A Study of PLX3397 in Patients With Unresectable or Metastatic KIT-mutated Melanoma

Study Overview
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Brief Summary
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The purpose of this Phase I/II study is to evaluate safety, pharmacokinetics, and preliminary efficacy of the investigational drug PLX3397 in subjects with unresectable or metastatic KIT-mutated melanoma.

Official Title
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A Phase I/II Open Label, Multicenter Study of PLX3397 in Patients With Unresectable or Metastatic KIT-mutated Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: PLX3397


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Unresectable stage III or stage IV melanoma which is histologically confirmed at the treating institution with KIT mutation(s) not known to be resistant to PLX3397 Presence of measurable lesions by Response Evaluation Criteria in Solid Tumors Eastern Cooperative Oncology Group (ECOG) performance Status (PS) 0-2 Life expectancy ≥ 3 months Adequate organ and bone marrow function Women of child-bearing potential must have a negative serum pregnancy test at Screening and must agree to use an effective form of contraception from the time of the negative pregnancy test up to 3 months after the last dose of study drug. Women of non-child-bearing potential must have been postmenopausal for ≥ 1 year or surgically sterile. Fertile men must agree to use an effective method of birth control during the study and for up to 3 months after the last dose of study drug. Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements Exclusion Criteria: Prior treatment with a KIT inhibitor for melanoma Presence of NRAS or BRAF mutation Exposure to any investigational drug within 28 days or unresolved adverse effects from previous therapy Symptomatic brain metastases. Active secondary malignancy unless the malignancy is not expected to interfere with the evaluation of safety and is approved by the Sponsor Concomitant treatment with other anti-neoplastic agents (hormonal therapy acceptable) Uncontrolled intercurrent or infectious illness Major surgical procedure or significant traumatic injury within 14 days of initiating study drug or anticipation of the need for major surgery during the study Previous radiotherapy to 25% or more of the bone marrow and/or radiation therapy within 28 days prior to study entry Inability to swallow capsules, or refractory nausea and vomiting, malabsorption, an external biliary shunt, or significant bowel resection that would preclude adequate absorption Congestive heart failure (CHF) New York (NY) Heart Association class III or IV; unstable coronary artery disease [myocardial infarction (MI) more than 6 months prior to study entry is permitted] or serious cardiac arrhythmia Baseline QT interval corrected using Fridericia equation (QTcF) ≥ 450 msec (for males) or ≥ 470 msec (for females) at Screening Active or chronic infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) Known chronic liver disease Women who are breast-feeding or pregnant

