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Phase II basket trial of perifosine monotherapy for recurrent gynecologic cancer with or without PIK3CA mutations

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Summary

Objective Perifosine exhibits anti-tumor activity by inhibiting AKT phosphorylation. The purpose of this phase II basket trial was to evaluate the efficacy and safety of perifosine monotherapy for ovarian, endometrial, and cervical cancers. Methods Recurrent or persistent ovarian, endometrial, or cervical cancer patients were assigned to PIK3CA wild-type or mutant groups. Each patient received 600 mg oral perifosine on day 1 followed by a maintenance dose of 100 mg daily. The primary endpoint was disease control rate; secondary endpoints included response rate, progression-free survival, overall survival, and safety. Immunohistochemical staining and targeted sequencing were used to explore new biomarkers in such patients. Results Sixteen and 5 ovarian, 17 and 7 endometrial, and 18 and 8 cervical cancer patients with PIK3CA wild-type and mutant, respectively, were enrolled. Disease control rates (wild-type/mutant) were 12.5/40.0%, 47.1/14.3%, and 11.1/25.0% in ovarian, endometrial, and cervical cancer, respectively. The most common grade 3/4 toxicities were anemia (22.5%) and anorexia (11.3%). Immunohistochemical staining revealed that the disease control rate in patients with negative phosphatase and tensin homolog (PTEN) expression was 50.0%, and the odds ratio of positive to negative patients was 0.24 in all patients. Conclusions Perifosine monotherapy showed good tolerability but expected efficacy was not achieved. Modest efficacy was demonstrated in ovarian cancer patients with PIK3CA mutations and endometrial cancer patients with PIK3CA wild-type; no difference was observed between PIK3CA wild-type and mutant in cervical cancer. Absence of PTEN expression may be predictive of clinical efficacy with perifosine monotherapy.

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Acknowledgements

This trial was supported by Yakult Honsha Co., Ltd. We would like to thank all patients, clinicians, and support staff who participated in this trial. We are grateful to Ichinosuke Hyodo and Fumitaka Nagamura for their helpful advice as members of the data monitoring committee. We also thank Atsushi Takamine and Takeshi Mimura for their helpful advice.

Funding

This work was sponsored by Yakult Honsha Co., Ltd.

Author information

Authors and Affiliations

  1. Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama, 350-1298, Japan

    Kosei Hasegawa

  2. Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 19-1, Uchimaru, Morioka, Iwate, 020-8505, Japan

    Masahiro Kagabu

  3. Department of Gynecology, Aichi Cancer Center Hospital, 1-1, Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan

    Mika Mizuno

  4. Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Katsutoshi Oda

  5. Department of Obstetrics and Gynecology, Keio University School of Medicine, 35, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Daisuke Aoki

  6. Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan

    Seiji Mabuchi & Tadashi Kimura

  7. Department of Obstetrics and Gynecology, Osaka International Cancer Center, 1-69, 3-Chome Otemae, Chuo-ku, Osaka-shi, Osaka, 541-8567, Japan

    Shoji Kamiura

  8. Department of Obstetrics and Gynecology, Hyogo Cancer Center, 13-70, Kitaoji, Akashi, Hyogo, 673-8558, Japan

    Satoshi Yamaguchi

  9. Department of Obstetrics and Gynecology, University of the Ryukyus Hospital, 207, Uehara, Nishihara, nakagami-gun, Okinawa, 903-0215, Japan

    Yoichi Aoki

  10. Gynecology Service, National Kyushu Cancer Center, 3-1-1, Notame, minami-ku, Fukuoka, 811-1395, Japan

    Toshiaki Saito

  11. Division of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Mayu Yunokawa

  12. Department of Gynecologic Oncology, Shikoku Cancer Center, 160, Minamiumemoto-machi-kou, Matsuyama, Ehime, 791-0280, Japan

    Kazuhiro Takehara

  13. Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan

    Aikou Okamoto & Kazunori Ochiai

Authors
  1. Kosei Hasegawa
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  2. Masahiro Kagabu
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  3. Mika Mizuno
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  4. Katsutoshi Oda
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  5. Daisuke Aoki
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  6. Seiji Mabuchi
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  7. Shoji Kamiura
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  8. Satoshi Yamaguchi
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  9. Yoichi Aoki
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  10. Toshiaki Saito
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  11. Mayu Yunokawa
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  12. Kazuhiro Takehara
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  13. Aikou Okamoto
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  14. Kazunori Ochiai
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  15. Tadashi Kimura
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Corresponding author

Correspondence to Kosei Hasegawa.

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Disclosure of potential conflict of interest

Kosei Hasegawa reports other from Yakult Honsha Co., Ltd., other from Ono Pharmaceutical Co., Ltd., other from Taiho Pharmaceutical Co., Ltd., other from Kyowa Hakko Kirin Co., Ltd., other from Chugai Pharmaceutical Co., Ltd., outside the submitted work; Daisuke Aoki reports grants from Chugai Pharmaceutical Co., Ltd., grants from Taiho Pharmaceutical Co., Ltd., personal fees from MSD K.K., personal fees from AstraZeneca K.K., personal fees from Ono Pharmaceutical Co., Ltd., personal fees from Kyowa Hakko Kirin Co., Ltd., personal fees from GlaxoSmithKline K.K., personal fees from Daiichi Sankyo Co., Ltd., personal fees from Taiho Pharmaceutical Co., Ltd., personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Nippon Kayaku Co., Ltd., personal fees from Becton, Dickinson and Company, personal fees from Novartis Pharma K.K., personal fees from Bristol-Myers K.K., personal fees from Janssen Pharmaceutical K.K., personal fees from Roche Diagnostics K.K., personal fees from Yakult Honsha Co., Ltd., outside the submitted work; Mayu Yunokawa reports grants from Yakult Honsha Co., Ltd., outside the submitted work; Kazunori Ochiai reports grants from Taiho Pharmaceutical Co., Ltd., grants from Zeria Pharmaceutical Co., Ltd., outside the submitted work; Tadashi Kimura reports personal fees from Yakult Honsha Co., Ltd., outside the submitted work; All other authors have no conflicts of interest to declare.

Ethical approval

The protocol was approved by the ethics committee of each participating institution. The trial was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines.

Informed consent

Written informed consent for inclusion, including in the biomarker analysis, was obtained from all patients prior to registration.

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Hasegawa, K., Kagabu, M., Mizuno, M. et al. Phase II basket trial of perifosine monotherapy for recurrent gynecologic cancer with or without PIK3CA mutations. Invest New Drugs 35, 800–812 (2017). https://doi.org/10.1007/s10637-017-0504-6

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  • DOI: https://doi.org/10.1007/s10637-017-0504-6

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