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

• ClinicalTrials.gov Identifier: NCT02371369
• Recruitment Status: Completed
• First Posted: February 25, 2015
• Results First Posted: January 10, 2020
• Last Update Posted: May 11, 2022
• Sponsor: Daiichi Sankyo
• Information provided by (Responsible Party): Daiichi Sankyo

Tracking Information

• First Submitted Date: February 19, 2015
• First Posted Date: February 25, 2015
• Results First Submitted Date: August 26, 2019
• Results First Posted Date: January 10, 2020
• Last Update Posted Date: May 11, 2022
• Actual Study Start Date: May 11, 2015
• Actual Primary Completion Date: March 27, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 6, 2020)

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 [ Time Frame: 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.

Original Primary Outcome Measures (submitted: February 19, 2015)

percentage of subjects achieving complete or partial response [ Time Frame: week 25 ]

The proportion of subjects who achieve a complete response (CR) or partial response (PR) at the Week 25 visit based on centrally read MRI scans and RECIST 1.1.

Current Secondary Outcome Measures (submitted: April 11, 2022)

• Mean Change From Baseline For Range of Motion (ROM) Score in Participants Receiving Pexidartinib Compared With Those on Placebo Up to Week 25 [ Time Frame: Baseline, Week 13, and 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.
• 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 [ Time Frame: 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.
• 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 [ Time Frame: at Week 9 , Week 17, and 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.
• 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 [ Time Frame: Baseline, Week 9, Week 17, and 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).
• 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 [ Time Frame: 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).
• Number of Responders to Pexidartinib With and Without Disease Progression [ Time Frame: By Week 96 ]
  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.
• Number of Responders to Pexidartinib With and Without Disease Progression Based on Tumor Volume Score [ Time Frame: By Week 120 ]
  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 [ 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 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 Tumor Volume Score (TVS) [ 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 TVS is defined from the date of the first recorded evidence of response to the first date of documented disease progression.
• Percentage of Participants Reporting Frequent (≥10%) Treatment-Emergent Adverse Events by Preferred Term [ Time Frame: After the first dose of treatment up to 28 days after the last dose ]
  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.

Original Secondary Outcome Measures (submitted: February 19, 2015)

• composite of patient reported outcomes [ Time Frame: week 25 ]
  evaluate composite patient-reported outcomes (PROs), including the Brief Pain Inventory (BPI) Worst Pain Numeric Rating Scale (NRS) item, Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function Scale, and Worst Stiffness NRS item, at Week 25;
• response based on Tumor Volume Score [ Time Frame: week 25 ]
  response based on Tumor Volume Score (TVS)
• range of motion [ Time Frame: week 25 ]
• duration of response. [ Time Frame: week 25 ]

Current Other Pre-specified Outcome Measures (submitted: January 6, 2020)

• 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 [ Time Frame: 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.
• Mean Change From Baseline For Range of Motion (ROM) Score in Participants Receiving Pexidartinib Compared With Those on Placebo by Week 49 [ Time Frame: 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.
• 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 [ Time Frame: 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.
• Mean Change From Baseline for Worst Stiffness Numeric Rating Scale Score (NRS) in Participants Receiving Pexidartinib Compared With Those on Placebo by Week 49 [ Time Frame: Baseline, Week 25, and 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).
• Mean Change From Baseline for Worst Pain Numeric Rating Scale Score (NRS) in Participants Receiving Pexidartinib Compared With Those on Placebo by Week 49 [ Time Frame: 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).
• 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 [ Time Frame: 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.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

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

Primary Purpose: Treatment

Condition

• Pigmented Villonodular Synovitis
• Giant Cell Tumors of the Tendon Sheath
• Tenosynovial Giant Cell Tumor

Intervention

• Drug: Pexidartinib
  Each capsule contains 200 mg of pexidartinib for oral administration
  Other Names:

  • PLX3397
  • Pexidartinib hydrochloride (HCl)
• Drug: Placebo
  Placebo capsule matching pexidartinib capsule for oral administration
  Other Name: Placebo Capsule

Study Arms

• Experimental: Part 1 - Pexidartinib
  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
  Intervention: Drug: Pexidartinib
• Placebo Comparator: Part 1 - Placebo
  Participants received blinded treatment of matching placebo (5 capsules per day) for 2 weeks, then matching placebo (4 capsules per day) for 22 weeks
  Intervention: Drug: Placebo
• Experimental: Part 2 - All Pexidartinib
  Participants received pexidartinib in Part 1 and in Part 2 at their prescribed dose
  Intervention: Drug: Pexidartinib
• Experimental: Part 2 - Placebo-Pexidartinib
  Participants received placebo in Part 1 and pexidartinib in Part 2 at their prescribed dose
  Interventions:

