Eligibility Criteria:

Eligibility Criteria for Step 0 (Pre-Registration)

- Patient must be = 18 years of age on day of consent.

- Patient must have pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC)

- Patient must have Stage IV disease (includes M1a, M1b, or recurrent earlier stage disease), according to the 8th edition of the lung cancer TNM classification system.

- Patient must have predominant non-squamous histology (patients with NSCLC NOS are eligible). Mixed tumors will be categorized by the predominant cell type. If small cell elements are present the patient is ineligible.

- Patient’s tumor(s) must be tested and known negative for EGFR TKI sensitizing mutations (EGFR Exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements (by FISH, NGS, or IHC) by routine CLIA-certified clinical testing methods. Negative circulating tumor DNA results alone are not acceptable. Prior testing for tumor PD-L1 status is not required.

- Patients WITHOUT tumors with known molecular alterations in ROS1, MET, RET (see below), or must have progressed radiographically (per local investigator assessment) following one, but only one, line of platinum-based chemotherapy AND one, but only one, line of prior immunotherapy. Lines of therapy are defined by clinical or radiographic progression. Patients may have received chemotherapy and immunotherapy either concurrently or sequentially in either order. (See note in Section 3.2 for patients who received prior adjuvant chemotherapy or chemoradiation.) Patient must have received at least 2 prior doses of checkpoint inhibitor therapy in an every 2, 3, or 4 week schedule. No submission of molecular testing is required and patients may be registered for Step 0 then proceed directly to Step 1 screening.

–OR-

Patients with tumors with known molecular alterations in ROS1, MET, and RETmust have progressed radiographically (per local investigator clinical assessment) on atleast one line of prior chemotherapy or targeted therapy, but there is no limit on number of prior number of

therapies. Reciept of prior immunotherapy is allowed but not required. See note in Section 3.2 for patients who received prior adjuvant chemotherapy or chemoradiation.

• Known molecular alterations in ROS1, MET, and RET are defined as below ROS1 gene rearrangement by FISH or DNA analysis. In addition to above requirements, these patients must have progressed on at least one prior ROS1 TKI therapy
• MET exon 14 splice mutations on DNA analysis. In addition to above requirements, prior MET directed TKI therapy is optional.
• MET mutations predicted to be sensitive to MET inhibitor. In addition to above requirements, prior MET directed TKI therapy is optional.
• High MET amplification by FISH (characterized by a fluorescence in situ hybridization MET/CEP7 ratio of 5 or greater); OR MET amplification by DNA NGS CLIA certified assay. In addition to above requirements, prior MET directed TKI therapyis optional.

RET gene rearrangement by FISH or DNA analysis. In addition to above requirements, prior RET directed TKI therapy is optional.

NOTE:

During Step 0 screening, CLIA reports of the testing results must be submitted via Medidata Rave for central review (see section 4.2.4) for instructions.The central review will be performed by the Study Chair, Co-Chair, Biology Co-Chair, and/or a delegate to determine that the results indicate a patient’s eligibility for targeted therapy. CLIA reports that contain information pertaining to any of the above mutations will be uploaded to Medidata Rave for central review of documentation for determination of patient eligibility for targeted therapy (Arm T). Central testing of tissue will not be performed. Institutions will be notified of the patient’s eligibility status for Arm T within two (2) business days of submission of the molecular testing reports. Patients with tumors with the above known

molecular alterations are eligible for cohort Arm Z following Step 1 eligibility review.

Patients without tumors with the above known molecular alterations are eligible for randomization to Arm A, B or C following Step 1 eligibility review

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 (in the opinion of the treating physician) are eligible for this trial.

- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents (such as anthracycline or HER2-directed antibody therapy, but not prior checkpoint inhibitor therapy), must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients must be class 2B or better. (Appendix XI)

- Patient must have ECOG performance status 0-1

Eligibility Criteria for Step 1 (Randomization/Registration) for All Treatment Arms

- Patient must have met the eligibility criteria outlined in Section 3.1

- Patient must have measurable disease as defined by RECIST v1.1 criteria in Section 6. Measurements must be obtained within 4 weeks prior to randomization/registration.