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PLX3397<br>Part 1: Open label, multicenter study includes a dose evaluation portion in which the safety profile of PLX3397 as a single oral agent will be evaluated Part 2: An expansion cohort in which the efficacy and safety of PLX3397 administered at the recommended Phase 2 dose will be evaluated in patients with unresectable stage III or stage IV KIT-mutated melanoma. | Drug: PLX3397<br> <br> * Other names: Pexidartinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Best Overall Response Following Twice Daily Administration of PL3397 at 1000 mg/Day In Participants With Unresectable or Advanced KIT-mutated Melanoma | For the assessment of best overall response, participants were classified by RECIST v1.1: complete response (CR), disappearance of all target lesions and normalization of tumor marker level; partial response (PR), at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; stable disease (SD); neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study; progressive disease (PD), at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study and the sum must also demonstrate an absolute increase of at least 5 mm; or not evaluable (NE) for analysis. | within 18 months postdose | 
| Objective Response Rate (ORR) Following Twice Daily Administration of PL3397 at 1000 mg/Day In Participants With Unresectable or Advanced KIT-mutated Melanoma | Objective response rate was defined as complete response (CR) or partial response (PR). | within 18 months postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response Following Twice Daily Administration of PL3397 at 1000 mg/Day In Participants With Unresectable or Advanced KIT-mutated Melanoma | Duration of Response (DoR) was defined as the time from the first documentation of objective tumor response (complete response [CR] or partial response [PR]) to the first documentation of disease progression or to death due to any cause, whichever occurred first. DoR was to only be calculated for the subgroup of participants with an objective tumor response. | within 18 months postdose | 
| Progression-free Survival Following Twice Daily Administration of PL3397 at 1000 mg/Day In Participants With Unresectable or Advanced KIT-mutated Melanoma | Progression-free survival (PFS) was to be calculated for each participant as the number of days from study enrollment to the date of the first documented disease progression or date of death from any cause, whichever occurred first. | within 18 months postdose | 
| Overall Survival Twice Daily Administration of PL3397 at 1000 mg/Day In Participants With Unresectable or Advanced KIT-mutated Melanoma | Overall survival (OS) was defined as the time from study enrollment to death from any cause, censoring at the date of last contact or the end of the study. | within 18 months postdose | 
| Disease Control Rate Following Twice Daily Administration of PL3397 at 1000 mg/Day In Participants With Unresectable or Advanced KIT-mutated Melanoma | Disease control rate (DCR) was defined as the percentage of participants who had achieved complete response (CR), partial response (PR), or stable disease (SD). | within 18 months postdose | 
| Summary of Pharmacokinetic Parameter of Maximum Concentration (Cmax) of PL3397 at Days 1 and 15 Following Twice Daily Administration of PL3397 at 1000 mg/Day in Participants With Unresectable or Advanced KIT-mutated Melanoma |  | Cycle 1, Day 1 and Day 15 at predose, 0.5 h, 1h, 2h, 4h, and 6h postdose | 
| Summary of Pharmacokinetic Parameter of Area Under the Curve From Zero to 6 Hours (AUC0-6) of PL3397 at Days 1 and 15 Following Twice Daily Administration of PL3397 at 1000 mg/Day in Participants With Unresectable or Advanced KIT-mutated Melanoma |  | Cycle 1, Day 1 and Day 15 at predose, 0.5 h, 1h, 2h, 4h, and 6h postdose | 
| Summary of Pharmacokinetic Parameter of Time to Maximum Concentration and Last Measurable Time of PL3397 at Days 1 and 15 Following Twice Daily Administration of PL3397 at 1000 mg/Day in Participants With Unresectable or Advanced KIT-mutated Melanoma |  | Cycle 1, Day 1 and Day 15 at predose, 0.5 h, 1h, 2h, 4h, and 6h postdose | 
| Summary of Pharmacokinetic Parameter of Accumulation Ratio of Day 15 to Day 1 for AUC0-6h (Robs) of PL3397 at Day 15 Following Twice Daily Administration of PL3397 at 1000 mg/Day in Participants With Unresectable or Advanced KIT-mutated Melanoma |  | Cycle 1, Day 1 and Day 15 at predose, 0.5 h, 1h, 2h, 4h, and 6h postdose | 
| Summary of Pharmacokinetic Parameter of Accumulation Ratio of Day 15 to Day 1 for Cmax (Rcmax) of PL3397 at Day 15 Following Twice Daily Administration of PL3397 at 1000 mg/Day in Participants With Unresectable or Advanced KIT-mutated Melanoma |  | Cycle 1, Day 1 and Day 15 at predose, 0.5 h, 1h, 2h, 4h, and 6h postdose | 
| Summary of Most Common (≥50% of Participants) Treatment-emergent Adverse Events Following Twice Daily Administration of PL3397 at 1000 mg/Day In Participants With Unresectable or Advanced KIT-mutated Melanoma |  | within 28 days after administration of the last dose of study drug, up to 18 months postdose | 
| Summary of Treatment-emergent Adverse Events Grade ≥ 3 Following Twice Daily Administration of PL3397 at 1000 mg/Day In Participants With Unresectable or Advanced KIT-mutated Melanoma | Grade ≥ 3 was used to indicate moderate-to-severe treatment-emergent adverse events in which moderate was defined as discomfort enough to cause interference with normal daily activities and severe defined as the inability to perform normal daily activities. | within 28 days after administration of the last dose of study drug, up to 18 months postdose | 
| Summary of Most Common (≥50%) Drug-related Treatment-emergent Adverse Events Following Twice Daily Administration of PL3397 at 1000 mg/Day In Participants With Unresectable or Advanced KIT-mutated Melanoma |  | within 28 days after administration of the last dose of study drug, up to 18 months postdose | 
| Summary of Drug-related Treatment-emergent Adverse Events Grade ≥ 3 Following Twice Daily Administration of PL3397 at 1000 mg/Day In Participants With Unresectable or Advanced KIT-mutated Melanoma | Grade ≥ 3 was used to indicate moderate-to-severe treatment-emergent adverse events in which moderate was defined as discomfort enough to cause interference with normal daily activities and severe defined as the inability to perform normal daily activities. | within 28 days after administration of the last dose of study drug, up to 18 months postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PLX3397, Kit-mutant Melanoma, Unresectable or Metastatic KIT-mutated Melanoma, Developmental Phase I/II