A Randomized Phase II Trial of Erlotinib, Cabozantinib, or Erlotinib Plus Cabozantinib as 2nd or 3rd Line Therapy in Patients With EGFR Wild-Type NSCLC
A Randomized Phase II Trial of Erlotinib, Cabozantinib, or Erlotinib Plus Cabozantinib as 2nd or 3rd Line Therapy in Patients With EGFR Wild-Type NSCLC
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.
PRIMARY OBJECTIVES:
I. To compare the progression-free survival (PFS) associated with patients treated with erlotinib (erlotinib hydrochloride) versus (vs) erlotinib plus cabozantinib (cabozantinib-s-malate).
II. To compare the PFS associated with patients treated with erlotinib vs cabozantinib.
SECONDARY OBJECTIVES:
I. To evaluate overall survival in the three treatment arms. II. To evaluate best objective response rate in the three treatment arms. III. To define the toxicity associated with each regimen. IV. To conduct correlative science studies that will help to select predictive biomarkers of response to therapy, including mesenchymal-epidermal transition (MET) expression and potentially other tissue biomarkers, plasma biomarkers, and bone scans.
OUTLINE: Patients are randomized to 1 of 3 treatment arms.
ARM A (erlotinib): Patients receive erlotinib orally (PO) daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM B (cabozantinib): Patients receive cabozantinib PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM C (erlotinib+cabozantinib): Patients receive erlotinib as patients in Arm A and cabozantinib as patients in Arm B. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM Z: Patients achieving disease progression in Arm A or Arm B may receive erlotinib and cabozantinib as patients in Arm C. Courses 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 2 years and then every 6 months for 3 years.
Criteria:
Tumor with a sensitizing mutation in epidermal growth factor receptor (EGFR), defined as follows:
Inclusion Criteria:
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:
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
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