A Phase 3 interventional study of Pexidartinib and Placebo in Pigmented Villonodular Synovitis, Giant Cell Tumors of the Tendon Sheath and Tenosynovial Giant Cell Tumor, sponsored by Daiichi Sankyo. Completed at 39 sites in 12 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-05-11.
Sponsored by Daiichi Sankyo · Phase 3, Interventional, and Treatment
This is a Phase 3 clinical study, which aims to evaluate the effectiveness of an investigational drug called pexidartinib for the treatment of certain tumors for which surgical removal could cause more harm than good.
The main purpose of this study is to gather information about the investigational drug pexidartinib, which may help to treat tumors of pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS).
The study consists of two parts with a follow-up period. In Part 1, eligible study participants will be assigned to receive either pexidartinib or matching placebo for 24 weeks. A number of assessments will be carried out during the course of the study, including physical examinations, blood tests, imaging studies, electrocardiograms, and questionnaires. MRI scans will be used to evaluate the response of the tumors to the treatment. Some subjects, assigned to placebo in Part 1 transitioned to pexidartinib for Part 2.
Then a protocol amendment was written to allow only pexidartinib patients to continue into Part 2. Part 2 is a long-term treatment phase in which all participants receive open-label pexidartinib. There was also a follow-up period added to Part 2.
Symptomatic disease because of active PVNS or GCT-TS, defined as one or more of the following:
Adequate hematologic, hepatic, and renal function, defined by:
Exclusion Criteria
Participants received blinded treatment of pexidartinib,1000 mg (5 capsules per day ) for 2 weeks, then 800 mg (4 capsules per day) for 22 weeks
Drug: Pexidartinib
Participants received blinded treatment of matching placebo (5 capsules per day) for 2 weeks, then matching placebo (4 capsules per day) for 22 weeks
Drug: Placebo
Participants received pexidartinib in Part 1 and in Part 2 at their prescribed dose
Drug: Pexidartinib
Participants received placebo in Part 1 and pexidartinib in Part 2 at their prescribed dose
Drug: Pexidartinib · Drug: Placebo
Each capsule contains 200 mg of pexidartinib for oral administration
Also known as: PLX3397, Pexidartinib hydrochloride (HCl)
Placebo capsule matching pexidartinib capsule for oral administration
Also known as: Placebo Capsule
Percentage of Participants With Symptomatic, Locally Advanced Tenosynovial Giant Cell Tumor (TGCT) Achieving Complete or Partial Response to Pexidartinib Compared With That of Placebo Per Response Evaluation Criteria in Solid Tumors Version 1.1 at Week 25
Complete response (CR) and partial responses (PR) were 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 was defined as disappearance of all tumors and a PR was defined as at least a 30% decrease in the sum of diameters of target tumors using the baseline sum diameters as the reference.
Time frame: Week 25
Mean Change From Baseline For Range of Motion (ROM) Score in Participants Receiving Pexidartinib Compared With Those on Placebo Up to Week 25
Range of motion (ROM) of the joint was assessed by a qualified, independent, and blinded or third-party assessors at the clinical site. Measurements were recorded in degrees. At baseline, the plane of movement with the smallest relative value (worst) was identified and this plane was used for evaluating the relative change of motion subsequently. Only the plane with the worst impaired ROM at baseline was selected for subsequent analyses.
Time frame: Baseline, Week 13, and Week 25
Percentage of Participants With Symptomatic, Locally Advanced Tenosynovial Giant Cell Tumor (TGCT) Achieving Complete or Partial Response Based on Tumor Volume Score (TVS) After Receiving Pexidartinib Compared With Those on Placebo at Week 25
Complete response (CR) and partial response (PR) were assessed using tumor volume score (TVS). A CR was defined as disappearance of all tumors and a PR was 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.
Time frame: Week 25
Mean Change From Baseline in the Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function Score in Participants Receiving Pexidartinib Compared With Those on Placebo Up to Week 25
The Patient-reported Outcomes Measurement Information System (PROMIS) physical function scale was used to assess physical function of the upper and lower limbs. The scale ranged 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.
Time frame: at Week 9 , Week 17, and Week 25
Mean Change From Baseline for Worst Stiffness Numeric Rating Scale Score (NRS) in Participants Receiving Pexidartinib Compared With Those on Placebo Up to Week 25
The Worst Stiffness Numeric Rating Scale (NRS) was a 1-item, self-administered questionnaire assessing the "worst" stiffness in the last 24 hours. The NRS for this item ranged from 0 (no stiffness) to 10 (stiffness as bad as you can imagine).
