Eligibility Criteria:

Step 0 Pre-registration Eligibility Criteria

- Patient must be = 18 years of age.

-Patient must have active advanced melanoma, defined as unresectable stage IIIB-IV by AJCC 8th edition.

- Patient must have melanoma originating from cutaneous, acral-lentiginous, or mucosal primary sites. Patients with melanoma of unknown primary site are eligible. Patients must not have melanoma from an ocular primary site.

- Patient must have had measurable disease by imRECIST prior to start of initial anti-PD-1 therapy as defined in Section 6.1.

- Patient must be actively receiving standard of care anti-PD-1 therapy, currently be 52 weeks (+/- 2 weeks) from start of anti-PD-1 therapy, and have not experienced a toxicity that prevents them from continuing on therapy. Permitted systemic anti-PD-1 therapy regimens include:

• Nivolumab 240mg IV Q2weeks or 480mg IV Q4weeks
• Pembrolizumab 200mg IV Q3weeks or 400mg IV Q6weeks
• Nivolumab 1mg/kg plus Ipilimumab 3mg/kg IV Q3weeks induction x 4 doses, followed by Nivolumab 240mg IV Q2weeks or 480mg IV Q4weeks maintenance
• Nivolumab 3mg/kg plus Ipilimumab 1mg/kg IV Q3weeks induction x 4 doses, followed by Nivolumab 240mg IV Q2weeks or 480mg IV Q4weeks maintenance
• Pembrolizumab 2mg/kg (or 200mg flat dose) plus Ipilimumab 1mg/kg IV Q3weeks induction x 4 doses, followed by Pembrolizumab 200mg IV Q3weeks or 400mg IV Q6weeks maintenance

- Patient must not be receiving concurrent anti-tumor therapies in addition to the standard of care anti-PD-1 regimens. Patients who are receiving bisphosphonates and RANKL inhibitors for management of bone metastases are eligible.
- Patient must have an ECOG performance status of 0-2.

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Patients with detectable viral loads are excluded as it is unclear if these patients have a low risk of melanoma progression off anti-PD-1 treatment.

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

- Patient must not have brain metastases.

- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

- Patient must have experienced complete response, partial response, or stable disease on restaging CT scans by imRECIST that is maintained on restaging scans obtained at week 52 (+/- 2 weeks) from start of initial anti-PD-1 therapy.

- Patient must have completed an FDG-PET/CT scan at week 52 (+/- 2 weeks) from start of initial anti-PD-1 therapy

- Patients with PET/CT positive for hypermetabolic lesions: If a core needle, punch or excisional biopsy and pathological

review of a representative lesion was not performed prior to pre-registration (Step 0) must either: 

• Be amenable to undergo a biopsy. Patient must not be on anticoagulation therapy or, if on anti-coagulation therapy, patient must be able to hold treatment for a biopsy procedure (core needle, punch or excisional biopsy). Anti-coagulation therapy is defined as low molecular weight heparin, warfarin, factor Xa inhibitor, or direct thrombin inhibitor.

• Have documentation of inability to perform the biopsy due to feasibility or safety concerns.

Women must not be pregnant or breast-feeding due to potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the anti-PD-1 regimens being used.

All females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy.

A female of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Women of childbearing potential and sexually active males must not conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse from the time of study registration and continuing until at least 5 months after the last dose of anti-PD-1 treatment for female patients and for at least 7 months after the last dose of anti-PD-1 treatment for male patients who are sexually active with a WOCBP.

- Patient must have adequate organ and marrow function as defined below: (these labs must be obtained = 4 weeks prior to protocol registration)

Leukocytes = 3,000/mcL

Absolute neutrophil count = 1,500/mcL

Platelets = 100,000/mcL

Total bilirubin = institutional upper limit of normal (ULN) (patients with history of Gilbert’s syndrome are permitted to have a total bilirubin > 1.5 x institutional ULN)

AST(SGOT)/ALT(SGPT) = 2.5 × institutional ULN

Creatinine = 1.5 x institutional ULN

Step 1 Registration Eligibility Criteria

- Patient met all eligibility criteria outlined in Section 3.1

- Patient must register to Step 1 within 4 weeks of registration to Step 0.

- Patients must meet one of the following criteria:

- Patient had no positive hypermetabolic lesions on the week 52 FDG-PET/CT.

