Musculoskeletal Diseases

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Wounds and Injuries

Nervous System Diseases

Rare Diseases

Synovitis

Giant Cell Tumors

Giant Cell Tumor of Tendon Sheath

Synovitis, Pigmented Villonodular

Joint Diseases

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Tendinopathy

Muscular Diseases

Pigmented Villonodular Synovitis

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

Participants received blinded treatment of matching placebo (5 capsules per day) for 2 weeks, then matching placebo (4 capsules per day) for 22 weeks

Participants received pexidartinib in Part 1 and in Part 2 at their prescribed dose

Participants received placebo in Part 1 and pexidartinib in Part 2 at their prescribed dose

Each capsule contains 200 mg of pexidartinib for oral administration

Pexidartinib

Placebo capsule matching pexidartinib capsule for oral administration

Placebo

Global Team Leader

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.

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) in Part 1, Open-label (no masking) in Part 2

Phase 3 Study of Pexidartinib for Pigmented Villonodular Synovitis (PVNS) or Giant Cell Tumor of the Tendon Sheath (GCT-TS)

A Double-blind, Randomized, Placebo-controlled Phase 3 Study of Orally Administered PLX3397 in Subjects With Pigmented Villonodular Synovitis or Giant Cell Tumor of the Tendon Sheath

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/

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.

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.

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.

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).

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).

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.

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.

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.

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).

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.

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.

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.

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.

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.

Daiichi Sankyo

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

Pexidartinib: Each capsule contains 200 mg of pexidartinib for oral administration

Pexidartinib (Part 1)

Participants received blinded treatment of matching placebo (5 capsules per day) for 2 weeks, then matching placebo (4 capsules per day) for 22 weeks

Placebo: Placebo capsule matching pexidartinib capsule for oral administration

Placebo (Part 1)

Participants received pexidartinib in Part 1 and in Part 2 at their prescribed dose

Pexidartinib: Each capsule contains 200 mg of pexidartinib for oral administration

Pexidartinib (Parts 1 and 2)

Participants received placebo in Part 1 and pexidartinib in Part 2 at their prescribed dose

Pexidartinib: Each capsule contains 200 mg of pexidartinib for oral administration

Placebo: Placebo capsule matching pexidartinib capsule for oral administration

Placebo (Part 1), Crossover Pexidartinib (Part 2)

All participants who received pexidartinib in Part 1 and Part 2 (placebo crossed over to pexidartinib)

All Pexidartinib Treated

Participants received Pexidartinib,1000 mg (5 capsules per day ) for 2 weeks, then 800 mg (4 capsules per day) for 22 weeks in Part 1 of study. Eligible participants from this group also received Pexidartinib in Part 2 at their prescribed dose.

Pexidartinib: Each capsule contains 200 mg of pexidartinib for oral administration

Pexidartinib Part 1, Then Pexidartinib Part 2

Participants received treatment of matching placebo (5 capsules per day) for 2 weeks, then matching placebo (4 capsules per day) for 22 weeks in Part 1 of study. Eligible participants from this group also received Pexidartinib in Part 2 at their prescribed dose.

Placebo: Placebo capsule matching pexidartinib capsule for oral administration. Pexidartinib: Each capsule contains 200 mg of pexidartinib for oral administration (Part 2).

Placebo Part 1, Then Pexidartinib Part 2

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Canada

Netherlands

Hungary

United States

Denmark

Poland

Italy

United Kingdom

Australia

France

Germany

Spain

Region of Enrollment

Enrollment was stopped on 30 Sep 2016; no new participants received the study drug. After Part 1, those who wished to continue were un-blinded; those on placebo were discontinued.

Treatment comparison between the pexidartinib and placebo groups at Week 25

Complete Response (CR)

Partial Response (PR)

Response (CR or PR)

Participants received treatment of Pexidartinib,1000 mg (5 capsules per day ) for 2 weeks, then 800 mg (4 capsules per day) for 22 weeks Pexidartinib: Each capsule contains 200 mg of Pexidartinib for oral administration.

Pexidartinib Part 1

Participants received treatment of matching placebo (5 capsules per day) for 2 weeks, then matching placebo (4 capsules per day) for 22 weeks Placebo: Placebo capsule matching Pexidartinib capsule for oral administration.

Placebo Part 1

Best overall response was assessed in the Intent-to-Treat (ITT) population.

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

Baseline

Week 13

Week 25

Range of motion was assessed in the ITT population in participants where data were available.

Mean Change From Baseline For Range of Motion (ROM) Score in Participants Receiving Pexidartinib Compared With Those on Placebo Up to Week 25

Best overall response was assessed in the ITT population.

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

Treatment comparison between pexidartinib and placebo groups at Week 25

Week 9

Week 17

Physical function was assessed in the ITT population in participants where data were available.

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

Worst stiffness was assessed in the ITT population.

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

Participants received treatment of Pexidartinib,1000 mg (5 capsules per day ) for 2 weeks, then 800 mg (4 capsules per day) for 22 weeks

Pexidartinib: Each capsule contains 200 mg of Pexidartinib for oral administration.

Participants received treatment of matching placebo (5 capsules per day) for 2 weeks, then matching placebo (4 capsules per day) for 22 weeks

Placebo: Placebo capsule matching Pexidartinib capsule for oral administration.

Worst pain was assessed in the ITT population.

