Phase 3 Study of Pexidartinib for Pigmented Villonodular Synovitis (PVNS) or Giant Cell Tumor of the Tendon Sheath (GCT-TS)
Condition: Pigmented Villonodular Synovitis; Giant Cell Tumors of the Tendon Sheath; Tenosynovial Giant Cell Tumor
MeSH terms: Neoplasms; Giant Cell Tumors; Giant Cell Tumor of Tendon Sheath; Synovitis, Pigmented Villonodular; Synovitis
Intervention: Pexidartinib; Placebo
Intervention description: Each capsule contains 200 mg of pexidartinib for oral administration; Placebo capsule matching pexidartinib capsule for oral administration
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
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
Enrollment: 120.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: PLX3397; Pexidartinib; Colony Stimulating Factor 1 Receptor (CSF-1R) inhibitor

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.