- Patients with positive hypermetabolic lesion(s) on the week 52 FDG-PET/CT (positive hypermetabolic = SUV > pooled mediastinal blood), one of the following must have occurred:

A representative lesion was biopsied (core needle, punch or excisional biopsy) within 14 days of registration to Step 0 and subsequent pathology review performed to determine the presence or absence of viable tumor

Documentation is present that the patient is not able to undergo biopsy of a hypermetabolic lesion due to feasibility or safety concerns, i.e., the lesion location that is not amenable to biopsy

*DTL Required- Physicians must sign toxicity grid

***Effective June 19, 2020 the QOL component is closed to accrual***

CURRENT SITES CREDENTIALED: SJMH, Sparrow, Holy Cross, LVHN

-Preoperative biopsy for confirmation of RCC must be performed within four (4) months prior to randomization.
- Patients with newly diagnosed higher risk RCC of any histology including sarcomatoid or "unknown" histology.
- Clinical stage = T2NxM0 disease or TanyN+ disease for which radical or partial nephrectomy is planned.
-Patients must have no clinical or radiological evidence of distant metastases (M0)
-No concurrent or prior systemic or local anti-cancer therapy for RCC is permitted.
-ECOG PS must be 0-1
-Patient must have no prior history of RCC that was resected with curative intent within the past 5 years.
-No active known or suspected autoimmune disease.

Eligibility Criteria

Eligibility Criteria for Preregistration (Step 0: Screening):

- Patient must be ≥ 21 years of age.

- Patient must speak English or Spanish.

- Patient must have biopsy-proven (consisting of ≥ 12 tissue cores) adenocarcinoma of the prostate with cancer present in at least one biopsy core in the most recent biopsy using initial TRUS biopsy or TRUS biopsy followed by multiparametric Magnetic Resonance Imaging (mpMRI) of the prostate and a confirmatory targeted biopsy.

- Patient must be on active surveillance [local – Gleason 3+3 or Gleason 3+4) very low, low and favorable intermediate risk as defined by the National Comprehensive Cancer Network (NCCN)].

- Patient’s baseline biopsy must occurred at least 6 months but not more than 18 months prior to preregistration to Step 0. 

NOTE: Patient is to be scheduled for a follow-up prostate biopsy 6 months after the initiation of treatment on this study. 3.1.6 Patient must have a serum PSA < 10 ng/mL or PSAD <0.15 ng/mL/ g obtained within 30 days of registration. 3.1.7 Patient must have an ECOG performance status 0-1.

- Patient must be willing to abstain from consumption of any supplements containing green tea catechins.

- Patient must be willing to restrict tea consumption to less than three (3) servings of hot tea or three (3) servings of iced tea per week (serving size of 8 oz).

- Patient must be willing to discontinue current vitamin/mineral supplement use and use one provided by study.

- Patient must be willing to take study agent or placebo at the dose specified with meals.

- Patient must have the ability to understand and the willingness to sign a written informed consent document.

- Patient must not have had prior treatment for prostate cancer, including focal therapy, with surgery, irradiation, local ablative (i.e., cryosurgery or high-intensity focused ultrasound), or androgen\u0002deprivation therapy.

- Patient must not have a history of renal or hepatic disease, including history of hepatitis B (HBV Core Antibody) and C (HCV Core Antibody).

- Patient must not have prostate cancer with distant metastases.

- Patient must not have undergone treatment of hormone therapy, immunotherapy, chemotherapy and/or radiation for any malignancies within the past 2 years. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

- Patient must not receive any other investigational agents while on this study. 

- Patient must not have a history of allergic reactions attributed to tea or other compounds of similar chemical or biologic composition to green tea extracts.

- Patients must have adequate organ and marrow function as defined below, obtained within 30 days prior to registration:

- Absolute neutrophil count ≥ 1,200/mm3 (≥1.2 k/µL) 

- Platelets ≥ 75,000/mm3 (≥ 75k/µL) 

- Total bilirubin ≤ 1.2 mg/dL (or ≤ 3.0 mg/dL for patients with Gilbert’s syndrome)  

-Patient have Gilbert’s syndrome? (Yes or No)

- AST (SGOT)/ALT (SGPT) ≤ 1.5 × ULN 

- Serum creatinine ≤ 1.5 x ULN 

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

- Sexually active males must use an accepted and effective method of double barrier contraception (vasectomy must be combined with a physical barrier method) or abstain from sexual intercourse for the duration of their participation in the study.

