Neoadjuvant Pimicotinib Combined With Surgery Versus Upfront Surgery for Diffuse Tenosynovial Giant Cell Tumor

Official title

Neoadjuvant Pimicotinib Combined With Surgery Versus Upfront Surgery for Diffuse Tenosynovial Giant Cell Tumor: A Randomized, Open-label Trial

Overview

Tenosynovial giant cell tumor (TGCT) is a rare neoplasm predominantly occurring in young and middle-aged adults, characterized by high recurrence and high disability rates. Surgery represents the first-line treatment at present. Although surgical resection can eradicate lesions, repeated surgical interventions constitute the major disease-related burden. Particularly for patients with diffuse-type TGCT (D-TGCT), postoperative recurrence rates can exceed 50%. Pimicotinib is a highly selective colony-stimulating factor 1 receptor (CSF1R) inhibitor. The phase III MANEUVER trial has verified its prominent tumor shrinkage effect and symptomatic improvement in patients with unresectable, symptomatic TGCT, with an objective response rate (ORR) of 54%. In addition, pimicotinib demonstrates a favorable safety profile; most adverse events are mild in severity, mainly including pruritus, edema, fatigue and elevated creatine kinase, without severe hepatotoxicity. Neoadjuvant therapy followed by surgery falls within the scope of multimodal treatment, which is mostly applied to recurrent and refractory cases rather than the standard upfront regimen for treatment-naive patients. Clinical case reports and real-world observations have preliminarily validated the feasibility and clinical value of sequential systemic targeted therapy followed by surgical resection. To date, systematic and standardized clinical data regarding neoadjuvant strategies remain scarce, especially randomized controlled evidence comparing neoadjuvant targeted therapy plus surgery versus primary upfront surgery. This study aims to compare the efficacy and safety of neoadjuvant pimicotinib combined with surgery versus upfront primary surgery in the management of D-TGCT, so as to generate evidence-based rationale for developing more effective and safe therapeutic regimens for D-TGCT.

Interventions

• Drug Pimicotinib
  Pimicotinib 50 mg orally once daily for 12 consecutive weeks.
• Procedure Tumor resection surgery
  Open surgery will be performed based on patient and tumor characteristics discussed at the multidisciplinary team (MDT) meeting. The specific surgical plan will be determined by the surgeon based on clinical judgment. Surgical procedures will follow national guidelines.

Primary outcome measures

• Event-free survival [Time frame: 2 years]

Secondary outcome measures (6)

• Local recurrence rate [Time frame: 2 year]
• Surgical complication rate [Time frame: 2 years]
• Change in range of motion [Time frame: 2 years]
• Change in Brief Pain Inventory (BPI) [Time frame: 2 years]
• Change in stiffness Numerical Rating Scale (NRS) [Time frame: 2 years]
• Change in Patient-Reported Outcomes Measurement Information System-Physical Function (PROMIS-PF) score [Time frame: 2 years]

Eligibility criteria

Inclusion criteria

• Male or female subjects aged ≥18 years
• Histologically confirmed tenosynovial giant cell tumor (TGCT)
• Resectable diffuse tenosynovial giant cell tumor (D-TGCT) were determined by multidisciplinary team (MDT) discussion.
• Measurable disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 with at least one lesion of ≥2 cm
• Symptomatic disease with a worst pain of at least 4 or/and a worst stiffness of at least 4 (based on a scale of 0-10 with 10 describing the worst condition) prior to randomization Adequate organ and bone marrow function
• Adequate organ function and bone marrow function
• Willing and able to complete patient-reported outcome (PRO) assessments throughout the study.

Exclusion criteria

• Prior treatment with highly selective Colony-Stimulating Factor 1 (CSF1)/ Colony-Stimulating Factor 1 Receptor (CSF1R) inhibitors before randomization
• Presence of another malignancy requiring active treatment, in the investigator's judgment, which may interfere with study participation or results
• Known metastatic TGCT
• Severe concomitant arthropathy, severe illness, or uncontrolled infection in the affected joint
• Significant factors affecting oral drug absorption
• Concomitant use of strong Cytochrome P450 3A4 (CYP3A4) inhibitors or inducers within 14 days before randomization
• Impaired cardiac function or severe cardiac disease
• Known active Human Immunodeficiency Virus (HIV) infection, active hepatitis B, active hepatitis C, or active tuberculosis before randomization
• Known active liver or biliary disease, or other conditions that may cause abnormal liver function tests during the study
• Pregnant or lactating female (pregnancy defined as from conception until termination)
• Fertile males or non-sterilized females who do not agree to use effective contraception from at least 14 days before randomization until 6 months after the last dose of study drug
• Other serious comorbidities that, in the investigator's judgment, may affect protocol compliance, interfere with interpretation of study results, or increase the patient's risk of safety events

