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

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.