Nivolumab, Cabozantinib S-Malate, and Ipilimumab in Treating Patients With Recurrent Stage IV Non-small Cell Lung Cancer
Nivolumab, Cabozantinib S-Malate, and Ipilimumab in Treating Patients With Recurrent Stage IV Non-small Cell Lung Cancer
This partially randomized phase II trial studies how well nivolumab, cabozantinib s-malate,
 and ipilimumab work in treating patients with stage IV non-small cell lung cancer that has
 come back. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may
 help the body's immune system attack the cancer, and may interfere with the ability of tumor
 cells to grow and spread. Cabozantinib s-malate may stop the growth of tumor cells by
 blocking some of the enzymes needed for cell growth. Giving nivolumab, cabozantinib s-malate,
 and ipilimumab may work better than cabozantinib s-malate alone in treating patients with
 stage IV non-small cell lung cancer.
PRIMARY OBJECTIVES:

 I. To demonstrate whether combination therapy of nivolumab and cabozantinib s-malate
 (cabozantinib), or of nivolumab and cabozantinib, and ipilimumab as compared to nivolumab
 alone, extends progression-free survival (PFS) for this patient population with non-squamous
 non-small cell lung cancer (NSCLC).

 SECONDARY OBJECTIVES:

 I. To estimate the overall survival for each arm of the trial. II. To estimate the best
 overall response rate for each arm of the trial. III. To estimate the progression free
 survival of the targeted therapy arm of the trial.

 IV. To describe the toxicity profile of monotherapy with nivolumab, and the combination of
 nivolumab and cabozantinib, and the combination of nivolumab and cabozantinib and ipilimumab,
 in this patient population with non-squamous NSCLC.

 CORRELATIVE OBJECTIVES:

 I. To adjust progression free survival for each arm based on PD-L1 tumor status.

 IMAGING OBJECTIVES:

 I. To describe time point tumor response assessment, overall best response and
 progression-free survival using the conventional Response Evaluation Criteria in Solid Tumors
 (RECIST) 1.1 criteria and the exploratory uni-dimensional immune response criteria (iRRC) and
 the imaging (i)RECIST criteria with all measurements performed by the central review.

 II. To compare RECIST 1.1 imaging response assessment measurements (time point response
 assessment and overall best response) assess by site study personnel to those performed by
 central review.

 EXPLORATORY TOBACCO USE OBJECTIVES:

 I. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other
 forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported
 cancer-treatment toxicity (adverse events (both clinical and hematologic) and dose
 modifications).

 II. To determine the effects of tobacco on patient-reported physical symptoms and
 psychological symptoms.

 III. To examine quitting behaviors and behavioral counseling/support and cessation medication
 utilization.

 IV. To explore the effect of tobacco use and exposure on treatment duration, relative dose
 intensity, and therapeutic benefit.

 OUTLINE: Patients are randomized to 1 of 3 arms. Patients with ROS1 gene rearrangement, MET
 exon 14 splice mutations, MET high amplification, or RET gene rearrangement are assigned to
 Arm T.

 ARM A: Patients receive nivolumab intravenously (IV) over 60 minutes on day 1. Cycles repeat
 every 28 days in the absence of disease progression or unacceptable toxicity.

 ARM B: Patients receive nivolumab IV over 60 minutes on day 1 and cabozantinib s-malate
 orally (PO) daily on days 1-28. Cycles repeat every 28 days in the absence of disease
 progression or unacceptable toxicity.

 ARM C: Patients receive nivolumab IV over 60 minutes on day 1, cabozantinib s-malate PO daily
 on days 1-28, and ipilimumab IV over 90 minutes every 8 weeks. Cycles for nivolumab and
 cabozantinib s-malate repeat every 28 days in the absence of disease progression or
 unacceptable toxicity.

 ARM T: Patients with ROS1 gene rearrangement, MET exon 14 splice mutations, MET high
 amplification, or RET gene rearrangement receive nivolumab IV over 60 minutes on day 1 and
 cabozantinib s-malate PO daily on days 1-28. Cycles repeat every 28 days in the absence of
 disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 3 months for up to 3
 years.
Inclusion Criteria:

 -  ELIGIBILITY CRITERIA FOR STEP 0

 -  Patients with tumors with the following molecular alterations must submit testing
 results via Medidata Rave to determine eligibility to Arm T; the study chair,
 co-chair, biology co-chair, or a delegate must review the molecular testing and agree
 that the testing meets one of the molecular eligibility criteria below:

 -  ROS1 gene rearrangement by fluorescence in situ hybridization (FISH) or
 deoxyribonucleic acid (DNA) analysis (may have progressed on prior crizotinib
 therapy)

 -  MET exon 14 splice mutations on DNA analysis (may have progressed on prior
 crizotinib therapy)