- Patients must have archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen available for Gleason Score confirmation and % Ki-67 Expression (5% or more) in tumor tissue for eligibility and stratification. Tumor tissue can be submitted any time during screening.

- Tumor tissue specimen has been collected and is ready to ship to H. Lee Moffitt Cancer Center & Research Institute as indicated in Section 10. H. Lee Moffitt Cancer Center & Research Institute will perform Gleason Score confirmation and % Ki-67 Expression (5% or more) in tumor tissue and notify the ECOG-ACRIN Operations Office and submitting institution within 3-4 business days of receipt of the tumor tissue specimen. 

Eligibility Criteria for Randomization (Step 1):

- Screened patients will remain on the study and be randomized if they meet the above and following criteria. No specific timeframe between registration and randomization needs to be observed. However, as stated above intervention is to commence 6 months prior to planned prostate biopsy:

- Patient must meet all Step 0 eligibility criteria at the time of their registration to Step 1.

- Patient must have Gleason Score (3+3) or predominant Gleason pattern 3 (3+4), ≤ 33% of biopsy cores, and ≤ 50% involvement of any biopsy core confirmed via central review. 

-  Patient must have % Ki-67 Expression of 5% or more in at least 1 core positive for tumor confirmed via central review.

Arm C Closed to Patient Accrual - Effective 04/25/2025

**DTL is required for this study- Physicians must sign the toxicity grids

Current sites credentialed: SJMH (AA, Brighton, Canton, Chelsea), St. Mary's Livonia, Genesys, Oakland

Eligibility Criteria:

Eligibility Criteria – Step 1 Registration and Randomization

- Patient must be ≥18 years of age.

- Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision \u0002making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible. - Patient must have a diagnosis of high grade upper tract urothelial carcinoma proven by biopsy within 60 days prior to registration with one of the following:

• Upper urinary tract mass on cross-sectional imaging or

• Tumor directly visualized during upper urinary tract endoscopy before referral to medical oncology. NOTE: Biopsy is SOC and required for enrollment to study. This is vital for best practice.

- Patients must not have any component of small cell carcinoma. Other variant histologic types are permitted provided the predominant (≥ 50%) subtype is urothelial carcinoma.

- Patient must have adequate organ and marrow function as defined below (these labs must be obtained ≤ 14 days prior to registration).

- Leukocytes ≥ 3,000/mcL 

- Platelets ≥ 100,000/mcL 

- Total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN) (or ≤ 2.5 × ULN for patients with Gilbert’s disease) 

- Gilbert’s disease? ______ (Yes or No)

-AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional 

- Hgb ≥ 9 g/dL 

- NOTE: Packed red blood transfusion is allowed to achieve this parameter as per treating investigator.

- Patients must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy. A patient of childbearing potential is defined as any patient, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Patient of childbearing potential? 

- Patients of childbearing potential and sexually active patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse from the time of registration, while on study treatment and for at least 6 months after the last dose of protocol treatment.

- Patient must have no evidence of metastatic disease or clinically enlarged lymph nodes (≥1.0 cm short axis) on imaging required within 28 days prior to registration (solitary slightly enlarged lymph node with negative biopsy is allowed).  

NOTE: Patients with elevated alkaline phosphatase, calcium or suspicious bone pain/tenderness should also undergo baseline bone scans to evaluate for bone metastasis.

- Patient must not have another active (or within 2 years) second malignancy other than resected non-melanoma skin cancers, resected in situ breast, cervical or other in situ carcinoma, and either clinically insignificant per the investigator (e.g. ≤Gleason 3+4) on surveillance or previously treated prostate cancer with no rising PSA and no plan to treat. NOTE: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients in whom concomitant or prior bladder/urethra predominant (≥50%) urothelial carcinoma have been surgically resected and demonstrated to be only non-invasive cancer (< cT1N0) are eligible regardless of time elapsed.

- Patient must not have any uncontrolled illness including, but not limited to, ongoing or active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), symptomatic congestive heart failure (CHF), myocardial infarction (MI) in last 3 months, or unstable angina pectoris, significant uncontrolled cardiac arrhythmia, liver cirrhosis, interstitial lung disease, or psychiatric illness/social situations that would limit compliance with study requirements.

