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

Abstract

The 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).

Keywords: Dose escalation; Follicular lymphoma; Marginal zone lymphoma; PI3Kδ inhibitor; Zandelisib.

Conflict of interest statement

Hideki Goto received personal fees from Celgene/BMS, Eisai, Janssen, Chugai, Novartis, SymBio, and Daiichi-Sankyo. Koji Izutsu received research grants from Novartis, Eisai, Kyowa Kirin, MSD, Takeda, Janssen, Mundipharma, Chugai, AbbVie, Bayer, Ono, Gilead, Zenyaku, Celgene, Solasia, Symbio, Astellas, Astellas Amgen, and Daiichi-Sankyo, and personal fees from Kyowa Kirin, MSD, Takeda, Janssen, Bristol-Myers Squibb, Dainippon Sumitomo, Mundipharma, Nihon Mediphysics, Chugai, Astra Zeneca, AbbVie, Bayer, Ono, and Celgene. Daisuke Ennishi declares no competing interests. Yuko Mishima received research fees from Kyowa Kirin, Taiho, Eisai, and Bristol-Myers Squibb, and personal fee from Chugai. Shinichi Makita received personal fees from Celgene/BMS, CSL Behring, Eisai, Chugai, Novartis, SymBio, and Takeda, and consulted for Celgene/BMS, Daiichi-Sankyo, and Takeda. Koji Kato received research grants from Chugai, Takeda, Kyowa Kirin, AbbVie, Novartis, Eisai, Janssen, Celgene/BMS, Ono, and Daiichi-Sankyo, and personal fees from Kyowa Kirin, Novartis, Takeda, and Chugai. Miyoko Hanaya is an employee of Kyowa Kirin Co., Ltd. Satoshi Hirano is an employee of Kyowa Kirin Co., Ltd. Kazuya Narushima is an employee of Kyowa Kirin Co., Ltd. Takanori Teshima received research grants and personal fees from Novartis. Hirokazu Nagai received grants from AbbVie, Solasia, HUYA, Otsuka, and IQVIA, and grants and personal fees from Janssen, Celgene, Mundi, Bayer, Takeda, Kyowa Kirin, Eisai, Bristol-Myers Squibb, Ono, Gilead, Zenyaku, AstraZeneca, and SymBio, and personal fees from Roche and Sanofi. Kenichi Ishizawa received grants from Pfizer, Kyowa Kirin, Sanofi, AbbVie, Otsuka, and Takeda, and personal fees from Chugai, Kyowa Kirin, MSD, Janssen, Celgene, Eisai, Ono, Novartis, and Takeda.

© 2022. The Author(s).

Figures

Fig. 1

Patient disposition. DLT dose-limiting toxicity, PD progressive disease, TEAE treatment-emergent adverse event

Fig. 2

Time course of zandelisib treatment; the median duration of exposure was 14.2 months (range 1.4–20.6). Adverse events included diarrhea, pneumonia, hepatobiliary disorders, neutrophil count decreased, rash, stomatitis and other ≥ Grade 3 adverse events resulting in drug interruption, dosing schedule change, or discontinuation. CR complete response, CS continuous schedule, FL follicular lymphoma, IDT intermittent dosing treatment, MZL marginal zone lymphoma, PD progressive disease, PR partial response, SD stable disease

Fig. 3

Mean (+ standard deviation) zandelisib plasma concentration–time profiles for a Cycle 1 (day 1 and day 2) and b Cycle 2 (day 1 and day 2)

Fig. 4

Waterfall plot of change in tumor size. *Patient with marginal zone lymphoma; all other patients are those with follicular lymphoma. SPD sum of perpendicular diameters

Fig. 5

Kaplan–Meier curves of a duration of response and b progression-free survival