A Phase 1 Trial of OPB-111077 in Combination with Bendamustine (B) and Rituximab (R) in Patients with Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL): Preliminary Results of Dose-Escalation Stage

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.4464-4464
• Main Authors: Toubai, Tomomi, Kuroda, Junya, Suehiro, Youko, Mishima, Yuko, Sunami, Kazutaka, Kato, Koji, Uoshima, Nobuhiko, Kumode, Takahiro, Ota, Ai, Mitsuki, Kaori, Yokota, Daisuke, Sano, Yuri, Terui, Yasuhito
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-179716

Background OPB-111077, a first-in-class small molecule, is an orally available antitumor agent with an inhibitory effect on mitochondrial oxidative phosphorylation (OXPHOS). OPB-111077 inhibits mitochondrial respiratory chain complex I, which leads to inhibition of energy production and activation of the AMPK-mTOR energy stress sensor pathway, as well as inhibition of the signal transducer and activator of transcription (STAT) 3 pathway. In non-clinical studies using cultured cells and murine xenograft models, OPB-111077 showed antitumor effects in a variety of tumor cell lines, including hematological and solid tumors, and OPB-111077 in combination with an alkylating agent has a potential synergistic antitumor effect for malignant lymphoma. Here we report the preliminary results from the dose-escalation (DE) stage of an ongoing phase 1 trial (NCT04049825) of OPB-111077 in combination with bendamustine (B) and rituximab (R) in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Method This trial is composed of 2 stages. OPB-111077 is administered in combination with B in a DE stage and with B and R in a dose-expansion (EX) stage. The DE stage uses a 3+3 design. The objectives of the DE stage are to evaluate the tolerability and safety of OPB-111077 in combination with B and to determine the recommended dose for the EX stage based on dose-limiting toxicity (DLT). A secondary objective is to evaluate efficacy. Response assessment is based on IWG Lugano response criteria for non-Hodgkin lymphoma (NHL) (2014). Key eligibility criteria include age 20 to 80 years (inclusive), at least initial standard treatment, measurable lesions, and Eastern Cooperative Oncology Group performance status score of 0 or 1. OPB-111077 is orally administered once daily on Days 3 to 6, Days 10 to 13, and Days 17 to 20 of each cycle. The duration of each cycle is 21 days, except for Cycle 1, which is 23 days. The dose in the first cohort is 200 mg/day, increasing as appropriate to 400 mg/day in Cohort 2 and then to 600 mg/day in Cohort 3. B is administered intravenously at 120 (or 90) mg/m 2 once daily on Days 1 and 2 of each cycle for up to 6 cycles. Results As of 31 Jan 2023, 16 patients had been treated with OPB-111077 + B (120 mg/m 2) at OPB-111077 doses of 200 mg (Cohort 1, n = 3), 400 mg (Cohort 2, n = 6), and 600 mg (Cohort 3, n = 7). Patients had received 1 to 6 prior lines of chemotherapy, median age was 70.0 (range 54 - 79) years, and 56.3% wer