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NCT Number: NCT02401815

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

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.

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Key information

Conditions

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

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Sylvester Comprehensive Cancer Center/ UMHC, Miami, Florida, United States

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

CGT9486

Drug

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

Pexidartinib

Drug

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

Other names: PLX3397

Sunitinib

Drug

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

Primary outcomes

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

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

    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.

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

    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)

    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.

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

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

    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.

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

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

    Cmax was taken directly from bioanalytical data.

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

    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

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

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

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

    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.

  7. Part 2e: RP2D of CGT9486 in Combination With Sunitinib

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

    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.

  8. Part 2b: RP2D of PLX9486 in Combination With Pexidartinib

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

    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.

  9. Part 2b: 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: 868 days)

    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.

  10. 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)

    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.

Secondary outcomes

  1. 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

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

    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.

  2. Part 1: 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: 670 days)

    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.

  3. Part 1: 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: 670 days)

    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.

  4. 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

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

    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.

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

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

    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.

  6. 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)

    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.

  7. Part 2: Overall Survival

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

    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.

  8. Part 2: Overall Survival at Month 12

    Time frame: Month 12

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

  9. Part 2: PFS at Month 6

    Time frame: Month 6

    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. Percentage of participants with PFS at Month 6 are reported.

  10. 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)

    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.

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

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

    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.

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

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

    Cmax was taken directly from bioanalytical data.

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

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

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

Sponsors and collaborators

Lead sponsor

Cogent Biosciences, Inc.

Industry

Collaborators

  • Plexxikon

Registry information

Official study 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

Important dates

Study start
2015
Primary completion
2020
Study completion
2020
First posted
Mar 30, 2015
Registry last updated
Feb 14, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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