Gastrointestinal Stromal Tumors
Conditions
Keywords
Gastrointestinal Stromal Tumors, KIT, Biomarkers, PLX9486, PLX3397, Sunitinib, CGT9486, GIST
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.
Interventions
DRUGCGT9486
CGT9486 will be administered per dose and schedule specified in the arm.
DRUGPexidartinib
Pexidartinib capsules will be administered per dose and schedule specified in the arm.
DRUGSunitinib
Sunitinib will be administered per dose and schedule specified in the arm.
Sponsors
Plexxikon
Cogent Biosciences, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Recommended Phase 2 Dose (RP2D) of CGT9486 | 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. |
| Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 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. |
| Part 1: Area Under The Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24) of CGT9486 | 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. |
| Part 1: Maximum Observed Plasma Concentration (Cmax) of CGT9486 | 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. |
| Part 1: Time to Reach Cmax (Tmax) of CGT9486 | 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. |
| Part 1: Half Life (T1/2) of PLX9486 | 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. |
| Part 2e: RP2D of CGT9486 in Combination With Sunitinib | 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. |
| Part 2b: RP2D of PLX9486 in Combination With Pexidartinib | 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. |
| Part 2b: Number of Participants With Any TEAEs and Treatment-Related TEAEs | 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. |
| Part 2e: Number of Participants With Any TEAEs and Treatment-Related TEAEs | 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
| Measure | Time frame | Description |
|---|---|---|
| Part 2: AUC0-24 of CGT9486 in Combination With Pexidartinib or Sunitinib | 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. |
| 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) | 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. |
| Part 2: Tmax of CGT9486 in Combination With Pexidartinib or Sunitinib | 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. |
| Part 2: Cmax of CGT9486 in Combination With Pexidartinib or Sunitinib | 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. |
| 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) | 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. |
| 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) | 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. |
| 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) | 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. |
| 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) | 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. |
| Part 2: 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: 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. |
| Part 2: Overall Survival | 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. |
| Part 2: Overall Survival at Month 12 | Month 12 | Percentage of participants who survived at Month 12 have been reported. |
| Part 2: PFS at Month 6 | 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. |
| Part 2: 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: 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. |
Countries
United States
Participant flow
Recruitment details
This study included a dose escalation portion (Part 1) in which the safety profile and recommended phase 2 dose (RP2D) of CGT9486 as a single oral agent was evaluated in participants with solid tumors (including gastrointestinal stromal tumor \[GIST\]), followed by signal-seeking extension cohorts of CGT9486 in combination with pexidartinib or sunitinib (Part 2). Parts 2a, 2c, 2d, and 2f were not conducted due to business decisions.
Pre-assignment details
A total of 51 participants were enrolled; 24 participants were enrolled across 5 cohorts in Part 1, 12 participants were enrolled across 2 cohorts in Part 2b, and 18 participants (including 3 re-enrolled) were enrolled across 3 cohorts in Part 2e. 1 participant enrolled in Part 1 and 2 participants enrolled in Part 2b and subsequently were re-enrolled in Part 2e with new identification numbers unique to Part 2e. Participant numbers were not reassigned or reused.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: CGT9486 (Single-Agent) Participants received doses of CGT9486 ranging from 250 to 1000 mg/day orally in 5 sequential dose escalation cohorts (CGT9486 250 mg QD, 350 mg QD, 500 mg QD, 1000 mg QD, and 500 mg BID). Treatment was continued until participant discontinuation, withdrawal, or study termination. | 24 |
