Erlotinib Hydrochloride and Cabozantinib-s-Malate Alone or in Combination as Second or Third Line Therapy in Treating Patients With Stage IV Non-small Cell Lung Cancer
Condition: Recurrent Lung Non-Small Cell Carcinoma; Stage IV Lung Non-Small Cell Cancer AJCC v7
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Cabozantinib S-malate; Erlotinib Hydrochloride; Laboratory Biomarker Analysis
Intervention description: Given PO; Given PO; Correlative studies
Intervention MeSH terms: Erlotinib Hydrochloride
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 125.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase II trial studies how well giving erlotinib hydrochloride and
      cabozantinib-s-malate alone or in combination works as second or third line therapy in
      treating patient with stage IV non-small cell lung cancer. Erlotinib hydrochloride and
      cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes
      needed for cell growth. It is not yet known whether giving erlotinib hydrochloride together
      with cabozantinib-s-malate is more effective than erlotinib hydrochloride or
      cabozantinib-s-malate alone in treating non-small cell lung cancer.
    

Eligibility criteria:

        Criteria:

          -  Tumor with a sensitizing mutation in epidermal growth factor receptor (EGFR), defined
             as follows:

               -  EGFR mutation testing of tumor has been performed and did not demonstrate an EGFR
                  tyrosine kinase inhibitor sensitizing mutation; at minimum, testing for EGFR exon
                  19 deletion and exon 21 L858R mutations must have been included; OR

               -  EGFR mutation testing has been attempted and is inconclusive (for example, due to
                  lack of sufficient deoxyribonucleic acid [DNA] yield); OR

               -  EGFR mutation status is unknown but tumor is positive for at least one
                  alternative driver mutation, i.e: Kirsten rat sarcoma viral oncogene homolog
                  (KRAS) mutation, v-raf murine sarcoma viral oncogene homolog B (BRAF) mutation,
                  human epidermal growth factor receptor 2 (HER2) mutation, ret proto-oncogene
                  (RET) rearrangement/fusion, or one not listed following approval by the study
                  chair prior to registration

        Inclusion Criteria:

          -  INCLUSION CRITERIA STEP 1:

          -  Cytologically or histologically confirmed non-small cell lung carcinoma (NSCLC)

          -  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

          -  Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th
             edition of the lung cancer TNM classification system

          -  Patients must have measurable disease as defined by Response Evaluation Criteria in
             Solid Tumors (RECIST) version (v) 1.1 criteria; baseline measurements and evaluation
             of all sites of disease must be obtained within 4 weeks prior to registration

          -  Prior to registration, the investigator/site must confirm that sufficient pathology
             material representative of patient's cancer is available for submission for MET
             immunohistochemical (IHC) testing

          -  Patients must have received one or two lines of prior chemotherapy (first line
             platinum-doublet based chemotherapy plus switch maintenance chemotherapy counts as one
             line of therapy); 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

          -  Any prior chemotherapy (based on administration schedule) must have been completed in
             greater than or equal to the time frames specified in the protocol

          -  Patients must have discontinued treatment with any other type of investigational agent
             >= 4 weeks prior to registration

          -  Patients must have recovered to baseline or Common Terminology Criteria for Adverse
             Events (CTCAE) v 4.0 =< grade 1 from toxicity due to all prior therapies except
             alopecia and other non-clinically significant adverse events (AEs)

          -  Patients with no known brain metastasis at baseline must have baseline brain imaging
             within 12 weeks prior to study registration not demonstrating brain metastases;
             patients with brain metastases at baseline must have baseline brain imagining within 4
             weeks prior to study registration and meet all of the specific criteria for brain mets
             listed in the protocol

          -  Radiation related toxicities must have resolved to =< grade 1 prior to registration

          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status
             between 0-2

          -  Patients must have an anticipated life expectancy greater than 3 months

          -  Acceptable bone marrow, renal and hepatic function within 2 weeks prior to
             registration as defined in the protocol

          -  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

          -  INCLUSION CRITERIA STEP 2:

          -  Patients must have met all eligibility requirements for Step 1 at time of registration
             to Step 1 to be eligible for Step 2

          -  Patients must have radiographic progressive disease per RECIST v1.1 criteria after >=
             2 courses of therapy on Arm A or Arm B

          -  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

          -  Patients must have recovered to baseline (pre-Step 1) or CTCAE version 4.0 <= grade 1
             from toxicity due to all prior therapies except alopecia and other non-clinically
             significant AEs

        Exclusion Criteria:

          -  EXCLUSION CRITERIA STEP 1:

          -  Patients without sufficient pathology material representative of the patient's cancer
             (tumor block or 10 unstained slides)

          -  Prior erlotinib, other EGFR tyrosine kinase inhibitor therapy, vascular endothelial
             growth factor receptor (VEGFR) tyrosine kinase inhibitor therapy, Met tyrosine kinase
             inhibitor therapy, or Met monoclonal antibody (MetMAb); prior antibody therapy such as
             bevacizumab or cetuximab is allowed with a washout period depending on dosing interval
             and investigational nature

          -  Prior radiation therapy to the thoracic cavity, abdomen, or pelvis within 3 months
             prior to registration, to bone or brain metastasis within 14 days prior to
             registration, or to any other site within 28 days prior to registration

          -  History of the following: Clinically-significant gastrointestinal (GI) bleeding within
             6 months prior to registration; Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood
             within 3 months prior to registration; Any other signs indicative of pulmonary
             hemorrhage within 3 months prior to registration

          -  Radiographic or other evidence of the following within 28 days prior to registration:
             • Tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or
             anus), or any evidence of endotracheal or endobronchial tumor; Cavitating pulmonary
             lesion(s); Tumor in contact with, invading or encasing any major blood vessels

          -  Psychiatric illness/social situations that would limit compliance with study
             requirements

          -  History of major thrombotic events (deep vein thrombosis [DVT] or pulmonary embolism
             [PE]) within 6 months prior to registration

          -  Concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or
             warfarin-related agents, heparin, low molecular weight heparin (LMWH), thrombin or
             Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). (low dose aspirin
             [=< 81 mg/day] and prophylactic LMWH are permitted)

          -  Concomitant treatment of strong cytochrome P450 3A4 (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; Any history of congenital long QT syndrome; 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

          -  GI disorders particularly those associated with a high risk of perforation or fistula
             formation specified in the protocol

          -  Other disorders associated with a high risk of fistula formation including
             percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months prior to
             registration

          -  Uncontrolled, significant, intercurrent or recent illness

          -  Prior malignancy within 2 years prior to registration which required systemic
             treatment or is currently active

          -  Pregnant or breast-feeding

          -  Patients with known human immunodeficiency virus (HIV) disease taking antiretroviral
             therapy

          -  Known chronic active hepatitis B

          -  EXCLUSION CRITERIA (STEP 2):

          -  Intervening anticancer treatment or major surgical procedure(s) between Step 1 and
             Step 2, except palliative radiation to the bone finishing >= 2 weeks prior to
             registration to Step 2

          -  Central nervous system (CNS) progression; patients with stable CNS disease are allowed

          -  Intercurrent illness or disease complication that the investigator believes would
             limit the ability to safely tolerate the combination of erlotinib and cabozantinib