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

Study Overview
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Brief Summary
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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
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This study includes a dose escalation portion (Part 1) in which the safety profile and recommended phase 2 dose (RP2D) of PLX9486 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 PLX9486 + pexidartinib combination [Part 2b] and the PLX9486 + sunitinib combination [Part 2e]) was planned to be accrued using standard 3+3 study designs. Parts 2a, 2c, 2d, and 2f were not conducted due to business decisions.

Official Title
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A Phase 1b and 2a Study to Assess Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of PLX9486 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

Conditions
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Gastrointestinal Stromal Tumors

Intervention / Treatment
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* Drug: PLX9486
* Drug: Pexidartinib
* Drug: Sunitinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: PLX9486 250 mg QD<br>Participants will receive PLX9486 250 milligrams (mg) orally once daily (QD) in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination. | Drug: PLX9486<br>* PLX9486 will be administered per dose and schedule specified in the arm.<br>* Other names: CGT9486;|
| Experimental: Part 1: PLX9486 350 mg QD<br>Participants will receive PLX9486 350 mg orally QD in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination. | Drug: PLX9486<br>* PLX9486 will be administered per dose and schedule specified in the arm.<br>* Other names: CGT9486;|
| Experimental: Part 1: PLX9486 500 mg QD<br>Participants will receive PLX9486 500 mg orally QD in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination. | Drug: PLX9486<br>* PLX9486 will be administered per dose and schedule specified in the arm.<br>* Other names: CGT9486;|
| Experimental: Part 1: PLX9486 1000 mg QD<br>Participants will receive PLX9486 1000 mg orally QD in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination. | Drug: PLX9486<br>* PLX9486 will be administered per dose and schedule specified in the arm.<br>* Other names: CGT9486;|
| Experimental: Part 1: PLX9486 500 mg BID<br>Participants will receive PLX9486 500 mg orally twice daily (BID) in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination. | Drug: PLX9486<br>* PLX9486 will be administered per dose and schedule specified in the arm.<br>* Other names: CGT9486;|
| Experimental: Part 2b: PLX9486 500 mg QD + Pexidartinib 600 mg (Fasting)<br>Participants in fasting condition will receive PLX9486 500 mg orally QD in combination with pexidartinib 600 mg (administered as 1 capsule of 200 mg in the morning and 2 capsules of 200 mg in the evening) orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination. | Drug: PLX9486<br>* PLX9486 will be administered per dose and schedule specified in the arm.<br>* Other names: CGT9486;Drug: Pexidartinib<br>* Pexidartinib capsules will be administered per dose and schedule specified in the arm.<br>* Other names: PLX3397;|
| Experimental: Part 2b: PLX9486 500 mg QD + Pexidartinib 600 mg (Non-Fasting)<br>Participants in non-fasting condition will receive PLX9486 500 mg orally QD in combination with pexidartinib 600 mg (administered as 1 capsule of 200 mg in the morning and 2 capsules of 200 mg in the evening) orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination. | Drug: PLX9486<br>* PLX9486 will be administered per dose and schedule specified in the arm.<br>* Other names: CGT9486;Drug: Pexidartinib<br>* Pexidartinib capsules will be administered per dose and schedule specified in the arm.<br>* Other names: PLX3397;|
| Experimental: Part 2e: PLX9486 500 mg QD + Sunitinib 25 mg<br>Participants will receive PLX9486 500 mg orally QD in combination with sunitinib 25 mg orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination. | Drug: PLX9486<br>* PLX9486 will be administered per dose and schedule specified in the arm.<br>* Other names: CGT9486;Drug: Sunitinib<br>* Sunitinib will be administered per dose and schedule specified in the arm.<br>|