- Patient must not have received prior radiation therapy to ≥ 25% of the bone marrow for other diseases.

- Patient must not have received prior systemic anthracycline therapy.

NOTE: Patients who have received prior intravesical chemotherapy at any time for non-muscle invasive urothelial carcinoma of the bladder are eligible. 

- Patient must not have an active autoimmune disease requiring immunosuppressive therapy within 2 years prior to registration or a history of inflammatory bowel disease (IBD, colitis, or Crohn’s disease), systemic lupus erythematosus, Sarcoidosis syndrome, Wegener syndrome or immune-related pneumonitis or interstitial lung disease. Patients with well-controlled hyper/hypothyroidism, celiac controlled by diet alone, diverticulosis, diabetes mellitus type I, vitiligo, alopecia, psoriasis, eczema, lichen planus, or similar skin/mucosa condition are eligible.

- Patient must not be on or have used immunosuppressive medication within 14 days prior to the first dose of MEDI4736 (MEDI4736 (durvalumab)). The following are exceptions to this criterion:

• Intranasal, inhaled, intra-auricular, topical steroids, or local steroid injections (e.g. intra-articular injection).  

• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent at the time of enrollment.

• Steroids as premedications for hypersensitivity reactions (e.g. CT scan premedication).

- Patient must not have a concomitant primary urothelial carcinoma of the bladder and/or urethra.

NOTE: Patients in whom concomitant or prior bladder/urethra predominant (≥50%) urothelial carcinoma have been surgically resected and demonstrated to be only non\u0002invasive cancer (<cT1N0) are eligible regardless of time elapsed.

- Patient must not have prior history of muscle-invasive urothelial carcinoma with or without systemic chemotherapy (T2-4a and/or N1) within 2 years prior to registration.

NOTE: Patients who have no evidence of disease (NED) for more than 2 years from the latest therapy (surgery, radiation, chemotherapy, or clinical trial) are eligible.

-  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

NOTE: These patients must be stable on their anti-retroviral regimen with evidence of at least two undetectable viral loads within the past 6 months on the same regimen; the most recent undetectable viral load must be within the past 12 weeks. They must have a CD4 count of greater than 250 cells/mcL over the past 6 months on this same anti\u0002retroviral regimen and must not have had a CD4 count  <200 cells/mcL over the past 2 years, unless it was deemed related to the cancer and/or chemotherapy induced bone marrow suppression. They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months.

NOTE: For patients who have received chemotherapy in the past 6 months, a CD4 count <250 cells/mcL during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy. They must have an undetectable viral load and a CD4 count ≥250 cells/mcL within 7 days of registration.

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. NOTE: Testing for HIV, Hepatitis B or Hepatitis C is not required unless clinically indicated.

- Patients with a history of hepatitis C virus (HCV) infection must have been treated and have undetectable viral load. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

- Patient must not have received live attenuated vaccine within 30 days prior to the first dose of MEDI4736 (durvalumab), while on protocol treatment and within 30 days after the last dose of MEDI4736 (durvalumab).

- Patient must not have had a major surgical procedure (as defined by the Investigator) within 28 days prior to registration.

- Patient must not have a history of allogenic organ transplantation.

- Patient must have a body weight of > 30 kg.

- Patient must have a life expectancy of ≥ 12 weeks.

- Patient must have a creatinine clearance > 15 ml/min as by Cockroft\u0002Gault or 24-hour creatinine clearance within 28 days prior to registration.

NOTE: Patients will be assigned to cisplatin-ineligible and cisplatin-eligible cohorts based on their creatinine clearance, ECOG performance status, and grade (if any) of peripheral neuropathy and hearing loss in keeping with SOC cisplatin contraindications. Patients that are cisplatin\u0002eligible will be randomized to either Arm A or Arm B.

- Patients that meet the following criteria will be assigned to the cisplatin-ineligible Arm C:

            - Creatinine clearance of >15 ml/min and ≤50 ml/min.

            - Patient must have an absolute neutrophil count (ANC)) ≥ 1,000/mcL obtained ≤ 14 days prior                 to registration. 

            - Patient must have ECOG Performance Status 0-2.

- Patients that meet the following criteria will be randomized to cisplatin-eligible Arm A or Arm B:

            - Patient must have an absolute neutrophil count (ANC) ≥ 1,500/mcL obtained ≤ 14 days prior                  to randomization. 

