An Exploratory Study of Treatment Sensitivity and Prognostic Factors in a Efficacy and Safety Study of mFOLFOX6 + Bevacizumab Versus mFOLFOX6 + Panitumumab Therapy in Patients With Chemotherapy-naïve Unresectable Advanced or Recurrent Colorectal Cancer

An Exploratory Study of Treatment Sensitivity and Prognostic Factors in a Phase III, Randomized, Controlled Study Comparing the Efficacy and Safety of mFOLFOX6 + Bevacizumab Therapy vs. mFOLFOX6 + Panitumumab Therapy in Patients With Chemotherapy-naïve Wild-type RAS(KRAS/NRAS) Unresectable Advanced or Recurrent Colorectal Cancer

The purpose of this study is to investigate biomarkers which may be predictors of efficacy and safety of treatment with mFOLFOX6 + bevacizumab versus mFOLFOX6 + panitumumab therapy in patients with chemotherapy-naïve unresectable advanced or recurrent colorectal cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab; Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, bevacizumab

Detailed Description

The drug being tested in this study is called Panitumumab. This exploratory study will investigate biomarkers which may be predictors of efficacy and safety of treatment with mFOLFOX6 + bevacizumab versus mFOLFOX6 + panitumumab therapy in patients with chemotherapy-naïve unresectable advanced or recurrent colorectal cancer.

Tumor tissue samples obtained from the participants who enrolled in the safety/efficacy study of Panitumumab + mFOLFOX versus bevacizumab + mFOLFOX (PARADIGM Study: NCT02394795) and provided consent for this additional study will be used. Mutations, amplification and rearrangement of predefined tumor-associated genes will be investigated using DNA collected from tumor samples used for assessing RAS mutations and plasma free DNA collected before administration of cycle 1 and at the discontinuation of the protocol treatment in the main study.