| Part 2b: CGT9486 500 mg QD + Pexidartinib 600 mg Participants received 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 was continued until participant discontinuation, withdrawal, or study termination. | 12 |
| Part 2e: CGT9486 + Sunitinib Participants received CGT9486 500 mg orally QD in combination with sunitinib 25 mg orally, CGT9486 1000 mg orally QD in combination with sunitinib 25 mg orally, or CGT9486 1000 mg orally QD in combination with sunitinib 37.5 mg orally; in 28-day dosing cycles. Treatment was continued until participant discontinuation, withdrawal, or study termination. | 15 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose Escalation (up to 670 Days) | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation (up to 670 Days) | Clinical Progression | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation (up to 670 Days) | Death | 1 | 2 | 3 | 5 | 4 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation (up to 670 Days) | Progressive Disease (Per RECIST) | 0 | 2 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation (up to 670 Days) | Withdrawal by Subject | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Dose Extension Part 2b (up to 868 Days) | Death | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Dose Extension Part 2b (up to 868 Days) | Other than specified | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Dose Extension Part 2b (up to 868 Days) | Progressive Disease (Per RECIST) | 0 | 0 | 0 | 0 | 0 | 0 | 5 | 0 | 0 | 0 |
| Dose Extension Part 2b (up to 868 Days) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 | 0 |
| Dose Extension Part 2e (up to 868 Days) | Clinical Progression | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Dose Extension Part 2e (up to 868 Days) | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 4 |
| Dose Extension Part 2e (up to 868 Days) | Other than specified | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 3 |
| Dose Extension Part 2e (up to 868 Days) | Progressive Disease (Per RECIST) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 |
| Dose Extension Part 2e (up to 868 Days) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Part 1: CGT9486 (Single-Agent) | Part 2b: CGT9486 500 mg QD + Pexidartinib 600 mg | Part 2e: CGT9486 + Sunitinib | Total |
|---|---|---|---|---|
| Age, Continuous | 58.0 years STANDARD_DEVIATION 11.91 | 64.4 years STANDARD_DEVIATION 10.43 | 60.1 years STANDARD_DEVIATION 9.41 | 60.1 years STANDARD_DEVIATION 10.98 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 11 Participants | 14 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 9 Participants | 12 Participants | 42 Participants |
| Sex: Female, Male Female | 9 Participants | 3 Participants | 8 Participants | 20 Participants |
| Sex: Female, Male Male | 15 Participants | 9 Participants | 7 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 3 / 4 | 3 / 3 | 5 / 7 | 4 / 7 | 2 / 4 | 0 / 8 | 1 / 3 | 1 / 5 | 4 / 10 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 3 / 3 | 7 / 7 | 7 / 7 | 4 / 4 | 8 / 8 | 3 / 3 | 5 / 5 | 10 / 10 |
| serious Total, serious adverse events | 0 / 3 | 2 / 4 | 1 / 3 | 1 / 7 | 3 / 7 | 2 / 4 | 0 / 8 | 1 / 3 | 1 / 5 | 4 / 10 |
Outcome results
Primary
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
Population: PK population included all participants who had adequate PK data. Here, 'number analyzed signifies participants evaluable at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 1: Area Under The Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24) of CGT9486 | Cycle 1, Day 1 | 9240 nanograms (ng)*hour/milliliter (mL) | Geometric Coefficient of Variation 8.7 |
| Part 1: CGT9486 (Single-Agent) | Part 1: Area Under The Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24) of CGT9486 | Cycle 1, Day 15 | 18500 nanograms (ng)*hour/milliliter (mL) | Geometric Coefficient of Variation 43.7 |