            -  Patient must have ECOG Performance Status 0-1.

            - Patient must have left ventricular ejection fraction (LVEF) ≥ 50% by (either MUGA or 2-D                    echocardiogram) obtained within 28 days prior to randomization.

            - Patient must not have peripheral neuropathy ≥ Grade 2 or hearing loss ≥ Grade 3.

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED: SJMH TH (Ann Arbor, Brighton, Chelsea, Canton), Livonia, Sparrow

Eligibility Criteria:

3.1.1 Patient must be ≥ 18 years of age.

3.1.2 Patient must have a pathologically (histologically or cytologically) proven diagnosis of renal cell carcinoma (RCC) prior to randomization.

3.1.3 Patient may have any RCC histology except a histology that has a sarcomatoid component.

3.1.4 Patient must have primary site addressed by local therapy. If the primary RCC is intact, the patient must undergo local treatment to the primary before randomization.

3.1.5 Patient must not have brain metastases.

3.1.6 Patient must have favorable or intermediate International Metastatic RCC Database Consortium (IMDC) risk (0-2) at the time of randomization (refer to Appendix III for modified IMDC risk categories).

3.1.7 Patient must have a total of between 2 and 5 metastatic lesions, as defined by RECIST criteria in Section 6.1.2 with imaging obtained within 45 days prior to randomization.

3.1.8 Patient must have a documentation from a radiation oncologist confirming that all sites are amenable to SAbR

3.1.9 Patient may have received prior therapy in the adjuvant setting as long as potential trial participants have recovered from clinically significant adverse events of their most recent therapy/intervention prior to enrollment.

3.1.10 Patient must not have metastasis involving the following locations: ultra-central (within 2cm of carina) lung, invading gastrointestinal tract (such as esophagus, stomach, intestines, colon, rectum), skin, and scalp.

3.1.11 Patient must not have received any prior systemic therapy (except for adjuvant setting, see 3.1.9) for metastatic RCC.

3.1.12 Patient must not have severe, active comorbidity defined as any of the following:

• Active autoimmune disease requiring ongoing therapy including systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications daily. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

• History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies • Active tuberculosis (PPD response without active TB is allowed)

• Uncontrolled hypertension (systolic BP >190mmHg or diastolic BP >110mmHg)

• Major surgery within 30 days prior to randomization • Any serious (requiring hospital stay or long-term rehab) non-healing wound, ulcer, or bone fracture within 30 days prior to randomization

• Any arterial thrombotic (STEMI, NSTEMI, CVA, etc.) events within 180 days prior to randomization

• Moderate or severe hepatic impairment (child-Pugh B or C)

• Untreated PE or DVT is not allowed. Treated PE or DVT is allowed > 30 days from diagnosis and when not resulting in respiratory impairment.

• Unstable cardiac arrhythmia within 180 days prior to randomization

• History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel obstruction, or gastric outlet obstruction within 180 days prior to randomization

• History of or active inflammatory bowel disease. • Malabsorption syndrome within 30 days prior to randomization

3.1.13 Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

3.1.14 Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

**PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST**

**Effective 08/05/2020, the QOL Component is Closed to Accrual**

-Diagnosis of CLL according to the NCI/IWCLL criteria or SLL

according to the WHO criteria.

-This includes previous documentation of:

• Biopsy-proven small lymphocytic lymphoma

OR

• Diagnosis of CLL according to the NCI/IWCLL criteria as

evidenced by all of the following:

• Peripheral blood lymphocyte count of greater than 5 x109/L

• Immunophenotype consistent with CLL defined as:

• The predominant population of lymphocytes share both Bcell

antigens [CD19, CD20 (typically dim expression), or

CD23] as well as CD5 in the absence of other pan-T-cell

markers (CD3, CD2, etc).

• Clonality as evidenced by ? or ? light chain restriction

(typically dim immunoglobulin expression)

• Negative FISH analysis for t(11;14)(IgH/CCND1) on peripheral

blood or tissue biopsy (e.g. marrow aspirate) or negative

immunohistochemical stains for cyclin D1 staining on involved

tissue biopsy (e.g. marrow aspirate or lymph node biopsy.

