, or persistent QTc prolongation (> 480 msec, QTc Fridericia).
• If female, subject must not be pregnant or breastfeeding and be either postmenopausal (for at least 12 consecutive months), OR permanently surgically sterile OR for women of childbearing potential practicing at least 1 protocol specified method of female birth control AND 1 protocol specified method of male birth control (vasectomy or condoms), starting at Screening through at least6 months after the last dose of study drug.
• Subject has unresolved AEs ≥ Grade 2 (NCI CTCAE v5.0) from prior anticancer therapy except for:
  • Alopecia;
  • Peripheral neuropathy (peripheral neuropathy ≥ Grade 3 will be excluded);
  • Anemia or thrombocytopenia (the latter cytopenias must be Grade 4 to trigger exclusion, Grade 3 with symptoms or bleeding, respectively, or return within 72 hours despite transfusion support);
  • Subjects with irreversible toxicity not reasonably expected to be exacerbated by any of the investigational products may be included (e.g., hearing loss) after consultation with the Study Medical Monitor.

Eligibility last updated 2/11/22. Questions regarding updates should be directed to the study team contact.

• 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.

STEP 1 REGISTRATION
•DISEASE-RELATED CRITERIA

• All patients must have a histologically or cytologically proven diagnosis of adenocarcinoma of the prostate. Patients with pure small cell carcinoma* (SCC), sarcomatoid, or squamous cell carcinoma are not eligible. (*morphology must be consistent with SCC; synaptophysin or chromogranin positive by immunohistochemical staining is insufficient to diagnose SCC).
• Patients must have an intact prostate.
• Patients must have at least one of the following scans performed, showing evidence of metastatic disease:
  • technetium bone scan; OR
  • CT of abdomen & pelvis; OR
  • MRI of pelvis..
• Scans must be performed between 42 days prior to start of first hormonal therapy and 14 days following start of first hormonal therapy. Metastatic disease that is detected by PET scan only (NaF, PSMA, FACBC, C11) but not conventional imaging (Tc99 bone scan, CT or MRI) or solitary metastases by conventional imaging, must be confirmed histologically or cytologically.
• Patients with known brain metastases are not eligible. Brain imaging studies are not required for eligibility if the patient has no neurologic signs or symptoms suggestive of brain metastasis. If brain imaging studies are performed, they must be negative for disease.

STEP 1 REGISTRATION
•PRIOR/CONCURRENT THERAPY CRITERIA

• Patients must have received no more than 28 weeks of SST, as measured from the date of first hormonal therapy (LHRH agonist or LHRH antagonist) or surgical castration. SST is defined as current NCCN guidelines for metastatic prostate cancer.
• No prior local therapy for prostate adenocarcinoma is allowed (e.g., brachytherapy, HIFU, cryotherapy, laser ablative therapies). Any prior therapy for benign conditions, such as obstruction, are acceptable (e.g., transurethral resection of the prostate, greenlight laser ablation, microwave ablation).
• Patients must not have received any prior systemic therapy for prostate cancer, outside of line of SST to be used for duration of study.
• Patients must not have progressed while on SST.
• Patients with oligometastatic prostate cancer may receive metastasis directed therapy to up to four sites of disease prior to randomization.

STEP 1 REGISTRATION
•CLINICAL/LABORATORY CRITERIA:

• Patients must be ≥ 18 years of age.
• Patients must have a complete physical examination and medical history within 28 days prior to registration.
• Patients must have a documented PSA:
  • Prior to initiation of SST;
  • Within 28 days prior to registration;
  • Any additional PSAs measured while receiving SST should be recorded.
• Patients must have a testosterone lab documented within 28 days prior to registration. Any additional testosterone labs measured while receiving SST should be recorded as well as pretreatment initiation if available.
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, adequately treated Stage 0, 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 three years.

STEP 1 REGISTRATION
•SPECIMEN SUBMISSION CRITERIA

• Patients must be offered the opportunity to participate in translational medicine studies and specimen banking for future studies.

STEP 1 REGISTRATION - QUALITY OF LIFE CRITERIA

• Patients who can complete Patient-Reported Outcome instruments in English, Spanish or French, must participate in the quality of life studies.

STEP 1 REGISTRATION - REGULATORY CRITERIA

• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.
• As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.

STEP 2 RANDOMIZATION
•DISEASE-RELATED CRITERIA

• Patients must have no evidence of disease progression during the 28 weeks of SST, as shown by:
  • PSA measure;
  • imaging (bone scan and one of the following: CT of abdomen & pelvis, MRI of abdomen & pelvis, CT of abdomen & MRI of pelvis) within 42 days prior to randomization.
• Patients must have no evidence of symptomatic deterioration (as defined by physician discretion) within 28 days prior to randomization.
• Patients must have consultation with a urologist and have surgically resectable disease regardless of definitive treatment intent or randomization.

STEP 2 RANDOMIZATION - PRIOR/CONCURRENT THERAPY CRITERIA

• Patients must have received at least 22 and no more than 28 weeks of SST, as measured from the date of first hormonal therapy (LHRH agonist or LHRH antagonist) or surgical castration. SST is defined by current NCCN guidelines for metastatic prostate cancer.
• Patients must not be planning to receive docetaxel after randomization.
• Any toxicities from SST must have resolved to ≤ Grade 1 (CTCAE Version 5.0) prior to randomization.
• Patients may have received elective metastasis directed therapy to oligometastatic sites (≤ 4 sites). All treatment must be completed prior to randomization.

STEP 2 RANDOMIZATION - CLINICAL/LABORATORY CRITERIA

• Patients must have a PSA performed within 28 days prior to randomization.
• Patients must have a testosterone < 50 ng/dL within 28 days prior to randomization.
• Patients must have a Zubrod performance status of 0 – 1 within 28 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.