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

NCT02401815 | Completed Phase 1 Results FDA Drug

• 1 other identifier: PLX121-01
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 6

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.

Conditions

Gastrointestinal Stromal Tumors

Keywords

Gastrointestinal Stromal Tumors; KIT; Biomarkers; PLX9486; PLX3397; Sunitinib; CGT9486; GIST

Outcome Measures

Primary Outcomes (10)

• 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.

  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.

  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.

  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.

  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.

  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.

  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.

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

• Part 2b: RP2D of PLX9486 in Combination With Pexidartinib

  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.

  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.

  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

  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.

  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 (13)

• 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

  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

  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

  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

  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

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

Study Arms (10)

Part 1: CGT9486 250 mg QD

EXPERIMENTAL

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.

Drug: CGT9486

Part 1: CGT9486 350 mg QD

EXPERIMENTAL

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

Drug: CGT9486

Part 1: CGT9486 500 mg QD

EXPERIMENTAL

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

Drug: CGT9486

Part 1: CGT9486 1000 mg QD

EXPERIMENTAL

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

Drug: CGT9486

Part 1: CGT9486 500 mg BID

EXPERIMENTAL

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.

Drug: CGT9486

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

EXPERIMENTAL

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.

Drug: CGT9486; Drug: Pexidartinib

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

EXPERIMENTAL

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.

Drug: CGT9486; Drug: Pexidartinib

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

EXPERIMENTAL

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.

Drug: CGT9486; Drug: Sunitinib

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

EXPERIMENTAL

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.

Drug: CGT9486; Drug: Sunitinib

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

EXPERIMENTAL

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.

Drug: CGT9486; Drug: Sunitinib

Interventions

CGT9486 DRUG

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

Part 1: CGT9486 1000 mg QD; Part 1: CGT9486 250 mg QD; Part 1: CGT9486 350 mg QD; Part 1: CGT9486 500 mg BID; Part 1: CGT9486 500 mg QD; Part 2b: CGT9486 500 mg QD + Pexidartinib 600 mg (Fasting); Part 2b: CGT9486 500 mg QD + Pexidartinib 600 mg (Non-Fasting); Part 2e: CGT9486 1000 mg QD + Sunitinib 25 mg; Part 2e: CGT9486 1000 mg QD + Sunitinib 37.5 mg; Part 2e: CGT9486 500 mg QD + Sunitinib 25 mg

Pexidartinib DRUG

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

Also known as: PLX3397

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

Sunitinib DRUG

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

Part 2e: CGT9486 1000 mg QD + Sunitinib 25 mg; Part 2e: CGT9486 1000 mg QD + Sunitinib 37.5 mg; Part 2e: CGT9486 500 mg QD + Sunitinib 25 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Cogent Biosciences, Inc.: lead
• Plexxikon: collaborator

Study Sites (6)

Sylvester Comprehensive Cancer Center/ UMHC

Miami, Florida, 33136, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

OSU Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Related Publications (1)

• 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.

  PMID: 34236401 DERIVED

MeSH Terms

Conditions

Gastrointestinal Stromal Tumors

Interventions

pexidartinib; Sunitinib

Condition Hierarchy (Ancestors)

Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: VP, Head of Clinical Development Operations
• Organization: Cogent Biosciences, Inc.

clinops@cogentbio.com

617-945-5576

Study Officials

• Jessica Sachs, MD

  Cogent Biosciences, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 19, 2015
• First Posted: March 30, 2015
• Study Start: March 6, 2015
• Primary Completion: May 11, 2020
• Study Completion: May 11, 2020
• Last Updated: February 14, 2025
• Results First Posted: February 14, 2025

Record last verified: 2025-01

Locations

US (6)