Safety and Efficacy Study of mFOLFOX6 + Panitumumab Combination Therapy and 5-FU/LV + Panitumumab Combination Therapy in Participants With Chemotherapy-naïve Unresectable Advanced Recurrent Colorectal Carcinoma

A Phase 2 Randomized Study Comparing the Efficacy and Safety of mFOLFOX6+Panitumumab Combination Therapy and 5-FU/LV+Panitumumab Combination Therapy in the Patients With Chemotherapy-Naive Unresectable Advanced Recurrent Colorectal Carcinoma of KRAS Wild-Type After 6 Cycles of Combination Therapy With mFOLFOX6+Panitumumab

The purpose of this study is to exploratorily examine efficacy and safety in the participants with chemotherapy-naïve unresectable, advanced/recurrent colorectal carcinoma of Kirsten rat sarcoma-2 virus (KRAS) wild-type who have been treated with 6 cycles (2 weeks/cycle) of first-line mFOLFOX6 + panitumumab combination therapy and then assigned to two groups i.e., a group receiving 5-FU/LV + panitumumab combination therapy and a group receiving mFOLFOX6 + panitumumab combination therapy.

The drug being tested in this study is called panitumumab. Panitumumab is being tested to treat people who have advanced/recurrent colorectal carcinoma of KRAS wild-type. This study will look at the efficacy and safety of 5-FU/LV + panitumumab(Pmab) combination therapy or mFOLFOX6 + Pmab combination therapy in the participants.

The study will enroll 164 patients. All participants will receive 6 cycles of Protocol Treatment [1]: Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6.

Then they will be randomly assigned (by chance, like flipping a coin) to one of the treatment groups.

• Group A
• Group B

This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately 20 months.

Inclusion Criteria for enrollment:

1. Participants with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer)

2. Participants with measurable lesion(s) according to the RECIST ver. 1.1

3. Participants who have not received chemotherapy for colorectal cancer. Participants who experience relapse more than 6 months after the final dose of perioperative adjuvant chemotherapy with fluoropyrimidine agents may be enrolled.

4. Aged ≥ 20 years at the time of enrollment

5. Participants classified as KRAS wild-type. However, the criteria will be changed to all patients who are verified to be of KRAS and NRAS wild-type when the KRAS and NRAS tests come to be covered by National Health Insurance, and the tests become feasible at medical institutions.

6. Participants who satisfy the following criteria for the major organ function in tests performed within 14 days prior to enrollment

   1. Neutrophil count ≥ 1.5 × 10^3/μL
   2. White blood cell count ≥ 3.0 × 10^3/μL
   3. Platelet count ≥ 10.0 × 10^4/μL
   4. Hemoglobin ≥ 9.0 g/dL
   5. Total bilirubin ≤ 2.0 mg/dL
   6. AST ≤ 100 U/L (≤ 200 U/L if liver metastases are present)
   7. ALT ≤ 100 U/L (≤ 200 U/L if liver metastases are present)
   8. Serum creatinine ≤ 1.5 mg/dL

7. Participants who are assessed at Eastern Cooperative Oncology Group (ECOG) performance status (P.S.) of 0 or 1

8. Life expectancy of ≥ 6 months after enrollment

9. Participants who have given written consent to take part in the study after detailed explanation of the study prior to enrollment

Inclusion criteria for randomization:

1. Participants who have received 6 cycles of mFOLFOX6 + panitumumab combination therapy
2. Participants who are assessed at ECOG P.S. of 0-1 in the 6th cycle.
3. Participants for whom PD or not evaluable has been denied on the RECIST 1.1 based on imaging tests conducted after the day of administration in the 6th cycle within 14 days (2 weeks).

Exclusion Criteria for enrollment:

1. Radiotherapy received for a measurable lesion
2. Radiotherapy received within 28 days (4 weeks) prior to enrollment for a lesion other than measurable lesions. However, treatment to relieve pain associated with metastatic bone tumors was allowed.
3. Known brain metastasis or strongly suspected of brain metastasis
4. 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.).
5. Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.)
6. Participants who do not want to use contraception to prevent pregnancy, and women who are pregnant or breast-feeding, or test positive for pregnancy
7. Active hemorrhage requiring blood transfusion
8. Disease requiring systemic steroids for treatment (excluding topical steroids)
9. Intestinal resection and colostomy within 2 weeks prior to enrollment
10. History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.)
11. Serious drug hypersensitivity
12. Local or systemic active infection requiring treatment, or fever indicating infection
13. Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhea (incapacitating symptoms despite adequate treatment)
14. Active hepatitis B and/or active hepatitis C
15. Known human immunodeficiency virus infection
16. Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study

Exclusion criteria for randomization:

1. Participants in whom interstitial pneumonia has been newly diagnosed during the period from registration to randomization
2. Participants who have received radiotherapy during the period from registration to randomization
3. Other Participants judged by the investigator or sub-investigator to be ineligible for enrollment in the study