| Part 1: CGT9486 350 mg QD | Part 1: Area Under The Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24) of CGT9486 | Cycle 1, Day 1 | 7200 nanograms (ng)*hour/milliliter (mL) | Geometric Coefficient of Variation 20.7 |
| Part 1: CGT9486 350 mg QD | Part 1: Area Under The Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24) of CGT9486 | Cycle 1, Day 15 | 21300 nanograms (ng)*hour/milliliter (mL) | Geometric Coefficient of Variation 27.7 |
| Part 1: CGT9486 500 mg QD | Part 1: Area Under The Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24) of CGT9486 | Cycle 1, Day 1 | 5980 nanograms (ng)*hour/milliliter (mL) | Geometric Coefficient of Variation 41.7 |
| Part 1: CGT9486 500 mg QD | Part 1: Area Under The Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24) of CGT9486 | Cycle 1, Day 15 | 15400 nanograms (ng)*hour/milliliter (mL) | Geometric Coefficient of Variation 65.8 |
| Part 1: CGT9486 1000 mg QD | Part 1: Area Under The Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24) of CGT9486 | Cycle 1, Day 15 | 22100 nanograms (ng)*hour/milliliter (mL) | Geometric Coefficient of Variation 56 |
| Part 1: CGT9486 1000 mg QD | Part 1: Area Under The Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24) of CGT9486 | Cycle 1, Day 1 | 11000 nanograms (ng)*hour/milliliter (mL) | Geometric Coefficient of Variation 26.3 |
| Part 1: CGT9486 500 mg BID | Part 1: Area Under The Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24) of CGT9486 | Cycle 1, Day 1 | NA nanograms (ng)*hour/milliliter (mL) | — |
| Part 1: CGT9486 500 mg BID | Part 1: Area Under The Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24) of CGT9486 | Cycle 1, Day 15 | 24800 nanograms (ng)*hour/milliliter (mL) | Geometric Coefficient of Variation 51.4 |
Primary
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
Population: Half life of PLX9486 can only be determined in participants who participated in the PK substudy. Sampling schedule in other Part 1 and Part 2 cohorts do not allow for determination of t1/2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 1: Half Life (T1/2) of PLX9486 | 75.4 hours | Standard Deviation 26.1 |
Primary
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
Population: PK population included all participants who had adequate PK data. Here, 'number analyzed' signifies participants evaluable at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 1: Maximum Observed Plasma Concentration (Cmax) of CGT9486 | Cycle 1, Day 1 | 499 ng/mL | Geometric Coefficient of Variation 6.92 |
| Part 1: CGT9486 (Single-Agent) | Part 1: Maximum Observed Plasma Concentration (Cmax) of CGT9486 | Cycle 1, Day 15 | 869 ng/mL | Geometric Coefficient of Variation 38.4 |
| Part 1: CGT9486 350 mg QD | Part 1: Maximum Observed Plasma Concentration (Cmax) of CGT9486 | Cycle 1, Day 1 | 332 ng/mL | Geometric Coefficient of Variation 17.9 |
| Part 1: CGT9486 350 mg QD | Part 1: Maximum Observed Plasma Concentration (Cmax) of CGT9486 | Cycle 1, Day 15 | 1010 ng/mL | Geometric Coefficient of Variation 27.5 |
| Part 1: CGT9486 500 mg QD | Part 1: Maximum Observed Plasma Concentration (Cmax) of CGT9486 | Cycle 1, Day 1 | 382 ng/mL | Geometric Coefficient of Variation 6.48 |
| Part 1: CGT9486 500 mg QD | Part 1: Maximum Observed Plasma Concentration (Cmax) of CGT9486 | Cycle 1, Day 15 | 714 ng/mL | Geometric Coefficient of Variation 64.9 |
| Part 1: CGT9486 1000 mg QD | Part 1: Maximum Observed Plasma Concentration (Cmax) of CGT9486 | Cycle 1, Day 15 | 1060 ng/mL | Geometric Coefficient of Variation 59 |
| Part 1: CGT9486 1000 mg QD | Part 1: Maximum Observed Plasma Concentration (Cmax) of CGT9486 | Cycle 1, Day 1 | 558 ng/mL | Geometric Coefficient of Variation 28.1 |
| Part 1: CGT9486 500 mg BID | Part 1: Maximum Observed Plasma Concentration (Cmax) of CGT9486 | Cycle 1, Day 1 | 331 ng/mL | Geometric Coefficient of Variation 22.8 |
| Part 1: CGT9486 500 mg BID | Part 1: Maximum Observed Plasma Concentration (Cmax) of CGT9486 | Cycle 1, Day 15 | 1150 ng/mL | Geometric Coefficient of Variation 52.4 |
Primary
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)
Population: Safety population included all participants treated with at least 1 dose of any study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Part 1: CGT9486 350 mg QD | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 4 Participants |