| Experimental: Part 2e: PLX9486 1000 mg QD + Sunitinib 25 mg<br>Participants will receive PLX9486 1000 mg orally QD in combination with sunitinib 25 mg orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination. | Drug: PLX9486<br>* PLX9486 will be administered per dose and schedule specified in the arm.<br>* Other names: CGT9486;Drug: Sunitinib<br>* Sunitinib will be administered per dose and schedule specified in the arm.<br>|
| Experimental: Part 2e: PLX9486 1000 mg QD + Sunitinib 37.5 mg<br>Participants will receive PLX9486 1000 mg orally QD in combination with sunitinib 37.5 mg orally in 28-day dosing cycles. Treatment will continue until participant discontinuation, withdrawal, or study termination. | Drug: PLX9486<br>* PLX9486 will be administered per dose and schedule specified in the arm.<br>* Other names: CGT9486;Drug: Sunitinib<br>* Sunitinib will be administered per dose and schedule specified in the arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Area under the curve (AUC) of PLX9486 |  | 1 year | 
| Part 1: Maximum concentration (Cmax) of PLX9486 |  | 1 year | 
| Part 1: Time to peak concentration (Tmax) of PLX9486 |  | 1 year | 
| Part 1: Half life (T1/2) of PLX9486 |  | 1 year | 
| Part 1: Number of Treatment Emergent Adverse Events (TEAEs) as assessed by CTAE v.4.0 |  | 1 year | 
| Part 1: To identify the recommended Phase 2 dose (RP2D) of PLX9486 for further evaluation in dose extension |  | 1 year | 
| Part 2b: Number of patients with treatment-related adverse events as assessed by CTCAE v4.0 (PLX9486 in combination of PLX3397) |  | 1 year | 
| Part 2b: To determine the clinical benefit rate of PLX9486 and PLX3397 treatment at applicable RP2D in Part 2b |  | 1 year | 
| Part 2b: To identify the recommended phase 2 dose (RP2D) of PLX9486 in combination with PLX3397 for further evaluation |  | 1 year | 
| Part 2e: Number of patients with treatment-related adverse events as assessed by CTCAE v4.0 (PLX9486 in combination with sunitinib) |  | 1 year | 
| Part 2e: To determine the clinical benefit rate of PLX9486 and sunitinib treatment at applicable RP2D in Part 2e |  | 1 year | 
| Part 2e: To identify the recommended phase 2 dose (RP2D) of PLX9486 in combination with sunitinib for further evaluation |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: To determine the overall response rate (ORR) of PLX9486 treatment | Overall response rate is defined by the proportion of patients who achieve a complete response (CR) or partial response (PR) by RECIST 1.1. | 1 year | 
| Part 1: To determine the duration of response rate of PLX9486 treatment | Duration of tumor response based on MRI and RECIST 1.1. | 1 year | 
| Part 1: To determine the progression-free survival of PLX9486 treatment | Progressive free survival (PFS) as defined by the number of days from the first day of treatment (C1D1) to the date of the first documented disease progression or date of death, whichever occurs first. | 6 months | 
| Part 2: Area under the curve (AUC) of PLX9486 in combination with PLX3397 or sunitinib. |  | 1 year | 
| Part 2: Maximum concentration (Cmax) of PLX9486 in combination with PLX3397 or sunitinib. |  | 1 year | 
| Part 2: Time to peak concentration (Tmax) of PLX9486) in combination with PLX3397 or sunitinib. |  | 1 year | 
| Part 2: Half life (T1/2) of PLX9486 in combination with PLX3397 or sunitinib. |  | 1 year | 
| Part 2: Number of participants with Treatment Emergent Adverse Events (TEAEs) as assessed by CTCAE v4.0 (PLX9486 in combination with PLX3397 or sunitinib) |  | 1 year | 
| Part 2: To determine the overall response rate of PLX9486 treatment in combination with PLX3397 or sunitinib. | Overall response rate (ORR) as defined by the proportion of patients who achieve a complete response (CR) or partial response (PR) by RECIST 1.1. | 1 year | 
| Part 2: To determine the duration of response rate of PLX9486 treatment in combination with PLX3397 or sunitinib. | Duration of tumor response based on MRI and RECIST 1.1. | 1 year | 
| Part 2: To determine the progression-free survival of PLX9486 treatment in combination with PLX3397 or sunitinib. | Progressive free survival (PFS) as defined by the number of days from the first day of treatment (C1D1) to the date of the first documented disease progression or date of death, whichever occurs first. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KIT, Gastrointestinal Stromal Tumors, Biomarkers, PLX9486, PLX3397, Sunitinib, CGT9486