A Study of the Efficacy and Safety of Pexidartinib in Adult Subjects With TGCT

Study Overview
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Brief Summary
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This study will assess pexidartinib in adult participants with symptomatic TGCT that is associated with severe morbidity or functional limitations and not amendable to improvement with surgery.

Detailed Description
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Participants with symptomatic TGCT will be administered pexidartinib 400 mg twice daily continuously with 28-day treatment cycle until criteria for discontinuation are reached. Participants who complete primary endpoint assessments may be eligible to continue receiving pexidartinib until disease progression, unacceptable toxicity, the occurrence of other termination criteria, or withdrawal from the study. Eligible participants' status will be collected every 6 months as a long term follow-up at least 2 years.

Official Title
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Multicenter, Single Arm Study of the Efficacy and Safety of Pexidartinib in Adult Subjects With Tenosynovial Giant Cell Tumor

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 ≥ 18 years (Age ≥ 20 years in Taiwan). A diagnosis of TGCT (i) that has been histologically confirmed by a pathologist 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 1.1 (except that a minimal size of 2 cm is required), assessed from MRI scan by a central radiologist. Stable prescription of analgesic regimen during the 2 weeks prior to enrollment. Women of childbearing potential must have a negative serum pregnancy test within the 14-day period prior to enrollment (Where demanded by local regulations, this test may be required within 72 hours of enrollment). Females of reproductive potential should be advised to use an effective, non-hormonal method of contraception during treatment with pexidartinib and for 1 month after the last dose. Males with female partners of reproductive potential should be advised to use an effective method of contraception during treatment with pexidartinib and for 1 month after the last dose. Female partners of male participants should concurrently use effective contraceptive methods (hormonal or non-hormonal). Women of nonchildbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥ 1 year. Women who have documentation of at least 12 months of spontaneous amenorrhea and have a follicle stimulating hormone level > 40 mIU/mL will be considered postmenopausal. Adequate hematologic, hepatic, and renal function, defined by: Absolute neutrophil count ≥ 1.5 × 109/L Hemoglobin > 10 g/dL Platelet count ≥ 100 × 109/L Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.0 × upper limit of normal (ULN) Total bilirubin and direct bilirubin ≤ 1.0 × ULN Alkaline phosphatase ≤ 1.0 × ULN Creatinine clearance (CLcr) > 15 mL/min Willingness and ability to complete the PROMIS Physical Function Scale. Willingness and ability to use a diary. Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements. Exclusion Criteria: Investigational drug/device use within 28 days of enrolment. Previous use of pexidartinib or any biologic treatment targeting colony stimulating factor 1 (CSF-1) or the CSF-1 receptor; previous use of oral tyrosine kinase inhibitors are allowed (eg, imatinib or nilotinib). Active cancer except for tumor for which a participant is enrolled in the study, (either concurrent or within the last year of starting study drug) that requires therapy (eg, surgical, chemotherapy, or radiation therapy), with the exception of adequately treated basal or squamous cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix or breast, or prostate carcinoma with a prostate-specific antigen value < 0.2 ng/mL. Known metastatic TGCT. Active or chronic infection with hepatitis C or known positive hepatitis B surface antigen, or known active or chronic infection with human immunodeficiency virus. Active liver or biliary tract disease Known active tuberculosis. 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 (CYP) 3A inducers, including St John's wort, proton pump inhibitors (PPIs), and other products known to cause hepatotoxicity. Women who are breastfeeding. A screening Fridericia corrected QT interval (QTcF) ≥ 450 ms (men) or ≥ 470 ms (women). MRI contraindications. History of hypersensitivity to any excipients in the investigational product. Inability to swallow capsules.

