Neoplasms

All Conditions

Digestive System Diseases

Adenocarcinoma

Colorectal Neoplasms

Rectal Neoplasms

Colonic Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Antibodies

Antibodies, Monoclonal

Immunomodulating Agents

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

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.

Cabozantinib

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.

Alexis Leal, MD

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.

This is an open-label, single-arm, 2-stage, phase II study of cabozantinib in combination with nivolumab in patients with refractory metastatic CRC. Up to 46 evaluable patients will be treated with cabozantinib 40 mg orally daily in combination with nivolumab 480 mg IV every 28 days. One cycle is defined as 28 days.

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

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

De-identified IPD will be available to other researchers for the purposes of investigating the research objectives of this clinical trial.

De-identified patient samples will be collected, processed and analyzed by our research laboratory collaborators to investigate our experimental objectives and endpoints outlined in the protocol. Research samples will be banked and additional testing/experiments may be undertaken pending the acquisition of additional funding to support this work.

De-identified IPD will be shared with study Sponsors (Bristol Myers Squibb and Exelixis) as well as collaborating CRO (Criterium doing business as AGICC (Academic GI Cancer Consortium)) during regular study teleconferences.

Future plans for sharing of IPD from final trial results have not yet been determined

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.

ORR is defined using the RECIST 1.1 criteria as the proportion of subjects with a confirmed complete response (CR) or confirmed partial response (PR).

PFS will be defined as the time from administration of the initial dose of study treatment to evidence of radiographic progression as defined by RECIST 1.1 criteria or death from any cause without evidence of disease progression, whichever occurs first.

OS will be defined as the time from administration of the initial dose of study treatment until death from any cause.

Safety and tolerability analysis of cabozantinib in combination with nivolumab summarized by dose and severity as assessed by the CTCAE version 5.0 and relationship to study drugs.

Exploratory analysis of predictive and pharmacodynamic markers by obtaining pre- and on-treatment whole blood samples pretreatment and +/- 5 days of Cycle 2 Day 1 of treatment for each patient and archived for future studies and analysis.

Exploratory analysis of predictive and pharmacodynamic markers by obtaining pre- and on-treatment tumor biopsies pre-treatment and +/- 5 days of Cycle 2 day 1 of treatment for a cohort of 20 patients for VECTRA analysis to evaluate for immune cell infiltration. Tissue will be archived for future studies.

Spots Global Cancer Trial Database for Study of Cabozantinib and Nivolumab in Refractory Metastatic Microsatellite Stable (MSS) Colorectal Cancer

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