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

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.

Study Overview

• Status: Completed
• 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 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.

This study will enroll a total of approximately 800 participants (400 per group).

Participants will be randomized to either the mFOLFOX6 + panitumumab arm (Group P) or mFOLFOX6 + bevacizumab arm (Group B) at 1:1 ratio at the time of registration.

Group P and Group B treatment regimen shown below should be administered once every two weeks, following dose, schedule and route of administration.

Group P; mFOLFOX6 + panitumumab combination therapy, once every two weeks 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

Group B; mFOLFOX6 + bevacizumab combination therapy, once every two weeks 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

This trial is conducted by multicenter and is scheduled for 12 months as whole administration period.

• Study Type: Interventional
• Enrollment (Actual): 823
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Akita, Japan
  • Aomori, Japan
  • Chiba, Japan
  • Fukui, Japan
  • Fukuoka, Japan
  • Gifu, Japan
  • Ibaraki, 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
    • Konan, Aichi, Japan
    • Nagakute, Aichi, Japan
    • Nagoya, Aichi, Japan
    • Okazaki, Aichi, Japan
    • Toyoake, 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
  • 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
    • Meguro-ku, Tokyo, Japan
    • Minato-ku, Tokyo, Japan
    • Musashino, Tokyo, Japan
    • Ota-ku, Tokyo, Japan
    • Shinagawa-ku, Tokyo, Japan
    • Shinjuku-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
    • Ube, Yamaguchi, Japan
  • Yamanashi
    • Kofu, Yamanashi, Japan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.

2. Patients who have given written consent to take part in the study after detailed explanation of the study prior to enrollment
3. Aged ≥20 to <80 years at the time of informed consent
4. Patients with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer)
5. Patients with lesion(s) that can be evaluated. It is not essential to be evaluated the tumor according to the RECIST ver. 1.1.
6. 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.

7. 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)

8. 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
   • AST ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present)
   • ALT ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present)
   • Serum creatinine ≤ 1.5 mg/dL
   • PT-INR < 1.5 (< 3.0 for patients treated with oral warfarin)

   • Satisfies at least one of these conditions

     1. Urine protein (dip stick method) ≤ 1+
     2. UPC (urine protein creatinine) ratio ≤ 1.0
     3. Urinary protein ≤ 1000 mg/ 24hours
9. ECOG performance status (PS) of 0 or 1
10. Life expectancy of ≥ 3 months (90 days) after enrollment

Exclusion Criteria:

1. Radiotherapy received within 4 weeks (28 days) prior to enrollment. Treatments aimed at relieving pain for bone metastases are excluded.
2. Known brain metastasis or strongly suspected of brain metastasis
3. 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.).
4. Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.)
5. Patients who do not want to use contraception to prevent pregnancy, and women who are pregnant or breast-feeding, or test positive for pregnancy
6. Nonhealing surgical wound (excluding implanted venous reservoirs)
7. Active hemorrhage requiring blood transfusion
8. Disease requiring systemic steroids for treatment (excluding topical steroids)
9. The patient who has placed colonic stent
10. Intestinal resection within 4 weeks prior to enrollment or colostomy within 2 weeks prior to enrollmentt
11. History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.)
12. 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)
13. Serious drug hypersensitivity
14. Local or systemic active infection requiring treatment, or fever indicating infection
15. NYHA class II or higher heart failure or serious heart disease
16. Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhoea (incapacitating symptoms despite adequate treatment)
17. Poorly controlled hypertension
18. Poorly controlled diabetes mellitus
19. Active hepatitis B
20. Known HIV infection
21. Peripheral neuropathy of ≥ Grade 2 by CTCAE (Japanese edition JCOG version 4.03)
22. Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study (e.g. Patients who might agree to participate under compulsion).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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
Active Comparator: 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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS) in Participants With Left-sided Tumors	PFS was 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. 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
Progression-Free Survival (PFS) in All Participants	PFS was 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 60 months
Response Rate (RR) in All Participants	RR was defined as number of participants who achieve Complete Response (CR) and Partial Response (PR) as the best overall response per RECIST version 1.1.The best overall response was CR, followed by PR, stable disease (SD), progressive disease (PD), and not evaluable (NE). CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters as the best overall response after randomization., SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).	Up to approximately 60 months
Duration of Response (DOR)	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 60 months
Number of Participants Treated With Curative Surgical Resection After Chemotherapy	Curative surgical resection was defined as complete resection.	Up to approximately 60 months
Number of Participants With Treatment-emergent Adverse Events (TEAE)	Adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. A TEAE was defined as an adverse event with an onset that occurred in the treatment period after receiving the protocol treatment.	Up to approximately 60 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 (Actual): January 14, 2022
• Study Completion (Actual): January 14, 2022

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): November 1, 2023
• Last Update Submitted That Met QC Criteria: January 12, 2023
• Last Verified: January 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-3001; U1111-1164-9167 (Other Identifier: WHO); JapicCTI-142731 (Registry Identifier: JapicCTI); jRCTs031180246 (Registry Identifier: Japan Registry of Clinical Trials); UMIN000016776 (Registry Identifier: UMIN Clinical Trials Registry)

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