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, Inc.51 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Gastrointestinal Stromal Tumors

Interventions

CGT9486DRUG

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

PexidartinibDRUG

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

SunitinibDRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (6)

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

Outcomes

Primary Outcomes

Part 1: Recommended Phase 2 Dose (RP2D) of CGT9486

RP2D was determined by incidence of dose limiting toxicity (DLT) using Common Terminology Criteria for Adverse Events (CTCAE) V4.03. DLTs: AEs that occurred during Cycle 1, possibly/probably related to study drug, and met 1 of the following criteria: Hematologic Toxicities: Grade 4 neutropenia for \>7 days, Grade ≥3 neutropenia with fever, Grade 4 thrombocytopenia, Grade ≥3 thrombocytopenia for \>7 days, Grade 4 anemia; Other Toxicities: Any Grade ≥3 (AE or laboratory) toxicity despite adequate supportive care except for following: Grade ≥3 nausea, vomiting, or diarrhea that resolved to Grade ≤2 within 72 hours; Grade 3 fatigue that resolved to Grade ≤2 within 14 days; Grade ≥3 asymptomatic changes in alkaline phosphatase, hypomagnesemia, hyperglycemia, or hypophosphatemia; Grade 3 increases in transaminases for ≤5 days; Any other Grade ≥3 toxicity for which further dose escalation deemed inappropriate.

Time frame: Cycle 1 of Part 1 (Cycle length = 28 days)

Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

An adverse event (AE) was any untoward medical occurrence in a participant administered study drug, which did not necessarily have a causal relationship with the treatment. An AE could be any unfavorable and unintended sign (for example, including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug, whether or not it was considered to be study drug related. This included any newly occurring event or previous condition that had increased in severity or frequency since the administration of study drug. A treatment-emergent AE (TEAE) was an AE that started or worsened in severity on or after the date of the initial dose of study drug. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.

Time frame: From the date of first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 670 days)

Part 1: Area Under The Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24) of CGT9486

AUC0-24 was determined by the linear trapezoidal rule for the ascending portion and by the log trapezoidal rule for the descending portion of the plasma profile. For BID dosing, Cycle 1 Day 15 AUC0-24 was calculated as 2 x area under the concentration time curve from time zero to 12 hours after dosing (AUC0-12). Missing concentration data were excluded from Pharmacokinetic (PK) analysis.

Time frame: Predose, 1, 3, 5, 7, 9, and 24 hours postdose at Cycle 1 Day 1 and Cycle 1 Day 15

Part 1: Maximum Observed Plasma Concentration (Cmax) of CGT9486

Cmax was taken directly from bioanalytical data.

Time frame: Predose, 1, 3, 5, 7, 9, and 24 hours postdose at Cycle 1 Day 1 and Cycle 1 Day 15

Part 1: Time to Reach Cmax (Tmax) of CGT9486

Tmax was taken directly from merged clinical and bioanalytical data, with time presented as nominal time relative to dose.

Time frame: Predose, 1, 3, 5, 7, 9, and 24 hours postdose at Cycle 1 Day 1 (Day -10 for 350 mg QD cohort) and Cycle 1 Day 15

Part 1: Half Life (T1/2) of PLX9486

Participants in a selected Part 1 cohort (350 mg QD) participated in a PK substudy to obtain more complete information on the PK profile of PLX9486. Participants received a single dose of 350 mg of PLX9486 10 days prior to the start of repeated QD dosing and plasma concentrations were followed 0.5, 1, 2, 4, 6, and 9 hours postdose, and then once daily for 9 additional days prior to Cycle 1 Day 1.

Time frame: Predose, 0.5, 1, 2, 4, 9, 24, 49, 72, 96, 120, 144, 168, 192, 216 hours postdose on Day -10

Part 2e: RP2D of CGT9486 in Combination With Sunitinib

RP2D was determined by incidence of DLT using CTCAE version 4.03 for severity grade. DLTs were defined as AEs that occurred during Cycle 1, classified as possibly/probably related to study drug, and met 1 of the following criteria: Hematologic Toxicities: Grade 4 neutropenia for \>7 days, Grade ≥3 neutropenia with fever, Grade 4 thrombocytopenia, Grade ≥3 thrombocytopenia for \>7 days or with bleeding, Grade 4 anemia; Other Toxicities: Any Grade ≥3 (AE or laboratory) toxicity despite adequate supportive care except for the following: Grade ≥3 nausea, vomiting, or diarrhea that resolved to Grade ≤2 within 72 hours; Grade 3 fatigue that resolved to Grade ≤2 within 14 days; Grade ≥3 asymptomatic changes in alkaline phosphatase, hypomagnesemia, hyperglycemia, or hypophosphatemia; Grade 3 increases in transaminases for ≤5 days; Any other Grade ≥3 toxicity for which further dose escalation deemed inappropriate.

