Cabozantinib S-Malate and Erlotinib Hydrochloride for Patients with EGFR and C-Met Co-expressing Metastatic Pancreatic Cancer

Inclusion Criteria

• The subject has a biopsy-proven diagnosis of adenocarcinoma of the pancreas (or recurrence of previously resected disease) with metastatic disease that is measurable per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• The subject must have an archived tissue sample such as a prior surgical sample or biopsy sample that is adequate for testing
• The subject must have EGFR and c-Met overexpressed in tumor as determined by immunohistochemistry (IHC) test score of 2+ for both markers
• The subject has demonstrated radiographic progression after front-line treatment (prior adjuvant therapy allowed if >= 6 months elapsed between end of adjuvant therapy and metastatic relapse)
• The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• The subject has recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v.)4.03 from toxicities related to any prior treatments, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy
• The absolute neutrophil count (ANC) >= 1500/mm^3 without colony stimulating factor support (within 7 days before the first dose of study treatment)
• Platelets >= 100,000/mm^3 (within 7 days before the first dose of study treatment)
• Hemoglobin >= 9 g/dL (within 7 days before the first dose of study treatment)
• Bilirubin =< 1.5 x the upper limit of normal (ULN); for subjects with known Gilbert’s disease, bilirubin =< 3.0 mg/dL (within 7 days before the first dose of study treatment)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x the ULN (within 7 days before the first dose of study treatment)
• Serum albumin >= 2.8 g/dl (within 7 days before the first dose of study treatment)
• Serum creatinine =< 1.5 x the ULN or creatinine clearance (CrCl) >= 40 mL/min; for creatinine clearance estimation, the Cockcroft and Gault equation should be used (within 7 days before the first dose of study treatment)
• Urine protein to creatinine ratio (UPCR) =< 1 (within 7 days before the first dose of study treatment)
• Serum phosphorus, calcium, magnesium and potassium >= lower limit of normal (LLN) (within 7 days before the first dose of study treatment)
• Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test < 1.3 x the ULN within 7 days before the first dose of study treatment
• The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document
• The subject has a life expectancy of 12 weeks or greater
• The subject is able to tolerate oral medications and no evidence of ongoing malabsorption
• All sexually active subjects of reproductive potential must agree to use both a medically accepted barrier method (e.g., male or female condom) and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s);
• Female subjects of childbearing potential must not be pregnant at screening; females of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e., females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy or bilateral oophorectomy); however, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons

Exclusion Criteria

• The subject has received cytotoxic chemotherapy or biologic agents (e.g., cytokines or antibodies) within 14 days, or nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment
• Prior treatment with cabozantinib or erlotinib
• Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before the first dose of study treatment; systemic treatment with radionuclides within 6 weeks before the first dose of study treatment; subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 14 days before the first dose of study treatment
• The subject has received any other type of investigational agent within 28 days before the first dose of study treatment
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of study treatment; eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment
• Concomitant anticoagulation at therapeutic doses with oral anticoagulants (e.g., warfarin, direct thrombin and factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel) * Note: Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose low molecular weight heparin (LMWH) are permitted; anticoagulation with therapeutic doses of LMWH is allowed in subjects 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
• The subject has experienced any of the following: * Clinically-significant gastrointestinal (GI) bleeding within 6 months before the first dose of study treatment * Hemoptysis of >= 0.5 teaspoon (2.5 ml) of red blood within 3 months before the first dose of study treatment * Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment; and * Clinically confirmed history of interstitial lung disease (ILD)
• The subject has radiographic evidence of cavitating pulmonary lesion(s)
• The subject has tumor invading a major blood vessel (encasement of local vascular structures is not exclusionary)
• The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib; which in the opinion of the investigator places the subject at greater risk of perforation
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * 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 anti-hypertensive treatment within 7 days of the first dose of study treatment ** Any history of congenital long QT syndrome ** Any of the following within 6 months before the first dose of study treatment: *** 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 including: ** Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction ** Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before first dose of study treatment; Note: Complete healing of an intra-abdominal abscess must be confirmed prior first dose of study treatment * Other clinically significant disorders that would preclude safe study participation
• Major surgery within 12 weeks before the first dose of study treatment; complete wound healing from major surgery must have occurred 1 month before the first dose of study treatment; minor surgery (including uncomplicated tooth extractions) within 28 days before the first dose of study treatment with complete wound healing at least 10 days before the first dose of study treatment; subjects with clinically relevant ongoing complications from prior surgery are not eligible
• Fridericia's correction formula (QTcF) > 500 msec within 1 month before the first dose of study treatment: * Three electrocardiography (ECG)s must be performed for eligibility determination; if the average of these three consecutive results for QTcF is =< 500 msec, the subject meets eligibility in this regard
• Pregnant or lactating females
• Active smoker
• Inability to swallow intact tablets
• Previously identified allergy or hypersensitivity to components of the study treatment formulations
• Diagnosis of another malignancy within 2 years before the first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy; malignancy felt by investigator to potentially affect subject survival or ability to evaluate disease response