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

Number of responses

Week 12 (Day 84); Without disease progression

Week 12 (Day 84); With disease progression

Week 24 (Day 168); Without disease progression

Week 24 (Day 168); With disease progression

Week 48 (Day 336); Without disease progression

Week 48 (Day 336); With disease progression

Week 72 (Day 504); Without disease progression

Week 72 (Day 504); With disease progression

Week 96 (Day 672); Without disease progression

Week 96 (Day 672); With disease progression

Part 1: Participants received treatment of pexidartinib,1000 mg (5 capsules per day ) for 2 weeks, then 800 mg (4 capsules per day) for 22 weeks

Part 2: Participants also received pexidartinib at their prescribed dose.

Pexidartinib: Each capsule contains 200 mg of pexidartinib for oral administration

Pexidartinib Part 1 and Part 2

Participants that received placebo in part 1 and received Pexidartinib in Part 2 at their prescribed dose.

Pexidartinib: Each capsule contains 200 mg of pexidartinib for oral administration

Placebo Part 1, Pexidartinib Part 2

All participants who received Pexidartinib in Part 1 and Part 2 as well as those who only received Pexidartinib in Part 2.

The overall number of responses and the number of participants with and without disease progression were assessed in the ITT population, specifically among the Pexidartinib Part 1, Pexidartinib Part 2; Pexidartinib Part 2 only, All Pexidartinib Treated participants, . Participants randomized to Placebo Part 1 only were not analyzed.

Number of Responders to Pexidartinib With and Without Disease Progression

Number of responders

Week 120 (Day 840); Without disease progression

Week 120 (Day 840); With disease progression

Participants received treatment of Pexidartinib,1000 mg (5 capsules per day ) for 2 weeks, then 800 mg (4 capsules per day) for 22 weeks in Part 1 and also received Pexidartinib in Part 2 at their prescribed dose.

Pexidartinib: Each capsule contains 200 mg of pexidartinib for oral administration

Pexidartinib in Part 1 and Part 2

Participants received treatment of matching placebo (5 capsules per day) for 2 weeks, then matching placebo (4 capsules per day) for 22 weeks in Part 1 and also received Pexidartinib in Part 2 at their prescribed dose.

Placebo: Placebo capsule matching Pexidartinib capsule for oral administration Pexidartinib: Each capsule contains 200 mg of Pexidartinib for oral administration.

All participants who received pexidartinib in Part 1 and Part 2 as well as those who received pexidartinib in Part 2 only.

The overall number of responses and the number of participants with and without disease progression was assessed in the ITT population, specifically among the Pexidartinib Part 1, Pexidartinib Part 2; Pexidartinib Part 2 only; and All Pexidartinib Treated participants. Participants who received Placebo Part 1 only were not analyzed.

Number of Responders to Pexidartinib With and Without Disease Progression Based on Tumor Volume Score

Part 1: Participants received treatment of pexidartinib,1000 mg (5 capsules per day ) for 2 weeks, then 800 mg (4 capsules per day) for 22 weeks Part 2: Participants also received pexidartinib at their prescribed dose.

Pexidartinib: Each capsule contains 200 mg of pexidartinib for oral administration

DOR was assessed in the ITT population, specifically among the Pexidartinib Part 1, Pexidartinib Part 2; Pexidartinib Part 2 only. Participants randomized to Placebo Part 1 only were not analyzed. DOR was based on numbers of responders only.

Duration of Response (DOR) Based on RECIST 1.1

Duration of Response (DOR) Based on Tumor Volume Score (TVS)

Any Hair color changes

Grade ≥3 Hair color changes

Any Pruritis

Grade ≥3 Pruritis

Any Rash maculopapular

Grade ≥3 Rash maculopapular

Any Pruritis generalized

Grade ≥3 Pruritis generalized

Any Erythema

Grade ≥3 Erythema

Any Dry skin

Grade ≥3 Dry skin

Any Photosensitivity reaction

Grade ≥3 Photosensitivity reaction

Any Nausea

Grade ≥3 Nausea

Any Diarrhea

Grade ≥3 Diarrhea

Any Vomiting

Grade ≥3 Vomiting

Any Abdominal Pain

Grade ≥3 Abdominal Pain

Any Dry mouth

Grade ≥3 Dry mouth

Any Constipation

Grade ≥3 Constipation

Any Stomatitis

Grade ≥3 Stomatitis

Any Fatigue

Grade ≥3 Fatigue

Any Edema peripheral

Grade ≥3 Edema peripheral

Any Face edema

Grade ≥3 Face edema

Any Asthenia

Grade ≥3 Asthenia

Any Pyrexia

Grade ≥ Pyrexia

Any AST increased

Grade ≥3 AST increased

Any ALT increased

Grade ≥3 ALT increased

Any ALP increased

Grade ≥3 ALP increased

Any LDH increased

Grade ≥3 LDH increased

Any Weight increased

Grade ≥3 Weight increased

Any Dysgeusia

Grade ≥3 Dysgeusia

Any Headache

Grade ≥3 Headache

Any Dizziness

Grade ≥3 Dizziness

Any Paresthesia

Grade ≥3 Paresthesia

Any Memory impairment

Grade ≥3 Memory impairment

Any Arthralgia

Grade ≥3 Arthralgia

Any Pain in extremity

Grade ≥3 Pain in extremity

All safety events were assessed in the Safety Analysis Set.

Spots Global Cancer Trial Database for giant cell tumors of the tendon sheath