Nivolumab, Cabozantinib S-Malate, and Ipilimumab in Treating Patients With Recurrent Stage IV Non-small Cell Lung Cancer
Condition: Metastatic Lung Non-Squamous Non-Small Cell Carcinoma; Recurrent Lung Non-Squamous Non-Small Cell Carcinoma; Stage IV Lung Non-Small Cell Cancer AJCC v7
MeSH terms: Carcinoma; Carcinoma, Non-Small-Cell Lung
Intervention: Cabozantinib; Ipilimumab; Nivolumab
Intervention description: Given PO; Given IV; Given IV
Intervention MeSH terms: Nivolumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Nivolumab; Cabozantinib; Ipilimumab; NSCLC

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria (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

        Inclusion Criteria (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

          -  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

          -  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

          -  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)

          -  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

               -  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

        Exclusion Criteria (Step 1):

          -  Small cell elements are present

          -  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); 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

          -  Prior radiation therapy for bone metastasis within 2 weeks; any other radiation
             therapy within 4 weeks prior to registration

          -  Known leptomeningeal disease

          -  Impaired decision-making capacity (IDMC)

          -  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

          -  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

          -  Concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin,
             carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort)

          -  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

          -  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

          -  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

          -  Any 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

          -  Currently active other malignancies which require systemic treatment

          -  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

          -  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

          -  Ongoing major illness or psychosocial issues that would limit compliance with the
             protocol

          -  Pregnant or breast-feeding

          -  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