Patient must have an anticipated life expectancy greater than 3 months.

- Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to randomization/registration:

- Chemotherapy/targeted oral therapy administered in a daily or weekly schedule must be completed = 1 week prior to randomization/registration

- Any chemotherapy administered in an every 2 week or greater schedule must be completed = 2 weeks prior to randomization/registration.

- Additionally, patient should be recovered to equal to or less than grade 1 toxicities related to any prior treatment, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy (as determined by the treating physician).

- Patient must not have had any prior radiation therapy for bone metastasis within 2 weeks, or any other radiation therapy within 4 weeks prior to randomization/registration.

- Patient must have acceptable bone marrow, renal, hepatic, and coagulation function, obtained within 2 weeks prior to randomization/registration as defined below:

ULN = institutional upper limit of normal; LLN = institutional lower limit of normal
• Leukocytes = 3,000/mcL

• Absolute neutrophil count = 1,500/mcL
• Platelets = 100,000/mcL
• Hemoglobin = 9 g/dL
• Total bilirubin = 1.5 x institutional ULN
• AST(SGOT) and ALT(SGPT) = 2.5 × ULN

• Creatinine = 1.5 x ULN
OR
Calculated (Crockoft-Gault formula) or measured creatinine clearance = 50 mL/min/1.73m2 (normalized to BSA) for patients with creatinine levels greater than 1.5 times the institutional normal Creatinine = 1.5 X ULN or creatinine clearance = 50ml/min/1.73m2

- Women must not be pregnant or breast-feeding due to the unknown effects of cabozantinib and nivolumab on human development and for the potential 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 within 14 days prior to randomization/registration to rule out pregnancy.

A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has 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 expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for up to 7 months after completion of treatment on the study (see Appendix VI).

- Patient must not have history of the following:

- Clinically significant gastrointestinal bleeding within 6 months prior to randomization/registration.

- Pulmonary hemorrhage or hemoptysis of = 0.5 teaspoon (2.5 mL) of red blood within 3 months prior to randomization/registration.

- Any grade drug induced pneumonitis within 3 months prior to randomization/registration. Prior immune mediated pneumonitis of grade 3 or 4 are not eligible regardless of time window.

- Current radiographic evidence of cavitating pulmonary lesion(s).

- Current radiographic evidence of tumor invading any major blood vessels.

- Evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or mainstem endobronchial tumor within 28 days prior to randomization/registration.

- Peptic ulcer disease, inflammatory bowel, known malabsorption syndrome, bowel obstruction or gastric outlet obstruction (PEG tube placement) within 3 months prior to randomization/registration.

- Abdominal fistula, GI perforation, intra-abdominal abscess within 6 months prior to randomization/registration.

- Grade 3 or greater infection, or infection requiring intravenous systemic treatment within 28 days prior to randomization/registration. Patients should be off antibiotics at the time of randomization/registration.

- Serious non-healing wound/ulcer/bone fracture within 28 days prior to randomization/registration.

- History of organ transplant.

- Concurrent symptomatic untreated hypothyroidism within 7 days prior to randomization/registration.

- History of major surgery (within 3 months, with wound healing within 28 days, prior to randomization/registration), minor surgery (within 28 days prior to randomization/registration), other minor procedures (within 7 days prior to randomization/registration) or clinically relevant ongoing complications from prior surgery.

• Unstable angina pectoris
• Clinically-significant cardiac arrhythmias

• Stroke (including TIA, or other ischemic event)
• Myocardial infarction
• Thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose.
  

- Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg systolic, or > 90 mm Hg diastolic within 7 days of registration despite optimal antihypertensive treatment

- History of the following within 6 months prior to therapy:

-NOTE: Subjects with a diagnosis of DVT (but not PE) within 6 months are allowed if stable, asymptomatic, and treated with LMWH for at least 2 weeks before first dose

Patient must not receive concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel) within 7 days prior to randomization/registration. Allowed anticoagulants are the following:

- Low-dose aspirin (100 mg po daily or less) is permitted.

