Phase I studies of darinaparsin in patients with relapsed or refractory peripheral T-cell lymphoma: a pooled analysis of two phase I studies conducted in Japan and Korea

Michinori Ogura, Won-Seog Kim, Toshiki Uchida, Naokuni Uike, Youko Suehiro, Kenichi Ishizawa, Hirokazu Nagai, Fumiko Nagahama, Yusuke Sonehara, Kensei Tobinai, Michinori Ogura, Won-Seog Kim, Toshiki Uchida, Naokuni Uike, Youko Suehiro, Kenichi Ishizawa, Hirokazu Nagai, Fumiko Nagahama, Yusuke Sonehara, Kensei Tobinai

Abstract

Objective: Two phase I studies of darinaparsin including Japanese and Korean patients with relapsed/refractory peripheral T-cell lymphoma were performed to evaluate its safety (primary purpose), efficacy and pharmacokinetic profile (ClinicalTrials.gov: NCT01435863 and NCT01689220).

Methods: Patients received intravenous darinaparsin for 5 consecutive days at 200 mg/m2/day in 4-week cycles, 300 mg/m2/day in 4-week cycles or 300 mg/m2/day in 3-week cycles.

Results: Seventeen Japanese and 6 Korean patients were enrolled and treated. Drug-related adverse events developed in 18 patients (78%). Dose-limiting toxicity, grade 3 hepatic dysfunction, was reported on Day 15 of cycle 1 in 1 Japanese patient who received 300 mg/m2/day. The most common drug-related, grade ≥ 3 adverse events were lymphopenia (9%), neutropenia (9%) and thrombocytopenia (9%). No deaths occurred. In 14 evaluable patients, 1 and 3 patients had complete response and partial response, respectively. The plasma concentration-time profiles of arsenic, a surrogate marker for darinaparsin, were similar between Japanese and Korean patients. No significant difference was found in its pharmacokinetic profile.

Conclusions: These data indicate the good tolerability and potential efficacy of darinaparsin in patients with relapsed/refractory peripheral T-cell lymphoma. Darinaparsin 300 mg/m2/day for 5 consecutive days in 3-week cycles is the recommended regimen for phase II study.

Keywords: Asia; darinaparsin; peripheral T-cell lymphoma; pharmacokinetics; phase I.

© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.
Figure 1.
Time-course changes in mean ΔQTcF from the time-matched baseline after the intravenous administration of darinaparsin. Bars represent means ± standard deviation.
Figure 2.
Figure 2.
Scatter diagram of ΔQTcF versus plasma darinaparsin concentration.
Figure 3.
Figure 3.
Maximum tumor shrinkage rates from baseline in 14 evaluable patients with PTCL. AITL, angioimmunoblastic T-cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; ALCL ALK (−), anaplastic lymphoma kinase-negative anaplastic large cell lymphoma.
Figure 4.
Figure 4.
(a) Time-course changes in plasma arsenic concentrations on Day 1 during the 5-day consecutive, intravenous infusion of darinaparsin 300 mg/m2/day to Japanese, Korean and Caucasian patients with PTCL. (b) Time-course changes in plasma trough concentrations of arsenic during 8 days after the onset of administration. Bars represent means ± standard deviation.

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