-No prior chemotherapy, BTK inhibitor therapy, venetoclax, small

molecule signaling inhibitor, or monoclonal anti-body therapy for

treatment of CLL or SLL

-Has met at least one of the following indications for treatment:

• Evidence of progressive marrow failure as manifested by the development of worsening anemia (Hg < 11 g/dl) and/or thrombocytopenia (Platelets < 100 x 109/L)

• Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly.

• One or more of the following disease-related symptoms:

• Weight loss = 10% within the previous 6 months

• Grade 2 or 3 fatigue attributed to CLL

• Fevers >100.5oF for 2 weeks without evidence of infection

• Clinically significant night sweats without evidence of infection

• Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of >50% over a two-month period or an anticipated doubling time of less than six months.

-ECOG performance status between 0-2.

-Life expectancy of = 12 months

-No deletion of 17p13 on cytogenetic analysis by FISH

-No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. -Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from

participation.

-No current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted.

-No previous autoimmune complications (e.g. autoimmune hemolytic anemia or immune thrombocytopenia) that have developed since the initial diagnosis of CLL and have required treatment with high dose corticosteroids (e.g. equivalent of >20 mg/day of prednisone), monoclonal antibody based therapy, or chemotherapy. Prior use of corticosteroids for reasons other than treatment of autoimmune complications is allowed.

-No major surgery within 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug.

-No radiation therapy = 4 weeks prior to registration

-Patients may not be on any other investigational agents

-Patients may not have received warfarin or another vitamin K antagonist in the preceding 30 days.

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (Brighton, Ann Arbor, Canton, Chelsea), Livonia, Genesys, Hurley, LVHN

Eligibility Criteria:

Eligibility Criteria for Preregistration to Step 0

3.1.1 Patient must be ≥ 18 and ≤ 75 years of age.

3.1.2 Patient must have an ECOG performance status between 0-3

3.1.3 Patient must be newly diagnosed with B-ALL or is suspected to have ALL

3.1.4 Patient must not have a diagnosis of BCR/ABL T-ALL.

3.1.5 Patient must not have received chemotherapy for B-ALL. Patients who received up to five days of hydroxyurea or steroids of any kind with the aim to reduce disease burden prior to study registration to Step 1 are eligible.

3.1.6 Patients who started any kind of TKI prior to study registration to Step 1 are allowed to proceed on the study if they received no more than 14 days of TKI.

3.1.7 Patient must not have unstable epilepsy that requires treatment.

3.1.8 Patients with lymphoid blast crisis CML are not eligible

Eligibility Criteria for Registration to Step 1

3.2.1 Patient must have a diagnosis of Ph+ ALL that has been determined locally and bone marrow and/or peripheral blood was sent and receipt confirmed for central confirmation or determined centrally by the ECOG-ACRIN Leukemia Laboratory at MD Anderson Cancer Center.

3.2.2 Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.

***PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL ELGIBILITY LIST***

**ePRO training required prior to first patient enrollment.**

Ages Eligible for Study:	18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Eligibility Criteria:

Step 0 Preregistration

3.1.1 Patient must be = 18 years of age.

3.1.2 Patient must have the ability to understand and the willingness to sign an informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be eligible.

3.1.3 Patient must have an ECOG performance status (PS) of 0-2 (PS 3 allowed if secondary to pain).

3.1.4 Patient must have newly diagnosed multiple myeloma (MM) by International Myeloma Working Group (IMWG) criteria.

3.1.5 Patients must be considered ineligible for autologous stem cell transplantation by the treating physician, or willing to delay stem cell transplantion until first relapse or later.

NOTE: Stem cell collection is allowed on study.

3.1.6 Patient must agree to register to the mandatory RevREMS program and be willing and able to comply with the requirements of RevREMS. See Section 8 for details.

3.1.7 Patient must not have any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure), or known sensitivity to mammalian-derived products.

3.1.8 Patient must be able to undergo diagnostic bone marrow aspirate following preregistration.

NOTE: Bone marrow aspirate specimen must be submitted to Adaptive Biotechnologies for clonoSEQ® Assay.

NOTE: Adaptive Biotechnologies will release results to the diagnostic Portal from the Clonality (ID) test within fourteen (14) days of receipt and reconciliation of fresh bone marrow specimen to the submitting institution.

Eligibility Criteria- Step 1 Registration

3.2.1 Patient must meet all eligibility criteria in Section 3.1 with exception of Section 3.1.5.

3.2.2 Institution must have received the Clonality (ID) test results from Adaptive Biotechnologies and dominant sequences must have been identified.