- Anticoagulation with therapeutic doses of LMWH is allowed in patients who are on a stable dose of LMWH for at least 6 weeks prior to study randomization/registration, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor within this time period.

- Patient must not receive concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone (> 1 mg daily dosing), phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s Wort) within 7 days prior to randomization/registration.

- Patient must have corrected QT interval calculated by the Fridericia formula (QTcF) = 500 ms within 28 days prior to randomization/registration.

- Patient must be able to swallow tablets.

- Patient must not be on systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to randomization/registration, with the following exceptions:

- Inhaled or topical steroids and adrenal replacement doses = 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

- Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption).

- Physiologic replacement doses of systemic corticosteroids are permitted, if < 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.

- Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.

-Patients with new or progressive brain metastases (active brain metastases) are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of study treatment.

- Patient must meet one of the following criteria with respect to brain metastases:

Patients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study randomization/registration not demonstrating brain metastases

-OR-

Patients with known brain metastases must have baseline brain imaging and completed treatment to all symptomatic brain metastases (with whole brain radiation or radiosurgery; or complete neurosurgical resection = 3 months prior to randomization/registration) = 4 weeks prior to randomization/registration. They must be clinically stable. Known leptomeningeal disease is not allowed.

- Patient must not have known active autoimmune disease or known history of autoimmune disease for which recurrence may affect vital organ function or require immune suppressive treatment including systemic corticosteroids (e.g., immune-related neurologic disease, multiple sclerosis, autoimmune neuropathy, Guillian-Barre syndrome, etc.).

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

- For patients with known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy at time of registration/randomization, if indicated.

- Patients with a known 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 at time of registration/randomization.

- Additional Eligibility Criteria for Step 1 (Randomization) Arms A-C

- Patient must not be eligible for the targeted therapy arm (Arm T) per one of the following criteria

• Patient did not have a known molecular alteration in ROS1, RET, or MET and did not have central review of tissue
• Central review report the patient is not eligible for Arm T based on molecular report.
  

- Patient must have progressed radiographically (per local investigator clinical assessment) following one, and only one, line of platinum-based chemotherapy AND one, and only one, line of prior immunotherapy. Patients may have received these lines of treatment together or sequentially. Patient must have received at least 2 prior doses of checkpoint inhibitor therapy (of only one type), in an every 2, 3, or 4 week schedule.

-NOTE: The requirement for prior chemotherapy will be met if patients have recurrence within 6 months after prior adjuvant platinum based chemotherapy for early stage disease, or recurrence within 6 months after prior radiotherapy plus platinum based chemotherapy for locally advanced disease.

-NOTE: Patients with unresectable stage III A/B NSCLC who have received chemo and radiation then consolidation durvalumab, followed by progression pts are eligible if progression happens while on after >2 doses of durvalumab. Prior bevacizumab with chemo is also allowed.

- Patient must not have had any prior anti-MET therapy, such as crizotinib or cabozantinib.

- Patient must not have had any prior allergic reaction or hypersensitivity to study drug components or related drugs (multitargeted small molecule tyrosine kinase inhibitors or checkpoint inhibitor monoclonal antibodies).

- Patients must not have had history of life-threatening toxicity related to prior immune therapy (eg.anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g., hypo/hyperthyroidism)

Additional Eligibility Criteria for Step 1 (Registration) Targeted Arm T

- Patient was registered to Step 0, Targeted Arm and central review results report the patient is eligible for Arm T

- Patients with ROS1 gene rearrangements must have progressed on at least one prior ROS1 targeted therapy such as crizotinib.

- Patient must have progressed radiographically (per local investigator clinical assessment) on at least one line of prior chemotherapy or targeted therapy, but there is no limit on number of prior number. Prior immunotherapy is allowed but not required. Prior bevacizumab with chemo is allowed.

