Cabozantinib Plus Durvalumab with or Without Tremelimumab in Patients with Gastroesophageal Cancer and Other Gastrointestinal Malignancies

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 SolidTumors (RECIST) version 1.1

6. Patients must consent to undergo a required screening/baseline biopsy procedure (andpotentially another tumor biopsy at time of disease response and progression) forcorrelative testing.

7. Patients with gastric, gastroesophageal, or esophageal adenocarcinoma must showevidence of progression or intolerance to at least one previous standard of caresystemic therapy.

8. Patients with CRC must show evidence of progression or intolerance to at least 2previous standard of care systemic therapy. Ras wild type patients should failepidermal growth factor receptor (EGFR) monoclonal antibody (panitumumab orcetuximab) to be eligible.

9. Patients with HCC must must be treatment naive or show evidence of diseaseprogression or intolerance to at least 1 previous standard of care systemic therapy.

10. Patients should have known tumor results for microsatellite instability (MSI) ormismatch repair (MMR) proteins. If unknown, analysis will be obtained through localpathology lab using archival tissue if available or the baseline tumor biopsy.

11. Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any priortreatments unless AE(s) are clinically nonsignificant and/or stable on supportivetherapy.

12. Body weight > 66 lbs (30 kg)

13. Adequate organ and marrow function.

14. Evidence of post-menopausal status or negative urinary or serum pregnancy test forfemale pre-menopausal patients.

15. Women of child-bearing potential and men with partners of child-bearing potentialmust 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 oftherapy. Men of child-bearing potential must not donate sperm while on this studyand for 180 Days after their last study treatment.

Exclusion Criteria:

1. Prior treatment with a Programmed cell death protein 1 (PD1) or (PD-L1) inhibitor,including durvalumab, or anti PD-L2 (HCC and gastric / esophageal cancer patientswith prior exposure to these agents are eligible).

2. Prior treatment with cabozantinib or other Receptor for hepatocyte growth factor (MET) or Dual MET/ Hepatocyte growth factor (HGF) monoclonal antibodies or MET/HGFtyrosine kinase inhibitors (TKIs), including crizotinib, foretinib, tivantinib,rilotumumab, and onartuzumab.

3. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscesswithin 6 months before first dose.

• Evidence of tumor invading the GI tract, (Defined as T4 primary tumor inpatients with gastric, gastroesophageal and esophageal adenocarcinoma and CRC).

• Gastric or esophageal varices that are untreated or incompletely treated withbleeding or high risk for bleeding. Subjects treated with adequate endoscopictherapy (according to institutional standards) without any episodes ofrecurrent GI bleeding requiring transfusion or hospitalization for at least 6months prior to study entry are eligible.

4. Evidence of active peptic ulcer disease, inflammatory bowel disease (eg, Crohn'sdisease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis,acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, orgastric outlet obstruction.

5. Inability to swallow tablets.

6. Uncontrollable ascites or pleural effusion.

7. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial diseasemanifestation.

8. Clinically significant hematuria, hematemesis, or hemoptysis of >0.5 tsp (2.5ml) ofred blood, or other history of significant bleeding within 12 weeks.

• Any sign indicative of pulmonary hemorrhage within 3 months.

• Lesions invading any major blood vessels. HCC subjects with lesions invading thehepatic portal vasculature are eligible.

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 ofradiation within 4 weeks of the first dose of study drug

11. Major surgery (eg, Gastrointestinal (GI) surgery, removal or biopsy of brainmetastasis) within 8 weeks before first dose of study treatment.

12. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids orsystemic 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 humanimmunodeficiency virus. HCC patients with hepatitis B or C infection are allowed perprotocol specific criteria.

17. Receipt of live attenuated vaccine within 30 days prior to the first dose.

18. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 millimeterof mercury (mm Hg) systolic or > 90 mm Hg diastolic despite optimal antihypertensivetreatment.

19. Stroke, including transient ischemic attack (TIA), myocardial infarction (MI), orother ischemic event, or thromboembolic event (eg, deep venous thrombosis, pulmonaryembolism) within 6 months before first dose. Participants with a diagnosis of deepvenous thrombosis (DVT) within 6 months are allowed if stable, asymptomatic, andtreated with Low Molecular Weight Heparin (LMWH) for at least 2 weeks before firstdose.

20. Has untreated central nervous system (CNS) metastases and/or carcinomatousmeningitis

21. Clinically significant disorders that would preclude safe study participation.

22. History of another primary malignancy except for:

• Malignancy treated with curative intent/ resection and with no known activedisease before the first dose of investigational product (IP) and of lowpotential risk for recurrence.

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease.

• Adequately treated carcinoma in situ without evidence of disease.

24. Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, directthrombin and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel).Allowed anticoagulants are the following:

a. Low-dose aspirin for cardioprotection (per local applicable guidelines) is permitted.

b. Low-dose (prophylactic) low molecular weight heparins (LMWH) are permitted. c. Anticoagulation with therapeutic doses of LMWH is allowed in subjects with no known brain metastases, clinically significant hemorrhage, or complications from a thromboembolic event on the anticoagulation regimen (subjects with HCC must also have a screening platelet count >100,000/μl), and who have been on a stable dose of LMWH for at least 1 week before first dose.

25. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.