Panitumumab and RAS, Diagnostically-useful Gene Mutation for mCRC
PARADIGM
A Phase III, Randomized, Controlled Study of mFOLFOX6 + Bevacizumab Combination Therapy Versus mFOLFOX6 + Panitumumab Combination Therapy in Chemotherapy-naive Patients With KRAS/NRAS Wild-type, Incurable/Unresectable, Advanced/Recurrent Colorectal Cancer
5 other identifiers
interventional
823
1 country
155
Brief Summary
The purpose of this study is to verify the efficacy of mFOLFOX6 + panitumumab combination therapy and mFOLFOX6 + bevacizumab combination therapy in first-line treatment of chemotherapy-naive patients with KRAS/NRAS wild-type, incurable/unresectable, advanced/recurrent colorectal cancer.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3 colorectal-cancer
Started May 2015
Typical duration for phase_3 colorectal-cancer
155 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
March 16, 2015
CompletedFirst Posted
Study publicly available on registry
March 20, 2015
CompletedStudy Start
First participant enrolled
May 29, 2015
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 14, 2022
CompletedStudy Completion
Last participant's last visit for all outcomes
January 14, 2022
CompletedResults Posted
Study results publicly available
November 1, 2023
CompletedNovember 1, 2023
January 1, 2023
6.6 years
March 16, 2015
January 12, 2023
January 12, 2023
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
OS in Participants With Left-sided Tumors
OS was measured as the time from the date of randomization to the date of death due to any cause. The left-sided tumors were defined as primary tumors occupying a left-sided site include the descending colon, sigmoid colon, and rectum.
Up to approximately 60 months
Overall Survival (OS) in All Participants
OS was measured as the time from the date of randomization to the date of death due to any cause.
Up to approximately 60 months
Secondary Outcomes (6)
Progression-Free Survival (PFS) in Participants With Left-sided Tumors
Up to approximately 60 months
Progression-Free Survival (PFS) in All Participants
Up to approximately 60 months
Response Rate (RR) in All Participants
Up to approximately 60 months
Duration of Response (DOR)
Up to approximately 60 months
Number of Participants Treated With Curative Surgical Resection After Chemotherapy
Up to approximately 60 months
- +1 more secondary outcomes
Study Arms (2)
Group P; mFOLFOX6 + panitumumab combination therapy
EXPERIMENTALOXA: 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.
Group B; mFOLFOX6 + bevacizumab combination therapy
ACTIVE COMPARATOROXA: 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.
Interventions
oxaliplatin (OXA), levofolinate calcium (l-LV), panitumumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion
oxaliplatin (OXA), levofolinate calcium (l-LV), bevacizumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion
Eligibility Criteria
You may qualify if:
- Investigator and subinvestigator judge a candidate is understand clinical trial and comply this protocol.
- Investigator is those who participate in conducting a study and oversight the study duties at a site.
- Patients who have given written consent to take part in the study after detailed explanation of the study prior to enrollment
- Aged ≥20 to \<80 years at the time of informed consent
- Patients with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer)
- Patients with lesion(s) that can be evaluated. It is not essential to be evaluated the tumor according to the RECIST ver. 1.1.
- Patients who have not received chemotherapy for colorectal cancer. Patients who experience relapse more than 24 weeks (168 days) after the final dose of perioperative adjuvant chemotherapy with fluoropyrimidine agents may be enrolled. Patients who have received perioperative adjuvant chemotherapy including oxaliplatin are excluded.
- Patients classified as KRAS/NRAS wild-type by KRAS/NRAS testing. KRAS/NRAS test will be performed using the in vitro diagnostic listed in the National Health Insurance.
- Patients with no mutation in any of the codons shown below are considered wild type. It is not considered wild type if either of the codons are not evaluable or not tested.
- KRAS: EXON2 (codon 12, 13), EXON3 (codon 59, 61), EXON4 (codon 117, 146) NRAS：EXON2 (codon 12, 13), EXON3 (codon 59, 61), EXON4 (codon 117, 146)
- Patients who satisfy the following criteria for the major organ function in tests performed within 14 days prior to enrollment
- Neutrophil count ≥ 1.5×10\^3/µL
- Platelet count ≥ 1.0×10\^4/µL
- Hemoglobin ≥ 9.0 g/dL
- Total bilirubin ≤ 2.0 mg/dL
- +10 more criteria
You may not qualify if:
- Radiotherapy received within 4 weeks (28 days) prior to enrollment. Treatments aimed at relieving pain for bone metastases are excluded.