NOTE: The requirement for prior chemotherapy will be met if patients have recurrence within 6 months after prior adjuvant platinum based chemotherapy for early stage disease, or recurrence within 6 months after prior radiotherapy plus platinum based chemotherapy for locally advanced disease.

NOTE: Patients with unresectable stage III NSCLC who have received chemo and radiation then consolidation durvalumab, followed by progression are eligible if progression happens after >2 doses of durvalumab. Prior bevacizumab with chemo is also allowed.

STEP 2 Eligibility Criteria (Crossover Arm Z)

- Patients must have met all eligibility requirements for Step 1 (see Section 3.2) at time of registration to Step 1 to be eligible for Step 2.

- Patients must have radiographic progressive disease per RECIST criteria (see Section 6.1.4) after = 2 cycles of therapy on Arm C.

- Patients must not have intervening anticancer treatment or major surgical procedure(s) between Step 1 and Step 2, except palliative radiation to the bone finishing = 1 week prior to registration to Step 2.

- Patients may not have central nervous system progression, but patients with stable CNS disease are allowed.

- Patients must be registered to Step 2 within 4 weeks of the last dose of treatment administration from Step 1.

- Patients must have an ECOG performance status between 0-2 (see Appendix V)

- Patients must have recovered to baseline (pre-Step 1) or CTCAE v.5.0 = Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.

-Patient must have acceptable bone marrow, renal, hepatic, and coagulation function, obtained within 2 weeks prior to randomization/registration as defined below:

ULN = institutional upper limit of normal; LLN = institutional lower limit of normal

- Leukocytes = 3,000/mcL

- Absolute neutrophil count = 1,500/mcL

- Platelets = 100,000/mcL

- Hemoglobin = 9 g/dL

- Total bilirubin = 1.5 x institutional ULN

- AST(SGOT) and ALT(SGPT) = 2.5 × ULN

- Creatinine =1.5 x ULN

OR

- Calculated (Crockoft-Gault formula) or measured creatinine clearance = 50 mL/min/1.73m2 (normalized to BSA) for patients with creatinine levels greater than 1.5 times the institutional normal Creatinine = 1.5 X ULN or creatinine clearance

= 50ml/min/1.73m2

- Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) = 500 ms within 28 days before registration.

- No intercurrent illness or disease complication that the investigator believes would limit the ability to safely tolerate the combination of cabozantinib and nivolumab.

*DTL Required- Physicians must sign toxicity grid

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

CURRENT SITES CREDENTIALED: Trinity Health IHA (AA-MI349, Brighton-MI350, Chelsea-MI351, Canton-MI352), Livonia, Oakland, Sparrow

Eligibility Criteria:

 Eligibility Criteria (Step 1 Registration)

-Patient must be ≥ 70 years of age.

- Patient must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) with PD-L1 TPS range of 1-49%.

- Patient must have Stage IIIB, IIIC or IV disease and not be candidates for combined chemo-radiation. NOTE: Prior chemo-RT for stage III with recurrence is allowed.

-Patient must have a tumor that is negative for EGFR mutation/ALK translocations or other actionable first line mutations in which patients would receive first-line oral tyrosine kinase inhibitors. -Patient must have an ECOG Performance Status of 2.

-Patient must agree not to father children while on study and for 6 months after the last dose of protocol treatment.

- Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decisionmaking capacity (IDMC) who have a legally authorized representative.

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

Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months of Step 1 registration are eligible for this trial.

- 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 undetectable HCV viral.

- 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 be English or Spanish speaking to be eligible for the QOL component of the study. 

