*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Canton, Chelsea), St. Mary's Livonia, Genesys, Hurley, St. John, Macomb, LVHN, Sparrow, Oakland, Saginaw, Holy Cross

Eligibility Criteria:

Patient must have a pathologically-confirmed diagnosis of non-squamous, non-small cell lung cancer (NSCLC).

- Patient must have advanced disease, defined as - either stage IV disease, stage IIIB disease not amenable to definitive multi-modality therapy, or recurrent disease after a prior diagnosis of stage I-III disease. All staging is via the American Joint Committee on Cancer (AJCC)/IASLC 8th edition staging criteria.

- Patient must have somatic activating sensitizing mutation in EGFR (e.g. but not limited to Exon 19 deletion, L858R, G709X, G719X, exon 19 insertions, L861Q, S768I). Patients with non-sensitizing mutations in EGFR (EGFR exon 20 insertions) are not eligible. Test results originating from a CLIA-certified or similarly accredited laboratory are acceptable; no specific assay is mandated. If there is any question as to whether an EGFR mutation is sensitizing, please contact the primary study team.

- Patient must not have received any prior treatment with an EGFR TKI or with an anti-VEGF agent.

-Patients that have received prior radiation therapy are eligible. Radiation (WBRT or stereotactic radiation) must have been completed at least two weeks prior to study registration.

- Patient must not have any risk factors for anti-VEGF administration, specifically, hemoptysis, active cardiovascular disease, uncontrolled hypertension, significant proteinuria (screening urine dipstick >3+) and tumor invading major blood vessels.

- Patient must have measurable disease as defined in Section 6.1.2. Baseline measurements of sites of disease must be obtained within 4 weeks prior to study registration. If a potential target lesion is previously irradiated without subsequent growth and/or is radiated after the imaging from which baseline measurements are obtained, they cannot be included as target lesions, and additional target lesions are required to meet criteria for measurable disease.

- Patient must not have had any prior systemic treatment for metastatic disease.

-Patient must be = 18 years of age.

- Patient must have an ECOG Performance status of 0 to 2

- Women 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 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 expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for 2 weeks prior to the start of treatment, while on study treatment, and for

• 6 weeks after the last dose of protocol treatment for female patients on the AZD9291 (osimertinib) alone arm
• 4 months after the last dose of protocol treatment for male patients on AZD9291 (osimertinib) alone arm
• 6 months after the last dose of protocol treatment for all patients on AZD9291 (osimertinib) plus bevacizumab combination arm

NOTE: Female patients should also not breastfeed while on treatment and for 6 months after the last dose bevacizumab.

- Patient must have adequate organ and marrow function as defined below (must be obtained =14 days prior to registration):

Leukocytes = 3,000/mcL

Absolute neutrophil count = 1,500/mcL

Platelets = 100,000/mcL

Hemoglobin = 9 g/dL

Total bilirubin and creatinine = 1.5 x institutional upper limit of normal (ULN)

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

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months 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 an undetectable HCV viral load.

- Patients with treated brain metastases are eligible if neurologically stable without glucocorticoid therapy after the stated washout period from RT or surgery provided the metastatic lesions are non-hemorrhagic.

 -Patients with untreated brain metastases or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required provided the metastatic lesions are non-hemorrhagic and are neurologically stable without glucocorticoid therapy.

- 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 the ability to understand and the willingness to sign a written informed consent document and comply with study requirements

- Patient must not have had treatment with any investigational drug within five half-lives or 3 months (whichever is greater), prior to study initiation.

- Patient must not be currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (see Appendix VII). For any patient currently receiving such inducers of CYP3A4, they must discontinue use prior to first dose of study treatment. All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.

-Patient must not have any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of registration, with the exception of alopecia and grade 2 prior platinum-therapy–related neuropathy.

- Patient must not have any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator’s opinion makes it challenging for the patient to participate in the study. Screening for chronic conditions is not required.

- Patient must not have refractory nausea and vomiting, chronic gastrointestinal diseases, the inability to swallow the osimertinib tablets or previous significant bowel resection that would preclude adequate absorption of osimertinib.

- Patient must not have a medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.

-Patient must not have a history of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.

- Patient must not have mean resting corrected QT interval (QTc) > 470 msec obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value.

-Patient must not have any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second-degree heart block.

- Patient must not have any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including: potassium LLN; magnesium LLN; calcium LLN), congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes.

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, Genesys, Hurley, holy cross

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 decision\u0002making 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.** 

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: TH IHA (Ann Arbor, Brighton, Canton, Chelsea), Livonia, Sparrow, Oakland, Lehigh, GenHur

Eligibility Criteria:

3.1.1 Patient must be > 18 years of age.

3.1.2 Patient must have Stage II to select Stage IIIB (N2 but excluding N3) non-small cell lung cancer (NSCLC) of any histology using IASLC 8th Edition. Stage is assessed at time of initiating pre-operative chemoimmunotherapy.

3.1.3 Patient must fall into one of the following categories:

• Planning to undergo, be currently undergoing, or recently completed any standard of care neoadjuvant chemoimmunotherapy with plans to undergo surgical resection.  

• Recently completed any standard of care neoadjuvant chemoimmunotherapy AND completed surgical resection and are awaiting pCR status.

• Recently completed any standard of care neoadjuvant chemoimmunotherapy AND completed surgical resection with confirmed non-path CR status. NOTES:

• Patient must have completed at least 3 cycles of neoadjuvant chemo-immunotherapy before surgery in order to be eligible for Step 1 randomization.

• Patients who have completed their surgical resection prior to enrollment in Step 0 Registration must have their surgery date within a window that will allow initiation of EA5231 treatment (Cycle 1 Day 1) to commence within 4-12 weeks following surgery. 

3.2.1 Patient must have completed R0 resection after standard of care neoadjuvant chemo-immunotherapy (minimum three cycles completed) for Stage II to select Stage IIIB (N2 but excluding N3) non small cell lung cancer (NSCLC) of any histology using IASLC 8th Edition

3.2.2 Patient must have non-pathological CR status post-surgery. The pathological CR/non-pathological CR status will be determined by local pathology using IASLC criteria (8) and using the surgical sample tissue.

3.2.3 Patient must have an ECOG Performance Status of 0- < 2 (or Karnofsky > 60%).

3.2.4 Patient must not have any known EGFR or ALK genetic alterations. Mutation negative status will be determined per local institutional practices and consistent with NCCN guidelines.

3.2.5 Patient must have undergone a chest CT after surgery and within 28 days prior to Step 1 randomization.

3.2.6 Patient must have recovered from clinically significant adverse events of their most recent therapy/intervention prior to Step 1 randomization.  

3.2.7 Patient must not have experienced a toxicity that led to the permanent discontinuation of prior immunotherapy.

3.2.8 Patient must not be receiving ongoing steroids at a dose of prednisone 10 mg or higher (or equivalent) at the time of Step 1 randomization. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) are allowed. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) are allowed.

3.2.9 Patient must not have received or have a plan to receive post-operative radiation therapy (PORT).

3.2.10 Patient must not have a history of treatment-related pneumonitis requiring ongoing steroids or supplemental oxygen use.

3.2.11 Patient must not have a history of interstitial lung disease (ILD).

3.2.12 Patient must not have diagnosis of ataxia telangiectasia.

3.2.13 Patient must not have history of active primary immunodeficiency.

3.2.14 Patient must not have history of allogenic organ transplantation.

3.2.15 Patient must have body weight > 30 kg. 

**PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL 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, SJMO

-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.

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.

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 (

- 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.