E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Tenosynovial Giant Cell Tumor |
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E.1.1.1 | Medical condition in easily understood language |
TGCT is a rare tumor arising from the joints (i.e. synovium of joints, bursae, and tendon sheaths) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10048683 |
E.1.2 | Term | Advanced cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate anti-tumor activity of vimseltinib using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by blinded independent radiological review (IRR) |
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E.2.2 | Secondary objectives of the trial |
• To assess anti-tumor activity of vimseltinib using tumor volume score (TVS) and modified RECIST (mRECIST) by blinded IRR • To assess the effects of vimseltinib on range of motion (ROM) • To assess the effects of vimseltinib on physical function, worst stiffness, worst pain, and quality of life (QoL) using patient-reported outcome (PRO) measures • To assess safety and tolerability of vimseltinib |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female participants ≥18 years of age 2. Histologically confirmed diagnosis of TGCT (formerly known as pigmented villonodular synovitis [PVNS] or giant cell tumor of the tendon sheath [GCT-TS]). Tumor biopsy to confirm TGCT diagnosis will be required if no histology/pathology is available a. Participants should have TGCT in a single joint and must have TGCT in joints where ROM can be assessed 3. Disease for which surgical resection will potentially cause worsening functional limitation or severe morbidity as judged by surgical consultation or a multidisciplinary tumor board 4. Symptomatic disease with at least moderate pain per BPI Worst Pain or at least moderate stiffness per Worst Stiffness NRS item (defined as a score of 4 or more, with 10 describing the worst condition) within the screening period, prior to the first dose, and documented in the medical record 5. Participant should complete 14 consecutive days of questionnaires during the screening period and must meet minimum requirements outlined in Protocol Table 4 6. An analgesic regimen, if used, needs to be stable (ie, no change in dose) as judged by the Investigator for at least 2 weeks prior to the first dose of study drug 7. Measurable disease per RECIST v1.1 with at least one lesion having a minimum tumor size of 2 cm as assessed from magnetic resonance imaging (MRI) scans by a central radiologist 8. Adequate organ function and bone marrow reserve as indicated by the following laboratory assessments performed within 21 days prior to the first dose of study drug: a. Bone marrow function: absolute neutrophil count (ANC) ≥1500/μL; hemoglobin ≥10 g/dL; platelet count ≥lower limit of normal (LLN) b. Hepatic function: total serum bilirubin ≤upper limit of normal (ULN); serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ULN c. Renal function: serum creatinine ≤1.5×ULN or creatinine clearance ≥50 mL/min based either on urine collection or Cockcroft-Gault estimation d. Electrolytes ≥LLN for: potassium, magnesium, and calcium 9. Able to take oral medication 10. Participants of reproductive potential must: a. Have a negative serum beta-human chorionic gonadotropin (β-hCG) pregnancy test at screening (female participants) b. Agree to follow the contraception requirements outlined in the protocol 11. The participant is capable of understanding and complying with the protocol and has signed the informed consent form (ICF). A signed ICF must be obtained before any study-specific procedures are performed. 12. Willing and able to complete the PRO assessments on an electronic device |
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E.4 | Principal exclusion criteria |
1. Previous use of systemic therapy (investigational or approved) targeting CSF1 or CSF1R including vimseltinib; previous therapy with imatinib and nilotinib is allowed 2. Treatment for TGCT, including investigational therapy, during the screening period. NOTE: Participants may not be part of an ongoing or have prior participation in a non TGCT investigational drug study within 30 days of screening. Ongoing participation in a noninterventional study (including observational studies) is permitted. 3 days, or if the half-life is not available, the interval must be ≥28 days prior to the first administration of study drug 3. Known metastatic TGCT or other active cancer that requires concurrent treatment (exceptions will be considered on a case-by-case basis depending on tumor type, stage, location, planned treatment, and expected recovery after discussion and approval by Sponsor) 4. Baseline prolongation of the QT interval corrected by Fridericia's formula (QTcF) based on repeated demonstration of QTcF >450 ms in males or >470 ms in females or history of long QT syndrome 5. Receive concurrent treatment with any prohibited medications • Acetaminophen usage exceeding 3 g/day • Proton-pump inhibitors taken within 4 days prior to the first dose of study drug • Medications that are breast cancer resistance protein (BCRP) or organic cation transporter 2 (OCT2) substrates taken within at least 4 days or 5×half-life (whichever is longer) prior to the first dose of study drug • Medications with a known risk of prolonging the QT interval within at least 14 days or 5×half-life (whichever is longer) prior to the first dose of study drug (see Appendix 1) • Prophylactic use of myeloid growth factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte macrophage-colony-stimulating factor [GM-CSF]) 6. Major surgery within 14 days of the first dose of study drug; following major surgeries >14 days prior to the first dose of study drug, all surgical wounds must be healed and free of infection or dehiscence 7. Any clinically significant comorbidities, such as significant concomitant arthropathy not related to TGCT in the affected joint, or any other serious medical or psychiatric condition(s), known current alcohol abuse, which in the judgment of the Investigator, could compromise compliance with the protocol, interfere with the interpretation of study results, or predispose the participant to safety risks 8. Active liver or biliary disease including evidence of fatty liver, non-alcoholic steatohepatitis (NASH), or cirrhosis 9. Malabsorption syndrome or other illness that could affect oral absorption as judged by the Investigator 10. Known active human immunodeficiency virus (HIV), acute or chronic hepatitis B, acute or chronic hepatitis C, or known active mycobacterium tuberculosis infection 11. If female, the participant is pregnant or breastfeeding 12. Known allergy or hypersensitivity to any component of the study drug 13. Contraindication to MRI |
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E.5 End points |
E.5.1 | Primary end point(s) |
Objective response rate (ORR, including complete response [CR] and partial response [PR]) per RECIST v1.1 at Week 25 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key Secondary Endpoints: • ORR per TVS at Week 25 • Change from baseline in active ROM of the affected joint, relative to a reference standard, at Week 25 • Change from baseline in the Patient-reported Outcomes Measurement Information System (PROMIS) physical function score at Week 25 • Change from baseline in the Worst Stiffness numeric rating scale (NRS) score at Week 25 • Change from baseline in EQ-VAS (EuroQol Visual Analogue Scale) at Week 25 • Response of at least a 30% improvement in the mean Brief Pain Inventory (BPI) Worst Pain NRS score without a 30% or greater increase in narcotic analgesic use at Week 25
Other Secondary Endpoints: • ORR per RECIST v1.1 • ORR assessed by mRECIST at Week 25 • Duration of response (DOR; time from first PR or CR to disease progression or death) assessed using RECIST v1.1, TVS, and mRECIST • Incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events, related TEAEs, dose reductions, dose interruptions, and discontinuation of study drug due to adverse event • Changes from baseline in laboratory parameters, electrocardiograms (ECGs), and vital signs |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 25 and monitored throughout the study |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Part 1 is double blind period followed by Part 2 (open label) at Week 25 for all patients |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Switzerland |
Hong Kong |
Australia |
Canada |
United Kingdom |
United States |
France |
Germany |
Italy |
Netherlands |
Norway |
Poland |
Spain |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |