Cabozantinib and Erlotinib for Patients With EGFR and c-Met Co-expressing Metastatic Pancreatic Adenocarcinoma
Condition: Pancreatic Adenocarcinoma Metastatic
MeSH terms: Adenocarcinoma
Intervention: Cabozantinib 40 MG; Erlotinib 100Mg Tab
Intervention description: To be taken orally once daily; To be taken orally once daily
Intervention MeSH terms: Erlotinib Hydrochloride
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is an open-label, single arm, phase II trial. Safety will be monitored on an ongoing
      basis. Laboratory testing (chemistry, hematology tests) will be performed every 2 weeks for
      the first 8 weeks followed by assessments every 4 weeks. Other safety evaluations including
      EKGs, urinalysis, coagulation and thyroid function studies will be performed at regular
      intervals.

      Adverse event seriousness, severity grade, and relationship to study treatment will be
      assessed by the investigator. Severity grade will be defined by the National Cancer Institute
      (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

      Tumors will be assessed by contrast enhanced CT or MRI every 8 weeks. Pre-treatment tissue
      will be obtained via CT-guided FNA biopsy or collected during resection. However, archival
      tissue will also be requested, when available and if adequate for testing. Post-treatment
      tissue will be obtained on Day 15 (i.e., Week 3/Day 1) via CT-guided FNA biopsy. All tumor
      tissue from eligible patients will be utilized for the correlative studies which are outlined
      in this trial.

      Each subject's course will consist of three periods:

        -  A Pre-Treatment Period in which subjects are consented and undergo screening assessments
           to be qualified for the study;

        -  A Treatment Period in which subjects receive study treatment and undergo study
           assessments. Patients who meet the eligibility criteria will be treated with
           cabozantinib orally at 40 mg daily and erlotinib orally at 100 mg daily without breaks;

        -  A Post-Treatment Period in which subjects no longer receive study treatment but undergo
           follow-up study assessments and contacts.
    

Eligibility criteria:

        Inclusion Criteria

        A subject must fully meet all of the following criteria to be eligible for the study:

          1. 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 RECIST 1.1;

          2. The subject must have tumor that is amenable to fine needle biopsy via computerized
             tomography (CT) guided approach OR an archived tissue sample such as a prior surgical
             sample or biopsy sample that is adequate for testing;

          3. The subject must have EGFR and c-Met overexpressed in tumor as determined by
             immunohistochemistry (IHC) test score of 2+ for both markers;

          4. The subject has demonstrated radiographic progression after front-line treatment for
             locally advanced or metastatic disease (prior adjuvant therapy allowed if ≥ 6 months
             elapsed between end of adjuvant therapy and metastatic relapse);

          5. The subject is ≥ 18 years old on the day of consent;

          6. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0
             or 1;

          7. The subject has recovery to baseline or ≤ Grade 1 CTCAE v.4.03 from toxicities related
             to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on
             supportive therapy;

          8. The subject has organ and marrow function and laboratory values as follows within 7
             days before the first dose of study treatment:

               1. The ANC ≥ 1500/mm3 without colony stimulating factor support;

               2. Platelets ≥ 100,000/mm3;

               3. Hemoglobin ≥ 9 g/dL;

               4. Bilirubin ≤ 1.5 x the ULN. For subjects with known Gilbert's disease, bilirubin ≤
                  3.0 mg/dL;

               5. AST/ALT ≤ 3 x the ULN;

               6. Serum albumin ≥ 2.8 g/dl;

               7. 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:

             i. Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72); ii. Female:
             Multiply above result by 0.85; h. UPCR ≤ 1; i. Serum phosphorus, calcium, magnesium
             and potassium ≥ LLN; j. Prothrombin time (PT)/INR or partial thromboplastin time (PTT)
             test < 1.3 x the ULN within 7 days before the first dose of study treatment;

          9. The subject is capable of understanding and complying with the protocol requirements
             and has signed the informed consent document;

         10. The subject has a life expectancy of 12 weeks or greater;

         11. The subject is able to tolerate oral medications and no evidence of ongoing
             malabsorption;

         12. 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);

         13. 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

        A subject who meets any of the following criteria is ineligible for the study:

          1. The subject has received cytotoxic chemotherapy (including investigational cytotoxic
             chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or
             nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment;

          2. Prior treatment with cabozantinib or erlotinib;

          3. 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;

          4. Receipt of any type of small molecule kinase inhibitor (including investigational
             kinase inhibitor) within 14 days before the first dose of study treatment;

          5. The subject has received any other type of investigational agent within 28 days before
             the first dose of study treatment;

          6. 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;

          7. 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 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.

          8. The subject has experienced any of the following:

               1. clinically-significant GI bleeding within 6 months before the first dose of study
                  treatment;

               2. hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the
                  first dose of study treatment;

               3. any other signs indicative of pulmonary hemorrhage within 3 months before the
                  first dose of study treatment; and

               4. clinically confirmed history of interstitial lung disease (ILD).

          9. The subject has radiographic evidence of cavitating pulmonary lesion(s);

         10. The subject has tumor invading or encasing any major blood vessels;

         11. 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;

         12. The subject has uncontrolled, significant intercurrent or recent illness including,
             but not limited to, the following conditions:

             a. Cardiovascular disorders including: i. Congestive heart failure (CHF): New York
             Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of
             screening; ii. 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 of the first dose of study treatment; iii.
             Any history of congenital long QT syndrome; iv. 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. b. GI disorders particularly those associated with a high
                  risk of perforation or fistula formation including: i. 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 ii. 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 c. Other clinically significant disorders
                  that would preclude safe study participation;

         13. 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;

         14. QTcF > 500 msec within 1 month before the first dose of study treatment:

             a. Three ECGs 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.

         15. Pregnant or lactating females;

         16. Active smoker;

         17. Inability to swallow intact tablets;

         18. Previously identified allergy or hypersensitivity to components of the study treatment
             formulations;

         19. 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.