Time frame: Baseline, Week 9, Week 17, and Week 25
Percentage of Participants Who Responded With a Decrease of at Least 30% in the Mean Brief Pain Inventory Worst Pain Numeric Rating Scale Score Among Participants Receiving Pexidartinib Compared With Those on Placebo at Week 25
The Brief Pain Inventory (BPI) Worst Pain Numeric Rating Scale Score (NRS) was a 1-item, self-administered questionnaire assessing the "worst" pain in the last 24 hours. The NRS for this item ranged from 0 (no pain) to 10 (pain as bad as you can imagine).
Time frame: Week 25
Number of Responders to Pexidartinib With and Without Disease Progression
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. The overall number of responses and the number of participants with and without disease progression was assessed.
Time frame: By Week 96
Number of Responders to Pexidartinib With and Without Disease Progression Based on Tumor Volume Score
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. The overall number of responses and the number of participants with and without disease progression was assessed.
Time frame: By Week 120
Duration of Response (DOR) Based on RECIST 1.1
Duration of response (DOR) based on RECIST 1.1 is defined from the date of the first recorded evidence of response to the first date of documented disease progression.
Time frame: Date of first documentation of objective response up to date of first documentation of progressive disease, assessed up to end of study (approximately 71 months)
Duration of Response (DOR) Based on Tumor Volume Score (TVS)
Duration of response (DOR) based on TVS is defined from the date of the first recorded evidence of response to the first date of documented disease progression.
Time frame: Date of first documentation of objective response up to date of first documentation of progressive disease, assessed up to end of study (approximately 71 months)
Percentage of Participants Reporting Frequent (≥10%) Treatment-Emergent Adverse Events by Preferred Term
Treatment-emergent adverse events (TEAEs) were defined as adverse events that started or worsened 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 was used to grade adverse events. Any Grade and Grade ≥3 (severe) TEAEs are reported. TEAEs were coded using MedDRA version 17.1.
Time frame: After the first dose of treatment up to 28 days after the last dose
Percentage of Participants With Symptomatic, Locally Advanced Tenosynovial Giant Cell Tumor (TGCT) Achieving Complete or Partial Response to Pexidartinib Compared With That of Placebo Per Response Evaluation Criteria in Solid Tumors Version 1.1 by Week 49
Complete (CR) and partial responses (PR) were 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 was defined as disappearance of all tumors and a PR was defined as at least a 30% decrease in the sum of diameters of target tumors using the baseline sum diameters as the reference.
Time frame: By Week 49
Mean Change From Baseline For Range of Motion (ROM) Score in Participants Receiving Pexidartinib Compared With Those on Placebo by Week 49
Range of motion (ROM) of the joint was assessed by a qualified, independent, and blinded or third-party assessors at the clinical site. Measurements were recorded in degrees. At baseline, the plane of movement with the smallest relative value (worst) was identified and this plane was used for evaluating the relative change of motion subsequently. Only the plane with the worst impaired ROM at baseline was selected for subsequent analyses.
Time frame: By Week 49
Mean Change From Baseline in the Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function Score in Participants Receiving Pexidartinib Compared With Those on Placebo by Week 49
The Patient-reported Outcomes Measurement Information System (PROMIS) physical function scale was used to assess physical function of the upper and lower limbs. The scale ranged 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.
Time frame: By Week 49
Mean Change From Baseline for Worst Stiffness Numeric Rating Scale Score (NRS) in Participants Receiving Pexidartinib Compared With Those on Placebo by Week 49
The Worst Stiffness Numeric Rating Scale (NRS) was a 1-item, self-administered questionnaire assessing the "worst" stiffness in the last 24 hours. The NRS for this item ranged from 0 (no stiffness) to 10 (stiffness as bad as you can imagine).
Time frame: Baseline, Week 25, and Week 49
Mean Change From Baseline for Worst Pain Numeric Rating Scale Score (NRS) in Participants Receiving Pexidartinib Compared With Those on Placebo by Week 49
The Brief Pain Inventory (BPI) Worst Pain NRS was a 1-item, self-administered questionnaire assessing the "worst" pain in the last 24 hours. The NRS for this item ranged from 0 (no pain) to 10 (pain as bad as you can imagine).
Time frame: By Week 49
Percentage of Participants With Symptomatic, Locally Advanced Tenosynovial Giant Cell Tumor (TGCT) Achieving Complete or Partial Response Based on Tumor Volume Score (TVS) After Receiving Pexidartinib Compared With Those on Placebo by Week 49
Best overall response (CR or PR) was assessed using tumor volume score (TVS) in the ITT population. Tumor Volume Score 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.
