Randomized, placebo-controlled, double blind, phase II study of zaltoprofen for patients with diffuse-type and unresectable localized tenosynovial giant cell tumors.
Authors: Takeuchi Akihiko , Endo Makoto , Kawai Akira , Nishida Yoshihiro , Terauchi Ryu , Matsumine Akihiko , Aiba Hisaki , Nakamura Tomoki , Tandai Susumu , Ozaki Toshifumi , Hoshi Manabu , Yoshimura Kenichi , Nomura Akihiro , Murayama Toshinori , Tsuchiya Hiroyuki 
Published: June 2022

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Background:A tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue, and categorized localized (L-TGCT) or diffuse-type (D-TGCT). D-TGCT most commonly develops in the knee or ankle. We revealed that zaltoprofen, a nonsteroidal anti-inflammatory drug possessing the ability to activate peroxisome proliferator-activated receptor gamma (PPARγ), can inhibit the proliferation of TGCT stromal cells via PPARγ. PPARγ is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. Therefore, we conducted a randomized trial to evaluate whether zaltoprofen was effective for patients with TGCT. Methods:This study was a randomized, placebo-controlled, double-blind, multicenter trial to evaluate the safety and efficacy of zaltoprofen for patients with L-TGCT or D-TGCT. For the treatment group, zaltoprofen 480 mg/day was administered for 48 weeks. The primary outcome was the progression-free rate (PFR) at week 48 after treatment administration. Disease progression was defined as follows requiring surgical interventions: 1) repetitive joint swelling due to hemorrhage; 2) limited range of joint motion; 3) invasion of adjacent cartilage or bone; 4) severe joint space narrowing; or 5) increase in tumor size (target lesion). This study was registered at the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000025901). Results:We allocated forty-one patients to zaltoprofen (n = 21; Z) or placebo (n = 20; P) groups. The mean age was 44 years (range, 26 to 66) in the group Z and 47 years (range, 24 to 69) in the group P. TGCTs located at a knee in 26 patients and at an ankle in 15 patients. The primary outcome of PFR for the group Z was not higher than that for the group P at week 48 (84.0% vs. 90.0%; p = 0.619). The objective tumor response was graded as partial response (PR) in 1 patient, stable disease (SD) in 19, and progressive disease (PD) in 1 for the group Z, and SD in 17 and PD in 3 for the group P. The mean musculoskeletal tumor society scoring system for group Z was significantly improved from baseline to week 48 (83.8% vs. 93.0%, p = 0.02), whereas that for the group P was not significantly improved (82.2% vs. 86.8%; p = 0.167). During the study period, one severe adverse event was observed (grade 3 hypertension) in the group Z. Conclusions:To our knowledge, this was the first study to evaluate the efficacy of zaltoprofen in patients with TGCT. The TGCT patients in zaltoprofen group did not have higher PER compared with those in the placebo group at week 48. Zaltoprofen appeared to improve the limb-function. Both groups presented with a stable disease course for 48 weeks, therefore, the long-term clinical course of TGCT should be clarified. Further analysis with long-term administration of zaltoprofen is considered for the future study. Clinical trial information: UMIN000025901.