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

NCT03539822 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: HCC 22-192
• Study Type: interventional
• Target: 117
• Locations: 1 country
• Sites: 2

Brief Summary

The investigators propose to evaluate the safety of drug combinations in patients with advanced gastroesophageal cancer and other gastrointestinal (GI) malignancies. Finding effective novel therapies for patients with advanced gastric cancer and other GI malignancies is an area of 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 I/II, open label, multi-cohort trial looking at safety, tolerability and efficacy endpoints.

Conditions

Gastric Cancer; Esophageal Adenocarcinoma; Hepatocellular Carcinoma; Colorectal Cancer

Keywords

Cabozantinib; Durvalumab; Tremelimumab

Outcome Measures

Primary Outcomes (2)

• Phase I- Maximum Tolerated Dose (MTD)

  Defined as the highest dose studied for which the observed incidence of dose limiting toxicities (DLT) is less than 33%. Determined per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

  9 months

• Phase II- Overall Response Rate (ORR)

  Defined as the proportion of participants best response to treatment. Per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

  Every 8 weeks for 12 months

Secondary Outcomes (4)

• Proportion of participants with adverse events (AEs).

  18 months

• Overall Benefit Rate (OBR)

  18 months

• Progression Free Survival (PFS)

  24 months

• Overall Survival (OS)

  24 months

Study Arms (4)

Cabozantinib plus Durvalumab (Gastric & esophageal cancer cohort)

EXPERIMENTAL

Cabozantinib * By mouth (PO) once daily on days 1-28 of every 28 day cycle * Dose will be 40mg Durvalumab \*Flat dose of 1500mg intravenous (IV) Infusion on day 1 of every 28 day cycle

Drug: Cabozantinib; Drug: Durvalumab

Cabozantinib plus Durvalumab (Colorectal cancer cohort)

EXPERIMENTAL

Cabozantinib * By mouth (PO) once daily on days 1-28 of every 28 day cycle * Dose will be 40mg Durvalumab \*Flat dose of 1500mg intravenous (IV) Infusion on day 1 of every 28 day cycle

Drug: Cabozantinib; Drug: Durvalumab

Cabozantinib plus Durvalumab (Hepatocellular carcinoma cohort)

EXPERIMENTAL

Cabozantinib * By mouth (PO) once daily on days 1-28 of every 28 day cycle * Dose will be 40mg Durvalumab \*Flat dose of 1500mg intravenous (IV) Infusion on day 1 of every 28 day cycle

Drug: Cabozantinib; Drug: Durvalumab

Cabozantinib plus Durvalumab plus Tremelimumab (Hepatocellular carcinoma cohort)

EXPERIMENTAL

Cabozantinib * By mouth (PO) once daily on days 1-28 of every 28 day cycle * Dose will be 40mg Durvalumab \*Flat dose of 1500mg intravenous (IV) Infusion on day 1 of every 28 day cycle Tremelimumab \*Single dose of 300mg intavenous (IV) infusion on day 1 of cycle 1

Drug: Cabozantinib; Drug: Durvalumab; Drug: Tremelimumab

Interventions

Cabozantinib DRUG

by mouth

Also known as: multi-tyrosine kinase Inhibitor

Cabozantinib plus Durvalumab (Colorectal cancer cohort); Cabozantinib plus Durvalumab (Gastric & esophageal cancer cohort); Cabozantinib plus Durvalumab (Hepatocellular carcinoma cohort); Cabozantinib plus Durvalumab plus Tremelimumab (Hepatocellular carcinoma cohort)

Durvalumab DRUG

infusion

Also known as: anti-Programmed cell death protein 1 (PD-L1) inhibitor

Cabozantinib plus Durvalumab (Colorectal cancer cohort); Cabozantinib plus Durvalumab (Gastric & esophageal cancer cohort); Cabozantinib plus Durvalumab (Hepatocellular carcinoma cohort); Cabozantinib plus Durvalumab plus Tremelimumab (Hepatocellular carcinoma cohort)

Tremelimumab DRUG

infusion

Also known as: Anti-CTLA4 inhibitor

Cabozantinib plus Durvalumab plus Tremelimumab (Hepatocellular carcinoma cohort)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
• Histologically confirmed diagnosis of any of the following:
• Gastric or gastroesophageal junction adenocarcinoma
• Esophageal adenocarcinoma
• Colorectal adenocarcinoma (CRC)
• Hepatocellular carcinoma (HCC)
• Patients should have advanced (stage 4) or locally unresectable (stage III) disease.
• Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• 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.
• Patients with gastric, gastroesophageal, or esophageal adenocarcinoma must show evidence of progression or intolerance to at least one previous standard of care systemic therapy.
• 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.
• \. For cohort 3: Patients with HCC must show evidence of disease progression or intolerance to at least 1 previous systemic regimen (not more than 2 lines of prior therapy).
• \. For cohort 4: Patients with HCC must be treatment naïve or show evidence of disease progression or intolerance to at least 1 previous systemic regimen (not more than 2 lines of prior therapy).
• \. Patients should have known tumor results for microsatellite instability (MSI) or mismatch repair (MMR) proteins. If unknown, analysis will be obtained through local pathology lab using archival tissue if available or the baseline tumor biopsy.

You may not qualify if:

• 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 patients with prior exposure to these agents are eligible).
• 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), including crizotinib, foretinib, tivantinib, rilotumumab, and onartuzumab.
• Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose.
• \* Evidence of tumor invading the GI tract, (Defined as T4 primary tumor in patients with gastric, gastroesophageal and esophageal adenocarcinoma and CRC).
• \* Gastric or esophageal varices that are untreated or incompletely treated with bleeding or high risk for bleeding. Subjects treated with adequate endoscopic therapy (according to institutional standards) without any episodes of recurrent GI bleeding requiring transfusion or hospitalization for at least 6 months prior to study entry are eligible.
• 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.
• Inability to swallow tablets.
• Uncontrollable ascites or pleural effusion.
• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation.
• Clinically significant hematuria, hematemesis, or hemoptysis of \>0.5 tsp (2.5ml) of red 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 the hepatic portal vasculature are eligible.
• Any unresolved toxicity CTCAE Grade ≥2 from previous anticancer therapy
• 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
• Major surgery (eg, Gastrointestinal (GI) surgery, removal or biopsy of brain metastasis) within 8 weeks before first dose of study treatment.

Sponsors & Collaborators

• Anwaar Saeed: lead
• AstraZeneca: collaborator
• Exelixis: collaborator

Study Sites (2)

University of Kansas Cancer Center

Westwood, Kansas, 66205, United States

TERMINATED

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

MeSH Terms

Conditions

Stomach Neoplasms; Adenocarcinoma Of Esophagus; Carcinoma, Hepatocellular; Colorectal Neoplasms

Interventions

cabozantinib; durvalumab; tremelimumab

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Liver Neoplasms; Liver Diseases; Intestinal Neoplasms; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Anwaar Saeed, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Debra Diecks, RN

CONTACT

4126238364; diecksda@upmc.edu

Clare Grzejka, RN

CONTACT

4126234891; grzejkac@upmc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Model Details: Phase II has 4 disease cohorts, the first 3 with 29 patients each, the 4th cohort for advanced HCC patients with 24 patients, preceded by a 6-9 patient safety lead-in.

Study Record Dates

• First Submitted: May 16, 2018
• First Posted: May 29, 2018
• Study Start: October 22, 2018
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2029
• Last Updated: January 21, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)