Tenosynovial Giant Cell Tumor
Conditions
Keywords
Tenosynovial Giant Cell Tumor, TGCT, Giant Cell Tumor of Tendon Sheath, GCTTS, Pigmented Villonodular Synovitis, PVNS
Brief summary
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
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.
Interventions
DRUGPexidartinib
400 mg twice daily for a total daily dose of 800 mg (each capsule contains 200 mg of pexidartinib for oral administration)
Sponsors
Daiichi Sankyo Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting Toxicity (DLT) in Part 1 | Cycle 1, Day 1 to Cycle 1, Day 28 (each cycle is 28 days) | The number of participants with any-grade DLT treatment-emergent adverse events (TEAEs) were assessed. |
| Pharmacokinetic Parameter Maximum Concentration of Pexidartinib and ZAAD-1006a (Cmax) in Part 1 | Predose, 0.5 hours (hr), 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 24 hr post-dose of Cycle 1, Day 1 (C1D1) and Predose, 0.5 hr, 1 hr, 2 hr, 4 hr, and 6 hr postdose of Cycle 1, Day 15 (C1D15) (each cycle is 28 days) | Pharmacokinetic parameters were assessed using non-compartmental methods. Cmax is the maximum concentration of pexidartinib and ZAAD-1006a in plasma. |
| 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 | Predose, 0.5 hours (hr), 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 24 hrs post-dose of Cycle 1, Day 1 (C1D1) (each cycle is 28 days) | Pharmacokinetic parameters were assessed using non-compartmental methods. 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. |
| Pharmacokinetic Parameter Area Under the Concentration-Time Curve Up to Infinity of Pexidartinib and ZAAD-1006a (AUCinf) in Part 1 | Predose, 0.5 hours (hr), 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 24 hrs post-dose of Cycle 1, Day 1 (C1D1) (each cycle is 28 days) | Pharmacokinetic parameters were assessed using non-compartmental methods. AUCinf is the area under the concentration-time curve up to infinity of pexidartinib and ZAAD-1006a in plasma. |
| Pharmacokinetic Parameter Time to Reach Maximum Concentration of Pexidartinib and ZAAD-1006a (Tmax) in Part 1 | Predose, 0.5 hours (hr), 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 24 hr post-dose of Cycle 1, Day 1 (C1D1) and Predose, 0.5 hr, 1 hr, 2 hr, 4 hr, and 6 hr postdose of Cycle 1, Day 15 (C1D15) (each cycle is 28 days) | Pharmacokinetic parameters were assessed using non-compartmental methods. Tmax is the time to reach maximum concentration of pexidartinib and ZAAD-1006a in plasma. |
| Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST Version 1.1) in Part 2 | Week 25 | ORR will be assessed by centrally reviewed MRI scan based on RECIST version 1.1. Complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ORR Based on Tumor Volume Score (TVS) in Part 2 | Week 25 | ORR will be assessed by centrally reviewed MRI scan based on TVS. |
| Range of Motion (ROM) in Part 2 | Week 25 | Mean change from baseline in ROM of the affected joint, relative to a reference standard for the same joint will be assessed. |
| Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function Scale in Part 2 | Week 25 | Mean change from baseline score in the PROMIS Physical Function Scale will be assessed. |
| Brief Pain Inventory (BPI) Worst Pain Numeric Rating Scale (NRS) in Part 2 | Week 25 | 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). |
| Best Overall Response (BOR) Based on RECIST Version 1.1 in Part 2 | Post Week 25 visit or following discontinuation from Part 2 of the study (whichever occurs first), up to approximately 1 year 6 months | BOR will be assessed by centrally reviewed magnetic resonance imaging (MRI) scan based on RECIST version 1.1. |
| BOR Based on TVS in Part 2 | Post Week 25 visit or following discontinuation from Part 2 of the study (whichever occurs first), up to approximately 1 year 6 months | BOR will be assessed by centrally reviewed MRI scan based on TVS. |
| Duration of Response (DoR) Based on RECIST Version 1.1 in Part 2 | Post Week 25 visit or following discontinuation from Part 2 of the study (whichever occurs first), up to approximately 1 year 6 months | DoR will be assessed by centrally reviewed MRI scan based on RECIST version 1.1. |
| DoR 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 | DoR will be assessed by centrally reviewed MRI scan based on TVS. |
| 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 6 years 9 months | — |
Countries
Japan
Contacts
STUDY_DIRECTORGlobal Clinical Leader
Daiichi Sankyo
Participant flow
Recruitment details
A total of 9 participants who met all inclusion criteria and no exclusion criteria were enrolled in the study. These results are based on Part 1 of the study. All safety and pharmacokinetic primary outcome analysis data for Part 1 are reported. Part 2 of the study was not conducted. Eight patients remain in the study and are being followed until study completion. Only the final safety data of the patients who remain on study will be reported at the final database cut (estimated May 31, 2026).
