Phase 3 Study of Pexidartinib for Pigmented Villonodular Synovitis (PVNS) or Giant Cell Tumor of the Tendon Sheath (GCT-TS) (ENLIVEN)
Pigmented Villonodular Synovitis, Giant Cell Tumors of the Tendon Sheath, Tenosynovial Giant Cell Tumor
About this trial
This is an interventional treatment trial for Pigmented Villonodular Synovitis focused on measuring PLX3397, Pexidartinib, Colony Stimulating Factor 1 Receptor (CSF-1R) inhibitor
Eligibility Criteria
Inclusion Criteria
- 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
- Platelet count ≥ 100 × 10^9/L
- Serum creatinine ≤ 1.5 × ULN
- 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.
- Willingness and ability to use an electronic diary.
- Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements.
Exclusion Criteria
- 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.
Sites / Locations
- Mayo Clinic
- University of Southern California
- Stanford Cancer Center
- UCLA Medical Center
- Mayo Clinic Cancer Center
- Sylvester Comprehensive Cancer Center
- Moffitt Cancer Center
- Massachusetts General Hospital
- : Dana Farber Cancer Institute
- Michigan Comprehensive Cancer Center
- Mayo Clinic Cancer Center
- Washington University School of Medicine
- MD Anderson Cancer Center at Cooper
- Memorial Sloan Kettering Cancer Center
- Duke Cancer Center
- OHSU Knight Cancer Institute
- Vanderbilt-Ingram Cancer Center
- Huntsman Cancer Institute
- Seattle Cancer Care Alliance
- Chris O'Brien Lifehouse
- Princess Alexandra Hospital
- Peter MacCallum Cancer Centre
- Princess Margaret Hospital
- McGill University Health Centre
- Herlev Hospital
- Centre Leon Bérard
- Institut Gustave Roussy
- HELIOS Klinikum Berlin-Buch
- Universitätsklinikum Essen
- Military Hospital-State Health Center
- Istituto Ortopedico Rizzoli
- Istituto Nazionale Tumori-Fondazione IRCCS
- Leiden University Medical Center
- Radboud Univ. Medical Center
- Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie
- Hospital de la Santa Creu i Sant Pau
- Hospital Universitario Virgen del Rocío
- University College Hospital
- The Royal Marsden NHS Foundation Trust
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Experimental
Placebo Comparator
Experimental
Experimental
Part 1 - Pexidartinib
Part 1 - Placebo
Part 2 - All Pexidartinib
Part 2 - Placebo-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
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