- Known brain metastasis or strongly suspected of brain metastasis
- Synchronous cancers or metachronous cancers with a disease-free period of ≤ 5 years (excluding colorectal cancer) excluding mucosal cancers cured or be possibly cured by regional resection (esophageal, stomach, and cervical cancer, non-melanoma skin cancer, bladder cancer, etc.).
- Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.)
- Patients who do not want to use contraception to prevent pregnancy, and women who are pregnant or breast-feeding, or test positive for pregnancy
- Nonhealing surgical wound (excluding implanted venous reservoirs)
- Active hemorrhage requiring blood transfusion
- Disease requiring systemic steroids for treatment (excluding topical steroids)
- The patient who has placed colonic stent
- Intestinal resection within 4 weeks prior to enrollment or colostomy within 2 weeks prior to enrollmentt
- History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.)
- Patients with unstable angina, myocardial infarction, cerebral hemorrhage, arterial thromboembolism such as cerebral infarction, or have history of these desease less than 24 weeks (168 days) before registration (except for lacunar infarction asymptomatic)
- Serious drug hypersensitivity
- Local or systemic active infection requiring treatment, or fever indicating infection
- NYHA class II or higher heart failure or serious heart disease
- +7 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Takedalead
Study Sites (155)
Unknown Facility
Ichinomiya, Aichi-ken, Japan
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Komaki, Aichi-ken, Japan
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Kōnan, Aichi-ken, Japan
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Nagakute, Aichi-ken, Japan
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Nagoya, Aichi-ken, Japan
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Okazaki, Aichi-ken, Japan
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Toyoake, Aichi-ken, Japan
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Toyohashi, Aichi-ken, Japan
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Toyokawa, Aichi-ken, Japan
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Toyota, Aichi-ken, Japan
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Yatomi, Aichi-ken, Japan
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Daisen, Akita, Japan
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Hirosaki, Aomori, Japan
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Misawa, Aomori, Japan
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Kashiwa, Chiba, Japan
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Yachiyo, Chiba, Japan
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Matsuyama, Ehime, Japan
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Tōon, Ehime, Japan
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Tsuruga, Fukui, Japan
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Yoshida, Fukui, Japan
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Kitakyushu, Fukuoka, Japan
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Koga, Fukuoka, Japan
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Koga, Fukuoka, Japan
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Kurume, Fukuoka, Japan
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Omuta, Fukuoka, Japan
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Aizu-Wakamatsu, Fukushima, Japan
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Iwaki, Fukushima, Japan
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Kōriyama, Fukushima, Japan
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Shirakawa, Fukushima, Japan
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Hashima, Gifu, Japan
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Kakamigahara, Gifu, Japan
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Minokamo, Gifu, Japan
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Okazai, Gifu, Japan
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Ōgaki, Gifu, Japan
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Maebashi, Gunma, Japan
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Ōta, Gunma, Japan
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Fukuyama, Hiroshima, Japan
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Hakodate, Hokkaido, Japan
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Kitami, Hokkaido, Japan
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Kushiro, Hokkaido, Japan
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Obihiro, Hokkaido, Japan
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Otaru, Hokkaido, Japan
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Sapporo, Hokkaido, Japan
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Akashi, Hyōgo, Japan
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Amagasaki, Hyōgo, Japan
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Himeji, Hyōgo, Japan
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Kobe, Hyōgo, Japan
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Nishinomiya, Hyōgo, Japan
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Hitachi, Ibaraki, Japan
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Kasama, Ibaraki, Japan
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Ryūgasaki, Ibaraki, Japan
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Tsuchiura, Ibaraki, Japan
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Tsukuba, Ibaraki, Japan
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Hakusan, Ishikawa-ken, Japan
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Kaga, Ishikawa-ken, Japan
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Kahoku, Ishikawa-ken, Japan
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Kanazawa, Ishikawa-ken, Japan
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Nanao, Ishikawa-ken, Japan
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Morioka, Iwate, Japan
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Kida, Kagawa-ken, Japan
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Marugame, Kagawa-ken, Japan
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Takamatsu, Kagawa-ken, Japan
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Fujisawa, Kanagawa, Japan
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Hiratsuka, Kanagawa, Japan
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Isehara, Kanagawa, Japan
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Kamakura, Kanagawa, Japan
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Kanazawachō, Kanagawa, Japan
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Sagamihara, Kanagawa, Japan
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Yokohama, Kanagawa, Japan
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Yokosuka, Kanagawa, Japan
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Nankoku, Kochi, Japan
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Matsuzaka, Mie-ken, Japan
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Tsu, Mie-ken, Japan
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Yokkaichi, Mie-ken, Japan
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Ishinomaki, Miyagi, Japan
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Murata, Miyagi, Japan
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Natori-shi, Miyagi, Japan
