Zandelisib (ME-401) in Japanese patients with relapsed or refractory indolent non-Hodgkin’s lymphoma: an open-label, multicenter, dose-escalation phase 1 study

• DOI: 10.1007/s12185-022-03450-5
• Publication Date: 2022-09-15T07:03:41Z
• Authors: Hideki Goto; Koji Izutsu; Daisuke Ennishi; Yuko Mishima; Shinichi Makita; Koji Kato; Miyoko Hanaya; Satoshi Hirano; Kazuya Narushima; Takanori Teshima; Hirokazu Nagai; Kenichi Ishizawa
• Keywords: Diarrhea; 0301 basic medicine; Dose escalation; Lymphoma, Non-Hodgkin; 490; Angiogenesis Inhibitors; Follicular lymphoma; 3. Good health; 03 medical and health sciences; Japan; Marginal zone lymphoma; PI3K delta inhibitor; Zandelisib; Humans; Original Article; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Phosphoinositide-3 Kinase Inhibitors

AbstractThe selective phosphatidylinositol 3-kinase δ inhibitor zandelisib demonstrated favorable safety and efficacy [objective response rate (ORR) 79%] in patients with B-cell malignancies in a phase 1b study in the US and Switzerland. In this phase 1 dose-escalation study (NCT03985189), 9 Japanese patients with relapsed/refractory indolent non-Hodgkin’s lymphoma (R/R iNHL) received zandelisib on a continuous daily schedule (45 or 60 mg) until progressive disease/unacceptable toxicity. No dose-limiting toxicities were observed. The maximum tolerated dose was not reached. At a median follow-up of 17.5 months, Grade ≥ 3 treatment-emergent adverse events that occurred in 2 or more patients were neutrophil count decreased (55.6%; 5/9) and diarrhea (33.3%; 3/9). Immune-related toxicities, including hepatobiliary disorder, aspartate/alanine aminotransferase increased, diarrhea/colitis, organizing pneumonia, stomatitis, and rash, led to zandelisib discontinuation in 4 patients. The investigator-assessed ORR, based on modified Lugano criteria, was 100%, including 2 complete responses (22.2%; in follicular lymphoma patients receiving 60 mg/day). Median duration of response, progression-free survival, and time to response were 7.9, 11.1, and 1.9 months, respectively. Zandelisib demonstrated a manageable safety profile at 60 mg, the recommended phase 2 dose (RP2D) in Japanese patients. The RP2D resulted in favorable pharmacokinetics and anti-tumor efficacy in Japanese patients with R/R iNHL.Trial registration. NCT03985189 (ClinicalTrials.gov).