A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study)

Shoichi Hazama, Yusuke Nakamura, Hiroaki Tanaka, Kosei Hirakawa, Ko Tahara, Ryoichi Shimizu, Hiroaki Ozasa, Ryuichi Etoh, Fumiaki Sugiura, Kiyotaka Okuno, Takumi Furuya, Taku Nishimura, Koichiro Sakata, Kazuhiko Yoshimatsu, Hiroko Takenouchi, Ryouichi Tsunedomi, Yuka Inoue, Shinsuke Kanekiyo, Yoshitaro Shindo, Nobuaki Suzuki & 8 others Shigefumi Yoshino, Hirokazu Shinozaki, Akira Kamiya, Hiroyuki Furukawa, Takeharu Yamanaka, Tomonobu Fujita, Yutaka Kawakami, Masaaki Oka

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Background: We previously conducted a phase I trial for advanced colorectal cancer (CRC) using five HLA-A*2402-restricted peptides, three derived from oncoantigens and two from vascular endothelial growth factor (VEGF) receptors, and confirmed safety and immunological responses. To evaluate clinical benefits of cancer vaccination treatment, we conducted a phase II trial using the same peptides in combination with oxaliplatin-based chemotherapy as a first-line therapy.Methods: The primary objective of the study was the response rates (RR). Progression free survival (PFS), overall survival (OS), and immunological parameters were evaluated as secondary objective. The planned sample size was more than 40 patients for both HLA2402-matched and -unmatched groups. All patients received a cocktail of five peptides (3 mg each) mixed with 1.5 ml of IFA which was subcutaneously administered weekly for the first 12 weeks followed by biweekly administration. Presence or absence of the HLA-A*2402 genotype were used for classification of patients into two groups.Results: Between February 2009 and November 2012, ninety-six chemotherapy naïve CRC patients were enrolled under the masking of their HLA-A status. Ninety-three patients received mFOLFOX6 and three received XELOX. Bevacizumab was added in five patients. RR was 62.0% and 60.9% in the HLA-A*2402-matched and -unmatched groups, respectively (p = 0.910). The median OS was 20.7 months in the HLA-A*2402-matched group and 24.0 months in the unmatched group (log-rank, p = 0.489). In subgroup with a neutrophil/lymphocyte ratio (NLR) of < 3.0, patients in the HLA-matched group did not survive significantly longer than those in the unmatched group (log-rank, p = 0.289) but showed a delayed response.Conclusions: Although no significance was observed for planned statistical efficacy endpoints, a delayed response was observed in subgroup with a NLR of < 3.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination.Trial registration: Trial registration: UMIN000001791.

Original languageEnglish
Article number108
JournalJournal of Translational Medicine
Volume12
Issue number1
DOIs
Publication statusPublished - 2014 Apr 30

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oxaliplatin
HLA-A Antigens
Chemotherapy
Colorectal Neoplasms
Lymphocytes
Drug Therapy
Peptides
Research Design
Neutrophils
Therapeutics
Vascular Endothelial Growth Factor Receptor
Oncology
Biomarkers
Vaccination
Survival

Keywords

  • Chemotherapy
  • Colorectal cancer
  • FOLFOX
  • Peptide cocktail
  • Peptide vaccine
  • Phase II study

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study). / Hazama, Shoichi; Nakamura, Yusuke; Tanaka, Hiroaki; Hirakawa, Kosei; Tahara, Ko; Shimizu, Ryoichi; Ozasa, Hiroaki; Etoh, Ryuichi; Sugiura, Fumiaki; Okuno, Kiyotaka; Furuya, Takumi; Nishimura, Taku; Sakata, Koichiro; Yoshimatsu, Kazuhiko; Takenouchi, Hiroko; Tsunedomi, Ryouichi; Inoue, Yuka; Kanekiyo, Shinsuke; Shindo, Yoshitaro; Suzuki, Nobuaki; Yoshino, Shigefumi; Shinozaki, Hirokazu; Kamiya, Akira; Furukawa, Hiroyuki; Yamanaka, Takeharu; Fujita, Tomonobu; Kawakami, Yutaka; Oka, Masaaki.

In: Journal of Translational Medicine, Vol. 12, No. 1, 108, 30.04.2014.