 -  MET high amplification by FISH or DNA analysis or other MET mutations predicted
 to be sensitive to MET inhibitor (no prior targeted therapy allowed)

 -  RET gene rearrangement by FISH or DNA analysis (no prior targeted therapy
 allowed)

 -  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

 -  If patients do not have tumors with the above molecular alterations noted
 proceed directly to step 1

 -  ELIGIBILITY CRITERIA FOR STEP 1

 -  For patients with known molecular alterations, institution has been notified that
 patient is deemed eligible for Arm T per review of molecular testing reports

 -  Pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC)

 -  Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th
 edition of the lung cancer tumor, node, and metastasis (TNM) classification system

 -  Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS]
 are eligible); mixed tumors will be categorized by the predominant cell type; if small
 cell elements are present the patient is ineligible

 -  Tumors must be tested and known negative for EGFR tyrosine kinase inhibitor (TKI)
 sensitizing mutations (EGFR exon 19 deletions, L858R, L861Q, G719X) and ALK gene
 rearrangements by routine Clinical Laboratory Improvement Act (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 must have progressed radiographically following first line platinum-based
 chemotherapy, no additional lines of therapy are permitted

 -  NOTE: Prior adjuvant chemotherapy for early stage disease does not count as one
 line of therapy if 12 months or greater elapsed between completion of adjuvant
 therapy and initiation of first-line systemic therapy; if less than 12 months
 elapsed, adjuvant chemotherapy counts as one line of therapy

 -  Exception for targeted therapy sub-study (Arm T): At least one line of prior
 chemotherapy or targeted therapy is required, but there is no limit on number of
 prior treatments

 -  Patients must have measurable disease as defined by RECIST v. 1.1 criteria; baseline
 measurements and evaluation of ALL sites of disease must be obtained within 4 weeks
 prior to registration

 -  No prior anti-MET therapy such as crizotinib or cabozantinib, or PD-1/PD-L1 immune
 checkpoint inhibitor therapy (such as nivolumab, pembrolizumab, atezolizumab) or CTLA4
 inhibitor therapy (such as ipilimumab); no prior allergic reaction to small molecule
 tyrosine kinase inhibitors or monoclonal antibodies

 -  Exception for targeted therapy sub-study (Arm T): Prior crizotinib may be allowed
 depending on the gene alteration

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

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

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

 -  Additionally, patients should be recovered to equal to or less than grade 1
 toxicities related to any prior treatment, unless adverse event (AE)(s) are
 clinically nonsignificant and/or stable on supportive therapy

 -  No prior radiation therapy for bone metastasis within 2 weeks, any other radiation
 therapy within 4 weeks prior to registration

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

 -  Patients with known brain metastases must have baseline brain imaging within 4 weeks
 prior to study registration and meet all of the following criteria:

 -  Have completed treatment to all symptomatic brain metastases (with whole brain
 radiation or radiosurgery) >= 4 weeks prior to registration, or have undergone
 complete neurosurgical resection >= 3 months prior to registration

 -  Be clinically stable from brain metastases at time of screening, if no treatment
 was administered

 -  Known leptomeningeal disease is not allowed

 -  Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1

 -  NOTE: Participants with impaired decision-making capacity (IDMC) should not be
 allowed to participate in this study due to its complexity

 -  Patients must have anticipated life expectancy greater than 3 months

 -  Absolute neutrophil count >= 1,500/mm^3 (within 2 weeks prior to registration)

 -  Platelets >= 100,000/mm^3 (within 2 weeks prior to registration)

 -  Hemoglobin >= 9 g/dL (within 2 weeks prior to registration)

 -  Subject has prothrombin time (PT)/international normalized ratio (INR) and partial
 thromboplastin time (PTT) test =< 1.3 x the laboratory upper limit of normal (ULN)
 (within 2 weeks prior to registration)

 -  Total bilirubin =< 1.5 x ULN (within 2 weeks prior to registration)

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
 alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x ULN
 (within 2 weeks prior to registration)

 -  Serum albumin >= 2.8 g/dL (within 2 weeks prior to registration)

 -  Serum calcium (absolute or albumin corrected), magnesium and potassium >= lower limit
 of normal (LLN) (within 2 weeks prior to registration)

 -  NOTE: serum calcium, magnesium and potassium can be replaced if values are below
 LLN

 -  Creatinine =< 1.5 x ULN or calculated (Cockcroft-Gault formula) or measured creatinine
 clearance >= 50 mL/min/1.73 m^2 (normalized to body surface area [BSA]) for patients
 with creatinine levels greater than 1.5 times the institutional normal (within 2 weeks
 prior to registration)

 -  Screening urine dipstick must equal 0 or "trace"; if urine dipstick results are >= 1+,
 or if dipstick was not performed, calculation of urine protein creatinine (UPC) is
 required and patients must have a UPC ratio =< 1 to participate in the study (within 2
 weeks prior to registration)

