PHASE 1/2 STUDY OF DSP-7888 IN PATIENTS WITH HIGHER-RISK (HR) MYELODYSPLASTIC SYNDROMES (MDS) AFTER FAILURE OF AZACITIDINE (AZA) THERAPY
Author(s): ,
Kensuke Usuki
Affiliations:
Department of Hematology,NTT Medical Center Tokyo,Tokyo,Japan
,
Yasunori Ueda
Affiliations:
Department of Hematology/Oncology,Kurashiki Central Hospital,Kurashiki,Japan
,
Jiro Fujita
Affiliations:
Department of Hematology and Oncology,Osaka University, Graduate School of Medicine,Suita,Japan
,
Itaru Matsumura
Affiliations:
Department of Hematology and Rheumatology,Kindai University Hospital,Osakasayama,Japan
,
Nobuyuki Aotsuka
Affiliations:
Department of Hematology and Oncology,Japanese Red Cross Narita Hospital,Narita,Japan
,
Naohiro Sekiguchi
Affiliations:
Department of Hematology,National Hospital Organization, Disaster Medical Center,Tachikawa,Japan
,
Tomonori Nakazato
Affiliations:
Department of Hematology,Yokohama Municipal Citizen's Hospital,Yokohama,Japan
,
Hiromi Iwasaki
Affiliations:
Department of Hematology,National Hospital Organization Kyushu Medical Center,Fukuoka,Japan
,
Akinobu Watanabe
Affiliations:
Sumitomo Dainippon Pharma Co., Ltd.,Tokyo,Japan
,
Saori Sugimoto
Affiliations:
Sumitomo Dainippon Pharma Co., Ltd.,Tokyo,Japan
,
Erina Koga-Yamakawa
Affiliations:
Sumitomo Dainippon Pharma Co., Ltd.,Tokyo,Japan
,
Tomoki Naoe
Affiliations:
National Hospital Organization Nagoya Medical Center,Nagoya,Japan
,
Masahiro Kizaki
Affiliations:
Department of Hematology,Saitama Medical Center, Saitama Medical University,Kawagoe,Japan
,
Yuji Heike
Affiliations:
Laboratory for Joint Research and Development,St. Luke's International Hospital,Tokyo,Japan;Immunotherapy and Cell Therapy Service,St. Luke's International Hospital,Tokyo,Japan
,
Yasushi Miyazaki
Affiliations:
Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute,Nagasaki University,Nagasaki,Japan
Koichi Akashi
Affiliations:
Department of Medicine and Biosystemic Science, Faculty of Medicine,Kyushu University,Fukuoka,Japan
EHA Library. Usuki K. Jun 15, 2019; 266961; PS1344
Dr. Kensuke Usuki
Dr. Kensuke Usuki
Contributions
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Abstract

Abstract: PS1344

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

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.

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.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Azacitidine, High risk, Immunotherapy, WT1

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