| Part 1: CGT9486 500 mg QD | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Part 1: CGT9486 1000 mg QD | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 7 Participants |
| Part 1: CGT9486 500 mg BID | Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 7 Participants |
Primary
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)
Population: Safety population included all participants treated with at least 1 dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 1: Recommended Phase 2 Dose (RP2D) of CGT9486 | 1000 mg |
Primary
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
Population: PK population included all participants who had adequate PK data. Here, 'number analyzed' signifies participants evaluable at specified timepoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 1: Time to Reach Cmax (Tmax) of CGT9486 | Cycle 1, Day 1 (or Day -10) | 9 hours |
| Part 1: CGT9486 (Single-Agent) | Part 1: Time to Reach Cmax (Tmax) of CGT9486 | Cycle 1, Day 15 | 3 hours |
| Part 1: CGT9486 350 mg QD | Part 1: Time to Reach Cmax (Tmax) of CGT9486 | Cycle 1, Day 15 | 9 hours |
| Part 1: CGT9486 350 mg QD | Part 1: Time to Reach Cmax (Tmax) of CGT9486 | Cycle 1, Day 1 (or Day -10) | 16.5 hours |
| Part 1: CGT9486 500 mg QD | Part 1: Time to Reach Cmax (Tmax) of CGT9486 | Cycle 1, Day 15 | 7 hours |
| Part 1: CGT9486 500 mg QD | Part 1: Time to Reach Cmax (Tmax) of CGT9486 | Cycle 1, Day 1 (or Day -10) | 15 hours |
| Part 1: CGT9486 1000 mg QD | Part 1: Time to Reach Cmax (Tmax) of CGT9486 | Cycle 1, Day 1 (or Day -10) | 9 hours |
| Part 1: CGT9486 1000 mg QD | Part 1: Time to Reach Cmax (Tmax) of CGT9486 | Cycle 1, Day 15 | 6 hours |
| Part 1: CGT9486 500 mg BID | Part 1: Time to Reach Cmax (Tmax) of CGT9486 | Cycle 1, Day 15 | 5 hours |
| Part 1: CGT9486 500 mg BID | Part 1: Time to Reach Cmax (Tmax) of CGT9486 | Cycle 1, Day 1 (or Day -10) | 7 hours |
Primary
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)
Population: Safety population included all participants treated with at least 1 dose of any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 2b: Number of Participants With Any TEAEs and Treatment-Related TEAEs | Related TEAEs | 4 Participants |
| Part 1: CGT9486 (Single-Agent) | Part 2b: Number of Participants With Any TEAEs and Treatment-Related TEAEs | TEAEs | 4 Participants |
| Part 1: CGT9486 350 mg QD | Part 2b: Number of Participants With Any TEAEs and Treatment-Related TEAEs | Related TEAEs | 7 Participants |
| Part 1: CGT9486 350 mg QD | Part 2b: Number of Participants With Any TEAEs and Treatment-Related TEAEs | TEAEs | 8 Participants |
Primary
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.
Time frame: Cycle 1 of Part 2 b (Cycle length = 28 days)
Population: Safety population included all participants treated with at least 1 dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 2b: RP2D of PLX9486 in Combination With Pexidartinib | NA mg |
| Part 1: CGT9486 350 mg QD | Part 2b: RP2D of PLX9486 in Combination With Pexidartinib | NA mg |
Primary
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.
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)
Population: Safety population included all participants treated with at least 1 dose of any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 2e: Number of Participants With Any TEAEs and Treatment-Related TEAEs | TEAEs | 3 Participants |
| Part 1: CGT9486 (Single-Agent) | Part 2e: Number of Participants With Any TEAEs and Treatment-Related TEAEs | Related TEAEs | 3 Participants |
| Part 1: CGT9486 350 mg QD | Part 2e: Number of Participants With Any TEAEs and Treatment-Related TEAEs | TEAEs | 5 Participants |
| Part 1: CGT9486 350 mg QD | Part 2e: Number of Participants With Any TEAEs and Treatment-Related TEAEs | Related TEAEs | 5 Participants |
| Part 1: CGT9486 500 mg QD | Part 2e: Number of Participants With Any TEAEs and Treatment-Related TEAEs | TEAEs | 10 Participants |
| Part 1: CGT9486 500 mg QD | Part 2e: Number of Participants With Any TEAEs and Treatment-Related TEAEs | Related TEAEs | 9 Participants |
Primary
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)
Population: Safety population included all participants treated with at least 1 dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 2e: RP2D of CGT9486 in Combination With Sunitinib | 1000 mg |
Secondary
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.
