Neoplasms

Digestive System Diseases

All Conditions

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Irinotecan

Panitumumab

Topoisomerase I Inhibitors

Enzyme Inhibitors

Antineoplastic Agents, Immunological

Glutamine

Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28, panitumumab IV over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Glutaminase Inhibitor CB-839

Irinotecan Hydrochloride (phase I only)

Laboratory Biomarker Analysis

Pharmacological Study

During phase II at baseline and day 28 of cycle 1

Imaging with 11C-Glutamine PET/CT scans and 18F-FSPG PET/CT scans

Jordan Berlin, MD

This phase I/II trial studies the best dose and side effects of glutaminase inhibitor CB-839 and how well it works with panitumumab and irinotecan hydrochloride (phase I only) in treating patients with RAS wildtype colorectal cancer that has spread to other places in the body and does not respond to treatment. Glutaminase inhibitor CB-839 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as panitumumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving glutaminase inhibitor CB-839 with panitumumab and irinotecan hydrochloride may work better in treating patients with colorectal cancer.

Objectives:

Primary Objective of Phase I:

• Determine the safety and tolerability of CB-839 in combination with panitumumab and irinotecan.

Exploratory Objective of Phase I (Optional Imaging Sub-study):

• Correlate radiological features of pre- and post-treatment 11C-Glutamine PET/CT and 18F-FSPG PET/CT with clinical outcome.

Primary Objective of Phase II:

• Determine the efficacy of CB-839 in combination with panitumumab as measured by the response rate (RR).

Secondary Objectives of Phase II:

* Determine the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
* Perform the following correlative studies (in the phase 2 component):
* Correlate radiological features of pre- and post-treatment 18F-FSPG PET/CT with clinical outcome and biological correlates (tissue gene signature, exosomes).
* Collect blood samples during each radiotracer injection to assess pharmacokinetics.
* Collect pre-treatment biopsy tissue and prospectively correlate clinical outcome with a glutamine metabolism gene signature.
* Quantify exosomal content in the plasma.

Exploratory Objective of Phase II:

• Development of patient-derived organoids from pre-treatment tissue biopsy

OUTLINE: Phase I is a dose-escalation study of glutaminase inhibitor CB-839 in combination with standard doses of panitumumab and irinotecan hydrochloride. Phase II will study efficacy of glutaminase inhibitor CB-839 in combination with standard doses of panitumumab.

Patients receive glutaminase inhibitor CB-839 orally (PO) twice daily (BID) on days 1-28, panitumumab intravenously (IV) over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 28 days and then every 3 months for up to 1 year.

Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer

Phase I/II Study to Evaluate the Safety, Efficacy, and Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer

The maximum tolerated dose will be determined

Will use Simon's optimal 2-stage design to monitor efficacy in this trial.

The recommended phase 2 dose will be determined.

The disease control rate will be evaluated.

evaluate the relationship between 18F-FSPG uptake at baseline and change in tumor size at the time of objective response assessment using a standard linear regression analysis. The slope will describe the shape of the relationship between SUVmax and change in tumor size, while the coefficient of determination (R2) describes the strength of the relationship between the two measures. A similar linear regression analysis will be conducted to quantify the relationship between the change in SUVmax as measured from baseline to after one cycle of therapy and change in tumor size.

Plasma exosomal content will be assessed at pre-treatment, after one cycle of treatment, and at disease progression.

will use Cox proportional hazards model to estimate the association between PET SUVmax and OS.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer	NCT03263429	Colorectal Canc... Metastatic Colo... RAS Wild Type C... Refractory Colo...	Glutaminase Inh... Panitumumab Irinotecan Hydr... Laboratory Biom... Pharmacological... Imaging with 11...	18 Years -	Vanderbilt-Ingram Cancer Center
Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer	NCT03263429	Colorectal Canc... Metastatic Colo... RAS Wild Type C... Refractory Colo...	Glutaminase Inh... Panitumumab Irinotecan Hydr... Laboratory Biom... Pharmacological... Imaging with 11...	18 Years -	Vanderbilt-Ingram Cancer Center

Spots Global Cancer Trial Database for irinotecan hydrochloride (phase i only)