• Study Type: Observational
• Enrollment (Actual): 757

Contacts and Locations

Study Locations

• Japan
  • Akita, Japan
  • Aomori, Japan
  • Chiba, Japan
  • Fukui, Japan
  • Fukuoka, Japan
  • Gifu, Japan
  • Kagoshima, Japan
  • Kochi, Japan
  • Kumamoto, Japan
  • Kyoto, Japan
  • Miyazaki, Japan
  • Nagano, Japan
  • Nagasaki, Japan
  • Niigata, Japan
  • Okayama, Japan
  • Okinawa, Japan
  • Osaka, Japan
  • Saga, Japan
  • Saitama, Japan
  • Shizuoka, Japan
  • Tokushima, Japan
  • Toyama, Japan
  • Yamagata, Japan
  • Aichi
    • Ichinomiya, Aichi, Japan
    • Komaki, Aichi, Japan
    • Kounan, Aichi, Japan
    • Nagakute, Aichi, Japan
    • Nagoya, Aichi, Japan
    • Okazaki, Aichi, Japan
    • Toyohashi, Aichi, Japan
    • Toyokawa, Aichi, Japan
    • Toyota, Aichi, Japan
    • Yatomi, Aichi, Japan
  • Akita
    • Daisen, Akita, Japan
  • Aomori
    • Hirosaki, Aomori, Japan
    • Misawa, Aomori, Japan
  • Chiba
    • Kashiwa, Chiba, Japan
    • Yachiyo, Chiba, Japan
  • Ehime
    • Matsuyama, Ehime, Japan
    • Toon, Ehime, Japan
  • Fukui
    • Tsuruga, Fukui, Japan
    • Yoshida, Fukui, Japan
  • Fukuoka
    • Kitakyushu, Fukuoka, Japan
    • Koga, Fukuoka, Japan
    • Kurume, Fukuoka, Japan
    • Omuta, Fukuoka, Japan
    • Onga, Fukuoka, Japan
  • Fukushima
    • Aizuwakamatsu, Fukushima, Japan
    • Iwaki, Fukushima, Japan
    • Koriyama, Fukushima, Japan
    • Shirakawa, Fukushima, Japan
  • Gifu
    • Hashima, Gifu, Japan
    • Kakamigahara, Gifu, Japan
    • Minokamo, Gifu, Japan
    • Ogaki, Gifu, Japan
    • Okazai, Gifu, Japan
  • Gunma
    • Maebashi, Gunma, Japan
    • Ota, Gunma, Japan
  • Hiroshima
    • Fukuyama, Hiroshima, Japan
  • Hokkaido
    • Hakodate, Hokkaido, Japan
    • Kitami, Hokkaido, Japan
    • Kushiro, Hokkaido, Japan
    • Obihiro, Hokkaido, Japan
    • Otaru, Hokkaido, Japan
    • Sapporo, Hokkaido, Japan
  • Hyogo
    • Akashi, Hyogo, Japan
    • Amagasaki, Hyogo, Japan
    • Himeji, Hyogo, Japan
    • Kobe, Hyogo, Japan
    • Nishinomiya, Hyogo, Japan
  • Ibaraki
    • Hitachi, Ibaraki, Japan
    • Kasama, Ibaraki, Japan
    • Ryugasaki, Ibaraki, Japan
    • Tsuchiura, Ibaraki, Japan
    • Tsukuba, Ibaraki, Japan
  • Ishikawa
    • Hakusan, Ishikawa, Japan
    • Kaga, Ishikawa, Japan
    • Kahoku, Ishikawa, Japan
    • Kanazawa, Ishikawa, Japan
    • Nanao, Ishikawa, Japan
  • Iwate
    • Morioka, Iwate, Japan
  • Kagawa
    • Kida, Kagawa, Japan
    • Marugame, Kagawa, Japan
    • Takamatsu, Kagawa, Japan
  • Kanagawa
    • Fujisawa, Kanagawa, Japan
    • Hiratsuka, Kanagawa, Japan
    • Isehara, Kanagawa, Japan
    • Kamakura, Kanagawa, Japan
    • Kanazawa, Kanagawa, Japan
    • Sagamihara, Kanagawa, Japan
    • Yokohama, Kanagawa, Japan
    • Yokosuka, Kanagawa, Japan
  • Kochi
    • Nankoku, Kochi, Japan
  • Mie
    • Matsuzaka, Mie, Japan
    • Tsu, Mie, Japan
    • Yokkaichi, Mie, Japan
  • Miyagi
    • Ishinomaki, Miyagi, Japan
    • Natori, Miyagi, Japan
    • Osaki, Miyagi, Japan
    • Sendai, Miyagi, Japan
    • Shibata, Miyagi, Japan
  • Nagano
    • Matsumoto, Nagano, Japan
    • Saku, Nagano, Japan
  • Nagasaki
    • Omura, Nagasaki, Japan
    • Sasebo, Nagasaki, Japan
  • Nara
    • Ikoma, Nara, Japan
    • Tenri, Nara, Japan
    • Yamatotakada, Nara, Japan
  • Oita
    • Yufu, Oita, Japan
  • Okayama
    • Kurashiki, Okayama, Japan
  • Okinawa
    • Naha, Okinawa, Japan
    • Tomigusuku, Okinawa, Japan
    • Urasoe, Okinawa, Japan
  • Osaka
    • Hirakata, Osaka, Japan
    • Kawachinagano, Osaka, Japan
    • Moriguchi, Osaka, Japan
    • Neyagawa, Osaka, Japan
    • Osakasayama, Osaka, Japan
    • Suita, Osaka, Japan
    • Takatsuki, Osaka, Japan
  • Saitama
    • Kawagoe, Saitama, Japan
    • Kitaadachi, Saitama, Japan
    • Koshigaya, Saitama, Japan
  • Shiga
    • Moriyama, Shiga, Japan
    • Otsu, Shiga, Japan
  • Shimane
    • Izumi, Shimane, Japan
    • Izumo, Shimane, Japan
  • Shizuoka
    • Hamamatsu, Shizuoka, Japan
    • Izunokuni, Shizuoka, Japan
    • Sunto, Shizuoka, Japan
  • Tochigi
    • Shimotsuga, Tochigi, Japan
    • Shimotsuke, Tochigi, Japan
    • Utsunomiya, Tochigi, Japan
  • Tokushima
    • Komatsushima, Tokushima, Japan
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan
    • Chiyoda-ku, Tokyo, Japan
    • Chuo-ku, Tokyo, Japan
    • Itabashi-ku, Tokyo, Japan
    • Koto-ku, Tokyo, Japan
    • Machida, Tokyo, Japan
    • Minato-ku, Tokyo, Japan
    • Musashino, Tokyo, Japan
    • Shinagawa-ku, Tokyo, Japan
    • Shinjyuku-ku, Tokyo, Japan
  • Tottori
    • Yonago, Tottori, Japan
  • Toyama
    • Kurobe, Toyama, Japan
    • Takaoka, Toyama, Japan
  • Yamagata
    • Sakata, Yamagata, Japan
    • Tsuruoka, Yamagata, Japan
  • Yamaguchi
    • Iwakuni, Yamaguchi, Japan
  • Yamanashi
    • Kofu, Yamanashi, Japan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients who are enrolled in the main study and personally provided written consent after adequately explained about the contents of the additional study.