 -  No history of the following:

 -  Clinically-significant gastrointestinal bleeding within 6 months prior to
 registration

 -  Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months prior to
 registration

 -  Drug induced pneumonitis within 3 months prior to registration

 -  Signs indicative of pulmonary hemorrhage within 3 months before the first dose of
 study treatment

 -  Radiographic evidence of cavitating pulmonary lesion(s)

 -  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 before the first dose of cabozantinib

 -  No concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct
 thrombin and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel); allowed
 anticoagulants are the following:

 -  Low-dose aspirin for cardioprotection (per local applicable guidelines) is
 permitted

 -  Low molecular weight heparins (LMWH) or unfractionated heparin is permitted

 -  Anticoagulation with therapeutic doses of LMWH is allowed in subjects without
 known brain metastases who are on a stable dose of LMWH for at least 6 weeks
 before first dose of study treatment, and who have had no clinically significant
 hemorrhagic complications from the anticoagulation regimen or the tumor

 -  No concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin,
 carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort)

 -  No cardiovascular disorders including:

 -  Congestive heart failure (CHF): New York Heart Association (NYHA) class III
 (moderate) or class IV (severe) at the time of screening

 -  Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) >
 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive
 treatment within 7 days prior to registration

 -  Any of the following within 6 months prior to registration:

 -  Unstable angina pectoris

 -  Clinically-significant cardiac arrhythmias

 -  Stroke (including transient ischemic attack [TIA], or other ischemic event)

 -  Myocardial infarction

 -  No gastrointestinal disorders associated with a high risk of perforation or fistula
 formation within 3 months prior to registration:

 -  Active peptic ulcer disease

 -  Inflammatory bowel disease (including ulcerative colitis and Crohn's disease),
 diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis

 -  Known malabsorption syndrome

 -  Bowel obstruction or gastric outlet obstruction

 -  Percutaneous endoscopic gastrostomy (PEG) tube placement

 -  No gastrointestinal disorders associated with a high risk of perforation or fistula
 formation within 6 months prior to registration:

 -  Abdominal fistula

 -  Gastrointestinal perforation

 -  Intra-abdominal abscess; Note: Complete resolution of an intra-abdominal abscess
 must be confirmed prior to initiating treatment with cabozantinib even if the
 abscess occurred more than 6 months prior to registration

 -  None of the following conditions:

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

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

 -  History of organ transplant

 -  Concurrent symptomatic untreated hypothyroidism within 7 days prior to
 registration

 -  History of surgery as follows:

 -  Major surgery (as an example, surgery requiring anesthesia and a > 24 hour
 hospital stay) within 3 months prior to registration, with wound healing at
 least 28 days prior to registration

 -  Minor surgery within 28 days prior to registration with complete wound
 healing at least 10 days prior to registration

 -  Minor procedures within 7 days prior to registration such as thoracentesis,
 paracentesis, or 18 g or smaller needle biopsy of tumor

 -  Patients with clinically relevant ongoing complications from prior surgery
 are not eligible

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

 -  Patients must be able to swallow tablets

 -  No currently active other malignancies which require systemic treatment

 -  No patients that have a condition requiring systemic treatment with either
 corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
 medications within 14 days of study drug administration; 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, even 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

 -  No patients with 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; these include but are not
 limited to patients with a history of immune related neurologic disease, multiple
 sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia
 gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE),
 connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's,
 ulcerative colitis, autoimmune hepatitis; patients with a history of toxic epidermal
 necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
 excluded because of the risk of recurrence or exacerbation of disease; patients with
 vitiligo, endocrine deficiencies including type I diabetes mellitus or thyroiditis
 managed with replacement hormones including physiologic corticosteroids are eligible;
 patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and
 psoriasis controlled with topical medication and patients with positive serology, such
 as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the
 presence of target organ involvement and potential need for systemic treatment but
 should otherwise be eligible

 -  No ongoing major illness or psychosocial issues that would limit compliance with the
 protocol

 -  Women must not be pregnant or breast-feeding due to contraindications with the study
 agents

 -  All females 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 not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been
 naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
 at any time in the preceding 24 consecutive months)

 -  Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP
 must use an accepted and effective method of contraception or abstain from sexual
 intercourse for at least one week prior to the start of treatment, and continue for 5
 months after the last dose of protocol treatment for women of childbearing potential
 and 7 months after the last dose of protocol treatment for males who are sexually
 active with WOCBP

 -  Patients with known human immunodeficiency virus (HIV) disease taking antiretroviral
 therapy are excluded because there are no safety data with the combination of
 antiretroviral therapy and cabozantinib or ipilimumab or nivolumab with ipilimumab

 -  Patients with known chronic active hepatitis B (defined as a positive hepatitis B
 surface antigen and/or hepatitis B viral load in the last