Phase Ib study of FOLFOXIRI plus ramucirumab as first-line treatment for patients with metastatic colorectal cancer

Cancer Chemotherapy and Pharmacology volume 86, pages277–284(2020)Cite this article

Abstract

Purpose

Ramucirumab, an anti-vascular endothelial growth factor (VEGF) receptor2 monoclonal antibody, inhibits VEGF-A, VEGF-C, and VEGF-D binding and endothelial cell proliferation. We conducted a phase Ib study to determine the recommended phase II dose (RP2D) of fluorouracil, l-leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus ramucirumab.

Methods

This phase Ib study investigated three dose levels of FOLFOXIRI plus ramucirumab (three dose levels of irinotecan and fluorouracil with fixed dose of oxaliplatin 85 mg/m2 and ramucirumab 8 mg/kg on day 1, repeated every 2 weeks) in chemotherapy-naïve patients with metastatic colorectal cancer (mCRC). Dose-limiting toxicity (DLT) was assessed during the first cycle.

Results

A total of ten patients were enrolled. The first four patients received the treatment at dose level 0 (irinotecan 150 mg/m2 and fluorouracil 2400 mg/m2), and subsequent six patients were treated at dose level 1 (irinotecan 165 mg/m2 and fluorouracil 3200 mg/m2). No DLT was observed in the nine DLT-evaluable patients, which indicated that the RP2D was dose level 1. Grade 3 or worse adverse events included neutropenia (70%), hypertension (20%), and febrile neutropenia (10%). No treatment-related death was observed in any cycle. The overall response rate was 70%.

Conclusion

The RP2D of FOLFOXIRI plus ramucirumab was determined to be 8 mg/kg of ramucirumab, 165 mg/m2 of irinotecan, 85 mg/m2 of oxaliplatin, 200 mg/m2 of l-leucovorin, and 3200 mg/m2 of fluorouracil.

Trial registration number

UMIN000023277.

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Fig. 1

Data availability

The datasets analysed during this study are available from the corresponding author on reasonable request.

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Acknowledgments

The authors would like to thank the patients and their families who participated in this study. The authors would also like to thank the Clinical Research Center of Shizuoka Cancer Center for the study administration and data management and Editage for English language editing.

Funding

This study was supported by the Clinical Research Center of Shizuoka Cancer Center. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Affiliations

  1. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan

    Yosuke Kito & Kentaro Yamazaki

  2. Department of Medical Oncology, Ishikawa Prefectural Central Hospital, 2-1, Kuratsuki-higashi, Kanazawa, Ishikawa, 920-8530, Japan

    Yosuke Kito

  3. Cancer Treatment Center, Kansai Medical University Hospital, Osaka, Japan

    Hironaga Satake

  4. Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan

    Hironaga Satake & Hisateru Yasui

  5. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    Hiroya Taniguchi

  6. Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan

    Hiroya Taniguchi & Toshiki Masuishi

  7. Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    Takeshi Yamada & Toshikazu Moriwaki

  8. Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan

    Yoshiki Horie & Naoki Izawa

  9. Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan

    Taito Esaki

  10. Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan

    Tadamichi Denda

  11. Clinical Research Center, Shizuoka Cancer Center, Shizuoka, Japan

    Keita Mori

Authors
  1. Yosuke Kito
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  2. Hironaga Satake
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  3. Hiroya Taniguchi
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  4. Takeshi Yamada
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  5. Yoshiki Horie
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  6. Taito Esaki
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  7. Tadamichi Denda
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  8. Hisateru Yasui
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  9. Naoki Izawa
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  10. Toshiki Masuishi
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  11. Toshikazu Moriwaki
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  12. Keita Mori
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  13. Kentaro Yamazaki
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Contributions

YK and KY contributed equally to this study.

Corresponding author

Correspondence to Yosuke Kito.

Ethics declarations

Conflict of interest

Yosuke Kito has received honoraria for lecturing from Chugai Pharmaceutical. Hironaga Satake has received research funding from Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical, and honoraria from Bayer, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck Biopharma, MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, Sanofi, and Yakult Honsha. Hiroya Taniguchi has received research funding from MSD, Daiichi Sankyo, Takeda Pharmaceutical, Dainippon Sumitomo Pharma, Array BioPharma, Sysmex, Ono Pharmaceutical, and Novartis, and honoraria from Sanofi, MSD, Mitsubishi Tanabe Pharma, Nippon Kayaku, Taiho Pharmaceutical, Takeda Pharmaceutical, Yakult Honsha, Bayer, Merck Serono, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, MBL, Novartis, and Chugai Pharmaceutical. Takeshi Yamada has received honoraria from Ono Pharmaceutical, Eli Lilly, and Yakult Honsha. Taito Esaki has received research funding from MSD, Novartis, Dainippon Sumitomo, Ono Pharmaceutical, Daiichi Sankyo, Astellas, Amgen Astellas Biopharma, BeiGene, Pierre Fabre Medicament, Ignyta, Array BioPharma, Bayer, Taiho Pharmaceutical, and Eli Lilly and honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical, MSD, Eli Lilly, Daiichi Sankyo, Nihon Kayaku, Sanofi, Ono Pharmaceutical, Takeda Pharmaceutical, Bayer, Merck Serono, Bristol, and Eisai. Tadamichi Denda has received research funding from MSD and ONO Pharmaceutical, and honoraria from SAWAI Pharmaceutical and Sysmex. Hisateru Yasui has received research funding from MSD, Daiichi Sankyo, and Ono Pharmaceutical, and honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Daiichi Sankyo, TERUMO, Eli Lilly, Merk Biopharma, and Yakult Honsha. Naoki Izawa has received honoraria from Takeda Pharmaceutical, Eli Lilly, Ono Pharmaceutical, and Daiichi Sankyo. Toshiki Masuishi has received research funding from MSD, Daiichi Sankyo, and Ono Pharmaceutical and honoraria from Takeda, Chugai, Merck Serono, Taiho, Bayer, Lilly Japan, Yakult Honsha, and Sanofi. Toshikazu Moriwaki has received research funding from Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, MSD, and Yakult Honsha and honoraria from Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Sanofi, Ono Pharmaceutical, Eli Lilly, and Yakult Honsha. K. Yamazaki has received honoraria from Bayer, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck Serono, Taiho Pharmaceutical, Takeda Pharmaceutical, Yakult Honsha, Sanofi, Ono Pharmaceutical, and Bristol-Myers Squibb. The remaining authors have declared no conflicts of interest.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent to participate

Patients were informed of the investigational nature of the study and provided their written informed consent before registration.

Consent for publication

Patients signed informed consent regarding publishing their data.

Code availability

Kaplan–Meier curve analysis was performed using EZR (Bone Marrow Transplantation 2013: 48, 452–458).

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Kito, Y., Satake, H., Taniguchi, H. et al. Phase Ib study of FOLFOXIRI plus ramucirumab as first-line treatment for patients with metastatic colorectal cancer. Cancer Chemother Pharmacol 86, 277–284 (2020). https://doi.org/10.1007/s00280-020-04116-x

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Keywords

  • Metastatic colorectal cancer
  • FOLFOXIRI
  • Ramucirumab
  • Dose-limiting toxicity
  • Recommended phase II dose