Patient case: 54-year-old male with malignant hyperthermia; genetic feature: RYR1

Clinical trial: Cabozantinib in Combination With Durvalumab in Patients With Gastroesophageal Cancer and Other Gastrointestinal Malignancies (CAMILLA)

Summary: The investigators propose to evaluate cabozantinib in combination with durvalumab in previously treated patients with advanced gastroesophageal cancer and other gastrointestinal (GI) malignancies. Finding effective novel therapies after failing the current standard of care chemotherapy options for patients with advanced gastric cancer and other GI malignancies is an area or great unmet need. The investigators believe that modulating the tumor microenvironment with biologic agents like cabozantinib will have synergistic effect when combined with checkpoint-based immunotherapeutics like durvalumab in this patient population. This is a phase 1b, open label, single arm trial looking at safety, tolerability and preliminary efficacy endpoints.


Eligibility: Inclusion Criteria:
  1. Age ≥ 18 years
  2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
  3. Histologically confirmed diagnosis of any of the following:
  -  Gastric or gastroesophageal junction adenocarcinoma
  -  Esophageal adenocarcinoma
  -  Colorectal adenocarcinoma (CRC)
  -  Hepatocellular carcinoma (HCC)
  4. Patients should have advanced (stage 4) or locally unresectable (stage III) disease.
  5. Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
  6. Patients must consent to undergo a required screening/baseline biopsy procedure (and potentially another tumor biopsy at time of disease response and progression) for correlative testing.
  7. Patients with gastric, gastroesophageal, or esophageal adenocarcinoma must show evidence of progression or intolerance to at least two previous standard of care systemic therapy.
  8. Patients with CRC must show evidence of progression or intolerance to at least 2 previous standard of care systemic therapy. Ras wild type patients should fail epidermal growth factor receptor (EGFR) monoclonal antibody (panitumumab or cetuximab) to be eligible.
  9. Patients with HCC must show evidence of disease progression or intolerance to at least 1 previous standard of care systemic therapy.
  10. Adequate organ and marrow function.
  11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients.
  12. Women of child-bearing potential and men with partners of child-bearing potential must agree to use the highly effective forms of contraception prior to study entry, for the duration of study participation, and for 180 Days post completion of therapy. Men of child-bearing potential must not donate sperm while on this study and for 180 Days after their last study treatment.
  Exclusion Criteria:
  1. Prior treatment with a programmed death (PD)1 or PD-ligand (L)1 inhibitors or any agent directed to another co-inhibitory T cell receptor.
  2. Prior treatment with cabozantinib or other Receptor for hepatocyte growth factor (MET) or Dual MET/hepatocyte growth factor (HGF) monoclonal antibodies or MET/HGF tyrosine kinase inhibitors (TKIs).
  3. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose.
  4. Evidence of active peptic ulcer disease, inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
  5. Inability to swallow tablets.
  6. Uncontrollable ascites or pleural effusion
  7. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
  8. Clinically significant hematuria, hematemesis, or hemoptysis of >0.5 tsp (2.5ml) of red blood, or other history of significant bleeding within 12 weeks
  9. Any unresolved toxicity CTCAE Grade ≥2 from previous anticancer therapy
  10. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
  11. Major surgery (eg, Gastrointestinal (GI) surgery, removal or biopsy of brain metastasis) within 8 weeks before first dose of study treatment.
  12. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses.
  13. History of allogenic organ transplantation.
  14. Active or prior documented autoimmune or inflammatory disorders
  15. History of active primary immunodeficiency
  16. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus.
  17. Receipt of live attenuated vaccine within 30 days prior to the first dose.
  18. Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 millimeter of mercury (mm Hg) systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment.
  19. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 6 months before first dose
  20. Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis
  21. Clinically significant disorders that would preclude safe study participation.
  22. History of another primary malignancy except for:
  -  Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose and of low potential risk for recurrence
  -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  -  Adequately treated carcinoma in situ without evidence of disease
  24. Concomitant anticoagulation with oral anticoagulants (examples: warfarin, direct thrombin) or platelet inhibitors (clopidogrel).
  25. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

Relevance to patient case: not relevant