PS1344 PHASE 1/2 STUDY OF DSP‐7888 IN PATIENTS WITH HIGHER‐RISK (HR) MYELODYSPLASTIC SYNDROMES (MDS) AFTER FAILURE OF AZACITIDINE (AZA) THERAPY
Authors: Usuki K. , Ueda Y. , Fujita J. , Matsumura I. , Aotsuka N. , Sekiguchi N. , Nakazato T. , Iwasaki H. , Watanabe A. , Sugimoto S. , Koga‐Yamakawa E. , Naoe T. , Kizaki M. , Heike Y. , Miyazaki Y. , Akashi K. 
Published: June 2019

Background:Although azacitidine (AZA) is the standard frontline therapy for higher‐risk (HR) myelodysplastic syndromes (MDS), approximately 40% of patients fail to respond and almost all responders eventually relapse. The prognosis for patients after AZA failure is poor with no approved therapeutic options and a median overall survival (OS) of approximately 6 months from treatment failure (Prebet T, et al. J Clin Oncol. 2011;29:3322–7.). Wilms’ tumor 1 (WT1) is constantly expressed in the leukemic cells of acute leukemia and MDS, and it is considered a prominent therapeutic target for MDS. DSP‐7888 is a WT1‐based cancer vaccine containing peptides that induce WT1‐reactive cytotoxic T lymphocytes and helper T cells. A partial peptide of DSP‐7888, WT4869 showed preliminary clinical activity in HR‐MDS (Ueda Y, et al. Cancer Sci. 2017;108:2445–53.). We hypothesized that DSP‐7888 could have significant clinical activity in HR‐MDS.Aims:This uncontrolled, open‐label, multicenter Phase 1/2 clinical trial was designed to determine the recommended dose (RD) of DSP‐7888 and evaluate its safety and clinical activity, including OS, in patients with HR‐MDS after AZA treatment failure (NCT02436252).Methods:The RD of DSP‐7888 was determined in Phase 1 using a 3+3 design that included two dose levels (3.5 and 10.5 mg/body). Eligible patients had HR‐ or lower‐risk MDS but not chronic myelomonocytic leukemia or refractory anemia with excess blasts in transformation. To evaluate clinical activity, the Phase 2 trial included 42 patients with MDS who showed no response to AZA treatment (including eligible patients from Phase 1). Patients were administered DSP‐7888 in solution intradermally with the RD—100 μL at six sites for 10.5 mg. Study drug was given every 2 weeks for 6 months and then every 2 to 4 weeks until no clinical benefit was seen. The primary endpoint was OS. Written informed consent was obtained from all patients.Results:Overall 47 patients received DSP‐7888 in Phase 1 (n = 12) and Phase 2 (n = 35). No dose‐limiting toxicities (DLT) were observed for 3.5 mg or 10.5 mg in the DLT evaluation period (first 2 cycles of DSP‐7888 in Phase 1). RD was determined to be 10.5 mg.The safety population included all patients who received the study drug (N = 47). The most common adverse events (AEs) were injection site reactions (ISR) in 91.5% (n = 43) of all patients; 27.9% were grade 1, 37.2% grade 2, 34.9% grade 3, and no grade 4. Other than ISR, AEs related to study drug seen in >5% included pyrexia (10.6%) and febrile neutropenia (8.5%).The Phase 2 clinical activity analysis was performed on patients with HR‐MDS (N = 42) and included those from Phase 1 who met the criteria (n = 7); 76.2% were male and median age was 74.0 years (range: 63–93). The median OS was 8.5 months (90% CI: 6.8–11.1). The disease control rate was 19.5% with a median duration of response of 2.7 months. (The disease control rate included patients who had achieved a complete response [CR], partial response, marrow CR, or stable disease.) Hematologic improvement was seen in 9.8% of patients. The median time to transformation to acute myeloid leukemia or death was 5.7 months (90% CI: 3.6–7.1).Of the 42 patients, 37 were evaluable for WT1 reactive immune response and the results are shown in the Table.Summary/Conclusion:DSP‐7888 was tolerable and showed signs of clinical activity in patients with HR‐MDS; those who had a positive immune response showed a significantly longer OS than those who were negative. Identifying the optimal population for treatment with DSP‐7888 is important for further investigations.image