Time frame: By Week 49
Part 1 was a double-blind, randomized, Pexidartinib or placebo in participants with symptomatic TGCT for whom surgical resection would be associated with potentially worsening functional limitation or severe morbidity. Part 2 is a long-term treatment phase in which all eligible participants received open-label Pexidartinib.
| Milestone | Pexidartinib Part 1, Then Pexidartinib Part 2 | Placebo Part 1, Then Pexidartinib Part 2 |
|---|---|---|
| Started | 61 | 59 |
| Completed | 52 | 48 |
| Not completed | 9 | 11 |
| Withdrew: Physician decision | 0 | 3 |
| Withdrew: Adverse event | 8 | 0 |
| Withdrew: Withdrawal by subject | 1 | 6 |
| Withdrew: Disease progression | 0 | 1 |
| Withdrew: Protocol violation | 0 | 1 |
| Milestone | Pexidartinib Part 1, Then Pexidartinib Part 2 | Placebo Part 1, Then Pexidartinib Part 2 |
|---|---|---|
| Started | 48 | 30 |
| Completed | 0 | 0 |
| Not completed | 48 | 30 |
| Withdrew: Adverse event | 6 | 5 |
| Withdrew: Withdrawal by subject | 16 | 6 |
| Withdrew: Investigator decision | 1 | 2 |
| Withdrew: Death | 0 | 1 |
| Withdrew: Disease progression | 1 | 0 |
| Withdrew: Subject noncompliance | 1 | 0 |
| Withdrew: Lost to follow-up | 1 | 1 |
| Withdrew: Subject transitioned to commercial supply | 6 | 4 |
| Withdrew: Subject transitioned to another ds pexidartinib protocol | 15 | 9 |
| Withdrew: Surgical resection of tumor | 1 | 1 |
| Withdrew: Other | 0 | 1 |
Complete response (CR) and partial responses (PR) were 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 was defined as disappearance of all tumors and a PR was defined as at least a 30% decrease in the sum of diameters of target tumors using the baseline sum diameters as the reference.
| Percentage of participants | Pexidartinib Part 1 | Placebo Part 1 |
|---|---|---|
| Complete Response (CR) | 14.8 | 0 |
| Partial Response (PR) | 24.6 | 0 |
| Response (CR or PR) | 39.3 | 0 |
Range of motion (ROM) of the joint was assessed by a qualified, independent, and blinded or third-party assessors at the clinical site. Measurements were recorded in degrees. At baseline, the plane of movement with the smallest relative value (worst) was identified and this plane was used for evaluating the relative change of motion subsequently. Only the plane with the worst impaired ROM at baseline was selected for subsequent analyses.
| degrees | Pexidartinib Part 1 | Placebo Part 1 |
|---|---|---|
| Baseline | 62.5 ± 3.2 | 62.9 ± 2.9 |
| Week 13 | 13.0 ± 2.3 | 4.8 ± 2.6 |
| Week 25 | 15.1 ± 2.1 | 6.2 ± 2.4 |
Complete response (CR) and partial response (PR) were assessed using tumor volume score (TVS). A CR was defined as disappearance of all tumors and a PR was 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.
| Percentage of participants | Pexidartinib Part 1 | Placebo Part 1 |
|---|---|---|
| Complete Response (CR) | 4.9 | 0 |
| Partial Response (PR) | 50.8 | 0 |
| Response (CR or PR) | 55.7 | 0 |
The Patient-reported Outcomes Measurement Information System (PROMIS) physical function scale was used to assess physical function of the upper and lower limbs. The scale ranged 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.
| units on a scale | Pexidartinib Part 1 | Placebo Part 1 |
|---|---|---|
| Week 9 | 2.8 ± 1.0 | -0.4 ± 0.8 |
| Week 17 | 3.2 ± 1.1 | 0.2 ± 1.0 |
| Week 25 | 4.1 ± 1.1 | -0.9 ± 1.0 |
The Worst Stiffness Numeric Rating Scale (NRS) was a 1-item, self-administered questionnaire assessing the "worst" stiffness in the last 24 hours. The NRS for this item ranged from 0 (no stiffness) to 10 (stiffness as bad as you can imagine).
