CGT9486 (Formerly Known as PLX9486) as a Single Agent and in Combination With PLX3397 (Pexidartinib) or Sunitinib in Participants With Advanced Solid Tumors

NCT ID: NCT02401815

Last Updated: 2025-02-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 51 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-03-06
• Study Completion Date: 2020-05-11

Brief Summary

The goal of this clinical research study is to learn how CGT9486 (fka PLX9486) may affect cancer cells with certain mutations in the KIT gene, specifically in participants with types of advanced solid tumors including gastrointestinal stromal tumor (GIST).

CGT9486 (fka PLX9486) is designed to block KIT gene mutations. These mutations can cause cancer and cancer cell growth. By blocking these mutations, the drug may kill the cancer cells with the mutation and/or stop the tumor from growing. By combining CGT9486 (fka PLX9486) with PLX3397 and CGT9486 (fka PLX9486) with sunitinib, the investigators hope to block most KIT gene mutations that drive cancer growth.

Detailed Description

This study includes a dose escalation portion (Part 1) in which the safety profile and recommended phase 2 dose (RP2D) of CGT9486 as a single oral agent will be evaluated in participants with solid tumors (including GIST), followed by signal-seeking extension cohorts (Part 2). Enrollment in the combination treatment portions of the study (dose-finding for the CGT9486 + pexidartinib combination [Part 2b] and the CGT9486 + sunitinib combination [Part 2e]) is planned to be accrued using standard 3+3 study designs.

Parts 2a, 2c, 2d, and 2f are not conducted due to business decisions.

Conditions

Gastrointestinal Stromal Tumors

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part 1: CGT9486 250 mg QD

Participants will receive CGT9486 250 milligrams (mg) orally once daily (QD) in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.

Group Type: EXPERIMENTAL

CGT9486

Intervention Type: DRUG

CGT9486 will be administered per dose and schedule specified in the arm.

Part 1: CGT9486 350 mg QD

Participants will receive CGT9486 350 mg orally QD in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.

Group Type: EXPERIMENTAL

CGT9486

Intervention Type: DRUG

CGT9486 will be administered per dose and schedule specified in the arm.

Part 1: CGT9486 500 mg QD

Participants will receive CGT9486 500 mg orally QD in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.

Group Type: EXPERIMENTAL

CGT9486

Intervention Type: DRUG

CGT9486 will be administered per dose and schedule specified in the arm.

Part 1: CGT9486 1000 mg QD

Participants will receive CGT9486 1000 mg orally QD in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.

Group Type: EXPERIMENTAL

CGT9486

Intervention Type: DRUG

CGT9486 will be administered per dose and schedule specified in the arm.

Part 1: CGT9486 500 mg BID

Participants will receive CGT9486 500 mg orally twice daily (BID) in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.

Group Type: EXPERIMENTAL

CGT9486

Intervention Type: DRUG

CGT9486 will be administered per dose and schedule specified in the arm.

Part 2b: CGT9486 500 mg QD + Pexidartinib 600 mg (Fasting)

Participants in fasting condition will receive CGT9486 500 mg orally QD in combination with pexidartinib 600 mg (administered as 1 capsule of 200 mg in the morning and 2 capsules of 200 mg in the evening) orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.

Group Type: EXPERIMENTAL

CGT9486

Intervention Type: DRUG

CGT9486 will be administered per dose and schedule specified in the arm.

Pexidartinib

Intervention Type: DRUG

Pexidartinib capsules will be administered per dose and schedule specified in the arm.

Part 2b: CGT9486 500 mg QD + Pexidartinib 600 mg (Non-Fasting)

Participants in non-fasting condition will receive CGT9486 500 mg orally QD in combination with pexidartinib 600 mg (administered as 1 capsule of 200 mg in the morning and 2 capsules of 200 mg in the evening) orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.

Group Type: EXPERIMENTAL

CGT9486

Intervention Type: DRUG

CGT9486 will be administered per dose and schedule specified in the arm.

Pexidartinib

Intervention Type: DRUG

Pexidartinib capsules will be administered per dose and schedule specified in the arm.

Part 2e: CGT9486 500 mg QD + Sunitinib 25 mg

Participants will receive CGT9486 500 mg orally QD in combination with sunitinib 25 mg orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.

Group Type: EXPERIMENTAL

CGT9486

Intervention Type: DRUG

CGT9486 will be administered per dose and schedule specified in the arm.

Sunitinib

Intervention Type: DRUG

Sunitinib will be administered per dose and schedule specified in the arm.

Part 2e: CGT9486 1000 mg QD + Sunitinib 25 mg

Participants will receive CGT9486 1000 mg orally QD in combination with sunitinib 25 mg orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.

Group Type: EXPERIMENTAL

CGT9486

Intervention Type: DRUG

CGT9486 will be administered per dose and schedule specified in the arm.

Sunitinib

Intervention Type: DRUG

Sunitinib will be administered per dose and schedule specified in the arm.

Part 2e: CGT9486 1000 mg QD + Sunitinib 37.5 mg

Participants will receive CGT9486 1000 mg orally QD in combination with sunitinib 37.5 mg orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.

Group Type: EXPERIMENTAL

CGT9486

Intervention Type: DRUG

CGT9486 will be administered per dose and schedule specified in the arm.