3.2.3 Patient must have standard risk MM as defined by the Revised International Staging System (RISS) Stage I or II.31

NOTE: R-ISS Stage is based on serum ß2 microglobulin, albumin and LDH levels along with presence of chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization (iFISH). Presence of del(17p), t(4;14), and/or t(14;16) is considered high risk and absence of these, including any other findings, are standard risk.

R-ISS Stage

Stage I: ISS Stage I [ß2 microglobulin<3.5 mg/L, albumin>3.5 g/dL] AND standard-risk CA AND normal LDH

Stage II: Not R-ISS Stage I or III

Stage III: ISS Stage III [ß2 microglobulin>5.5 mg/L] AND high-risk CA OR high LDH (>upper limit of normal) [patients with Stage III are ineligible]

3.2.4 Patient must have measurable or evaluable disease as defined by having one or more of the following, obtained within 28 days prior to registration:

• = 1g/dL monoclonal protein (M-protein) on serum protein electrophoresis
• = 200 mg/24 hours of monoclonal protein on a 24-hour urine protein electrophoresis
• Involved free light chain = 10 mg/dL or = 100 mg/L AND abnormal serum immunoglobulin kappa to lambda free light chain ratio (< 0.26 or > 1.65)
• Monoclonal bone marrow plasmacytosis = 30% (evaluable disease)

3.2.5 Patients must have a SPEP UPEP, and serum FLC assay performed within 28 days prior to registration. In addition, a bone marrow biopsy and/or aspirate is required within 28 days if bone marrow is being followed for response.

NOTE: The serum free light chain test is required to be done if the patient does not have measurable disease in the serum or urine. Measurable disease in the serum is defined as having a serum M-spike = 1 g/dL. Measurable disease in the urine is defined as having a urine M-spike = 200mg/24 hr.

3.2.6 Patient must have adequate organ and marrow function as defined below (these must be obtained = 14 days prior to Step 1 registration)

- Calculated creatinine clearance >30 mL/min

- Absolute neutrophil count (ANC) =1000/mm3

- Untransfused Platelet count =75,000/mm3

- Hemoglobin =8.0 g/dL

- Total bilirubin = 1.5 x ULN (Institutional upper limit of normal)

- ALT and AST = 3 x ULN

3.2.7 Patient must have received no more than one cycle (28 days or less) of prior chemotherapy and no more than 160mg of prior dexamethasone (or equivalent dose of prednisone) for treatment of symptomatic myeloma. Patient must not have been exposed to daratumumab for treatment of symptomatic myeloma. Prior radiation therapy to symptomatic lesions is allowed provided there are no residual toxicity related to radiation and blood counts meet the study requirements. Radiation treatment must be completed at least 14 days prior to Step 1 registration.

3.2.8 Women must not be pregnant or breast-feeding due to the potential harm and teratogenic effects to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.

All females of childbearing potential must have a blood test or urine study with a sensitivity of at least 25 mIU/mL within 10-14 days prior to Step 1 registration to rule out pregnancy and again within 24 hours prior to the first dose of lenalidomide. Females of childbearing potential must also agree to ongoing pregnancy testing while on protocol treatment.

Please see Appendix V: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.

A female of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal

(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

3.2.9 Women of childbearing potential must not expect to conceive children by using accepted and effective method(s) of contraception [for this protocol defined as the use of TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME for 1) at least 28 days before starting protocol treatment; 2) while participating in the study; 3) during dose interruptions; and 4) for at least 3 months days after the last dose of protocol treatment] OR by practicing true abstinence from sexual intercourse for the duration of their participation in the study (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).

Men must not expect to father children by practicing true abstinence from sexual intercourse for the duration of their participation in the study (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception] OR use a latex condom during sexual contact with a female of child bearing potential while participating in the study and for at least 3 months after the last dose of protocol treatment even if they have had a successful vasectomy.

Men must also agree to abstain from donating sperm while on study treatment and for 3 months after the last dose of protocol treatment even if they have had a successful vasectomy. Both women and men must both agree to abstain from donating blood during study participation and for at least 28 days after the last dose of protocol treatment.

3.2.10 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial.

3.2.11 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

3.2.12 Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

3.2.13 Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

3.2.14 Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical

risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. Patients must not have evidence of current uncontrolled cardiovascular conditions, including hypertension, cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial infarction within 6 months prior to Step 1 registration.