| units on a scale | Pexidartinib Part 1 | Placebo Part 1 |
|---|---|---|
| Baseline | 5.6 ± 0.2 | 5.9 ± 0.3 |
| Week 9 | -1.5 ± 0.3 | -0.5 ± 0.3 |
| Week 17 | -2.4 ± 0.3 | -0.4 ± 0.3 |
| Week 25 | -2.5 ± 0.3 | -0.3 ± 0.3 |
The Brief Pain Inventory (BPI) Worst Pain Numeric Rating Scale Score (NRS) was a 1-item, self-administered questionnaire assessing the "worst" pain in the last 24 hours. The NRS for this item ranged from 0 (no pain) to 10 (pain as bad as you can imagine).
| percentage of participants | Pexidartinib Part 1 | Placebo Part 1 |
|---|---|---|
| Percentage of Participants Who Responded With a Decrease of at Least 30% in the Mean Brief Pain Inventory Worst Pain Numeric Rating Scale Score Among Participants Receiving Pexidartinib Compared With Those on Placebo at Week 25 | 31.1 | 15.3 |
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. The overall number of responses and the number of participants with and without disease progression was assessed.
| participants | Pexidartinib Part 1 and Part 2 | Placebo Part 1, Pexidartinib Part 2 | All Pexidartinib Treated |
|---|---|---|---|
| Number of responses | 23 | 12 | 35 |
| Week 12 (Day 84); Without disease progression | 23 | 12 | 35 |
| Week 12 (Day 84); With disease progression | 0 | 0 | 0 |
| Week 24 (Day 168); Without disease progression | 23 | 12 | 35 |
| Week 24 (Day 168); With disease progression | 0 | 0 | 0 |
| Week 48 (Day 336); Without disease progression | 15 | 9 | 24 |
| Week 48 (Day 336); With disease progression | 1 | 0 | 1 |
| Week 72 (Day 504); Without disease progression | 9 | 3 | 12 |
| Week 72 (Day 504); With disease progression | 1 | 0 | 1 |
| Week 96 (Day 672); Without disease progression | 2 | 1 | 3 |
| Week 96 (Day 672); With disease progression | 1 | 0 | 1 |
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. The overall number of responses and the number of participants with and without disease progression was assessed.
| participants | Pexidartinib in Part 1 and Part 2 | Placebo Part 1, Pexidartinib Part 2 | All Pexidartinib Treated |
|---|---|---|---|
| Number of responders | 34 | 18 | 52 |
| Week 12 (Day 84); Without disease progression | 33 | 18 | 51 |
| Week 12 (Day 84); With disease progression | 0 | 0 | 0 |
| Week 24 (Day 168); Without disease progression | 32 | 18 | 50 |
| Week 24 (Day 168); With disease progression | 0 | 0 | 0 |
| Week 48 (Day 336); Without disease progression | 22 | 13 | 35 |
| Week 48 (Day 336); With disease progression | 3 | 1 | 4 |
| Week 72 (Day 504); Without disease progression | 13 | 3 | 16 |
| Week 72 (Day 504); With disease progression | 3 | 1 | 4 |
| Week 96 (Day 672); Without disease progression | 3 | 1 | 4 |
| Week 96 (Day 672); With disease progression | 3 | 1 | 4 |
| Week 120 (Day 840); Without disease progression | 1 | 0 | 1 |
| Week 120 (Day 840); With disease progression | 3 | 1 | 4 |
Duration of response (DOR) based on RECIST 1.1 is defined from the date of the first recorded evidence of response to the first date of documented disease progression.
| months | Pexidartinib Part 1 and Part 2 | Placebo Part 1, Pexidartinib Part 2 |
|---|---|---|
| Duration of Response (DOR) Based on RECIST 1.1 | NA (31.01 to NA) | NA (39.0 to NA) |
Duration of response (DOR) based on TVS is defined from the date of the first recorded evidence of response to the first date of documented disease progression.
| months | Pexidartinib Part 1 and Part 2 | Placebo Part 1, Pexidartinib Part 2 |
|---|---|---|
| Duration of Response (DOR) Based on Tumor Volume Score (TVS) | 52.70 (38.60 to NA) | NA (NA to NA) |
Treatment-emergent adverse events (TEAEs) were defined as adverse events that started or worsened 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 was used to grade adverse events. Any Grade and Grade ≥3 (severe) TEAEs are reported. TEAEs were coded using MedDRA version 17.1.
