Clinical trial NCT02371369: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2015-02-25
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: 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
timeFrame: Week 25
Secondary outcomes:
measure: Mean Change From Baseline For Range of Motion (ROM) Score in Participants Receiving Pexidartinib Compared With Those on Placebo Up to Week 25
timeFrame: Baseline, Week 13, and Week 25
measure: 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
timeFrame: Week 25
measure: 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
timeFrame: at Week 9 , Week 17, and Week 25
measure: 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
timeFrame: Baseline, Week 9, Week 17, and Week 25
measure: 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
timeFrame: Week 25
measure: Number of Responders to Pexidartinib With and Without Disease Progression
timeFrame: By Week 96
measure: Number of Responders to Pexidartinib With and Without Disease Progression Based on Tumor Volume Score
timeFrame: By Week 120
measure: Duration of Response (DOR) Based on RECIST 1.1
timeFrame: 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)
measure: Duration of Response (DOR) Based on Tumor Volume Score (TVS)
timeFrame: 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)
measure: Percentage of Participants Reporting Frequent (≥10%) Treatment-Emergent Adverse Events by Preferred Term
timeFrame: After the first dose of treatment up to 28 days after the last dose
Other outcomes:
measure: 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
timeFrame: By Week 49
measure: Mean Change From Baseline For Range of Motion (ROM) Score in Participants Receiving Pexidartinib Compared With Those on Placebo by Week 49
timeFrame: By Week 49
measure: 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
timeFrame: By Week 49
measure: Mean Change From Baseline for Worst Stiffness Numeric Rating Scale Score (NRS) in Participants Receiving Pexidartinib Compared With Those on Placebo by Week 49
timeFrame: Baseline, Week 25, and Week 49
measure: Mean Change From Baseline for Worst Pain Numeric Rating Scale Score (NRS) in Participants Receiving Pexidartinib Compared With Those on Placebo by Week 49
timeFrame: By Week 49
measure: 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
timeFrame: By Week 49
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Center
state: California
city: Santa Monica
country: United States
facility: UCLA Medical Center
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic Cancer Center
state: Florida
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: : Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: Michigan Comprehensive Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Camden
country: United States
facility: MD Anderson Cancer Center at Cooper
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke Cancer Center
state: North Carolina
city: Portland
country: United States
facility: OHSU Knight Cancer Institute
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Sydney
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Herlev
country: Denmark
facility: Herlev Hospital
city: Lyon
country: France
facility: Centre Leon Bérard
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Berlin
country: Germany
facility: HELIOS Klinikum Berlin-Buch
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Budapest
country: Hungary
facility: Military Hospital-State Health Center
city: Bologna
country: Italy
facility: Istituto Ortopedico Rizzoli
state: BO
city: Milano
country: Italy
facility: Istituto Nazionale Tumori-Fondazione IRCCS
state: MI
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Nijmegen
country: Netherlands
facility: Radboud Univ. Medical Center
city: Warszawa
country: Poland
facility: Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: London
country: United Kingdom
facility: University College Hospital
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Daiichi Sankyo
name: Global Team Leader
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.