Rationale for and Design of the PARADIGM Study: Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naïve Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer

Takayuki Yoshino, Hiroyuki Uetake, Katsuya Tsuchihara, Kohei Shitara, Kentaro Yamazaki, Eiji Oki, Takeo Sato, Takeshi Naitoh, Yoshito Komatsu, Takeshi Kato, Kazunori Yamanaka, Kouji Iwasaki, Jumpei Soeda, Masamitsu Hihara, Takeharu Yamanaka, Atsushi Ochiai, Kei Muro

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Abstract

Background It remains unclear whether an anti-VEGF or anti-EGFR antibody with standard doublet chemotherapy is the optimal first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC). Here we outline the PARADIGM study (NCT02394795), designed to evaluate the superiority of panitumumab over bevacizumab, in combination with oxaliplatin/5-fluorouracil/leucovorin (mFOLFOX6) in patients with RAS wild-type chemotherapy-naïve mCRC. Patients and Methods Eligible patients are aged 20 to 79 years with an ECOG performance status of 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. A total of 800 patients are to be randomly assigned (1:1 ratio) to mFOLFOX6 plus panitumumab (n = 400) or bevacizumab (n = 400) and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, and 5-fluorouracil (5-FU) I.V. 400 mg/m2 on day 1; 5-FU continuous I.V. 2400 mg/m2 on days 1 to 3; and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg on day 1 every 2 weeks. The primary endpoint is overall survival forming the basis to detect a hazard ratio of 0.76 with a 1-sided type I error rate of 0.025 and 80% power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. A comprehensive biomarker analysis (NCT02394834) using archival tumor tissue and circulating tumor DNA samples collected at different time points (pretreatment and confirmed progressive disease) will investigate potential biomarkers related to primary and secondary resistance. The first patient was enrolled in May 2015 and the study is anticipated to complete in 2020.

Original languageEnglish
Pages (from-to)158-163
Number of pages6
JournalClinical Colorectal Cancer
Volume16
Issue number2
DOIs
Publication statusPublished - Jun 2017

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oxaliplatin
Drug Therapy
Fluorouracil
Colorectal Neoplasms
Leucovorin
Biomarkers
Vascular Endothelial Growth Factor A
Disease-Free Survival
Bevacizumab
panitumumab
Anti-Idiotypic Antibodies
Neoplasms
Survival Rate
Neoplasm Metastasis
Survival
Liver
DNA
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Gastroenterology

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Rationale for and Design of the PARADIGM Study : Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naïve Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer. / Yoshino, Takayuki; Uetake, Hiroyuki; Tsuchihara, Katsuya; Shitara, Kohei; Yamazaki, Kentaro; Oki, Eiji; Sato, Takeo; Naitoh, Takeshi; Komatsu, Yoshito; Kato, Takeshi; Yamanaka, Kazunori; Iwasaki, Kouji; Soeda, Jumpei; Hihara, Masamitsu; Yamanaka, Takeharu; Ochiai, Atsushi; Muro, Kei.

In: Clinical Colorectal Cancer, Vol. 16, No. 2, 06.2017, p. 158-163.

Research output: Contribution to journalArticle

Yoshino, T, Uetake, H, Tsuchihara, K, Shitara, K, Yamazaki, K, Oki, E, Sato, T, Naitoh, T, Komatsu, Y, Kato, T, Yamanaka, K, Iwasaki, K, Soeda, J, Hihara, M, Yamanaka, T, Ochiai, A & Muro, K 2017, 'Rationale for and Design of the PARADIGM Study: Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naïve Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer', Clinical Colorectal Cancer, vol. 16, no. 2, pp. 158-163. https://doi.org/10.1016/j.clcc.2017.01.001
Yoshino, Takayuki ; Uetake, Hiroyuki ; Tsuchihara, Katsuya ; Shitara, Kohei ; Yamazaki, Kentaro ; Oki, Eiji ; Sato, Takeo ; Naitoh, Takeshi ; Komatsu, Yoshito ; Kato, Takeshi ; Yamanaka, Kazunori ; Iwasaki, Kouji ; Soeda, Jumpei ; Hihara, Masamitsu ; Yamanaka, Takeharu ; Ochiai, Atsushi ; Muro, Kei. / Rationale for and Design of the PARADIGM Study : Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naïve Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer. In: Clinical Colorectal Cancer. 2017 ; Vol. 16, No. 2. pp. 158-163.
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abstract = "Background It remains unclear whether an anti-VEGF or anti-EGFR antibody with standard doublet chemotherapy is the optimal first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC). Here we outline the PARADIGM study (NCT02394795), designed to evaluate the superiority of panitumumab over bevacizumab, in combination with oxaliplatin/5-fluorouracil/leucovorin (mFOLFOX6) in patients with RAS wild-type chemotherapy-na{\"i}ve mCRC. Patients and Methods Eligible patients are aged 20 to 79 years with an ECOG performance status of 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. A total of 800 patients are to be randomly assigned (1:1 ratio) to mFOLFOX6 plus panitumumab (n = 400) or bevacizumab (n = 400) and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, and 5-fluorouracil (5-FU) I.V. 400 mg/m2 on day 1; 5-FU continuous I.V. 2400 mg/m2 on days 1 to 3; and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg on day 1 every 2 weeks. The primary endpoint is overall survival forming the basis to detect a hazard ratio of 0.76 with a 1-sided type I error rate of 0.025 and 80{\%} power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. A comprehensive biomarker analysis (NCT02394834) using archival tumor tissue and circulating tumor DNA samples collected at different time points (pretreatment and confirmed progressive disease) will investigate potential biomarkers related to primary and secondary resistance. The first patient was enrolled in May 2015 and the study is anticipated to complete in 2020.",
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T1 - Rationale for and Design of the PARADIGM Study