Research output: Contribution to journalArticle

Hazama, S, Nakamura, Y, Tanaka, H, Hirakawa, K, Tahara, K, Shimizu, R, Ozasa, H, Etoh, R, Sugiura, F, Okuno, K, Furuya, T, Nishimura, T, Sakata, K, Yoshimatsu, K, Takenouchi, H, Tsunedomi, R, Inoue, Y, Kanekiyo, S, Shindo, Y, Suzuki, N, Yoshino, S, Shinozaki, H, Kamiya, A, Furukawa, H, Yamanaka, T, Fujita, T, Kawakami, Y & Oka, M 2014, 'A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study)', Journal of Translational Medicine, vol. 12, no. 1, 108. https://doi.org/10.1186/1479-5876-12-108
Hazama, Shoichi ; Nakamura, Yusuke ; Tanaka, Hiroaki ; Hirakawa, Kosei ; Tahara, Ko ; Shimizu, Ryoichi ; Ozasa, Hiroaki ; Etoh, Ryuichi ; Sugiura, Fumiaki ; Okuno, Kiyotaka ; Furuya, Takumi ; Nishimura, Taku ; Sakata, Koichiro ; Yoshimatsu, Kazuhiko ; Takenouchi, Hiroko ; Tsunedomi, Ryouichi ; Inoue, Yuka ; Kanekiyo, Shinsuke ; Shindo, Yoshitaro ; Suzuki, Nobuaki ; Yoshino, Shigefumi ; Shinozaki, Hirokazu ; Kamiya, Akira ; Furukawa, Hiroyuki ; Yamanaka, Takeharu ; Fujita, Tomonobu ; Kawakami, Yutaka ; Oka, Masaaki. / A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study). In: Journal of Translational Medicine. 2014 ; Vol. 12, No. 1.
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abstract = "Background: We previously conducted a phase I trial for advanced colorectal cancer (CRC) using five HLA-A*2402-restricted peptides, three derived from oncoantigens and two from vascular endothelial growth factor (VEGF) receptors, and confirmed safety and immunological responses. To evaluate clinical benefits of cancer vaccination treatment, we conducted a phase II trial using the same peptides in combination with oxaliplatin-based chemotherapy as a first-line therapy.Methods: The primary objective of the study was the response rates (RR). Progression free survival (PFS), overall survival (OS), and immunological parameters were evaluated as secondary objective. The planned sample size was more than 40 patients for both HLA2402-matched and -unmatched groups. All patients received a cocktail of five peptides (3 mg each) mixed with 1.5 ml of IFA which was subcutaneously administered weekly for the first 12 weeks followed by biweekly administration. Presence or absence of the HLA-A*2402 genotype were used for classification of patients into two groups.Results: Between February 2009 and November 2012, ninety-six chemotherapy na{\"i}ve CRC patients were enrolled under the masking of their HLA-A status. Ninety-three patients received mFOLFOX6 and three received XELOX. Bevacizumab was added in five patients. RR was 62.0{\%} and 60.9{\%} in the HLA-A*2402-matched and -unmatched groups, respectively (p = 0.910). The median OS was 20.7 months in the HLA-A*2402-matched group and 24.0 months in the unmatched group (log-rank, p = 0.489). In subgroup with a neutrophil/lymphocyte ratio (NLR) of < 3.0, patients in the HLA-matched group did not survive significantly longer than those in the unmatched group (log-rank, p = 0.289) but showed a delayed response.Conclusions: Although no significance was observed for planned statistical efficacy endpoints, a delayed response was observed in subgroup with a NLR of < 3.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination.Trial registration: Trial registration: UMIN000001791.",
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T1 - A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study)