Eligibility Criteria (Step 2 Randomization)

- Patient must have completed the baseline Geriatric Assessment (GA) as outlined in Section 7.3, after Step 1 registration and prior to Step 2 randomization 

**Please see the current version of the protocol for the complete eligibility list.** 

*Credentials Required. Check your site's credentialing status. Note that the investigator registering must have completed training- check your investigator's specific status.
CURRENT SITES CREDENTIALED:
SJMH, Genesys Hurley, St. Alphonsus, Sparrow

Eligibility Criteria Step 1:
-ECOG Performance status: 0 or 1
-Patients must have unresectable stage III or stage IV disease.
-Patients must have measurable disease. All sites of disease must be evaluated within 4 weeks prior to randomization.
-Patients must have histological or cytological confirmation of melanoma that is metastatic or unresectable and clearly progressive.
-Patients must have BRAFV600E or BRAFV600K mutations, identified by an FDA-approved test at a CLIA-certified lab.
-Patients may have had prior systemic therapy in the adjuvant setting; however this adjuvant treatment must not have included a CTLA4 or PD1 pathway blocking antibody or a BRAF/MEK inhibitor. Also, patients may not have had any prior systemic treatment for advanced (measurable metastatic) disease. -Patients must have discontinued chemotherapy, immunotherapy or other investigational agents used in the adjuvant setting at least 4 weeks prior to entering the study and recovered from adverse events due to those agents. Mitomycin and nitrosoureas must have been discontinued at least 6 weeks prior to entering the study. Patients must have discontinued radiation therapy at least 2 weeks prior to entering the study and recovered from any adverse events associated with treatment. Prior surgery must be at least 4 weeks from registration and patients must be fully recovered from post surgical complications.
-Patients are ineligible if they have any currently active CNS metastases. Patients must not have taken any steroids within 14 days prior to randomization for the purpose of managing their brain metastases. Patients with only Whole Brain irradiation for treatment of CNS metastases are ineligible.
-Patients with a history of RAS mutation-positive tumors are not eligible regardless of interval from the current study.

Eligibility Criteria Step 2 (Crossover arm for patients that have progressive disease):
-The patient must have met all eligibility criteria in step 1 (except as detailed below) at the time of crossover.
- RECIST defined measurable disease is not required
-Only prior systemic therapy as part of step 1 is allowed.
-malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib, or history of retinal vein occlusion are acceptable for patients crossing over to ipilimumab + nivolumab treatment.
-history of autoimmune disease, excluding interstitial lung disease or pneumonitis, is allowed in patients crossing over to dabrafenib/trametinib therapy
-Patients can be less than 4 weeks from surgery or SRS to CNS metastases
-Patients with a history of cardiovascular risks that developed during step 1 of therapy should be discussed with study PI at time of crossover.
-Patients must have melanoma that is metastatic and clearly progressive on prior therapy.
-Patients must be at least 2 weeks and within 12 weeks from documented PD on Step 1 of current study. All sites of disease must be evaluated within 4 weeks prior to registration.
-Patients must have recovered from adverse events (toxicities resolved to grade 1 or less) of prior therapy. Patients with immune related toxicities from ipilimumab + nivolumab may continue onto Step 2 even if still on steroids to control side effects, so long as toxicity has resolved to grade 1 or less.
-Patients must have discontinued radiation therapy at least 2 weeks prior to registering to Step 2 of the study and recovered from any adverse events associated with treatment. Prior surgery must be at least 2 weeks from registration to Step 2 and patients must be fully recovered from post-surgical complications

 **EA Ipilimumab Investigator Training required** Check your site's credentialing status.
CURRENT SITES CREDENTIALED:
SJMH, Genesys Hurley, St. Alphonsus, Sparrow, Saginaw, Livonia

-ECOG Performance status must be 0-1
-Patient must have known BRAF mutational status of tumor; Wild-type (WT) or mutated, prior to randomization
-Patients must have unresectable stage III or stage IV melanoma. Patients must have histological or cytological confirmation of melanoma that is metastatic or unresectable and clearly progressive.
-Patients must have measurable disease.
-Patients may have had prior systemic therapy in the adjuvant setting (e.g. interferon, BRAF, or MEK agents). Patients may have had prior anti-CTLA-4 in the adjuvant setting, if at least one year from last dose of treatment has passed prior to beginning treatment. Patients may NOT have had any prior ipilimumab or PD-1/ PD-L1 agent in the adjuvant setting.
-Patients are ineligible if they have any currently active CNS mets. Patients must not have taken any steroids less than or equal to 14 days prior to randomization for the purpose of managing their brain mets. Patients with only Whole brain irradiation for treatment of CNS mets will be ineligible.
-Patients must not have autoimmune disorders or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (e.g., prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or ophthalmologic steroids. 

