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.

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.

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).

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 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.