PLX3397: A Study of the Efficacy and Safety of Pexidartinib in Adult Subjects With TGCT

Sponsor

Daiichi Sankyo Co., Ltd. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04488822

Collaborator

(none)

Enrollment

Locations

Arm

42.9

Anticipated Duration (Months)

3.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Tenosynovial Giant Cell Tumor	Drug: Pexidartinib	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

35 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 2, 2020

Actual Primary Completion Date :

Apr 25, 2022

Anticipated Study Completion Date :

Mar 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pexidartinib	Drug: Pexidartinib 400 mg twice daily for a total daily dose of 800 mg (each capsule contains 200 mg of pexidartinib for oral administration) Other Names: TURALIO™ PLX3397

Arm

Intervention/Treatment

Experimental: Pexidartinib

Drug: Pexidartinib

400 mg twice daily for a total daily dose of 800 mg (each capsule contains 200 mg of pexidartinib for oral administration)

Other Names:

TURALIO™

PLX3397

Outcome Measures

Primary Outcome Measures

Percentage of Asian Participants With Symptomatic Tenosynovial Giant Cell Tumor (TGCT) Achieving Complete or Partial Response to Pexidartinib Per Response Evaluation Criteria in Solid Tumors Version 1.1 at Week 25 [Week 25 postdose]
Complete response (CR) and partial responses (PR) will be assessed based on centrally-read magnetic resonance imaging (MRI) scans and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). A CR is defined as disappearance of all tumors and a PR is defined as at least a 30% decrease in the sum of diameters of target tumors using the baseline sum diameters as the reference.

Secondary Outcome Measures

Percentage of Participants With Symptomatic Tenosynovial Giant Cell Tumor (TGCT) Achieving Complete or Partial Response Based on Tumor Volume Score (TVS) by Centrally Reviewed MRI Scan [Week 25 postdose]
Complete response (CR) and partial response (PR) will be assessed using tumor volume score (TVS). A CR is defined as disappearance of all tumors and a PR is defined as at least a 30% decrease in the sum of diameters of target tumors using the baseline sum diameters as the reference. 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.
Mean Change From Baseline For Range of Motion (ROM) Score in Participants Receiving Pexidartinib [Baseline up to Week 25 postdose]
Range of motion (ROM) of the joint will be assessed by a qualified, independent, and blinded or third-party assessors at the clinical site. Measurements will be recorded in degrees. At baseline, the plane of movement with the smallest relative value (worst) will be identified and this plane will be used for evaluating the relative change of motion subsequently. Only the plane with the worst impaired ROM at baseline will be selected for subsequent analyses.
Mean Change From Baseline in the Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function Score in Participants Receiving Pexidartinib [Baseline up to Week 25 postdose]
The Patient-reported Outcomes Measurement Information System (PROMIS) physical function scale will be used to assess 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.
Best Overall Response of Pexidartinib Based on RECIST 1.1 and TVS by Centrally Reviewed MRI Scan [Baseline up to Week 157 postdose]
The overall number of responses and the number of participants with and without disease progression will be assessed. 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 is scored 10; a score of 0 indicates no evidence of tumor. The overall number of responses and the number of participants with and without disease progression will be assessed.
Duration of Response of Pexidartinib Based on RECIST 1.1 and TVS by Centrally Reviewed MRI Scan [Baseline up to Week 157 postdose]
Duration of response (DOR) based on RECIST 1.1 is defined as the date of the first recorded response to the first date of documented disease progression. 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 is scored 10; a score of 0 indicates no evidence of tumor. The Duration of response of participants with and without disease progression will be assessed.
Percentage of Participants Reporting Frequent (≥10%) Treatment-Emergent Adverse Events by Preferred Term [After the first dose of treatment up to 28 days after the last dose, up to approximately 1 year 6 months]
Treatment-emergent adverse events (TEAEs) are defined as adverse events that starts or worsens after the first dose of treatment and within 28 days after the last dose. The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 will be used to grade adverse events. Any Grade and Grade ≥3 (severe) TEAEs will be reported. TEAEs will be coded using MedDRA version 17.1.
Area Under the Concentration Time Curve From Time 0 to 6 Hours (AUC0-6) of Pexidartinib and its Primary Metabolite ZAAD-1006a [Week 1, Week 3 at predose, 0.5h, 1h, 2h, 4h, and 6h postdose, Week 5, Week 9 and Week 17]
Maximum Serum Concentration (Cmax) of Pexidartinib and its Primary Metabolite ZAAD-1006a [Week 1, Week 3 at predose, 0.5h, 1h, 2h, 4h, and 6h postdose, Week 5, Week 9 and Week 17]
Time to Reach Maximum Concentration (Tmax) of Pexidartinib and its Primary Metabolite ZAAD-1006a [Week 1, Week 3 at predose, 0.5h, 1h, 2h, 4h, and 6h postdose, Week 5, Week 9 and Week 17]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country
1	Beijing Ji Shui Tan Hospital	Beijing	China
2	Peking University Cancer Hospital	Beijing	China
3	The First Affiliated Hospital, Sun Yat-sen University	Guangzhou	China
4	The Second Affiliated Hospital of Zhejiang University School of Medicine	Hangzhou	China
5	Zhejiang Cancer Hospital	Hangzhou	China
6	Fudan University Shanghai Cancer Center	Shanghai	China
7	Shanghai General Hospital	Shanghai	China
8	National Taiwan University Hospital	Taipei	Taiwan
9	Taipei Veterans General Hospital	Taipei	Taiwan