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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Colorectal Carcinoma

Intervention / Treatment
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* Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab
* Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for enrollment: Participants with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer) Participants with measurable lesion(s) according to the RECIST ver. 1.1 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. Aged ≥ 20 years at the time of enrollment 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. Participants 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 White blood cell count ≥ 3.0 × 10^3/μL Platelet count ≥ 10.0 × 10^4/μL Hemoglobin ≥ 9.0 g/dL Total bilirubin ≤ 2.0 mg/dL AST ≤ 100 U/L (≤ 200 U/L if liver metastases are present) ALT ≤ 100 U/L (≤ 200 U/L if liver metastases are present) Serum creatinine ≤ 1.5 mg/dL Participants who are assessed at Eastern Cooperative Oncology Group (ECOG) performance status (P.S.) of 0 or 1 Life expectancy of ≥ 6 months after enrollment 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: Participants who have received 6 cycles of mFOLFOX6 + panitumumab combination therapy Participants who are assessed at ECOG P.S. of 0-1 in the 6th cycle. 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: Radiotherapy received for a measurable lesion 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. 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.) Participants who do not want to use contraception to prevent pregnancy, and women who are pregnant or breast-feeding, or test positive for pregnancy Active hemorrhage requiring blood transfusion Disease requiring systemic steroids for treatment (excluding topical steroids) Intestinal resection and colostomy within 2 weeks prior to enrollment History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.) Serious drug hypersensitivity Local or systemic active infection requiring treatment, or fever indicating infection Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhea (incapacitating symptoms despite adequate treatment) Active hepatitis B and/or active hepatitis C Known human immunodeficiency virus infection Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study Exclusion criteria for randomization: Participants in whom interstitial pneumonia has been newly diagnosed during the period from registration to randomization Participants who have received radiotherapy during the period from registration to randomization Other Participants judged by the investigator or sub-investigator to be ineligible for enrollment in the study

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A<br>Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by 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 7 until progressive disease or intolerance. | Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab<br>* oxaliplatin (OXA), levofolinate calcium (l-LV), panitumumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion<br>|
| Experimental: Group B<br>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 as protocol treatment 1 followed by Pmab 6 mg/kg, 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 7 until progressive disease or intolerance. | Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival Rate (PFS Rate) at 9 Months After Randomization | PFS rate was defined as the gross percentage of participants who survived with no evidence of progression from the day of randomization (Day 0) until 9 months after Day 0. The presence/absence of progressive disease (PD) was determined based on imaging, consideration of clinical PD, or survival research results. PD based on response evaluation criteria in solid tumors (RECIST) is 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). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Up to 9 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | The PFS is the period from the date of randomization (Day 0) until the date of judgment of progression from the date of randomization, or until death by all causes, whichever comes first. The presence/absence of progressive disease (PD) was determined based on imaging, consideration of clinical PD, or survival research results. PD based on response evaluation criteria in solid tumors (RECIST) is 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). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Up to approximately 31 months | 
| Overall Survival (OS) | OS was defined as the time from the day of randomization (Day 0) until death by all causes. | Up to approximately 31 months | 
| Response Rate (RR) | RR was defined as the percentage of participants who had shown complete response (CR) or partial response (PR) as the best overall response in accordance with the RECIST 1.1 criteria after randomization. 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 31 months | 
| Time to Treatment Failure (TTF) | TTF was defined as the time from the day of randomization (Day 0) until the day of protocol treatment discontinuation determination, the day of PD decision during protocol treatment, or death from any cause, whichever came the earliest. | Up to approximately 31 months | 
| Percentage of Participants With Adverse Events | Safety population was defined as all participants who received at least one dose of protocol treatment after randomization. | Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date) | 
| Percentage of Participants With Adverse Events by Severity Graded Using the Common Terminology Criteria for Adverse Events (CTCAE) Grade | An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. | Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date) | 
| Percentage of Participants With Grade 2 or Higher Peripheral Neuropathy | Peripheral neuropathy was defined as events classified with a preferred term (PT) of peripheral neuropathy according to Standardized MedDRA Queries. | Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date) | 
| Percentage of Participants With Grade 3 or Higher Skin Toxicity | Skin toxicity was defined as events classified with an system organ class of Skin and subcutaneous tissue disorders or a preferred term of paronychia. | Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic colorectal cancer, Panitumumab, mFOLFOX6, First-line