AU - Hazama, Shoichi

AU - Nakamura, Yusuke

AU - Tanaka, Hiroaki

AU - Hirakawa, Kosei

AU - Tahara, Ko

AU - Shimizu, Ryoichi

AU - Ozasa, Hiroaki

AU - Etoh, Ryuichi

AU - Sugiura, Fumiaki

AU - Okuno, Kiyotaka

AU - Furuya, Takumi

AU - Nishimura, Taku

AU - Sakata, Koichiro

AU - Yoshimatsu, Kazuhiko

AU - Takenouchi, Hiroko

AU - Tsunedomi, Ryouichi

AU - Inoue, Yuka

AU - Kanekiyo, Shinsuke

AU - Shindo, Yoshitaro

AU - Suzuki, Nobuaki

AU - Yoshino, Shigefumi

AU - Shinozaki, Hirokazu

AU - Kamiya, Akira

AU - Furukawa, Hiroyuki

AU - Yamanaka, Takeharu

AU - Fujita, Tomonobu

AU - Kawakami, Yutaka

AU - Oka, Masaaki

PY - 2014/4/30

Y1 - 2014/4/30

N2 - Background: We previously conducted a phase I trial for advanced colorectal cancer (CRC) using five HLA-A*2402-restricted peptides, three derived from oncoantigens and two from vascular endothelial growth factor (VEGF) receptors, and confirmed safety and immunological responses. To evaluate clinical benefits of cancer vaccination treatment, we conducted a phase II trial using the same peptides in combination with oxaliplatin-based chemotherapy as a first-line therapy.Methods: The primary objective of the study was the response rates (RR). Progression free survival (PFS), overall survival (OS), and immunological parameters were evaluated as secondary objective. The planned sample size was more than 40 patients for both HLA2402-matched and -unmatched groups. All patients received a cocktail of five peptides (3 mg each) mixed with 1.5 ml of IFA which was subcutaneously administered weekly for the first 12 weeks followed by biweekly administration. Presence or absence of the HLA-A*2402 genotype were used for classification of patients into two groups.Results: Between February 2009 and November 2012, ninety-six chemotherapy naïve CRC patients were enrolled under the masking of their HLA-A status. Ninety-three patients received mFOLFOX6 and three received XELOX. Bevacizumab was added in five patients. RR was 62.0% and 60.9% in the HLA-A*2402-matched and -unmatched groups, respectively (p = 0.910). The median OS was 20.7 months in the HLA-A*2402-matched group and 24.0 months in the unmatched group (log-rank, p = 0.489). In subgroup with a neutrophil/lymphocyte ratio (NLR) of < 3.0, patients in the HLA-matched group did not survive significantly longer than those in the unmatched group (log-rank, p = 0.289) but showed a delayed response.Conclusions: Although no significance was observed for planned statistical efficacy endpoints, a delayed response was observed in subgroup with a NLR of < 3.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination.Trial registration: Trial registration: UMIN000001791.

AB - Background: We previously conducted a phase I trial for advanced colorectal cancer (CRC) using five HLA-A*2402-restricted peptides, three derived from oncoantigens and two from vascular endothelial growth factor (VEGF) receptors, and confirmed safety and immunological responses. To evaluate clinical benefits of cancer vaccination treatment, we conducted a phase II trial using the same peptides in combination with oxaliplatin-based chemotherapy as a first-line therapy.Methods: The primary objective of the study was the response rates (RR). Progression free survival (PFS), overall survival (OS), and immunological parameters were evaluated as secondary objective. The planned sample size was more than 40 patients for both HLA2402-matched and -unmatched groups. All patients received a cocktail of five peptides (3 mg each) mixed with 1.5 ml of IFA which was subcutaneously administered weekly for the first 12 weeks followed by biweekly administration. Presence or absence of the HLA-A*2402 genotype were used for classification of patients into two groups.Results: Between February 2009 and November 2012, ninety-six chemotherapy naïve CRC patients were enrolled under the masking of their HLA-A status. Ninety-three patients received mFOLFOX6 and three received XELOX. Bevacizumab was added in five patients. RR was 62.0% and 60.9% in the HLA-A*2402-matched and -unmatched groups, respectively (p = 0.910). The median OS was 20.7 months in the HLA-A*2402-matched group and 24.0 months in the unmatched group (log-rank, p = 0.489). In subgroup with a neutrophil/lymphocyte ratio (NLR) of < 3.0, patients in the HLA-matched group did not survive significantly longer than those in the unmatched group (log-rank, p = 0.289) but showed a delayed response.Conclusions: Although no significance was observed for planned statistical efficacy endpoints, a delayed response was observed in subgroup with a NLR of < 3.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination.Trial registration: Trial registration: UMIN000001791.

KW - Chemotherapy

KW - Colorectal cancer

KW - FOLFOX

KW - Peptide cocktail

KW - Peptide vaccine

KW - Phase II study

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DO - 10.1186/1479-5876-12-108

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