Time frame: Cycle 1 of Part 2e (Cycle length = 28 days)

Part 2b: RP2D of PLX9486 in Combination With Pexidartinib

Time frame: Cycle 1 of Part 2 b (Cycle length = 28 days)

Part 2b: Number of Participants With Any TEAEs and Treatment-Related TEAEs

An AE was any untoward medical occurrence in a participant administered study drug, which did not necessarily have a causal relationship with the treatment. An AE could be any unfavorable and unintended sign (for example, including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug, whether or not it was considered to be study drug related. This included any newly occurring event or previous condition that had increased in severity or frequency since the administration of study drug. A TEAE was an AE that started or worsened in severity on or after the date of the initial dose of study drug. Treatment-related TEAEs included all events reported as "possibly related" or "probably related" to any of study treatment. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.

Time frame: From the date of first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 868 days)

Part 2e: Number of Participants With Any TEAEs and Treatment-Related TEAEs

Time frame: From the date of first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 825 days)

Secondary Outcomes

Part 1: Overall Response Rate (ORR): Percentage of Participants With Best Overall Response of Complete Response (CR) or Partial Response (PR), as Assessed Using RECIST V1.1

ORR was defined as the percentage of participants who achieved a best overall response of confirmed complete response (CR) or partial response (PR). CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Time frame: From the date of first dose of study drug until the first appearance of CR or PR (maximum exposure: 670 days)

Part 1: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1

PFS was defined as the number of days from the first day of treatment (Cycle 1 Day 1) to the date of the first documented disease progression or date of death, whichever occurred first. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study). The sum must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions was also considered progression. Median was calculated using Kaplan-Meier estimate.

Time frame: From the first date of treatment until the first documented disease progression or date of death (maximum exposure: 670 days)

Part 1: Duration of Response (DOR), as Assessed Using RECIST V1.1

DOR was defined as the number of days from the date of first response (PR or CR confirmed at least 28 days later) to the date of first documented disease progression/relapse or death, whichever occurred first. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (target or non-target) must had reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The sum must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions was also considered progression. Median was calculated using Kaplan-Meier estimate.

Data from ClinicalTrials.gov

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Time frame: From the date of first response (PR or CR) to the date of first documented disease progression/relapse or death, whichever occurred first (maximum exposure: 670 days)

Part 2: Overall Response Rate (ORR): Percentage of Participants With Best Overall Response of Complete Response (CR) or Partial Response (PR), as Assessed Using RECIST V1.1

ORR was defined as the percentage of participants who achieved a best overall response of confirmed CR or PR. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Time frame: From the date of first dose of study drug until the first appearance of CR or PR (maximum exposure: 868 days)

Part 2: Clinical Benefit Rate (CBR): Percentage of Participants With Clinical Benefit, as Assessed Using RECIST V1.1

Participants were considered to experience clinical benefit if they had a best overall response of stable disease (SD) that lasted for at least 16 weeks, or confirmed best overall response of PR or CR. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters. CR: Disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (target or non-target) must had reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The sum must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions was also considered progression.

Time frame: From the date of first dose of study drug until the first appearance of CR, PR, or SD (maximum exposure: 868 days)

Part 2: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1

Time frame: From the first date of treatment until the first documented disease progression or date of death (maximum exposure: 868 days)

Part 2: Overall Survival

Overall Survival was defined as the number of days from the first day of treatment (Cycle 1 Day 1) until the date of death. If a participant was lost to follow-up, overall survival was censored at the date of last contact. Median was calculated using Kaplan-Meier estimate.

Time frame: From the first day of treatment until the date of death (maximum exposure: 868 days)

Part 2: Overall Survival at Month 12

Percentage of participants who survived at Month 12 have been reported.

Time frame: Month 12

Part 2: PFS at Month 6

Time frame: Month 6

Part 2: Duration of Response (DOR), as Assessed Using RECIST V1.1

Time frame: From the date of first response (PR or CR) to the date of first documented disease progression/relapse or death, whichever occurred first (maximum exposure: 868 days)

Part 2: AUC0-24 of CGT9486 in Combination With Pexidartinib or Sunitinib

AUC0-24 was determined by the linear trapezoidal rule for the ascending portion and by the log trapezoidal rule for the descending portion of the plasma profile. Missing concentration data were excluded from PK analysis.

Time frame: Predose, 1, 3, 5, 7, 9, and 24 hours postdose at Cycle 1 Day 1 and Cycle 1 Day 15

Part 2: Cmax of CGT9486 in Combination With Pexidartinib or Sunitinib

Cmax was taken directly from bioanalytical data.

Time frame: Predose, 1, 3, 5, 7, 9, and 24 hours postdose at Cycle 1 Day 1 and Cycle 1 Day 15

Part 2: Tmax of CGT9486 in Combination With Pexidartinib or Sunitinib

Tmax was taken directly from merged clinical and bioanalytical data, with time presented as nominal time relative to dose.

Time frame: Predose, 1, 3, 5, 7, 9, and 24 hours postdose at Cycle 1 Day 1 and Cycle 1 Day 15