  • Drug: Pexidartinib
  • Drug: Placebo

Publications *

• Healey JH, Tap WD, Gelhorn HL, Ye X, Speck RM, Palmerini E, Stacchiotti S, Desai J, Wagner AJ, Alcindor T, Ganjoo K, Martin-Broto J, Wang Q, Shuster D, Gelderblom H, van de Sande M. Pexidartinib Provides Modest Pain Relief in Patients With Tenosynovial Giant Cell Tumor: Results From ENLIVEN. Clin Orthop Relat Res. 2023 Jan 1;481(1):107-116. doi: 10.1097/CORR.0000000000002335. Epub 2022 Aug 24.
• Lewis JH, Gelderblom H, van de Sande M, Stacchiotti S, Healey JH, Tap WD, Wagner AJ, Pousa AL, Druta M, Lin CC, Baba HA, Choi Y, Wang Q, Shuster DE, Bauer S. Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors. Oncologist. 2021 May;26(5):e863-e873. doi: 10.1002/onco.13629. Epub 2020 Dec 24.
• Tap W. ENLIVEN study: Pexidartinib for tenosynovial giant cell tumor (TGCT). Future Oncol. 2020 Sep;16(25):1875-1878. doi: 10.2217/fon-2020-0307. Epub 2020 Aug 5.
• Tap WD, Gelderblom H, Palmerini E, Desai J, Bauer S, Blay JY, Alcindor T, Ganjoo K, Martin-Broto J, Ryan CW, Thomas DM, Peterfy C, Healey JH, van de Sande M, Gelhorn HL, Shuster DE, Wang Q, Yver A, Hsu HH, Lin PS, Tong-Starksen S, Stacchiotti S, Wagner AJ; ENLIVEN investigators. Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. Lancet. 2019 Aug 10;394(10197):478-487. doi: 10.1016/S0140-6736(19)30764-0. Epub 2019 Jun 19.
• Gelhorn HL, Tong S, McQuarrie K, Vernon C, Hanlon J, Maclaine G, Lenderking W, Ye X, Speck RM, Lackman RD, Bukata SV, Healey JH, Keedy VL, Anthony SP, Wagner AJ, Von Hoff DD, Singh AS, Becerra CR, Hsu HH, Lin PS, Tap WD. Patient-reported Symptoms of Tenosynovial Giant Cell Tumors. Clin Ther. 2016 Apr;38(4):778-93. doi: 10.1016/j.clinthera.2016.03.008. Epub 2016 Apr 1.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 13, 2017): 120
• Original Estimated Enrollment (submitted: February 19, 2015): 126
• Actual Study Completion Date: April 30, 2021
• Actual Primary Completion Date: March 27, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

1. Age ≥ 18 years.
2. A diagnosis of PVNS or GCT-TS (i) that has been histologically confirmed either by a pathologist at the treating institution or a central pathologist, and (ii) where surgical resection would be associated with potentially worsening functional limitation or severe morbidity (locally advanced disease), with morbidity determined consensually by qualified personnel (eg, two surgeons or a multi-disciplinary tumor board).
3. Measurable disease of at least 2 cm and otherwise based on RECIST 1.1, assessed from MRI scans by a central radiologist.

4. Symptomatic disease because of active PVNS or GCT-TS, defined as one or more of the following:

   1. a worst pain of at least 4 at any time during the week preceding the Screening Visit (based on scale of 0 to 10, with 10 representing "pain as bad as you can imagine").
   2. a worst stiffness of at least 4 at any time during the week preceding the Screening Visit (based on a scale of 0 to 10, with 10 representing "stiffness as bad as you can imagine").
5. Stable prescription of analgesic regimen during the 2 weeks prior to randomization.
6. During the 2 weeks prior to randomization, at least 4 of 7 consecutive days of Brief Pain Inventory (BPI) Worst Pain Numeric Rating Scale (NRS) items and Worst Stiffness NRS items completed correctly.
7. Women of childbearing potential must have a negative serum pregnancy test within the 14-day period prior to randomization. (Where demanded by local regulations, this test may be required within 72 hours of randomization.)
8. Males and females of childbearing potential are permitted in the study so long as they consent to avoid getting their partner pregnant or becoming pregnant, respectively, by using a highly effective contraception method, as described below, throughout the study and for up to 90 days after completion. Highly effective methods of contraception include: intra-uterine device (non-hormonal or hormonal), bilateral tubal occlusion, vasectomy, sexual abstinence, or barrier methods (eg, condom, diaphragm) used in combination with hormonal methods associated with inhibition of ovulation. Women of non-childbearing 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 (FSH) level > 40 milli-International units (mIU/mL) will be considered postmenopausal.

9. Adequate hematologic, hepatic, and renal function, defined by:

   • Absolute neutrophil count ≥ 1.5 × 10^9/L
   • aspartate aminotransferase/alanine (AST/ALT) ≤ 1.5 × upper limit of normal (ULN)
   • Hemoglobin > 10 g/dL
   • Total bilirubin ≤ 1.5 × ULN
   • Platelet count ≥ 100 × 10^9/L
   • Serum creatinine ≤ 1.5 × ULN
10. Willingness and ability to complete the Worst Pain NRS item, Worst Stiffness NRS item, Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function Scale, and other self-assessment instruments throughout the study.
11. Willingness and ability to use an electronic diary.
12. Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements.

Exclusion Criteria

1. Investigational drug use within 28 days of randomization.
2. Previous use of pexidartinib or any biologic treatment targeting CSF-1 or the CSF-1R; previous use of oral tyrosine kinase inhibitors, eg, imatinib or nilotinib, are allowed.
3. Active cancer (either concurrent or within the last year of starting study treatment) 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.
4. Known metastatic PVNS/GCT-TS.
5. Active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus or known active or chronic infection with human immunodeficiency virus.
6. Known active tuberculosis.
7. 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 the person's study participation or the interpretation of his or her results.
8. Women who are breastfeeding.
9. A screening Fridericia corrected QT interval (QTcF) ≥ 450 ms (men) or ≥ 470 ms (women).
10. MRI contraindications.
11. History of hypersensitivity to any excipients in the investigational product.
12. Inability to swallow capsules.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Denmark, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT02371369
• Other Study ID Numbers: PLX108-10; 2014-000148-14 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: 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 Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• URL: https://vivli.org/ourmember/daiichi-sankyo/

• Current Responsible Party: Daiichi Sankyo
• Original Responsible Party: Same as current
• Current Study Sponsor: Daiichi Sankyo
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Global Team Leader; Daiichi Sankyo

• PRS Account: Daiichi Sankyo
• Verification Date: April 2022