| Percentage of participants | Pexidartinib Part 1 | Placebo Part 1 | Pexidartinib Part 1 and Part 2 | Placebo Part 1, Pexidartinib Part 2 | All Pexidartinib Treated |
|---|---|---|---|---|---|
| Any Hair color changes | 67.2 | 3.4 | 73.8 | 83.3 | 76.9 |
| Grade ≥3 Hair color changes | 0 | 0 | 0 | 0 | 0 |
| Any Pruritis | 9.8 | 3.4 | 16.4 | 20.0 | 17.6 |
| Grade ≥3 Pruritis | 0 | 0 | 1.6 | 0 | 1.1 |
| Any Rash maculopapular | 9.8 | 1.7 | 14.8 | 10.0 | 13.2 |
| Grade ≥3 Rash maculopapular | 0 | 0 | 1.6 | 0 | 1.1 |
| Any Pruritis generalized | 8.2 | 0 | 8.2 | 10.0 | 8.8 |
| Grade ≥3 Pruritis generalized | 0 | 0 | 0 | 0 | 0 |
| Any Erythema | 1.6 | 0 | 3.3 | 20.0 | 8.8 |
| Grade ≥3 Erythema | 0 | 0 | 0 | 0 | 0 |
| Any Dry skin | 3.3 | 3.4 | 6.6 | 10.0 | 7.7 |
| Grade ≥3 Dry skin | 0 | 0 | 0 | 3.3 | 1.1 |
| Any Photosensitivity reaction | 0 | 0 | 1.6 | 10.0 | 4.4 |
| Grade ≥3 Photosensitivity reaction | 0 | 0 | 0 | 0 | 0 |
| Any Nausea | 37.7 | 40.7 | 44.3 | 20.0 | 36.3 |
| Grade ≥3 Nausea | 0 | 0 | 0 | 0 | 0 |
| Any Diarrhea | 19.7 | 25.4 | 26.2 | 30.0 | 27.5 |
| Grade ≥3 Diarrhea | 0 | 0 | 0 | 0 | 0 |
| Any Vomiting | 19.7 | 5.1 | 23.0 | 6.7 | 17.6 |
| Grade ≥3 Vomiting | 1.6 | 0 | 1.6 | 0 | 1.1 |
| Any Abdominal Pain | 16.4 | 10.2 | 21.3 | 6.7 | 16.5 |
| Grade ≥3 Abdominal Pain | 0 | 0 | 0 | 0 | 0 |
| Any Dry mouth | 9.8 | 3.4 | 13.1 | 13.3 | 13.2 |
| Grade ≥3 Dry mouth | 0 | 0 | 0 | 0 | 0 |
| Any Constipation | 11.5 | 5.1 | 14.8 | 10.0 | 13.2 |
| Grade ≥3 Constipation | 0 | 0 | 0 | 0 | 0 |
| Any Stomatitis | 6.6 | 1.7 | 8.2 | 10.0 | 8.8 |
| Grade ≥3 Stomatitis | 0 | 0 | 0 | 0 | 0 |
| Any Fatigue | 54.1 | 35.6 | 55.7 | 26.7 | 46.2 |
| Grade ≥3 Fatigue | 0 | 0 | 0 | 0 | 0 |
| Any Edema peripheral | 13.1 | 3.4 | 16.4 | 20.0 | 17.6 |
| Grade ≥3 Edema peripheral | 0 | 0 | 0 | 0 | 0 |
| Any Face edema | 13.1 | 1.7 | 14.8 | 20.0 | 16.5 |
| Grade ≥3 Face edema | 0 | 0 | 1.6 | 3.3 | 2.2 |
| Any Asthenia | 9.8 | 5.1 | 11.5 | 20.0 | 14.3 |
| Grade ≥3 Asthenia | 0 | 0 | 0 | 0 | 0 |
| Any Pyrexia | 6.6 | 1.7 | 8.2 | 13.3 | 9.9 |
| Grade ≥ Pyrexia | 0 | 0 | 0 | 0 | 0 |
| Any AST increased | 39.3 | 0 | 44.3 | 16.7 | 35.2 |
| Grade ≥3 AST increased | 9.8 | 0 | 9.8 | 6.7 | 8.8 |
| Any ALT increased | 27.9 | 1.7 | 31.1 | 23.3 | 28.6 |
| Grade ≥3 ALT increased | 9.8 | 0 | 9.8 | 10.0 | 9.9 |
| Any ALP increased | 14.8 | 0 | 14.8 | 3.3 | 11.0 |
| Grade ≥3 ALP increased | 6.6 | 0 | 6.6 | 3.3 | 5.5 |
| Any LDH increased | 11.5 | 0 | 11.5 | 10.0 | 11.0 |
| Grade ≥3 LDH increased | 1.6 | 0 | 1.6 | 0 | 1.1 |
| Any Weight increased | 3.3 | 0 | 4.9 | 10.0 | 6.6 |
| Grade ≥3 Weight increased | 0 | 0 | 0 | 0 | 0 |