Participants by arm
| Arm | Count |
|---|---|
| Pexidartinib Participants with TGCT who received oral pexidartinib 800 mg (400 mg twice daily \[BID\]). | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | Pexidartinib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 35.9 years STANDARD_DEVIATION 11.16 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 9 |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 0 / 9 |
Outcome results
Primary
Dose-limiting Toxicity (DLT) in Part 1
The number of participants with any-grade DLT treatment-emergent adverse events (TEAEs) were assessed.
Time frame: Cycle 1, Day 1 to Cycle 1, Day 28 (each cycle is 28 days)
Population: All DLT TEAEs were assessed in the DLT Evaluable Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pexidartinib | Dose-limiting Toxicity (DLT) in Part 1 | Any Grade DLT TEAE | 2 Participants |
| Pexidartinib | Dose-limiting Toxicity (DLT) in Part 1 | Any Grade Hepatic function abnormal | 1 Participants |
| Pexidartinib | Dose-limiting Toxicity (DLT) in Part 1 | Any Grade Alanine aminotransferase increased | 1 Participants |
| Pexidartinib | Dose-limiting Toxicity (DLT) in Part 1 | Any Grade Aspartate aminotransferase increased | 1 Participants |
| Pexidartinib | Dose-limiting Toxicity (DLT) in Part 1 | Any Grade Blood alkaline phosphatase increased | 1 Participants |
| Pexidartinib | Dose-limiting Toxicity (DLT) in Part 1 | Any Grade Gamma-glutamyltransferase increased | 1 Participants |
Primary
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. Complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions.
Time frame: Week 25
Population: Part 2 of this study was not conducted and efficacy data are not available for reporting. Only the final safety data of patients who remain in the study will be reported at the final database cut (estimated May 31, 2026).
Primary
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
Pharmacokinetic parameters were assessed using non-compartmental methods. 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.
Time frame: Predose, 0.5 hours (hr), 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 24 hrs post-dose of Cycle 1, Day 1 (C1D1) (each cycle is 28 days)
Population: Pharmacokinetic data were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pexidartinib | 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 | Pexidartinib, C1D1 | 62000 h*ng/mL | Geometric Coefficient of Variation 27.3 |
| Pexidartinib | 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 | ZAAD-1006a, C1D1 | 90900 h*ng/mL | Geometric Coefficient of Variation 48.4 |
Primary
Pharmacokinetic Parameter Area Under the Concentration-Time Curve Up to Infinity of Pexidartinib and ZAAD-1006a (AUCinf) in Part 1
Pharmacokinetic parameters were assessed using non-compartmental methods. AUCinf is the area under the concentration-time curve up to infinity of pexidartinib and ZAAD-1006a in plasma.
Time frame: Predose, 0.5 hours (hr), 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 24 hrs post-dose of Cycle 1, Day 1 (C1D1) (each cycle is 28 days)
Population: Pharmacokinetic data were assessed in participants with available data in the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pexidartinib | Pharmacokinetic Parameter Area Under the Concentration-Time Curve Up to Infinity of Pexidartinib and ZAAD-1006a (AUCinf) in Part 1 | Pexidartinib, C1D1 | 8700 h*ng/mL | Geometric Coefficient of Variation 28.1 |
| Pexidartinib | Pharmacokinetic Parameter Area Under the Concentration-Time Curve Up to Infinity of Pexidartinib and ZAAD-1006a (AUCinf) in Part 1 | ZAAD-1006a, C1D1 | 195000 h*ng/mL | Geometric Coefficient of Variation 40.2 |
Primary
Pharmacokinetic Parameter Maximum Concentration of Pexidartinib and ZAAD-1006a (Cmax) in Part 1
Pharmacokinetic parameters were assessed using non-compartmental methods. Cmax is the maximum concentration of pexidartinib and ZAAD-1006a in plasma.
