A Study of Pexidartinib in Tenosynovial Giant Cell Tumor in Japan

Study Overview
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Brief Summary
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This phase 2, multicenter, two-part, open-label, single-arm study will be conducted in Japan and will evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of pexidartinib in adult participants with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitation and not amenable to improvement with surgery.

Detailed Description
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This study will consist of 2 parts. In Part 1, pexidartinib 800 mg/day (400 mg twice a day [BID]) will be administered on an empty stomach and tolerability and PK of pexidartinib will be evaluated to determine the initiation of Part 2. In Part 2, pexidartinib 800 mg/day (400 mg BID) will be administered on an empty stomach and efficacy, safety, and PK of pexidartinib will be evaluated.

Official Title
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A Phase 2, Multicenter, Two-Part, Open-Label Study of Pexidartinib in Adult Subjects With Tenosynovial Giant Cell Tumor in Japan

Conditions
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Tenosynovial Giant Cell Tumor

Intervention / Treatment
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* Drug: Pexidartinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥20 years A diagnosis of TGCT (i) that has been histologically confirmed by a pathologist1 and (ii) associated with severe morbidity or functional limitations and not amenable to improvement with surgery determined consensually by qualified personnel (eg, 2 surgeons or a multi-disciplinary tumor board). Measurable disease as defined by RECIST version 1.1 (except that a minimal size of 2 cm is required), assessed from MRI scan by a central radiologist. Exclusion Criteria: Known metastatic TGCT. Pre-existing increased serum transaminases; total bilirubin or direct bilirubin (>upper limit of normal); or active liver or biliary tract disease, including increased alkaline phosphatase. Significant concomitant arthropathy in the affected joint, serious illness, uncontrolled infection, or a medical or psychiatric history that, in the Investigator's opinion, would likely interfere with a participant's study participation or the interpretation of his or her results. Use of strong cytochrome P450 3A inducers, including St John's wort, proton pump inhibitors and potassium-competitive acid blockers, or other products known to cause hepatotoxicity.

Ages Eligible for Study
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Minimum Age: 20 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: Pexidartinib<br>Participants with TGCT who will receive oral pexidartinib 800 mg (400 mg twice daily [BID]). | Drug: Pexidartinib<br>* 400 mg twice daily for a total daily dose of 800 mg (each capsule contains 200 mg of pexidartinib for oral administration)<br>* Other names: PLX3397;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting Toxicity (DLT) in Part 1 | The number of participants with dose-limiting toxicities will be assessed. | Cycle 1, Day 1 to Cycle 1, Day 28 (each cycle is 28 days) | 
| Analysis of Pharmacokinetic Parameter: Maximum Concentration of Pexidartinib and ZAAD-1006a (Cmax) in Part 1 | Cmax is the maximum concentration of pexidartinib and ZAAD-1006a in plasma. | Cycle 1, Day 1 to Cycle 1, Day 2 predose, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours postdose; Cycle 1, Day 15 predose, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours (each cycle is 28 days) | 
| Analysis of Pharmacokinetic Parameter: Area Under the Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration of Pexidartinib and ZAAD-1006a (AUClast) in Part 1 | AUClast is the area under the concentration-time curve from time zero to time of last measurable concentration of pexidartinib and ZAAD-1006a in plasma. | Cycle 1, Day 1 to Cycle 1, Day 2 predose, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours postdose; Cycle 1, Day 15 predose, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours (each cycle is 28 days) | 
| Analysis of Pharmacokinetic Parameter: Area Under the Concentration-Time Curve Up to Infinity of Pexidartinib and ZAAD-1006a (AUCinf) in Part 1 | AUCinf is the area under the concentration-time curve up to infinity of pexidartinib and ZAAD-1006a in plasma. | Cycle 1, Day 1 to Cycle 1, Day 2 predose, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours postdose; Cycle 1, Day 15 predose, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours (each cycle is 28 days) | 
| Analysis of Pharmacokinetic Parameter: Time to Reach Maximum Concentration of Pexidartinib and ZAAD-1006a (Tmax) in Part 1 | Tmax is the time to reach maximum concentration of pexidartinib and ZAAD-1006a in plasma. | Cycle 1, Day 1 to Cycle 1, Day 2 predose, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours postdose; Cycle 1, Day 15 predose, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours (each cycle is 28 days) | 
| Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST Version 1.1) in Part 2 | ORR will be assessed by centrally reviewed MRI scan based on RECIST version 1.1. | Week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR Based on Tumor Volume Score (TVS) in Part 2 | ORR will be assessed by centrally reviewed MRI scan based on TVS. | Week 25 | 
| Range of Motion (ROM) in Part 2 | Mean change from baseline in ROM of the affected joint, relative to a reference standard for the same joint will be assessed. | Week 25 | 
| Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function Scale in Part 2 | Mean change from baseline score in the PROMIS Physical Function Scale will be assessed. | Week 25 | 
| Brief Pain Inventory (BPI) Worst Pain Numeric Rating Scale (NRS) in Part 2 | Proportion of responders will be assessed based on the BPI Worst Pain NRS item and analgesic use by BPI-30 definition (ie, 30% or more improvement in average NRS). | Week 25 | 
| Best Overall Response (BOR) based on RECIST Version 1.1 in Part 2 | BOR will be assessed by centrally reviewed magnetic resonance imaging (MRI) scan based on RECIST version 1.1. | Post Week 25 visit or following discontinuation from Part 2 of the study (whichever occurs first), up to approximately 1 year 6 months | 
| BOR Based on TVS in Part 2 | BOR will be assessed by centrally reviewed MRI scan based on TVS. | Post Week 25 visit or following discontinuation from Part 2 of the study (whichever occurs first), up to approximately 1 year 6 months | 
| Duration of Response (DoR) Based on RECIST Version 1.1 in Part 2 | DoR will be assessed by centrally reviewed MRI scan based on RECIST version 1.1. | Post Week 25 visit or following discontinuation from Part 2 of the study (whichever occurs first), up to approximately 1 year 6 months | 
| DoR Based on TVS | DoR will be assessed by centrally reviewed MRI scan based on TVS. | Post Week 25 visit or following discontinuation from Part 2 of the study (whichever occurs first), up to approximately 1 year 6 months | 
| Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events |  | Baseline up to 28 +/- 7 days after last dose, up to approximately 3 years 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tenosynovial Giant Cell Tumor, TGCT, Giant Cell Tumor of Tendon Sheath, GCTTS, Pigmented Villonodular Synovitis, PVNS