Study of Cabozantinib and Nivolumab in Refractory Metastatic Microsatellite Stable (MSS) Colorectal Cancer

NCT04963283 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 21-2687.ccP30CA046934
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 5

Brief Summary

Data from a prior phase II study of single agent cabozantinib in metastatic, refractory colorectal cancer (NCT03542877) combined with the compelling preclinical data in colorectal mouse models utilizing cabozantinib combined with nivolumab have led to this concept for a clinical trial to combine cabozantinib and nivolumab in patients with metastatic MSS CRC in the third line setting and beyond.

Conditions

Colon Adenocarcinoma; Rectum Cancer; Rectal Cancer; Rectal Adenocarcinoma; Colorectal Cancer; Colorectal Adenocarcinoma; Colon Cancer

Keywords

cabozantinib; nivolumab; immunotherapy; opdivo; cabometyx

Outcome Measures

Primary Outcomes (1)

• Disease Control Rate (DCR)

  DCR is defined using the RECIST 1.1 criteria as the proportion of subjects who have achieved confirmed complete response (CR), confirmed partial response (PR) or stable disease (SD) at 16-weeks.

  Study start date to study end date, or death, whichever comes first, up to 24 months

Secondary Outcomes (6)

• Objective Response Rate (ORR)

  Study start date to study end date, or death, whichever comes first, up to 24 months

• Progression Free Survival (PFS)

  Study start date to study end date, or death, whichever comes first, up to 24 months

• Overall Survival (OS)

  Study start date to study end date, or death, whichever comes first, up to 24 months

• Safety and Tolerability

  Study start date to study end date, or death, whichever comes first, up to 24 months

• Exploratory Biomarker analysis - Whole Blood

  Study start date to study end date, up to 24 months

Study Arms (1)

Cabozantinib 40 mg orally daily in combination with nivolumab 480 mg IV every 28 days.

EXPERIMENTAL

Cabozantinib is supplied as 20-mg tablets and will be administered orally at a dose of 40 mg/day. Nivolumab is supplied in 100 mg/Vial (10 mg/mL) vials and will be administered IV at a dose of 480 mg every 28 days.

Drug: Cabozantinib; Drug: Nivolumab

Interventions

Cabozantinib DRUG

Cabozantinib is a multi-targeted inhibitor of RTKs. The targets of cabozantinib include several RTKs known to play important roles in tumor cell proliferation and/or tumor neovascularization, namely MET, VEGFR2 (also known as KDR), AXL, and RET. Other recognized targets of cabozantinib include ROS1, TRKA, TRKB, TIE2, TYRO3, and MER, two additional members of the VEGFR family (VEGFR1, VEGFR3), and the closely related RTKs KIT and FLT-3. The mode of action for cabozantinib is similar to other drugs targeting RTKs: binding in a fully reversible manner to a region of the kinase domain (including the ATP-binding site) which forces the kinase activation loop into a pseudo-inactive conformation, thereby inhibiting subsequent catalytic activity.

Also known as: Cabometyx

Cabozantinib 40 mg orally daily in combination with nivolumab 480 mg IV every 28 days.

Nivolumab DRUG

Nivolumab is a human monoclonal antibody that targets the programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. Nivolumab binds specifically to the human PD-1 receptor and inhibits the interaction of PD-1 with its ligands, programmed death ligands-1 (PD-L1) and 2 (PD-L2), which promotes immune responses and antigen-specific T-cell responses to foreign- and self- antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using standard mammalian cell cultivation and chromatographic purification technologies.

Also known as: Opdivo

Cabozantinib 40 mg orally daily in combination with nivolumab 480 mg IV every 28 days.

Eligibility Criteria

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

You may qualify if:

• The subject has a histologic or cytologic diagnosis of colorectal adenocarcinoma that is metastatic or unresectable;
• The patient either did not tolerate, is refractory to or progressed (or relapsed) following treatment with a fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab;
• Prior epidermal growth factor inhibitor therapy is required for patients with left-sided, RAS wild-type tumors;
• Patients must be microsatellite stable (MSS), microsatellite-low (MSI-L) or have proficient mismatch repair (pMMR;
• Prior TAS-102 (Lonsurf) treatment is not required;
• Patients must have known extended RAS and BRAF status as per local standard of practice;
• Measurable disease per RECIST v.1.1 as determined by the investigator;
• The subject has had an assessment of all known disease sites e.g. by computerized tomography (CT) scan and/or magnetic resonance imaging (MRI) within 28 days before the first dose of cabozantinib;
• The subject is ≥ 18 years old on the day of consent;
• The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
• Recovery to baseline or ≤ Grade 1 CTCAE v.5.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy;
• Adequate archival tissue available from primary or metastatic site for biomarker analysis (20 unstained FFPE slides and/or tumor block with minimum of 15 slides needed for eligibility). Tissue from the primary site is preferable for analysis, but if unavailable, tissue from a metastatic site may be utilized;
• \. Subjects enrolled in Part 2 of this study must have a site of disease that is amenable to biopsy and be a candidate for tumor biopsy prior to the first dose of study drug to be considered for this study;
• subjects enrolled in Part 2 of the study will be required to undergo mandatory pre- and on-treatment tumor biopsies.
• subjects enrolled in Part 2 of the study will not be required to undergo a mandatory tumor biopsy and thus not required to have disease amenable to biopsy;

You may not qualify if:

• Known microsatellite-high (MSI-H) or deficient mismatch repair (dMMR) colorectal cancer.
• 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;
• Prior treatment with cabozantinib or other small molecule kinase inhibitors;
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways;
• 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;
• The subject has received any other type of investigational agent within 28 days before the first dose of study treatment;
• 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;
• The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3 x the laboratory ULN within 7 days before the first dose of study treatment;
• Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran). Direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
• Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
• Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor;
• Clinically significant hematuria, hematemesis, or hemoptysis of \> 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose of study treatment;
• The subject has radiographic evidence of cavitating pulmonary lesion(s) or known endobronchial disease manifestation;
• The subject has tumor invading or encasing any major blood vessels;
• The subject has evidence of clinically significant bleeding from 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 study treatment;

Sponsors & Collaborators

• University of Colorado, Denver: lead
• Criterium, Inc.: collaborator
• National Cancer Institute (NCI): collaborator
• Bristol-Myers Squibb: collaborator
• Exelixis: collaborator

Study Sites (5)

University of Colorado Hospital

Aurora, Colorado, 80012, United States

Location

UCHealth Memorial Hospital Central

Colorado Springs, Colorado, 80909, United States

Location

UCHealth Harmony Campus

Fort Collins, Colorado, 80528, United States

Location

UCHealth Family Medicine - Greeley

Greeley, Colorado, 80634, United States

Location

UCHealth Medical Center of the Rockies

Loveland, Colorado, 80538, United States

Location

MeSH Terms

Conditions

Colonic Neoplasms; Rectal Neoplasms; Colorectal Neoplasms

Interventions

cabozantinib; Nivolumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Alexis Leal, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a Phase 2, single-arm, open-label study of cabozantinib in combination with nivolumab in subjects with metastatic CRC refractory to standard of care options. The primary endpoint is DCR at 16 weeks. A Simon 2-stage optimal design will be used.

Study Record Dates

• First Submitted: July 12, 2021
• First Posted: July 15, 2021
• Study Start: June 23, 2021
• Primary Completion: February 24, 2026
• Study Completion (Estimated): February 9, 2027
• Last Updated: March 31, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Through 12/2022 For 1 year thereafter
• Access Criteria: Research collaborator Access will be to de-identified individual patient data and via password protected, encrypted website or database access

Locations

US (5)