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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 51
- 试验地点
- 6
- 主要终点
- Part 1: Recommended Phase 2 Dose (RP2D) of CGT9486
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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
- •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
研究组 & 干预措施
Part 1: CGT9486 250 mg QD
Participants will receive CGT9486 250 milligrams (mg) orally once daily (QD) in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: CGT9486 (Drug)
Part 1: CGT9486 350 mg QD
Participants will receive CGT9486 350 mg orally QD in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: CGT9486 (Drug)
Part 1: CGT9486 500 mg QD
Participants will receive CGT9486 500 mg orally QD in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: CGT9486 (Drug)
Part 1: CGT9486 1000 mg QD
Participants will receive CGT9486 1000 mg orally QD in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: CGT9486 (Drug)
Part 1: CGT9486 500 mg BID
Participants will receive CGT9486 500 mg orally twice daily (BID) in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: CGT9486 (Drug)
Part 2b: CGT9486 500 mg QD + Pexidartinib 600 mg (Fasting)
Participants in fasting condition will receive CGT9486 500 mg orally QD in combination with pexidartinib 600 mg (administered as 1 capsule of 200 mg in the morning and 2 capsules of 200 mg in the evening) orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: CGT9486 (Drug)
Part 2b: CGT9486 500 mg QD + Pexidartinib 600 mg (Fasting)
Participants in fasting condition will receive CGT9486 500 mg orally QD in combination with pexidartinib 600 mg (administered as 1 capsule of 200 mg in the morning and 2 capsules of 200 mg in the evening) orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: Pexidartinib (Drug)
Part 2b: CGT9486 500 mg QD + Pexidartinib 600 mg (Non-Fasting)
Participants in non-fasting condition will receive CGT9486 500 mg orally QD in combination with pexidartinib 600 mg (administered as 1 capsule of 200 mg in the morning and 2 capsules of 200 mg in the evening) orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: CGT9486 (Drug)
Part 2b: CGT9486 500 mg QD + Pexidartinib 600 mg (Non-Fasting)
Participants in non-fasting condition will receive CGT9486 500 mg orally QD in combination with pexidartinib 600 mg (administered as 1 capsule of 200 mg in the morning and 2 capsules of 200 mg in the evening) orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: Pexidartinib (Drug)
Part 2e: CGT9486 500 mg QD + Sunitinib 25 mg
Participants will receive CGT9486 500 mg orally QD in combination with sunitinib 25 mg orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: CGT9486 (Drug)
Part 2e: CGT9486 500 mg QD + Sunitinib 25 mg
Participants will receive CGT9486 500 mg orally QD in combination with sunitinib 25 mg orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: Sunitinib (Drug)
Part 2e: CGT9486 1000 mg QD + Sunitinib 25 mg
Participants will receive CGT9486 1000 mg orally QD in combination with sunitinib 25 mg orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: CGT9486 (Drug)
Part 2e: CGT9486 1000 mg QD + Sunitinib 25 mg
Participants will receive CGT9486 1000 mg orally QD in combination with sunitinib 25 mg orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: Sunitinib (Drug)
Part 2e: CGT9486 1000 mg QD + Sunitinib 37.5 mg
Participants will receive CGT9486 1000 mg orally QD in combination with sunitinib 37.5 mg orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: CGT9486 (Drug)
Part 2e: CGT9486 1000 mg QD + Sunitinib 37.5 mg
Participants will receive CGT9486 1000 mg orally QD in combination with sunitinib 37.5 mg orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination.
干预措施: Sunitinib (Drug)
结局指标
主要结局
Part 1: Recommended Phase 2 Dose (RP2D) of CGT9486
时间窗: 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)
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- Part 1: Progression-Free Survival (PFS), as Assessed Using RECIST V1.1(From the first date of treatment until the first documented disease progression or date of death (maximum exposure: 670 days))
- Part 1: Overall Response Rate (ORR): Percentage of Participants With Best Overall Response of Complete Response (CR) or Partial Response (PR), as Assessed Using RECIST V1.1(From the date of first dose of study drug until the first appearance of CR or PR (maximum exposure: 670 days))
- Part 1: Duration of Response (DOR), as Assessed Using RECIST V1.1(From the date of first response (PR or CR) to the date of first documented disease progression/relapse or death, whichever occurred first (maximum exposure: 670 days))
- Part 2: Overall Response Rate (ORR): Percentage of Participants With Best Overall Response of Complete Response (CR) or Partial Response (PR), as Assessed Using RECIST V1.1(From the date of first dose of study drug until the first appearance of CR or PR (maximum exposure: 868 days))
- Part 2: Clinical Benefit Rate (CBR): Percentage of Participants With Clinical Benefit, as Assessed Using RECIST V1.1(From the date of first dose of study drug until the first appearance of CR, PR, or SD (maximum exposure: 868 days))
- 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))
- Part 2: Overall Survival(From the first day of treatment until the date of death (maximum exposure: 868 days))
- Part 2: Overall Survival at Month 12(Month 12)
- Part 2: PFS at Month 6(Month 6)
- 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))
- 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)
- 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)
- 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)