| Any Dysgeusia | 24.6 | 1.7 | 27.9 | 23.3 | 26.4 |
| Grade ≥3 Dysgeusia | 0 | 0 | 0 | 0 | 0 |
| Any Headache | 19.7 | 18.6 | 23.0 | 20.0 | 22.0 |
| Grade ≥3 Headache | 0 | 0 | 1.6 | 0 | 1.1 |
| Any Dizziness | 9.8 | 15.3 | 13.1 | 13.3 | 13.2 |
| Grade ≥3 Dizziness | 1.6 | 0 | 1.6 | 0 | 1.1 |
| Any Paresthesia | 1.6 | 1.7 | 8.2 | 10.0 | 8.8 |
| Grade ≥3 Paresthesia | 0 | 0 | 0 | 0 | 0 |
| Any Memory impairment | 0 | 1.7 | 1.6 | 10.0 | 4.4 |
| Grade ≥3 Memory impairment | 0 | 0 | 0 | 0 | 0 |
| Any Arthralgia | 23.0 | 25.4 | 27.9 | 30.0 | 28.6 |
| Grade ≥3 Arthralgia | 3.3 | 1.7 | 3.3 | 0 | 2.2 |
| Any Pain in extremity | 6.6 | 6.8 | 9.8 | 13.3 | 11.0 |
| Grade ≥3 Pain in extremity | 0 | 1.7 | 0 | 0 | 0 |
| Any Periorbital edema | 18.0 | 1.7 | 24.6 | 13.3 | 20.0 |
| Grade ≥3 Periorbital edema | 1.6 | 0 | 1.6 | 0 | 1.1 |
| Any Eyelid edema | 3.3 | 0 | 4.9 | 10.0 | 6.6 |
| Grade ≥3 Eyelid edema | 0 | 0 | 0 | 0 | 0 |
| Any Decreased appetite | 16.4 | 10.2 | 18.0 | 10.0 | 15.4 |
| Grade ≥3 Decreased appetite | 0 | 0 | 0 | 0 | 0 |
| Any Hypertension | 14.8 | 10.2 | 19.7 | 30.0 | 13.1 |
| Grade ≥3 Hypertension | 4.9 | 0 | 4.9 | 6.7 | 5.5 |
| Any Upper respiratory tract infection | 1.6 | 0 | 11.5 | 3.3 | 8.8 |
| Grade ≥3 Upper respiratory tract infection | 0 | 0 | 0 | 0 | 0 |
| Any Cough | 4.9 | 5.1 | 6.6 | 10.0 | 7.7 |
| Grade ≥3 Cough | 0 | 0 | 0 | 0 | 0 |
| Any Dyspnea | 1.6 | 0 | 4.9 | 10.0 | 7.7 |
| Grade ≥3 Dyspnea | 0 | 0 | 0 | 0 | 0 |
| Any Insomnia | 4.9 | 3.4 | 4.9 | 10.0 | 6.6 |
| Grade ≥3 Insomnia | 0 | 0 | 0 | 0 | 0 |
| Any Rash | 14.8 | 5.1 | 27.9 | 23.3 | 26.4 |
| Grade ≥3 Rash | 1.6 | 0 | 1.6 | 0 | 1.1 |
Complete (CR) and partial responses (PR) were 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 was defined as disappearance of all tumors and a PR was defined as at least a 30% decrease in the sum of diameters of target tumors using the baseline sum diameters as the reference.
| Percentage of participants | Pexidartinib Part 1 and Part 2 | Placebo Part 1, Pexidartinib Part 2 | All Pexidartinib Treated |
|---|---|---|---|
| Complete Response (CR) | 24.6 | 23.3 | 24.2 |
| Partial Response (PR) | 29.5 | 30.0 | 29.7 |
| Response (CR or PR) | 54.1 | 53.3 | 53.8 |
Range of motion (ROM) of the joint was assessed by a qualified, independent, and blinded or third-party assessors at the clinical site. Measurements were recorded in degrees. At baseline, the plane of movement with the smallest relative value (worst) was identified and this plane was used for evaluating the relative change of motion subsequently. Only the plane with the worst impaired ROM at baseline was selected for subsequent analyses.