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

Sites Currently Credentialed: SJMH (Ann Arbor, Canton, Chelsea), LVHN , St. Mary's Livonia, Holy Cross, St. John, St. John Macomb

Eligibility Criteria:

3.1.1 Age = 18 years.

3.1.2 Patients must have an ECOG performance Status: 0, 1, or 2 (However, those patients with a performance state of 3 because they are wheel chair bound due to congenital or traumatic events more than one year before the diagnosis of Merkel cell carcinoma are eligible)

3.1.3 Women must not be pregnant or breast-feeding due to the unknown effects of the study drug in this setting.

All women of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy.

A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 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).

3.1.4 Women of childbearing potential and sexually active males on Arm A MK-3475 (Pembrolizumab) must use accepted and effective method(s) of contraception or abstain from sex from time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment. For patients on Arm B only receiving radiation therapy, contraception use should be per institutional standard.

3.1.5 Patient must have a histological confirmation of diagnosis of Merkel cell carcinoma (MCC), pathologic stages (AJCC version 8) I-IIIb.

• Stage I patients with negative sentinel lymph node biopsy are ineligible. Patients who have a positive biopsy or for whom no biopsy was done are eligible.

• Patients with distant metastatic disease (stage IV) are not eligible.

• The primary tumor must have grossly negative margins. (Microscopically positive margins are allowed).

• Cancers of unknown primary that have regional disease only can be included.

• Complete nodal dissection is not required for eligibility.

3.1.6 Patients with all macroscopic Merkel cell carcinoma (either identified by physical exam or imaging) have been completely resected by surgery within 16 weeks before registration.

3.1.7 Patient may not have a history of distant metastatic disease.

NOTE: loco-regional recurrent disease is acceptable, as long as this is not metastatic (prior surgery with or without radiation therapy is acceptable).

3.1.8 For patients with initial presentation of Merkel cell carcinoma, patient must have no previous systemic therapy or radiation therapy prior to surgery for Merkel cell carcinoma and cannot have completed adjuvant radiation therapy for Merkel Cell Carcinoma more than 6 weeks prior to registration. Patients actively undergoing radiation therapy or having completed adjuvant radiation therapy within 6 weeks of registration are eligible, as long as resection date is within 16 weeks of registration.

3.1.9 Patient must have the following required values for initial laboratory tests obtained within 4 weeks prior to registration.

3.1.9.1 White Blood Count = 2000/uL

3.1.9.2 Absolute neutrophil count (ANC) = 1000/uL

3.1.9.3 Platelets = 75 x 103/uL

3.1.9.4 Hemoglobin = 8 g/dL (= 80 g/L; may be transfused)

3.1.9.5 Creatinine = 2.0 x ULN

3.1.9.6 AST and ALT = 2.5 x ULN

3.1.9.7 Total Bilirubin = 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)

3.1.10 Patients who are HIV+ with undetectable HIV viral load are eligible provided they meet all other protocol criteria for participation.

3.1.11 Patients with HBV or HCV infection are eligible provided viral loads are undetectable. Patients on suppressive therapy are eligible.

3.1.12 Patients must not be on active immunosuppression, have a history of life threating virus, have had other (beside non-melanoma skin cancers, or recent indolent cancers e.g.: resected low grade prostate cancer) invasive cancer diagnoses in the last two years, or have had immunotherapy of any kind within the last 2 years.

3.1.13 Patients must not have a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

3.1.14 Operative notes from patient’s surgical resection must be accessible.

*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 androgendeprivation 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 01/10/2024

ARM C Re-Activated to Patient Accrual- Effective 04/01/2024 

**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 making 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 noninvasive cancer (

- 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 antiretroviral 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 CockroftGault 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 cisplatineligible 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.