Description

Inclusion Criteria:

(1) Patients who are enrolled in the main study and personally provided written consent after adequately explained about the contents of the additional study

Exclusion Criteria:

(1) Patients who are determined by the investigator or researchers to be not suitable for participating in the additional study

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group P; mFOLFOX6 + panitumumab combination therapy; OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 panitumumab: 6 mg/kg mFOLFOX6 + panitumumab combination therapy, once every two weeks	Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab; oxaliplatin (OXA), levofolinate calcium (l-LV), panitumumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion
Group B; mFOLFOX6 + bevacizumab combination therapy; OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 bevacizumab: 5 mg/kg/ mFOLFOX6 + bevacizumab combination therapy, once every two weeks	Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, bevacizumab; oxaliplatin (OXA), levofolinate calcium (l-LV), bevacizumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	OS obtained in the main study will be stratified by the presence or absence of mutation of tumor-associated genes in tumor tissues at the baseline of the main study to evaluate the relationship between OS and gene mutations. OS will be measured as the time from the date of randomization to the date of death due to any causes.	Up to approximately 63 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	PFS obtained in the main study will be stratified by the presence or absence of mutation of tumor-associated genes in tumor tissues at the baseline of the main study to evaluate the relationship between the efficacy endpoint and gene mutations. PFS is defined as the time from the date of randomization to the earlier of Progressive Disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or death due to any cause.	Up to approximately 63 months
Response Rate (RR)	RR obtained in the main study will be stratified by the presence or absence of mutation of tumor-associated genes in tumor tissues at the baseline of the main study to evaluate the relationship between the efficacy endpoint and gene mutations. RR is defined as percentage of participants who achieve Complete Response (CR) and Partial Response (PR) as the best overall response per RECIST version 1.1.	Approximately 12 months
Duration of Response (DOR)	DOR obtained in the main study will be stratified by the presence or absence of mutation of tumor-associated genes in tumor tissues at the baseline of the main study to evaluate the relationship between the efficacy endpoint and gene mutations. DOR means that the period from the day when either CR or PR is first confirmed until the day of documented PD or the day of death due to all causes, whichever occurs earlier.	Up to approximately 63 months
Percentage of Participants who Proceeded to Surgical Resection	The outcome obtained in the main study will be stratified by the presence or absence of mutation of tumor-associated genes in tumor tissues at the baseline of the main study to evaluate the relationship between the efficacy endpoint and gene mutations.	Up to approximately 63 month
Percentage of Participants with Early Tumor Shrinkage	The outcome obtained in the main study will be stratified by the presence or absence of mutation of tumor-associated genes in tumor tissues at the baseline of the main study to evaluate the relationship between the efficacy endpoint and gene mutations.	Up to approximately 63 months
Degree of the Maximum Tumor Shrinkage (Depth of Response)	The outcome obtained in the main study will be stratified by the presence or absence of mutation of tumor-associated genes in tumor tissues at the baseline of the main study to evaluate the relationship between the efficacy endpoint and gene mutations.	Up to approximately 63 months
Evaluation of the Relationship of Each Biomarker in Plasma Free DNA and Tumor Samples at Baseline of the Main Study		Up to approximately 63 months
Evaluation of the Relationship between Each Biomarker in Plasma Free DNA at Baseline of the Main Study, and Efficacy Endpoints		Up to approximately 63 months
Evaluation of the Relationship between a Change in Each Biomarker in Plasma Free DNA at Baseline and the Discontinuation of the Protocol Treatment of the Main Study, and Efficacy Endpoints		Up to approximately 63 months
Evaluation of the Relationship between a Change in Each Biomarker in Tumor Tissue at Baseline and the Discontinuation of the Protocol Treatment of the Main Study, and Efficacy Endpoints		Up to approximately 63 months

Collaborators and Investigators

• Sponsor: Takeda
• Investigators: Study Director: Study Director, Takeda

Publications and helpful links

General Publications

• 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. Rationale for and Design of the PARADIGM Study: Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naive Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2017 Jun;16(2):158-163. doi: 10.1016/j.clcc.2017.01.001. Epub 2017 Jan 24.

Helpful Links

• To obtain more information on the study, click here/on this link

Study record dates

Study Major Dates

• Study Start (Actual): May 29, 2015
• Primary Completion (Estimated): March 31, 2025
• Study Completion (Estimated): March 31, 2025

Study Registration Dates

• First Submitted: March 16, 2015
• First Submitted That Met QC Criteria: March 19, 2015
• First Posted (Estimated): March 20, 2015

Study Record Updates

• Last Update Posted (Actual): December 5, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Metastatic colorectal cancer, Panitumumab, mFOLFOX6, Bevacizumab
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Bevacizumab; Leucovorin; Calcium; Levoleucovorin; Calcium, Dietary; Panitumumab
• Other Study ID Numbers: Panitumumab-4004; U1111-1167-3521 (Other Identifier: WHO); UMIN000016782 (Registry Identifier: UMIN Clinical Trials Registry); jRCT1080222785 (Registry Identifier: jRCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No