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: Pexidartinib<br> | 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 |
| --- | --- | --- |
| Overall Response Rate (ORR) of Pexidartinib Based on RECIST 1.1 of Asian Participants With Symptomatic Tenosynovial Giant Cell Tumor (TGCT) at Week 25 | For the assessment of tumor response, participants were classified into the best of the following tumor response categories based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by centrally reviewed MRI scan. 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; and overall response rate (ORR), defined as CR+PR, are presented. | At Week 25 postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) of Pexidartinib Based on TVS of Asian Participants With Symptomatic Tenosynovial Giant Cell Tumor (TGCT) at Week 25 | For the assessment of tumor response, participants were classified into the best of the following tumor response categories based on Tumor Volume Score (TVS) by centrally reviewed MRI scan. Tumor Volume Score (TVS) is a semi-quantitative MRI scoring system that describes tumor mass and is based on 10% increments of the estimated volume of the maximally distended synovial cavity or tendon sheath involved. A tumor that is equal in volume to that of a maximally distended synovial cavity or tendon sheath was scored 10; a score of 0 indicated no evidence of tumor. Complete response (CR), disappearance of lesion; partial response (PR), at least 50% decrease in volume score relative to baseline; overall response rate (ORR), defined as CR+PR, are presented. | At Week 25 postdose | 
| Mean Percent Change From Baseline for Range of Motion (ROM) Score in Participants Receiving Pexidartinib | Range of motion (ROM) of the joint was assessed by a qualified, independent, and blinded or third-party assessors at the clinical site. The relative ROM was calculated (expressed in percent) as follows: Relative ROM = 100 x (absolute ROM measured)/(reference ROM standard). The change from baseline in relative ROM at Week 25 was calculated as the difference in relative ROM at Week 25 visit minus relative ROM at Screening visit. | At Week 25 postdose | 
| Mean Change From Baseline in the Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function Score in Participants Receiving Pexidartinib | The Patient-reported Outcomes Measurement Information System (PROMIS) physical function scale was used to assess the physical function of the upper and lower limbs. The scale ranges from 1 defined as 'unable to do' or 'cannot do' to 5 defined as 'without any difficulty' or 'not at all', where higher scores represent better outcomes. | At Week 25 postdose | 
| Best Overall Response of Pexidartinib Based on RECIST 1.1 and TVS by Centrally Reviewed MRI Scan | Best overall response (CR or PR) of pexidartinib based on RECIST 1.1 and TVS are summarized. Tumor categories for RECIST v1.1 were as follows: complete response (CR), disappearance of all target lesions; partial response (PR), at least a 30% decrease in the sum of diameters of target lesions; stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease; progressive disease (PD), at least a 20% increase in the sum of diameters of target lesions; and not evaluable (NE). Tumor categories for TVS were as follows: complete response (CR), disappearance of all target lesions; partial response (PR), at least a 50% decrease in volume score relative to baseline; stable disease (SD), does not meet any of the prior criteria based on score during study; progressive disease (PD), at least a 30% increase in in volume relative to lowest score during the study whether at baseline or some other visit; and not evaluable (NE). | From baseline until disease progression or death (whichever occurs first), up to approximately 29 months | 
| Duration of Response of Pexidartinib Based on RECIST 1.1 and TVS by Centrally Reviewed MRI Scan | Duration of response (DOR) is defined as the date of the first recorded response to the first date of documented disease progression. | Time from the date of first documented response until documented disease progression or death from any cause (whichever occurs first), up to approximately 29 months | 
| Number of Participants Reporting Frequent (≥10%) Treatment-Emergent Adverse Events by Preferred Term | A Treatment-emergent adverse event (TEAE) is defined as an AE that occurs, having been absent before the first dose of study drug, or has worsened in severity or seriousness after the initiating the study drug until post-treatment visit (28 ± 7 days after the last dose of study drug). | Up to approximately 29 months | 
| Area Under the Plasma Concentration Time Curve From Time 0 to 6 Hours AUC(0-6h) in Participants Receiving Pexidartinib | AUC(0-6h) was calculated using standard non-compartmental analysis. AUC(0-6h) for Pexidartinib and primary metabolite, ZAAD-1006a, are presented. | Week 3: Cycle 1 Day 1 at pre-dose, 0.5h, 1h, 2h, 4h, and 6h post-dose (each cycle is 28 days) | 
| Maximum Plasma Concentration (Cmax) in Participants Receiving Pexidartinib | Cmax was calculated using standard non-compartmental analysis. Cmax for Pexidartinib and primary metabolite, ZAAD-1006a, are presented. | Week 3: Cycle 1 Day 1 at pre-dose, 0.5h, 1h, 2h, 4h, and 6h post-dose (each cycle is 28 days) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Participants Receiving Pexidartinib | Tmax was calculated using standard non-compartmental analysis. Tmax for Pexidartinib and primary metabolite, ZAAD-1006a, are presented. | Week 3: Cycle 1 Day 1 at pre-dose, 0.5h, 1h, 2h, 4h, and 6h post-dose (each cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tenosynovial Giant Cell Tumor, Pexidartinib, TURALIO™, PLX3397