Safety and efficacy of the EZH1/2 inhibitor valemetostat tosylate (DS-3201b) in pediatric patients with malignant solid tumors (NCCH1904): A multicenter phase I trial.

Abstract

10003 Background: Valemetostat tosylate (DS-3201b; valemetostat) is a first-in-class dual inhibitor targeting the epigenetic regulators EZH1 and EZH2. In Japan, valemetostat has been approved for the treatment of r/r adult T-cell leukemia/lymphoma and peripheral T-cell lymphoma. These enzymes are implicated in tumors characterized by SMARCB1/INI1 deficiencies, such as malignant rhabdoid tumors or epithelioid sarcoma, which frequently occur during childhood and adolescence. Valemetostat is expected to show antitumor activity against such malignancies. Methods: This open-label, multicenter phase I trial evaluated the safety, efficacy, and recommended phase 2 dose (RP2D) of valemetostat in pediatric patients with malignant solid tumors. Valemetostat was administered orally once daily in 28-day cycles. The dose-escalation phase used a 3 + 3 design, testing three dose levels (150, 200, and 250 mg/1.7 m 2 ). Following RP2D determination, 15 patients were enrolled in the expansion cohort. The primary endpoint was dose-limiting toxicity (DLT) incidence in the dose-escalation cohort. Results: Between March 2020 and January 2023, 30 pediatric patients were enrolled (median age: 8 yr; range: 3–19 yr). Among these, 13 (43.3%) patients were INI1-negative by immunohistochemistry. Diagnoses included atypical teratoid/rhabdoid tumor (AT/RT, n = 6), malignant rhabdoid tumor ( n = 1), neuroblastoma (NB, n = 8), and chordoma ( n = 3). No DLTs were observed among 12 evaluable patients, and 250 mg/1.7 m 2 was established as the RP2D. Common grade >3 adverse events included lymphocytopenia (26.7%), neutropenia (26.7%), and anemia (16.7%). Notable treatment-related adverse events included grade 3 pneumocystis pneumonia ( n = 1, 3.3%) and pneumonitis ( n = 2, 6.7%). One patient with NB developed acute lymphocytic leukemia as a secondary malignancy. Pharmacokinetic analysis revealed no significant differences in T max and T1/2 compared with the phase II study in Japanese adults (J201 study); however, C max and AUC tau were lower within the range of variation in adults. Objective response was observed in two of 14 patients (14.2%) with measurable disease, both with AT/RT. Long-term disease control exceeding 1 yr were noted in NB ( n = 2), chordoma ( n = 1), rhabdoid tumors (AT/RT; n = 1), and glioma ( n = 1). Conclusions: Valemetostat was safe in Japanese pediatric patients, demonstrating antitumor activity against INI1-negative tumors, such as AT/RT. These findings support further exploration of valemetosat in combination therapies targeting SMARCB1/INI1-deficient tumors. Additionally, the durable control of tumor observed in NB suggests potential efficacy of valemetostat against this malignancy. This study was supported by the Japan Agency for Medical Research and Development and Daiichi Sankyo Co., Ltd. Clinical trial information: jRCT2031190268 .