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Ōsaki, Miyagi, Japan
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Sendai, Miyagi, Japan
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Matsumoto, Nagano, Japan
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Saku, Nagano, Japan
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Ōmura, Nagasaki, Japan
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Sasebo, Nagasaki, Japan
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Ikoma, Nara, Japan
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Tenri, Nara, Japan
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Yamatotakada, Nara, Japan
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Yufu, Oita Prefecture, Japan
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Kurashiki, Okayama-ken, Japan
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Naha, Okinawa, Japan
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Tomigusuku, Okinawa, Japan
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Urasoe, Okinawa, Japan
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Hirakata, Osaka, Japan
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Kawachi-Nagano, Osaka, Japan
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Moriguchi, Osaka, Japan
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Neyagawa, Osaka, Japan
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Sayama, Osaka, Japan
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Suita, Osaka, Japan
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Kawagoe, Saitama, Japan
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Kitaadachi, Saitama, Japan
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Koshigaya, Saitama, Japan
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Moriyama, Shiga, Japan
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Ōtsu, Shiga, Japan
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Izumi, Shimane, Japan
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Izumo, Shimane, Japan
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Hamamatsu, Shizuoka, Japan
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Izunokuni, Shizuoka, Japan
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Sunto, Shizuoka, Japan
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Shimotsuga, Tochigi, Japan
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Shimotsuke, Tochigi, Japan
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Utsunomiya, Tochigi, Japan
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Komatsushimachō, Tokushima, Japan
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Bunkyo-ku, Tokyo, Japan
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Chiyoda-ku, Tokyo, Japan
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Chuo-ku, Tokyo, Japan
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Itabashi-ku, Tokyo, Japan
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Koto-ku, Tokyo, Japan
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Machida, Tokyo, Japan
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Meguro-ku, Tokyo, Japan
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Minato-ku, Tokyo, Japan
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Musashino, Tokyo, Japan
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Ōta-ku, Tokyo, Japan
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Shinagawa-ku, Tokyo, Japan
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Shinjuku-ku, Tokyo, Japan
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Yonago, Tottori, Japan
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Kurobe-shi, Toyama, Japan
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Takaoka, Toyama, Japan
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Sakata, Yamagata, Japan
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Tsuruoka, Yamagata, Japan
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Iwakuni, Yamaguchi, Japan
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Ube, Yamaguchi, Japan
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Kofu, Yamanashi, Japan
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Akita, Japan
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Aomori, Japan
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Chiba, Japan
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Fukui, Japan
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Fukuoka, Japan
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Gifu, Japan
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Ibaraki, Japan
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Kagoshima, Japan
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Kochi, Japan
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Kumamoto, Japan
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Kyoto, Japan
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Miyazaki, Japan
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Nagano, Japan
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Nagasaki, Japan
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Niigata, Japan
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Okayama, Japan
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Okinawa, Japan
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Osaka, Japan
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Saga, Japan
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Saitama, Japan
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Shizuoka, Japan
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Tokushima, Japan
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Toyama, Japan
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Yamagata, Japan
Related Publications (3)
Shitara K, Muro K, Watanabe J, Yamazaki K, Ohori H, Shiozawa M, Takashima A, Yokota M, Makiyama A, Akazawa N, Ojima H, Yuasa Y, Miwa K, Yasui H, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Mori I, Yamanaka K, Hihara M, Soeda J, Misumi T, Yamamoto K, Yamashita R, Akagi K, Ochiai A, Uetake H, Tsuchihara K, Yoshino T. Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer. Nat Med. 2024 Mar;30(3):730-739. doi: 10.1038/s41591-023-02791-w. Epub 2024 Feb 12.
PMID: 38347302DERIVEDWatanabe J, Muro K, Shitara K, Yamazaki K, Shiozawa M, Ohori H, Takashima A, Yokota M, Makiyama A, Akazawa N, Ojima H, Yuasa Y, Miwa K, Yasui H, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Hihara M, Soeda J, Misumi T, Yamamoto K, Akagi K, Ochiai A, Uetake H, Tsuchihara K, Yoshino T. Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2023 Apr 18;329(15):1271-1282. doi: 10.1001/jama.2023.4428.
PMID: 37071094DERIVEDYoshino 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.
PMID: 28237539DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Study Director
- Organization
- Takeda
Study Officials
- STUDY DIRECTOR
Study Director
Takeda
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
March 16, 2015
First Posted
March 20, 2015
Study Start
May 29, 2015
Primary Completion
January 14, 2022
Study Completion
January 14, 2022
Last Updated
November 1, 2023
Results First Posted
November 1, 2023
Record last verified: 2023-01
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF, CSR
- 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.
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.