Clinical trial NCT02401815: CGT9486 (Formerly Known as PLX9486) as a Single Agent and in Combination With PLX3397 (Pexidartinib) or Sunitinib in Participants With Advanced Solid Tumors
Official title: A Phase 1b and 2a Study to Assess Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of CGT9486 as a Single Agent and in Combination With PLX3397 or Sunitinib (Sutent®) in Patients With Advanced Solid Tumors and Patients With Locally Advanced, Unresectable, or Metastatic Gastrointestinal Stromal Tumor (GIST) Who Have Been Previously Treated With Imatinib Mesylate/KIT-Directed Tyrosine Kinase Inhibitor (TKI) Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Gastrointestinal Stromal Tumors
Keywords: Gastrointestinal Stromal Tumors
KIT
Biomarkers
PLX9486
PLX3397
Sunitinib
CGT9486
GIST
Lead sponsor: Cogent Biosciences, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Plexxikon
First posted: 2015-03-30
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Part 1: Recommended Phase 2 Dose (RP2D) of CGT9486
timeFrame: Cycle 1 of Part 1 (Cycle length = 28 days)
measure: Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From the date of first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 670 days)
measure: Part 1: Area Under The Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24) of CGT9486
timeFrame: Predose, 1, 3, 5, 7, 9, and 24 hours postdose at Cycle 1 Day 1 and Cycle 1 Day 15
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of CGT9486
timeFrame: Predose, 1, 3, 5, 7, 9, and 24 hours postdose at Cycle 1 Day 1 and Cycle 1 Day 15
measure: Part 1: Time to Reach Cmax (Tmax) of CGT9486
timeFrame: 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
measure: Part 1: Half Life (T1/2) of PLX9486
timeFrame: Predose, 0.5, 1, 2, 4, 9, 24, 49, 72, 96, 120, 144, 168, 192, 216 hours postdose on Day -10
measure: Part 2e: RP2D of CGT9486 in Combination With Sunitinib
timeFrame: Cycle 1 of Part 2e (Cycle length = 28 days)
measure: Part 2b: RP2D of PLX9486 in Combination With Pexidartinib
timeFrame: Cycle 1 of Part 2 b (Cycle length = 28 days)
measure: Part 2b: Number of Participants With Any TEAEs and Treatment-Related TEAEs
timeFrame: From the date of first dose of study drug up to 30 days after last dose of study drug (maximum exposure: 868 days)
measure: Part 2e: Number of Participants With Any TEAEs and Treatment-Related TEAEs
timeFrame: 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:
measure: 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
timeFrame: From the date of first dose of study drug until the first appearance of CR or PR (maximum exposure: 670 days)
measure: Part 1: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1
timeFrame: From the first date of treatment until the first documented disease progression or date of death (maximum exposure: 670 days)
measure: Part 1: Duration of Response (DOR), as Assessed Using RECIST V1.1
timeFrame: 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)
measure: 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
timeFrame: From the date of first dose of study drug until the first appearance of CR or PR (maximum exposure: 868 days)
measure: Part 2: Clinical Benefit Rate (CBR): Percentage of Participants With Clinical Benefit, as Assessed Using RECIST V1.1
timeFrame: From the date of first dose of study drug until the first appearance of CR, PR, or SD (maximum exposure: 868 days)
measure: Part 2: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1
timeFrame: From the first date of treatment until the first documented disease progression or date of death (maximum exposure: 868 days)
measure: Part 2: Overall Survival
timeFrame: From the first day of treatment until the date of death (maximum exposure: 868 days)
measure: Part 2: Overall Survival at Month 12
timeFrame: Month 12
measure: Part 2: PFS at Month 6
timeFrame: Month 6
measure: Part 2: Duration of Response (DOR), as Assessed Using RECIST V1.1
timeFrame: 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)
measure: Part 2: AUC0-24 of CGT9486 in Combination With Pexidartinib or Sunitinib
timeFrame: Predose, 1, 3, 5, 7, 9, and 24 hours postdose at Cycle 1 Day 1 and Cycle 1 Day 15
measure: Part 2: Cmax of CGT9486 in Combination With Pexidartinib or Sunitinib
timeFrame: Predose, 1, 3, 5, 7, 9, and 24 hours postdose at Cycle 1 Day 1 and Cycle 1 Day 15
measure: Part 2: Tmax of CGT9486 in Combination With Pexidartinib or Sunitinib
timeFrame: Predose, 1, 3, 5, 7, 9, and 24 hours postdose at Cycle 1 Day 1 and Cycle 1 Day 15
Other outcomes:
Locations:
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center/ UMHC
state: Florida
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Columbus
country: United States
facility: OSU Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: Cogent Biosciences, Inc.
name: Jessica Sachs, MD
role: STUDY_DIRECTOR
References:
citation: 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.