Time frame: Predose, 0.5 hours (hr), 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 24 hr post-dose of Cycle 1, Day 1 (C1D1) and Predose, 0.5 hr, 1 hr, 2 hr, 4 hr, and 6 hr postdose of Cycle 1, Day 15 (C1D15) (each cycle is 28 days)
Population: Pharmacokinetic data were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pexidartinib | Pharmacokinetic Parameter Maximum Concentration of Pexidartinib and ZAAD-1006a (Cmax) in Part 1 | Pexidartinib, C1D1 | 7920 ng/mL | Standard Deviation 1720 |
| Pexidartinib | Pharmacokinetic Parameter Maximum Concentration of Pexidartinib and ZAAD-1006a (Cmax) in Part 1 | Pexidartinib, C1D15 | 8810 ng/mL | Standard Deviation 1110 |
| Pexidartinib | Pharmacokinetic Parameter Maximum Concentration of Pexidartinib and ZAAD-1006a (Cmax) in Part 1 | ZAAD-1006a, C1D1 | 8000 ng/mL | Standard Deviation 1990 |
| Pexidartinib | Pharmacokinetic Parameter Maximum Concentration of Pexidartinib and ZAAD-1006a (Cmax) in Part 1 | ZAAD-1006a, C1D15 | 11700 ng/mL | Standard Deviation 3340 |
Primary
Pharmacokinetic Parameter Time to Reach Maximum Concentration of Pexidartinib and ZAAD-1006a (Tmax) in Part 1
Pharmacokinetic parameters were assessed using non-compartmental methods. Tmax is the time to reach maximum concentration of pexidartinib and ZAAD-1006a in plasma.
Time frame: Predose, 0.5 hours (hr), 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 24 hr post-dose of Cycle 1, Day 1 (C1D1) and Predose, 0.5 hr, 1 hr, 2 hr, 4 hr, and 6 hr postdose of Cycle 1, Day 15 (C1D15) (each cycle is 28 days)
Population: Pharmacokinetic data were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pexidartinib | Pharmacokinetic Parameter Time to Reach Maximum Concentration of Pexidartinib and ZAAD-1006a (Tmax) in Part 1 | Pexidartinib, C1D1 | 2.05 hours |
| Pexidartinib | Pharmacokinetic Parameter Time to Reach Maximum Concentration of Pexidartinib and ZAAD-1006a (Tmax) in Part 1 | Pexidartinib, C1D15 | 2.10 hours |
| Pexidartinib | Pharmacokinetic Parameter Time to Reach Maximum Concentration of Pexidartinib and ZAAD-1006a (Tmax) in Part 1 | ZAAD-1006a, C1D1 | 3.97 hours |
| Pexidartinib | Pharmacokinetic Parameter Time to Reach Maximum Concentration of Pexidartinib and ZAAD-1006a (Tmax) in Part 1 | ZAAD-1006a, C1D15 | 3.83 hours |
Secondary
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.
Time frame: Post Week 25 visit or following discontinuation from Part 2 of the study (whichever occurs first), up to approximately 1 year 6 months
Population: Part 2 of this study was not conducted and efficacy data are not available for reporting. Only the final safety data of patients who remain in the study will be reported at the final database cut (estimated May 31, 2026).
Secondary
BOR Based on TVS in Part 2
BOR will be assessed by centrally reviewed MRI scan based on TVS.
Time frame: Post Week 25 visit or following discontinuation from Part 2 of the study (whichever occurs first), up to approximately 1 year 6 months
Population: Part 2 of this study was not conducted and efficacy data are not available for reporting. Only the final safety data of patients who remain in the study will be reported at the final database cut (estimated May 31, 2026).
Secondary
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).
Time frame: Week 25
Population: Part 2 of this study was not conducted and efficacy data are not available for reporting. Only the final safety data of patients who remain in the study will be reported at the final database cut (estimated May 31, 2026).
Secondary
DoR Based on TVS
DoR will be assessed by centrally reviewed MRI scan based on TVS.
Time frame: Post Week 25 visit or following discontinuation from Part 2 of the study (whichever occurs first), up to approximately 1 year 6 months
Population: Part 2 of this study was not conducted and efficacy data are not available for reporting. Only the final safety data of patients who remain in the study will be reported at the final database cut (estimated May 31, 2026).
Secondary
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.
Time frame: Post Week 25 visit or following discontinuation from Part 2 of the study (whichever occurs first), up to approximately 1 year 6 months
Population: Part 2 of this study was not conducted and efficacy data are not available for reporting. Only the final safety data of patients who remain in the study will be reported at the final database cut (estimated May 31, 2026).
Secondary
Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events
Time frame: Baseline up to 28 (+/- 7 days) after last dose, up to approximately 6 years 9 months
Secondary
ORR Based on Tumor Volume Score (TVS) in Part 2
ORR will be assessed by centrally reviewed MRI scan based on TVS.
Time frame: Week 25
Population: Part 2 of this study was not conducted and efficacy data are not available for reporting. Only the final safety data of patients who remain in the study will be reported at the final database cut (estimated May 31, 2026).
Secondary
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.
Time frame: Week 25
Population: Part 2 of this study was not conducted and efficacy data are not available for reporting. Only the final safety data of patients who remain in the study will be reported at the final database cut (estimated May 31, 2026).
Secondary
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.
Time frame: Week 25
Population: Part 2 of this study was not conducted and efficacy data are not available for reporting. Only the final safety data of patients who remain in the study will be reported at the final database cut (estimated May 31, 2026).