3.2.15 Patient must not have peripheral neuropathy = Grade 2 on clinical examination or grade 1 with pain at time of Step 1 registration.

3.2.16 Patient must not have any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.

3.2.17 Patient may have a history of current or previous deep vein thrombosis (DVT) or pulmonary embolism (PE) but must be willing to take some form of anti-coagulation as prophylaxis if they are not currently on full-dose anticoagulation.

3.2.18 Patients with a history of chronic obstructive pulmonary disease (COPD) must have FEV1 testing done within 28 days prior to Step 1 registration and the forced expiratory volume in 1 second (FEV1) must be > 50% of predicted normal.

3.2.19 Patient must not have moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification.

NOTE: Patients who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to register.

3.2.20 Patient must not receive any other concurrent chemotherapy, or any ancillary therapy considered investigational while on this protocol.

NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment.

Eligibility Criteria- Step 2 Randomization

3.3.1 Institution must have received Tracking (MRD) test results from Adaptive Biotechnologies.

3.3.2 Patient must have completed the Step 1 Induction phase of this protocol without experiencing progression.

3.3.3 Patient must be registered to Step 2 within 8 weeks of completing Step 1 Induction Treatment, counting from last day of completion of last cycle.

3.3.4 Patient must not have received any non-protocol therapy outside of the assigned Step 1 Induction treatment including stem cell transplant.

3.3.5 Patient must have an ECOG performance status (PS) of 0-2. (PS 3 allowed if secondary to pain).

3.3.6 Any adverse event(s) related to Step 1 Induction Treatment must have resolved to grade 2 or less.

3.3.7 Patient must have adequate organ and marrow functions as defined below (these must be obtained within 14 days prior to Step 2 randomization).

3.3.7.1 Hemoglobin = 8 g/dL.

3.3.7.2 Platelet count = 50,000/mm3.

3.3.7.3 Absolute neutrophil count (ANC) = 1000/mm3.

3.3.7.4 Calculated creatinine clearance = 30 mL/min.

3.3.7.5 Total bilirubin = 1.5 x ULN (Institutional upper limit of normal).

3.3.7.6 ALT and AST < 3 X ULN

3.3.8 Women must not be pregnant or breast-feeding due to the potential harm and teratogenic effects to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.

All females of childbearing potential must have a blood test or urine study with a sensitivity of at least 25 mIU/mL within 10-14 days prior to Step 2 randomization to rule out pregnancy and again within 24 hours prior to the first dose of lenalidomide. Females of childbearing potential must also agree to ongoing pregnancy testing while on protocol treatment.

Please see Appendix V: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.

A female of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche

at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Female of childbearing potential? ______ (Yes or No)

Date of blood test or urine study: ___________.

3.3.9 Women of childbearing potential must not expect to conceive children by using accepted and effective method(s) of contraception [for this protocol defined as the use of TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME for 1) at least 28 days before starting protocol treatment; 2) while participating in the study; 3) during dose interruptions; and 4) for at least 3 months days after the last dose of protocol treatment] OR by practicing true abstinence from sexual intercourse for the duration of their participation in the study (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).

Men must not expect to father children by practicing true abstinence from sexual intercourse for the duration of their participation in the study (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable methods of contraception] OR use a latex condom during sexual contact with a female of child bearing potential while participating in the study and for at least 3 months after the last dose of protocol treatment even if they have had a successful vasectomy.

Men must also agree to abstain from donating sperm while on study treatment and for 3 months after the last dose of protocol treatment even if they have had a successful vasectomy. Both women and men must both agree to abstain from donating blood during study participation and for at least 28 days after the last dose of protocol treatment.

Eligibility Criteria:

-Patients must have a life expectancy of at least 24 months
-ECOG PS 0-3
-Patients must have a newly diagnosed colon or rectal cancer within 60 days of registration and have not yet received radiation or chemotherapy.
-Patients must have Stage I, II, or III disease at the time of enrollment and will be treated with curative-intent.
-Patients are not eligible if they are already enrolled on a treatment clinical trial at the time of registration. They can remain on the study if they subsequently enroll on a treatment clinical trial during the study time period.
-Patients who choose to not receive radiation and/or chemotherapy after a curative-intent surgery are eligible to participate.