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)
Population: Efficacy evaluable population included all participants who received at least 1 dose of study drug and had at least 1 post-baseline tumor assessment or discontinue study medication early due to disease progression or death. Here, 'Overall number of participants analyzed' signifies participants with best overall response of CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: CGT9486 1000 mg QD | Part 1: Duration of Response (DOR), as Assessed Using RECIST V1.1 | 224 days |
Secondary
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)
Population: Efficacy evaluable population included all participants who received at least 1 dose of study drug and had at least 1 post-baseline tumor assessment or discontinue study medication early due to disease progression or death.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: CGT9486 (Single-Agent) | 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 | 0 percentage of participants |
| Part 1: CGT9486 350 mg QD | 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 | 0 percentage of participants |
| Part 1: CGT9486 500 mg QD | 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 | 0 percentage of participants |
| Part 1: CGT9486 1000 mg QD | 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 | 14.3 percentage of participants |
| Part 1: CGT9486 500 mg BID | 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 | 0 percentage of participants |
Secondary
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)
Population: Efficacy evaluable population included all participants who received at least 1 dose of study drug and had at least 1 post-baseline tumor assessment or discontinue study medication early due to disease progression or death.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 1: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1 | 54 days |
| Part 1: CGT9486 350 mg QD | Part 1: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1 | 53 days |
| Part 1: CGT9486 500 mg QD | Part 1: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1 | 48 days |
| Part 1: CGT9486 1000 mg QD | Part 1: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1 | 144 days |
| Part 1: CGT9486 500 mg BID | Part 1: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1 | 186 days |
Secondary
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
Population: PK population included all participants who had adequate PK data. Here, 'number analyzed' signifies participants evaluable at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 2: AUC0-24 of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 7810 ng*hour/mL | Geometric Coefficient of Variation 31.6 |
| Part 1: CGT9486 (Single-Agent) | Part 2: AUC0-24 of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 15 | 20300 ng*hour/mL | Geometric Coefficient of Variation 53.2 |
| Part 1: CGT9486 350 mg QD | Part 2: AUC0-24 of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 7910 ng*hour/mL | Geometric Coefficient of Variation 21.9 |
| Part 1: CGT9486 350 mg QD | Part 2: AUC0-24 of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 15 | 19100 ng*hour/mL | Geometric Coefficient of Variation 32.5 |
| Part 1: CGT9486 500 mg QD | Part 2: AUC0-24 of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 9800 ng*hour/mL | Geometric Coefficient of Variation 69.4 |
| Part 1: CGT9486 500 mg QD | Part 2: AUC0-24 of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 15 | 26500 ng*hour/mL | Geometric Coefficient of Variation 61.3 |
| Part 1: CGT9486 1000 mg QD | Part 2: AUC0-24 of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 15 | 41400 ng*hour/mL | Geometric Coefficient of Variation 28.9 |
| Part 1: CGT9486 1000 mg QD | Part 2: AUC0-24 of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 14800 ng*hour/mL | Geometric Coefficient of Variation 16.3 |
| Part 1: CGT9486 500 mg BID | Part 2: AUC0-24 of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 12700 ng*hour/mL | Geometric Coefficient of Variation 28.5 |
| Part 1: CGT9486 500 mg BID | Part 2: AUC0-24 of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 15 | 38300 ng*hour/mL | Geometric Coefficient of Variation 43.3 |
Secondary
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)
Population: Efficacy evaluable population included all participants who received at least 1 dose of study drug and had at least 1 post-baseline tumor assessment or discontinue study medication early due to disease progression or death. Data for 3 re-enrolled participants is included in their initial cohort analysis but not in the Part 2e analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 2: Clinical Benefit Rate (CBR): Percentage of Participants With Clinical Benefit, as Assessed Using RECIST V1.1 | 100 percentage of participants |
| Part 1: CGT9486 350 mg QD | Part 2: Clinical Benefit Rate (CBR): Percentage of Participants With Clinical Benefit, as Assessed Using RECIST V1.1 | 37.5 percentage of participants |
