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Efficacy and safety of Wilms’ tumor 1 helper peptide OCV-501 in elderly patients with acute myeloid leukemia: a multicenter, randomized, double-blind, placebo-controlled phase 2 trial

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Abstract

Purpose

Complete remission (CR) of acute myeloid leukemia (AML) in elderly patients has a short duration, and there is no suitable post-remission therapy. We explored the role of the Wilms’ tumor 1 helper peptide OCV-501 to prevent recurrence after remission.

Methods

This placebo-controlled phase 2 study was designed to evaluate accurately the efficacy and immunogenicity of OCV-501 in elderly AML patients. Elderly AML patients who achieved first CR were randomly allocated to receive either OCV-501 (N = 69) or placebo (N = 65) once a week for eight weeks and then every two weeks until week 104. The primary endpoint was disease-free survival (DFS).

Results

Nineteen (27.5%) patients in the OCV-501 group and 23 (35.4%) patients in the placebo group completed the study without relapse. The median DFS in the OCV-501 and placebo groups was 12.1 and 8.4 months, respectively (p = 0.7671, hazard ratio [95% confidence interval]: 0.933 [0.590, 1.477]). The major drug adverse reactions were injection-site reactions. Although treatment with OCV-501 did not prolong DFS for elderly AML patients, post hoc analysis found that immune responders to OCV-501 whose specific IgG was > 10,000 ng/mL (N = 16) and whose WT1-specific interferon-γ response was > 10 pg/mL (N = 26) had significantly longer overall survival compared with placebo.

Conclusions

The placebo-controlled design of this study and quantitative immunological monitoring provides new insight into the relationship between peptide-induced immune responses and survival, suggesting future perspectives for cancer immunotherapy.

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Availability of data and material

The deidentified participant data, data dictionaries, study protocol, and statistical analysis plan will be shared on a request basis, upon provision of a methodologically sound meta-analysis proposal. There is no end date to the availability of the data. Please contact Masao Hirota directly to request data sharing.

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Acknowledgements

This paper is dedicated to the memory of Dr. Yuji Heike who made a great contribution to this study. Dr. Heike passed away in 2019. We would like to express our gratitude to Dr. Haruo Sugiyama for his valuable and constructive suggestions during the preparation of the manuscript. We thank all participating patients and their families and the study investigators. We thank Mr Yoshiyuki Shibasaki (Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan) for his helpful advice in the analysis of the results shown in fig. 5. We thank Mr. Keiji Kakumoto and Mr. Yusuke Kakumoto (Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan) for their statistical support in the ad hoc analyses. The authors also thank Alfredo Shimabuku, PhD, of Otsuka Pharmaceutical Co., who reviewed the drafts and final manuscript. We thank Dr. Tetsuji Asao (SunFlare Co., Ltd., Tokyo, Japan) for medical writing services, which were funded by Otsuka Pharmaceutical Co., Ltd.

Funding

This study was funded by Otsuka Pharmaceutical Co., Ltd.

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Authors and Affiliations

  1. Chugoku Central Hospital, Fukuyama, Japan

    Toru Kiguchi

  2. Ishikawa Prefectural Central Hospital, Kanazawa, Japan

    Masaki Yamaguchi

  3. National Hospital Organization Disaster Medical Center of Japan, Tokyo, Japan

    Naoki Takezako

  4. Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan

    Shuichi Miyawaki

  5. Otsuka Pharmaceutical Co., Ltd, Osaka, Japan

    Koichi Masui & Naoko Shimofurutani

  6. Otsuka Pharmaceutical Co., Ltd, Tokushima, Japan

    Yuichiro Ihara

  7. Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan

    Masao Hirota

  8. National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Tomoki Naoe

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  1. Toru Kiguchi
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Contributions

SM, NS, and TN contributed to the study design. SM and NS wrote the study protocol. TK, MY, NT, SM, KM, NS, and TN were responsible for clinical trial management. TK, MY, NT, SM, KM, YI, NS, and TN contributed to the interpretation of the results and writing of the draft of the manuscript. All authors, except YI and MH, contributed to data collection. All authors provided clinically important advice on feasible inclusion and exclusion criteria. All authors reviewed the draft and approved the final version of the manuscript for publication.

Corresponding author

Correspondence to Toru Kiguchi.

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Conflicts of interest

Toru Kiguchi reports grants and personal fees from Bristol-Myers Squibb Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., MSD Co., Ltd., Astellas Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Novartis Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharmaceutical Co., Ltd., Janssen Pharmaceutical Co., Ltd., Celgene Co., Ltd., SymBio Pharmaceutical Co., Ltd.; personal fees from Asahi Kasei Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Pfizer Co., Ltd., Eisai Co., Ltd., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., grants from Daiichi Sankyo Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Teijin Co., Ltd., Sanofi K.K., Ltd., Celltrion, Inc., outside the submitted work. Shuichi Miyawaki reports personal fees from Otsuka Pharmaceutical Co. Ltd. during the conduct of the study; personal fees from Astellas Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd. outside the submitted work. Tomoki Naoe reports grants and personal fees from Pfizer Co. Ltd., Astellas Pharmaceutical Co., Ltd, Fujifilm, Otsuka Pharmaceutical Co., Ltd.; grants from Sumitomo Dainippon Pharmaceutical Co., Ltd. outside the submitted work. Koichi Masui, Yuichiro Ihara, Masao Hirota, and Naoko Shimofurutani are employees of Otsuka Pharmaceutical Co., Ltd., Japan. Masaki Yamaguchi, and Naoki Takezako report nothing to disclosure.

Ethics approval

The study was conducted following the ethical principles originating in or derived from the Declaration of Helsinki, Good Clinical Practice guidelines, and the laws of applicable authorities. The study was designed and conducted by the sponsor (Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan) in collaboration with the principal investigators. The sponsor monitored study conduct, collected the data, and performed the statistical analyses. All authors reviewed the data and confirmed the integrity of the analyses.

Consent to participate

The study protocol and informed consent form were approved by the institutional review board at each participating study site. All patients gave written informed consent before initiation of any study-specific procedures.

Consent for publication

Not applicable as no patient-specific data were included in this article.

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Kiguchi, T., Yamaguchi, M., Takezako, N. et al. Efficacy and safety of Wilms’ tumor 1 helper peptide OCV-501 in elderly patients with acute myeloid leukemia: a multicenter, randomized, double-blind, placebo-controlled phase 2 trial. Cancer Immunol Immunother 71, 1419–1430 (2022). https://doi.org/10.1007/s00262-021-03074-4

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