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

NCT02371369 | Completed Phase 3 Results DMC

• 2 other identifiers: PLX108-102014-000148-14
• Study Type: interventional
• Target: 120
• Locations: 12 countries
• Sites: 39

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.

Conditions

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

Keywords

PLX3397; Pexidartinib; Colony Stimulating Factor 1 Receptor (CSF-1R) inhibitor

Outcome Measures

Primary Outcomes (1)

• 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.

  Week 25

Secondary Outcomes (10)

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

  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

  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

  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

  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

  Week 25

Other Outcomes (6)

• 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

  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

  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

  By Week 49

Study Arms (4)

Part 1 - Pexidartinib

EXPERIMENTAL

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

Part 1 - Placebo

PLACEBO COMPARATOR

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

Part 2 - All Pexidartinib

EXPERIMENTAL

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

Drug: Pexidartinib

Part 2 - Placebo-Pexidartinib

EXPERIMENTAL

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

Drug: Pexidartinib; Drug: Placebo

Interventions

Pexidartinib DRUG

Each capsule contains 200 mg of pexidartinib for oral administration

Also known as: PLX3397, Pexidartinib hydrochloride (HCl)

Part 1 - Pexidartinib; Part 2 - All Pexidartinib; Part 2 - Placebo-Pexidartinib

Placebo DRUG

Placebo capsule matching pexidartinib capsule for oral administration

Also known as: Placebo Capsule

Part 1 - Placebo; Part 2 - Placebo-Pexidartinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years.
• 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).
• Measurable disease of at least 2 cm and otherwise based on RECIST 1.1, assessed from MRI scans by a central radiologist.
• Symptomatic disease because of active PVNS or GCT-TS, defined as one or more of the following:
• 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").
• 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").
• Stable prescription of analgesic regimen during the 2 weeks prior to randomization.
• 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.
• 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.)
• 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.
• 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

You may not qualify if:

• Investigational drug use within 28 days of randomization.
• 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.
• 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.
• Known metastatic PVNS/GCT-TS.
• Active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus or known active or chronic infection with human immunodeficiency virus.
• Known active tuberculosis.
• Significant concomitant arthropathy in the affected joint, serious illness, uncontrolled infection, or a medical or psychiatric history that, in the Investigator's opinion, would likely interfere with the person's study participation or the interpretation of his or her results.
• Women who are breastfeeding.
• A screening Fridericia corrected QT interval (QTcF) ≥ 450 ms (men) or ≥ 470 ms (women).
• MRI contraindications.
• History of hypersensitivity to any excipients in the investigational product.
• Inability to swallow capsules.

Sponsors & Collaborators

• Daiichi Sankyo: lead

Study Sites (39)

Mayo Clinic

Scottsdale, Arizona, 85259-5499, United States

Location

University of Southern California

Los Angeles, California, 90033, United States

Location

Stanford Cancer Center

Palo Alto, California, 94305, United States

Location

UCLA Medical Center

Santa Monica, California, 90404, United States

Location

Mayo Clinic Cancer Center

Jacksonville, Florida, 32224, United States

Location

Sylvester Comprehensive Cancer Center

Miami, Florida, 33136, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

: Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Mayo Clinic Cancer Center

Rochester, Minnesota, 55905, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

MD Anderson Cancer Center at Cooper

Camden, New Jersey, 08103, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Duke Cancer Center

Durham, North Carolina, 27710, United States

Location

OHSU Knight Cancer Institute

Portland, Oregon, 97239, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

Chris O'Brien Lifehouse

Sydney, New South Wales, 2050, Australia

Location

Princess Alexandra Hospital

Woolloongabba, Queensland, 4102, Australia

Location

Peter MacCallum Cancer Centre

East Melbourne, Victoria, 3000, Australia

Location

Princess Margaret Hospital

Toronto, Ontario, M5G2M9, Canada

Location

McGill University Health Centre

Montreal, Quebec, H4A3J1, Canada

Location

Herlev Hospital

Herlev, 2730, Denmark

Location

Centre Leon Bérard

Lyon, 69373, France

Location

Institut Gustave Roussy

Villejuif, 94800, France

Location

HELIOS Klinikum Berlin-Buch

Berlin, 13125, Germany

Location

Universitätsklinikum Essen

Essen, 45147, Germany

Location

Military Hospital-State Health Center

Budapest, H1134, Hungary

Location

Istituto Ortopedico Rizzoli

Bologna, BO, 40136, Italy

Location

Istituto Nazionale Tumori-Fondazione IRCCS

Milan, MI, 20133, Italy

Location

Leiden University Medical Center

Leiden, 2333 ZA, Netherlands

Location

Radboud Univ. Medical Center

Nijmegen, 6525 GA, Netherlands

Location

Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie

Warsaw, 02-781, Poland

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08041, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

University College Hospital

London, NW12BU, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

London, SW36JJ, United Kingdom

Location

Related Publications (5)

• 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.

  PMID: 36001000 DERIVED

• 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.

  PMID: 33289960 DERIVED

• 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.

  PMID: 32755241 DERIVED

• 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.

  PMID: 31229240 DERIVED

• 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.

  PMID: 27041409 DERIVED

MeSH Terms

Conditions

Synovitis, Pigmented Villonodular; Giant Cell Tumor of Tendon Sheath

Interventions

pexidartinib

Condition Hierarchy (Ancestors)

Giant Cell Tumors; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Synovitis; Joint Diseases; Musculoskeletal Diseases; Tendinopathy; Muscular Diseases

Limitations and Caveats

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.

Results Point of Contact

• Title: Daiichi Sankyo
• Organization: Contact for Clinical Trial Information

CTRinfo@dsi.com

1-908-992-6400

Study Officials

• Global Team Leader

  Daiichi Sankyo

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) in Part 1, Open-label (no masking) in Part 2
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 19, 2015
• First Posted: February 25, 2015
• Study Start: May 11, 2015
• Primary Completion: March 27, 2017
• Study Completion: April 30, 2021
• Last Updated: May 11, 2022
• Results First Posted: January 10, 2020

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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.

Locations

US (19); PL (1); IT (2); CA (2); AU (3); DK (1); FR (2); DE (2); HU (1); NL (2); GB (2); ES (2)