FOLFOXIRI Plus Panitumumab In Kras and Braf Wild-Type Metastatic Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
The GONO-FOLFOXIRI regimen demonstrated higher activity and efficacy compared to FOLFIRI in a phase III trial. Panitumumab with oxaliplatin- or irinotecan-based doublets is feasible and associated with improved activity in KRAS codon 12-13 wild-type patients. BRAF and other RAS rare mutations have been suggested as additional potential biomarkers for anti-EGFR agents in metastatic colo-rectal cancer. The present study aims to demonstrate the feasibility and the activity of the first-line combination of the GONO-FOLFOXIRI regimen and Panitumumab in molecularly selected metastatic colo-rectal cancer patients.

Official Title
-----------------
Phase II Trial of FOLFOXIRI Plus Panitumumab as First-Line Treatment for Kras and Braf Wild-Type Metastatic Colorectal Cancer

Conditions
-----------------
Metastatic Colo-rectal Cancer

Intervention / Treatment
-----------------
* Drug: FOLFOXIRI + Panitumumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed colorectal adenocarcinoma; Availability of formalin-fixed paraffin embedded tumor block from primary or metastasis; KRAS and BRAF wild-type status of primary colorectal cancer or related metastasis; Unresectable and measurable metastatic disease according to RECIST criteria; Male or female, aged >/= 18 years and </= 75 years; ECOG PS < 2 if aged < 71 years; ECOG PS = 0 if aged 71-75 years; Life expectancy of more than 3 months; Adequate haematological function: ANC ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L, Hb ≥ 9 g/dL; Adequate liver function: serum bilirubin ≤ 1.5 x ULN; alkaline phosphatase and transaminases ≤ 2.5 x ULN (in case of liver metastases < 5 x ULN); Serum creatinine ≤ 1.5 x ULN; Previous adjuvant chemotherapy is allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse; At least 6 weeks from prior radiotherapy and 4 weeks from surgery; Written informed consent to experimental treatment and pharmacogenomic analyses; