An Open-Label, Multicenter, Single-Arm, Phase I Dose Escalation Study of OP-2100, an Orally Bioavailable Prodrug of Decitabine, for Patients with Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

Hypomethylating agents (HMA) are commonly used to treat high-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).Decitabine (DEC), one of the HMAs, is S phase-specifically incorporated into DNA to exert its effect, and sustained plasma concentration may increase its efficacy (Saunthararajah et al. J Clin Invest. 2015). Therefore, we developed OP-2100, an orally bioavailable prodrug of DEC. It showed equal efficacy to conventional HMAs in various blood cancer mouse models and exhibited a favorable safety profile in healthy mice (Watanabe et al. Blood. 2020; Ureshino et al. Mol Cancer Ther. 2021). In addition, it exhibited a sustained-release pharmacokinetic (PK) profile when orally administered to monkeys. In a phase I study, OP-2100 monotherapy showed the expected PK profile on patients with relapsed or refractory higher-risk MDS and CMML, and we reported the preliminary result.

We designed a single-arm, multicenter phase I study for Japanese patients with MDS or CMML with intermediate-risk, high-risk, or very high-risk by Revised International Prognostic Scoring System (IPSS-R) and relapsed, refractory, or intolerant to standard therapy. The primary objective was to determine the maximum tolerated dose following the incidence of dose-limiting toxicity (DLT) in the first cycle, whereas the secondary objectives were to evaluate the safety, PK, and efficacy. Treatment-emergent adverse events (TEAEs) and response to therapy were assessed per NCI CTCAE v5.0 and IWG 2018 response criteria, respectively. Oral administration of OP-2100 as a single agent was continued for the patients daily on days 1-5 of each 28-day cycle until meeting discontinuation criteria, including disease progression. The dose level was defined as 30, 50, 80, and 120 mg/day. The initial dose of 50 mg/day was determined based on the highest non-severely toxic dose of OP-2100 in monkeys and the PK of DACOGEN ^TM in humans. This study was implemented in the 3+3 design according to DLT incidence. The plasma concentration of DEC and OP-2100 was measured on days 1 and 5. Furthermore, the LINE-1 methylation, a common HMA pharmacodynamics marker, was measured. This study is registered in the Japan Registry for Clinical Trials (jRCT2071220035).

In total 3 patients with a history of azacitidine treatment for MDS were registered in the 50-mg initial cohort. These patients had been categorized as intermediate to high-risk in the IPSS-R, respectively. Table 1 shows patient characteristics. Out of 3, 2 patients did not experience DLT, while the 3rd one suffered from Grade 4 neutropenia, which was confirmed as DLT. As of April 30, the most common TEAEs were cytopenia of leukopenia, neutropenia, and thrombocytopenia, all of which were Grade 3 or 4. Other adverse events of Grade 3 or 4 include anemia, lymphopenia, COVID-19, and fall. In terms of efficacy, 2 patients had stable disease, while one had progressive, according to the IWG2018 response criteria. However, the 2 patients with stable disease still received administration up to 9 and 5 cycles, respectively (Figure 1). The PK profile of DEC after OP-2100 administration indicated sustained release, with an area under the curve (AUC) similar to that of DACOGEN ^TM (5-day regimen, 1-h continuous intravenous administration at 20 mg/m ²) and C _max approximately 1/5. The LINE-1 methylation exhibited the similar behavior as conventional HMAs.

The PK profile of DEC released from the prodrug after 50 mg of OP-2100 oral administration in 3 patients showed a similar AUC to that of the 5-day regimen of DACOGEN ^TM, and then C _max showed a low with sustained plasma concentration. Among the 3 patients, OP-2100 could be administered for at least 5 cycles in 2 patients. To determine maximum tolerated dose, enrollment for this study is ongoing.

Kimura:OHARA Pharmaceutical Co., Ltd.: Honoraria, Patents & Royalties, Research Funding. Usuki:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam Japan: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alxion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aperis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nippon Shinyaku: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ohara: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ono: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sando: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo-Dainippon: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; SymBio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Yauklt: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ichinohe:Repertoire Genesis Inc.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co.: Research Funding; Kyowa Kirin Co.: Research Funding; Chugai Pharmaceutical Co.: Research Funding. Ikezoe:Bristol-Myers Squibb Company, Novartis Pharma KK, Pfizer Japan Inc., Takeda: Honoraria; AsahiKasei Pharma, Nippon Shinyaku Co., Ltd: Research Funding. Kuroda:Bristol Myeres Squibb, Kyowa Kirin, Chugai, Japan Blood Product Organization, Daiichi Sankyo, Mochida, Ono, Sanofi, Eisai, Taiho, Sumitomo, Asahikasei, Otsuka, Takeda, Shionogi Janssen, Novartis, Abbvie, Pfizer, Nippion Shinyaku, Astellas: Consultancy, Honoraria, Research Funding. Watanabe:OHARA Pharmaceutical Co.: Research Funding. Ro:OHARA Pharmaceutical Co., Ltd: Current Employment. Endo:OHARA Pharmaceutical Co., Ltd.: Current Employment. Kagawa:OHARA Pharmaceutical Co., Ltd.: Current Employment. Kurahashi:OHARA Pharmaceutical Co., Ltd.: Current Employment. Naito:OHARA Pharmaceutical Co., Ltd.: Current Employment. Yamauchi:Nihon Kayaku: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Sumitomo Pharma: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Nihon Shinyaku: Honoraria, Research Funding; Janssen Pharma: Honoraria, Research Funding; Astellas: Honoraria, Research Funding.