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

Cogent Biosciences

Status and phase: Completed; Phase 2; Phase 1

Conditions: Gastrointestinal Stromal Tumors

Treatments: Drug: Pexidartinib; Drug: CGT9486; Drug: Sunitinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT02401815

PLX121-01

Details and patient eligibility

About

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.

Full 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.

Enrollment: 51 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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51 participants in 10 patient groups

Part 1: CGT9486 250 mg QD

Experimental group

Description:

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.

Treatment:

Drug: CGT9486

Part 1: CGT9486 350 mg QD

Experimental group

Description:

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

Treatment:

Drug: CGT9486

Part 1: CGT9486 500 mg QD

Experimental group

Description:

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

Treatment:

Drug: CGT9486

Part 1: CGT9486 1000 mg QD

Experimental group

Description:

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

Treatment:

Drug: CGT9486

Part 1: CGT9486 500 mg BID

Experimental group

Description:

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.

Treatment:

Drug: CGT9486

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

Experimental group

Description:

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.

Treatment:

Drug: CGT9486

Drug: Pexidartinib

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

Experimental group

Description:

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.

Treatment:

Drug: CGT9486

Drug: Pexidartinib

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

Experimental group

Description:

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.

Treatment:

Drug: Sunitinib

Drug: CGT9486

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

Experimental group

Description:

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.

Treatment:

Drug: Sunitinib

Drug: CGT9486

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

Experimental group

Description:

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.

Treatment:

Drug: Sunitinib

Drug: CGT9486