| Part 1: CGT9486 500 mg QD | Part 2: Clinical Benefit Rate (CBR): Percentage of Participants With Clinical Benefit, as Assessed Using RECIST V1.1 | 100 percentage of participants |
| Part 1: CGT9486 1000 mg QD | Part 2: Clinical Benefit Rate (CBR): Percentage of Participants With Clinical Benefit, as Assessed Using RECIST V1.1 | 60.0 percentage of participants |
| Part 1: CGT9486 500 mg BID | Part 2: Clinical Benefit Rate (CBR): Percentage of Participants With Clinical Benefit, as Assessed Using RECIST V1.1 | 85.7 percentage of participants |
Secondary
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
Population: PK population included all participants who had adequate PK data. Here, 'number analyzed' signifies participants evaluable at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 2: Cmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 15 | 991 ng/mL | Geometric Coefficient of Variation 53.9 |
| Part 1: CGT9486 (Single-Agent) | Part 2: Cmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 384 ng/mL | Geometric Coefficient of Variation 34.4 |
| Part 1: CGT9486 350 mg QD | Part 2: Cmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 412 ng/mL | Geometric Coefficient of Variation 26.8 |
| Part 1: CGT9486 350 mg QD | Part 2: Cmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 15 | 924 ng/mL | Geometric Coefficient of Variation 30.7 |
| Part 1: CGT9486 500 mg QD | Part 2: Cmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 512 ng/mL | Geometric Coefficient of Variation 69.2 |
| Part 1: CGT9486 500 mg QD | Part 2: Cmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 15 | 1200 ng/mL | Geometric Coefficient of Variation 61 |
| Part 1: CGT9486 1000 mg QD | Part 2: Cmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 866 ng/mL | Geometric Coefficient of Variation 10.9 |
| Part 1: CGT9486 1000 mg QD | Part 2: Cmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 15 | 2040 ng/mL | Geometric Coefficient of Variation 13.7 |
| Part 1: CGT9486 500 mg BID | Part 2: Cmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 681 ng/mL | Geometric Coefficient of Variation 28.1 |
| Part 1: CGT9486 500 mg BID | Part 2: Cmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 15 | 1850 ng/mL | Geometric Coefficient of Variation 42.5 |
Secondary
Part 2: 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.
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)
Population: Efficacy evaluable population included all participants who received at least 1 dose of study drug and had at least 1 post-baseline tumor assessment or discontinue study medication early due to disease progression or death. Here, 'Overall number of participants analyzed' signifies participants with best overall response of CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 2: Duration of Response (DOR), as Assessed Using RECIST V1.1 | 169 days |
| Part 1: CGT9486 500 mg QD | Part 2: Duration of Response (DOR), as Assessed Using RECIST V1.1 | NA days |
| Part 1: CGT9486 500 mg BID | Part 2: Duration of Response (DOR), as Assessed Using RECIST V1.1 | NA days |
Secondary
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)
Population: Efficacy evaluable population included all participants who received at least 1 dose of study drug and had at least 1 post-baseline tumor assessment or discontinue study medication early due to disease progression or death. Data for 3 re-enrolled participants is included in their initial cohort analysis but not in the Part 2e analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: CGT9486 (Single-Agent) | 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 | 33.3 percentage of participants |
| Part 1: CGT9486 350 mg QD | 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 | 0 percentage of participants |
| Part 1: CGT9486 500 mg QD | 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 | 33.3 percentage of participants |
| Part 1: CGT9486 1000 mg QD | 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 | 0 percentage of participants |
| Part 1: CGT9486 500 mg BID | 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 | 28.6 percentage of participants |
Secondary
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)
Population: Efficacy evaluable population included all participants who received at least 1 dose of study drug and had at least 1 post-baseline tumor assessment or discontinue study medication early due to disease progression or death. Data for 3 re-enrolled participants is included in their initial cohort analysis but not in the Part 2e analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 2: Overall Survival | 853 days |
| Part 1: CGT9486 350 mg QD | Part 2: Overall Survival | 414 days |
| Part 1: CGT9486 500 mg QD | Part 2: Overall Survival | NA days |
| Part 1: CGT9486 1000 mg QD | Part 2: Overall Survival | 362 days |
| Part 1: CGT9486 500 mg BID | Part 2: Overall Survival | NA days |
Secondary
Part 2: Overall Survival at Month 12
Percentage of participants who survived at Month 12 have been reported.