| degrees | Pexidartinib Part 1 and Part 2 | Placebo Part 1, Pexidartinib Part 2 | All Pexidartinib Treated |
|---|---|---|---|
| Baseline | 62.5 ± 24.8 | 66.5 ± 22.9 | 63.8 ± 24.2 |
| Week 25 | 15.6 ± 14.9 | 13.1 ± 12.9 | 14.8 ± 14.2 |
| Week 49 | 14.4 ± 19.5 | 12.0 ± 13.4 | 13.4 ± 17.3 |
The Patient-reported Outcomes Measurement Information System (PROMIS) physical function scale was used to assess physical function of the upper and lower limbs. The scale ranged 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.
| units on a scale | Pexidartinib Part 1 and Part 2 | Placebo Part 1, Pexidartinib Part 2 | All Pexidartinib Treated |
|---|---|---|---|
| Week 25 | 3.6 ± 4.9 | 4.9 ± 6.3 | 4.0 ± 5.4 |
| Week 49 | 4.7 ± 4.4 | 7.6 ± 6.3 | 5.8 ± 5.2 |
The Worst Stiffness Numeric Rating Scale (NRS) was a 1-item, self-administered questionnaire assessing the "worst" stiffness in the last 24 hours. The NRS for this item ranged from 0 (no stiffness) to 10 (stiffness as bad as you can imagine).
| units on a scale | Pexidartinib Part 1 and Part 2 | Placebo Part 1, Pexidartinib Part 2 | All Pexidartinib Treated |
|---|---|---|---|
| Baseline | 5.6 ± 1.7 | 5.7 ± 2.3 | 5.6 ± 1.9 |
| Week 25 | -2.7 ± 2.2 | -3.0 ± 3.1 | -2.8 ± 2.5 |
| Week 49 | -3.5 ± 1.9 | -2.2 ± 2.8 | -3.1 ± 2.3 |
The Brief Pain Inventory (BPI) Worst Pain NRS was a 1-item, self-administered questionnaire assessing the "worst" pain in the last 24 hours. The NRS for this item ranged from 0 (no pain) to 10 (pain as bad as you can imagine).
| units on a scale | Pexidartinib Part 1 and Part 2 | Placebo Part 1, Pexidartinib Part 2 | All Pexidartinib Treated |
|---|---|---|---|
| Baseline | 5.6 ± 1.6 | 5.2 ± 2.5 | 5.5 ± 1.9 |
| Week 25 | -2.7 ± 2.2 | -2.6 ± 3.1 | -2.7 ± 2.5 |
| Week 49 | -3.3 ± 1.7 | -2.8 ± 3.4 | -3.2 ± 2.3 |
Best overall response (CR or PR) was assessed using tumor volume score (TVS) in the ITT population. Tumor Volume Score 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.
| Percentage of participants | Pexidartinib Part 1 and Part 2 | Placebo Part 1, Pexidartinib Part 2 | All Pexidartinib Treated |
|---|---|---|---|
| Percentage of Participants With Symptomatic, Locally Advanced Tenosynovial Giant Cell Tumor (TGCT) Achieving Complete or Partial Response Based on Tumor Volume Score (TVS) After Receiving Pexidartinib Compared With Those on Placebo by Week 49 | 63.9 | 66.7 | 64.8 |
Collected over Adverse events were monitored throughout the study from the time the participant signed the informed consent form to 28 days after the final treatment dose, up to 71 months.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Pexidartinib (Part 1) | 0/61 (0%) | 8/61 (13.1%) | 60/61 (98.4%) |
| Placebo (Part 1) | 0/59 (0%) | 1/59 (1.7%) | 55/59 (93.2%) |
| Pexidartinib (Parts 1 and 2) | 0/61 (0%) | 12/61 (19.7%) | 61/61 (100%) |
| Placebo (Part 1), Crossover Pexidartinib (Part 2) | 1/30 (3.3%) | 9/30 (30%) | 30/30 (100%) |
| All Pexidartinib Treated | 1/91 (1.1%) | 21/91 (23.1%) | 91/91 (100%) |
| Event | Pexidartinib (Part 1) | Placebo (Part 1) | Pexidartinib (Parts 1 and 2) | Placebo (Part 1), Crossover Pexidartinib (Part 2) | All Pexidartinib Treated |
|---|---|---|---|---|---|
| Adenosquamous carcinoma of the cervixNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/61 | 0/59 | 0/61 | 1/30 | 1/91 |
| Rectal adenocarcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/61 | 0/59 | 0/61 | 1/30 | 1/91 |