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of M — Hangzhou

Publications

• Xu H, Niu X, Ravi V, Martin-Broto J, Razak AA, Saleh R, Zhou Y, Shen J, Liu T, Sankhala KK, Serrano C, Stacchiotti S, Wang J, Baldi GG, Feng Y, Hua Y, Li T, Rutkowski P, Zhang X, Tinoco G, Zou Q, Shan B, Zhu X, Gelderblom H. Pimicotinib versus placebo for tenosynovial giant cell tumour (MANEUVER): an international, randomised, placebo-controlled, phase 3 trial. Lancet. 2026 Mar 14;407(10533):1072- PMID 41796601
• van de Sande M, Blay JY, Tap W, Lee M, Kaiser E, Beaver S, Harrow B, Zeringo NA, Bernthal N. The economic and humanistic burden of tenosynovial giant cell tumor: a targeted literature review. Future Oncol. 2025 Aug;21(18):2385-2400. doi: 10.1080/14796694.2025.2520744. Epub 2025 Jun 22. PMID 40545745
• 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. 2 PMID 31229240
• Stacchiotti S, Durr HR, Schaefer IM, Woertler K, Haas R, Trama A, Caraceni A, Bajpai J, Baldi GG, Bernthal N, Blay JY, Boye K, Broto JM, Chen WT, Dei Tos PA, Desai J, Emhofer S, Eriksson M, Gronchi A, Gelderblom H, Hardes J, Hartmann W, Healey J, Italiano A, Jones RL, Kawai A, Leithner A, Loong H, Mascard E, Morosi C, Otten N, Palmerini E, Patel SR, Reichardt P, Rubin B, Rutkowski P, Sangalli C, S PMID 36502615
• Mosher H, Dean K, Meli G, Desrosiers J, Crawford B, Temple HT, Hornicek FJ, Rosenberg AE, Jonczak E, Palmerini E, Geiger EJ. Current Treatment Strategies for Diffuse Tenosynovial Giant Cell Tumor: A Review of the Literature. JB JS Open Access. 2026 Jan 13;11(1):e25.00313. doi: 10.2106/JBJS.OA.25.00313. eCollection 2026 Jan-Mar. PMID 41523664
• Mastboom MJL, Lips W, van Langevelde K, Mifsud M, Ng C, McCarthy CL, Athanasou NA, Gibbons CLMH, van de Sande MAJ. The effect of Imatinib Mesylate in diffuse-type Tenosynovial Giant Cell Tumours on MR imaging and PET-CT. Surg Oncol. 2020 Dec;35:261-267. doi: 10.1016/j.suronc.2020.08.030. Epub 2020 Aug 26. PMID 32932224
• Gelderblom H, Bhadri V, Stacchiotti S, Bauer S, Wagner AJ, van de Sande M, Bernthal NM, Lopez Pousa A, Razak AA, Italiano A, Ahmed M, Le Cesne A, Tinoco G, Boye K, Martin-Broto J, Palmerini E, Tafuto S, Pratap S, Powers BC, Reichardt P, Casado Herraez A, Rutkowski P, Tait C, Zarins F, Harrow B, Sharma MG, Ruiz-Soto R, Sherman ML, Blay JY, Tap WD; MOTION investigators. Vimseltinib versus placebo fo PMID 38843860
• Geiger EJ, Jensen AR, Singh AS, Nelson SD, Bernthal NM. Use of neoadjuvant pexidartinib with limb salvage surgery for diffuse tenosynovial giant cell tumor: A case report. J Orthop Sci. 2024 Jan;29(1):458-462. doi: 10.1016/j.jos.2022.10.016. Epub 2022 Nov 16. No abstract available. PMID 36402606

Identifiers

NCT: NCT07707882 · 2026-0643

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