T2 - Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naïve Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer

AU - Yoshino, Takayuki

AU - Uetake, Hiroyuki

AU - Tsuchihara, Katsuya

AU - Shitara, Kohei

AU - Yamazaki, Kentaro

AU - Oki, Eiji

AU - Sato, Takeo

AU - Naitoh, Takeshi

AU - Komatsu, Yoshito

AU - Kato, Takeshi

AU - Yamanaka, Kazunori

AU - Iwasaki, Kouji

AU - Soeda, Jumpei

AU - Hihara, Masamitsu

AU - Yamanaka, Takeharu

AU - Ochiai, Atsushi

AU - Muro, Kei

PY - 2017/6

Y1 - 2017/6

N2 - Background It remains unclear whether an anti-VEGF or anti-EGFR antibody with standard doublet chemotherapy is the optimal first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC). Here we outline the PARADIGM study (NCT02394795), designed to evaluate the superiority of panitumumab over bevacizumab, in combination with oxaliplatin/5-fluorouracil/leucovorin (mFOLFOX6) in patients with RAS wild-type chemotherapy-naïve mCRC. Patients and Methods Eligible patients are aged 20 to 79 years with an ECOG performance status of 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. A total of 800 patients are to be randomly assigned (1:1 ratio) to mFOLFOX6 plus panitumumab (n = 400) or bevacizumab (n = 400) and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, and 5-fluorouracil (5-FU) I.V. 400 mg/m2 on day 1; 5-FU continuous I.V. 2400 mg/m2 on days 1 to 3; and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg on day 1 every 2 weeks. The primary endpoint is overall survival forming the basis to detect a hazard ratio of 0.76 with a 1-sided type I error rate of 0.025 and 80% power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. A comprehensive biomarker analysis (NCT02394834) using archival tumor tissue and circulating tumor DNA samples collected at different time points (pretreatment and confirmed progressive disease) will investigate potential biomarkers related to primary and secondary resistance. The first patient was enrolled in May 2015 and the study is anticipated to complete in 2020.

AB - Background It remains unclear whether an anti-VEGF or anti-EGFR antibody with standard doublet chemotherapy is the optimal first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC). Here we outline the PARADIGM study (NCT02394795), designed to evaluate the superiority of panitumumab over bevacizumab, in combination with oxaliplatin/5-fluorouracil/leucovorin (mFOLFOX6) in patients with RAS wild-type chemotherapy-naïve mCRC. Patients and Methods Eligible patients are aged 20 to 79 years with an ECOG performance status of 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. A total of 800 patients are to be randomly assigned (1:1 ratio) to mFOLFOX6 plus panitumumab (n = 400) or bevacizumab (n = 400) and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, and 5-fluorouracil (5-FU) I.V. 400 mg/m2 on day 1; 5-FU continuous I.V. 2400 mg/m2 on days 1 to 3; and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg on day 1 every 2 weeks. The primary endpoint is overall survival forming the basis to detect a hazard ratio of 0.76 with a 1-sided type I error rate of 0.025 and 80% power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. A comprehensive biomarker analysis (NCT02394834) using archival tumor tissue and circulating tumor DNA samples collected at different time points (pretreatment and confirmed progressive disease) will investigate potential biomarkers related to primary and secondary resistance. The first patient was enrolled in May 2015 and the study is anticipated to complete in 2020.

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