Time frame: Month 12
Population: Efficacy evaluable population included all participants who received at least 1 dose of study drug and had at least 1 post-baseline tumor assessment or discontinue study medication early due to disease progression or death. Data for 3 re-enrolled participants is included in their initial cohort analysis but not in the Part 2e analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 2: Overall Survival at Month 12 | 66.7 percentage of participants |
| Part 1: CGT9486 350 mg QD | Part 2: Overall Survival at Month 12 | 55.6 percentage of participants |
| Part 1: CGT9486 500 mg QD | Part 2: Overall Survival at Month 12 | 100 percentage of participants |
| Part 1: CGT9486 1000 mg QD | Part 2: Overall Survival at Month 12 | 40.0 percentage of participants |
| Part 1: CGT9486 500 mg BID | Part 2: Overall Survival at Month 12 | 68.6 percentage of participants |
Secondary
Part 2: PFS at 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.
Time frame: Month 6
Population: Efficacy evaluable population included all participants who received at least 1 dose of study drug and had at least 1 post-baseline tumor assessment or discontinue study medication early due to disease progression or death. Data for 3 re-enrolled participants is included in their initial cohort analysis but not in the Part 2e analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 2: PFS at Month 6 | 100 percentage of participants |
| Part 1: CGT9486 350 mg QD | Part 2: PFS at Month 6 | 25.0 percentage of participants |
| Part 1: CGT9486 500 mg QD | Part 2: PFS at Month 6 | 100 percentage of participants |
| Part 1: CGT9486 1000 mg QD | Part 2: PFS at Month 6 | 60.0 percentage of participants |
| Part 1: CGT9486 500 mg BID | Part 2: PFS at Month 6 | 85.7 percentage of participants |
Secondary
Part 2: 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: 868 days)
Population: Efficacy evaluable population included all participants who received at least 1 dose of study drug and had at least 1 post-baseline tumor assessment or discontinue study medication early due to disease progression or death. Data for 3 re-enrolled participants is included in their initial cohort analysis but not in the Part 2e analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 2: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1 | 333 days |
| Part 1: CGT9486 350 mg QD | Part 2: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1 | 128 days |
| Part 1: CGT9486 500 mg QD | Part 2: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1 | NA days |
| Part 1: CGT9486 1000 mg QD | Part 2: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1 | 319 days |
| Part 1: CGT9486 500 mg BID | Part 2: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1 | NA days |
Secondary
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
Population: PK population included all participants who had adequate PK data. Here, 'number analyzed' signifies participants evaluable at specified timepoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: CGT9486 (Single-Agent) | Part 2: Tmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 8 hours |
| Part 1: CGT9486 (Single-Agent) | Part 2: Tmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 2, Day 15 | 5 hours |
| Part 1: CGT9486 350 mg QD | Part 2: Tmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 9 hours |
| Part 1: CGT9486 350 mg QD | Part 2: Tmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 2, Day 15 | 6 hours |
| Part 1: CGT9486 500 mg QD | Part 2: Tmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 9 hours |
| Part 1: CGT9486 500 mg QD | Part 2: Tmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 2, Day 15 | 3 hours |
| Part 1: CGT9486 1000 mg QD | Part 2: Tmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 2, Day 15 | 9 hours |
| Part 1: CGT9486 1000 mg QD | Part 2: Tmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 24 hours |
| Part 1: CGT9486 500 mg BID | Part 2: Tmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 1, Day 1 | 9 hours |
| Part 1: CGT9486 500 mg BID | Part 2: Tmax of CGT9486 in Combination With Pexidartinib or Sunitinib | Cycle 2, Day 15 | 3 hours |