Phase II trial of aflibercept with FOLFIRI as a second-line treatment for Japanese patients with metastatic colorectal cancer

Tadamichi Denda, Daisuke Sakai, Tetsuya Hamaguchi, Naotoshi Sugimoto, Takashi Ura, Kentaro Yamazaki, Hirofumi Fujii, Takeshi Kajiwara, Takako Eguchi Nakajima, Shin Takahashi, Satoshi Otsu, Yoshito Komatsu, Fumio Nagashima, Toshikazu Moriwaki, Taito Esaki, Takeo Sato, Michio Itabashi, Eiji Oki, Toru Sasaki, Yoshinori SunagaSamira Ziti-Ljajic, Claire Brillac, Takayuki Yoshino

Research output: Contribution to journalArticle

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Abstract

Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.

Original languageEnglish
Pages (from-to)1032-1043
Number of pages12
JournalCancer Science
Volume110
Issue number3
DOIs
Publication statusPublished - Mar 2019

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irinotecan
Fluorouracil
Colorectal Neoplasms
Pharmacokinetics
Therapeutics
Vascular Endothelial Growth Factor A
Disease-Free Survival
Safety
Survival
aflibercept
Appetite
Neutropenia
Drug Interactions

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Denda, T., Sakai, D., Hamaguchi, T., Sugimoto, N., Ura, T., Yamazaki, K., ... Yoshino, T. (2019). Phase II trial of aflibercept with FOLFIRI as a second-line treatment for Japanese patients with metastatic colorectal cancer. Cancer Science, 110(3), 1032-1043. https://doi.org/10.1111/cas.13943

Phase II trial of aflibercept with FOLFIRI as a second-line treatment for Japanese patients with metastatic colorectal cancer. / Denda, Tadamichi; Sakai, Daisuke; Hamaguchi, Tetsuya; Sugimoto, Naotoshi; Ura, Takashi; Yamazaki, Kentaro; Fujii, Hirofumi; Kajiwara, Takeshi; Nakajima, Takako Eguchi; Takahashi, Shin; Otsu, Satoshi; Komatsu, Yoshito; Nagashima, Fumio; Moriwaki, Toshikazu; Esaki, Taito; Sato, Takeo; Itabashi, Michio; Oki, Eiji; Sasaki, Toru; Sunaga, Yoshinori; Ziti-Ljajic, Samira; Brillac, Claire; Yoshino, Takayuki.

In: Cancer Science, Vol. 110, No. 3, 03.2019, p. 1032-1043.

Research output: Contribution to journalArticle

Denda, T, Sakai, D, Hamaguchi, T, Sugimoto, N, Ura, T, Yamazaki, K, Fujii, H, Kajiwara, T, Nakajima, TE, Takahashi, S, Otsu, S, Komatsu, Y, Nagashima, F, Moriwaki, T, Esaki, T, Sato, T, Itabashi, M, Oki, E, Sasaki, T, Sunaga, Y, Ziti-Ljajic, S, Brillac, C & Yoshino, T 2019, 'Phase II trial of aflibercept with FOLFIRI as a second-line treatment for Japanese patients with metastatic colorectal cancer', Cancer Science, vol. 110, no. 3, pp. 1032-1043. https://doi.org/10.1111/cas.13943
Denda, Tadamichi ; Sakai, Daisuke ; Hamaguchi, Tetsuya ; Sugimoto, Naotoshi ; Ura, Takashi ; Yamazaki, Kentaro ; Fujii, Hirofumi ; Kajiwara, Takeshi ; Nakajima, Takako Eguchi ; Takahashi, Shin ; Otsu, Satoshi ; Komatsu, Yoshito ; Nagashima, Fumio ; Moriwaki, Toshikazu ; Esaki, Taito ; Sato, Takeo ; Itabashi, Michio ; Oki, Eiji ; Sasaki, Toru ; Sunaga, Yoshinori ; Ziti-Ljajic, Samira ; Brillac, Claire ; Yoshino, Takayuki. / Phase II trial of aflibercept with FOLFIRI as a second-line treatment for Japanese patients with metastatic colorectal cancer. In: Cancer Science. 2019 ; Vol. 110, No. 3. pp. 1032-1043.
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abstract = "Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3{\%} (95{\%} confidence interval [CI]: 1.3{\%}-15.3{\%}), and the disease control rate (DCR) was 80.0{\%} (69.9{\%}-90.1{\%}). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15{\%}), clearance of 0.805 L/d (22{\%}) and volume of distribution of 6.2 L (18{\%}); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9{\%}) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28{\%}) for irinotecan and, at steady state, 72.6 L/h/m2 (56{\%}) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.",
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T1 - Phase II trial of aflibercept with FOLFIRI as a second-line treatment for Japanese patients with metastatic colorectal cancer

AU - Denda, Tadamichi

AU - Sakai, Daisuke

AU - Hamaguchi, Tetsuya

AU - Sugimoto, Naotoshi

AU - Ura, Takashi

AU - Yamazaki, Kentaro

AU - Fujii, Hirofumi

AU - Kajiwara, Takeshi

AU - Nakajima, Takako Eguchi

AU - Takahashi, Shin

AU - Otsu, Satoshi

AU - Komatsu, Yoshito

AU - Nagashima, Fumio

AU - Moriwaki, Toshikazu

AU - Esaki, Taito

AU - Sato, Takeo

AU - Itabashi, Michio

AU - Oki, Eiji

AU - Sasaki, Toru

AU - Sunaga, Yoshinori

AU - Ziti-Ljajic, Samira

AU - Brillac, Claire

AU - Yoshino, Takayuki

PY - 2019/3

Y1 - 2019/3

N2 - Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.

AB - Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.

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