Sunitinib

Intervention Type: DRUG

Sunitinib will be administered per dose and schedule specified in the arm.

Interventions

CGT9486

CGT9486 will be administered per dose and schedule specified in the arm.

Intervention Type: DRUG

Pexidartinib

Pexidartinib capsules will be administered per dose and schedule specified in the arm.

Intervention Type: DRUG

Sunitinib

Sunitinib will be administered per dose and schedule specified in the arm.

Intervention Type: DRUG

Other Intervention Names

PLX3397

Eligibility Criteria

Inclusion Criteria

• Male or female ≥18 years old.
• Part 1, Part 2b, Part 2d, and Part 2e: Participants with advanced solid tumors who have tumor progression following standard therapy, have treatment-refractory disease, or for whom there is no effective standard of therapy.
• Part 2d: Participants with non GIST solid tumors with KIT mutations, who are TKI naïve or have been previously treated with KIT directed TKI therapy who are appropriate for KIT directed TKI therapy
• Part 2a, Part 2c, and Part 2f (GIST participants): Histologically confirmed locally advanced, metastatic and/or unresectable GIST.
• Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test at Screening (≤7 days prior to the first dose of study drug) and must agree to use an effective form of contraception from the time of the negative pregnancy test up to 6 months after the last dose of study drug.
• Fertile men must agree to use an effective method of birth control during the study and for up to 6 months after the last dose of study drug.
• All associated toxicity from previous or concurrent cancer therapy must be resolved (to ≤ Grade 1 or Baseline) prior to study treatment administration.
• Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
• Life expectancy ≥3 months.
• Adequate hematologic, hepatic, and renal function:
• Left ventricular ejection fraction (LVEF) >50% per echocardiogram (ECHO) or multiple-gated acquisition (MUGA) for participants on the sunitinib arms (Parts 2e and f).

Exclusion Criteria

• Known or demonstrated wild type KIT or platelet-derived growth factor receptors (PDGF-R), or known or demonstrated mutations of PDGF R, sorbitol dehydrogenase (SDH), or neurofibromin 1 (NF 1) that are causative for the observed malignancy.
• For Part 1 (phase 1, single agent): Participants with a known or presumed pathogenic KIT exon 13 or 14 resistance mutation.
• Parts 2a and 2d: Participants with known or presumed pathogenic KIT exon 13 or 14 resistance mutations. (However, such participants are permitted on the combination arms of Parts 2b, 2c, 2e, or 2f.)
• Presence of symptomatic or uncontrolled brain or central nervous system metastases. Participants with stable, treated brain metastases are eligible for this trial. However, participants must not have required steroid treatment for their brain metastases within 30 days of Screening.
• Known or suspected allergy to the investigational agent or any agent given in association with this trial.
• Clinically significant cardiac disease
• Inability to take oral medication or significant nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption.
• Ongoing infection of ≥ Grade 2 severity.
• Non-healing wound, ulcer, or bone fracture.
• Known human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral therapy, participants with known active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy
• Hepatobiliary diseases including biliary tract diseases, autoimmune hepatitis, inflammation, fibrosis, or cirrhosis of liver caused by viral, alcohol, or genetic reasons. Gilbert's disease is allowed if total bilirubin is ≤1.5 * upper limit of normal (ULN).
• Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
• Females who are pregnant or nursing.
• Any psychological, familial, sociological, or geographical condition that could hamper compliance with the study protocol.
• Strong CYP3A4 inhibitors or inducers within 14 days or 5 drug half-lives of the agent, whichever is longer, of study drug initiation or the need to continue these drugs during this study.
• Major surgery or significant traumatic injury within 14 days of Cycle 1 Day 1.
• History (within 2 years prior to first study drug administration) of another malignancy unless the malignancy was treated with curative intent and likelihood of relapse is small (<5% in 2 years in the judgment of the investigator).
• Anti-cancer therapy within the period immediately before Cycle 1 Day 1

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Plexxikon

INDUSTRY

Sponsor Role: collaborator

Cogent Biosciences, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jessica Sachs, MD

Role: STUDY_DIRECTOR

Cogent Biosciences, Inc.

Locations

Sylvester Comprehensive Cancer Center/ UMHC

Miami, Florida, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States

Karmanos Cancer Institute

Detroit, Michigan, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

OSU Comprehensive Cancer Center

Columbus, Ohio, United States

Countries

United States

References

Wagner AJ, Severson PL, Shields AF, Patnaik A, Chugh R, Tinoco G, Wu G, Nespi M, Lin J, Zhang Y, Ewing T, Habets G, Burton EA, Matusow B, Tsai J, Tsang G, Shellooe R, Carias H, Chan K, Rezaei H, Sanftner L, Marimuthu A, Spevak W, Ibrahim PN, Inokuchi K, Alcantar O, Michelson G, Tsiatis AC, Zhang C, Bollag G, Trent JC, Tap WD. Association of Combination of Conformation-Specific KIT Inhibitors With Clinical Benefit in Patients With Refractory Gastrointestinal Stromal Tumors: A Phase 1b/2a Nonrandomized Clinical Trial. JAMA Oncol. 2021 Sep 1;7(9):1343-1350. doi: 10.1001/jamaoncol.2021.2086.

Reference Type: DERIVED

PMID: 34236401 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

PLX121-01

Identifier Type: -

Identifier Source: org_study_id