| Squamous cell carcinoma of skinNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/61 | 0/59 | 0/61 | 1/30 | 1/91 |
| Cardiac arrestCardiac disorders | 0/61 | 0/59 | 0/61 | 1/30 | 1/91 |
| Local swellingGeneral disorders | 0/61 | 0/59 | 0/61 | 1/30 | 1/91 |
| Non-cardiac chest painGeneral disorders | 0/61 | 0/59 | 0/61 | 1/30 | 1/91 |
| Neck painMusculoskeletal and connective tissue disorders | 0/61 | 0/59 | 0/61 | 1/30 | 1/91 |
| LymphangitisInfections and infestations | 0/61 | 0/59 | 0/61 | 1/30 | 1/91 |
| Rectal cancer stage IINeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/61 | 0/59 | 0/61 | 1/30 | 1/91 |
| Joint injuryInjury, poisoning and procedural complications | 0/61 | 0/59 | 0/61 | 1/30 | 1/91 |
| Event | Pexidartinib (Part 1) | Placebo (Part 1) | Pexidartinib (Parts 1 and 2) | Placebo (Part 1), Crossover Pexidartinib (Part 2) | All Pexidartinib Treated |
|---|---|---|---|---|---|
| Hair color changesSkin and subcutaneous tissue disorders | 41/61 | 2/59 | 44/61 | 25/30 | 69/91 |
| FatigueGeneral disorders | 33/61 | 21/59 | 35/61 | 8/30 | 43/91 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 14/61 | 15/59 | 19/61 | 15/30 | 34/91 |
| Aspartate aminotransferase increasedInvestigations | 24/61 | 0/59 | 28/61 | 6/30 | 34/91 |
| NauseaGastrointestinal disorders | 23/61 | 24/59 | 28/61 | 7/30 | 35/91 |
| HypertensionVascular disorders | 9/61 | 6/59 | 14/61 | 12/30 | 26/91 |
| DiarrheaGastrointestinal disorders | 13/61 | 15/59 | 19/61 | 10/30 | 29/91 |
| Alanine aminotransferase increasedInvestigations | 17/61 | 1/59 | 19/61 | 7/30 | 26/91 |
| Oedema peripheralGeneral disorders | 8/61 | 2/59 | 15/61 | 9/30 | 24/91 |
| PruritisSkin and subcutaneous tissue disorders | 10/61 | 2/59 | 10/61 | 9/30 | 19/91 |
| Age, Categorical(Participants) | Pexidartinib Part 1, Then Pexidartinib Part 2 | Placebo Part 1, Then Pexidartinib Part 2 | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 57 | 56 | 113 |
| >=65 years | 4 | 3 | 7 |
| Age, Continuous(years) | Pexidartinib Part 1, Then Pexidartinib Part 2 | Placebo Part 1, Then Pexidartinib Part 2 | Total |
|---|---|---|---|
| Mean | 44.6 ± 13.2 | 44.3 ± 13.6 | 44.5 ± 13.4 |
| Sex: Female, Male(Participants) | Pexidartinib Part 1, Then Pexidartinib Part 2 | Placebo Part 1, Then Pexidartinib Part 2 | Total |
|---|---|---|---|
| Female | 35 | 36 | 71 |
| Male | 26 | 23 | 49 |
| Race (NIH/OMB)(Participants) | Pexidartinib Part 1, Then Pexidartinib Part 2 | Placebo Part 1, Then Pexidartinib Part 2 | Total |
|---|---|---|---|
| American Indian or Alaska Native | 2 | 0 | 2 |
| Asian | 1 | 2 | 3 |
| Native Hawaiian or Other Pacific Islander | 2 | 2 | 4 |
| Black or African American | 3 | 1 | 4 |
| White | 52 | 54 | 106 |
| More than one race | 1 | 0 | 1 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Pexidartinib Part 1, Then Pexidartinib Part 2 | Placebo Part 1, Then Pexidartinib Part 2 | Total |
|---|---|---|---|
| Canada | 2 | 3 | 5 |
| Netherlands | 7 | 4 | 11 |
| Hungary | 2 | 1 | 3 |
| United States | 23 | 22 | 45 |
| Denmark | 1 | 2 | 3 |
| Poland | 2 | 0 | 2 |
| Italy | 8 | 9 | 17 |
| United Kingdom | 0 | 1 | 1 |
| Australia | 5 | 7 | 12 |
| France | 2 | 5 | 7 |
| Germany | 4 | 2 | 6 |
| Spain | 5 | 3 | 8 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
Supporting information: Study protocol, Sap, Csr
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