Phase 1 Study of PLX7486 as Single Agent in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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The objective of this study is to determine the safety, pharmacokinetics, maximum tolerated dose/recommended Phase 2 dose, and efficacy of PLX7486.

Detailed Description
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Part 1. Open-label, sequential PLX7486 TsOH single-agent dose escalation in approximately 60 patients with solid tumors.

Official Title
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A Phase 1 Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of PLX7486 as a Single Agent in Patients With Advanced Solid Tumors

Conditions
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Solid Tumor, Tumors of Any Histology With Activating Trk (NTRK) Point or NTRK Fusion Mutations, Tenosynovial Giant Cell Tumor

Intervention / Treatment
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* Drug: PLX7486 TsOH


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male or female ≥18 years old Patients with histologically confirmed solid tumors who: o Part 1: have tumor progression following standard therapy, have treatment-refractory disease, or for whom there is no effective standard of therapy Women of child-bearing potential must have a negative pregnancy test within 7 days of initiation of dosing and must agree to use an acceptable method of birth control. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year. Fertile men must also agree to use an acceptable method of birth control while on study drug and up to 3 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 Patients with stable, treated brain metastases are eligible for this trial. However, patients must not have required steroid treatment for their brain metastases within 30 days of Screening. Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements Karnofsky performance status ≥70% Life expectancy ≥3 months Adequate hematologic, hepatic, and renal function Exclusion Criteria Other than the primary malignancy, active cancer (either concurrent or within the last 3 years) that requires non-surgical therapy (e.g., chemotherapy or radiation therapy), with the exception of surgically treated basal or squamous cell carcinoma of the skin, melanoma in situ, or carcinoma in-situ of the cervix Chemotherapy within 28 days prior to C1D1 Biological therapy within 5 half-lives prior to C1D1 Radiation therapy within 28 days or 5 half-lives prior to C1D1, whichever is longer Investigational drug use within 28 days or 5 half-lives, whichever is longer, prior to C1D1 Part 1 only: (a) Patients with active or a history of glucose intolerance or diabetes mellitus and (b) Hemoglobin A1c ≥7% ≥Grade 2 sensory neuropathy at baseline Uncontrolled intercurrent illness (i.e., active infection) or concurrent condition that, in the opinion of the Investigator, would interfere with the study endpoints or the patient's ability to participate Refractory nausea and vomiting, malabsorption, small bowel resection that, in the opinion of the Investigator, would preclude adequate absorption Mean QTcF ≥450 msec (for males) or ≥470 msec (for females) at Screening The presence of a medical or psychiatric condition that, in the opinion of the Principal Investigator, makes the patient inappropriate for inclusion in this study

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: PLX7486-TsOH, Dose escalation and RP2D<br>Part 1: Open-label, sequential PLX7486-TsOH single-agent dose escalation in approximately 60 patients with solid tumors. | Drug: PLX7486 TsOH<br>* PLX7486 TsOH capsules, 50mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of PLX7486 as single agent as measured by adverse events and serious adverse events. |  | 1 year | 
| Area under the plasma concentration-time curve [AUC0-t, AUC0-inf] | Area under the plasma concentration-time curve [AUC0-t, AUC0-inf] will be used to assess the pharmacokinetic profile of PLX7486. | 1 year | 
| Peak concentration (Cmax) | Peak concentration (Cmax) will be used to assess the pharmacokinetic profile of PLX7486. | 1 year | 
| Time to peak concentration (Tmax) | Time to peak concentration (Tmax) will be used to assess the pharmacokinetic profile of PLX7486. | 1 year | 
| Half life (t1/2) | Half life (t1/2) will be used to assess the pharmacokinetic profile of PLX7486. | 1 year | 
| Terminal elimination rate constant (Kel) | Terminal elimination rate constant (Kel) will be used to assess the pharmacokinetic profile of PLX7486. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) | Duration of response is defined as the number of days from the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, whichever occurs first. | 1 year | 
| Progression-Free Survival (PFS) | Progression-free survival (PFS) is defined as the number of days from start of therapy to the date of documented disease progression/relapse, whichever occurs first. | 6 month | 
| Overall Response Rate (ORR) |  | 1year | 
| Overall Survival (OS) |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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solid tumors, activating NTRK point or fusion mutations, Tenosynovial giant cell tumor, TGCT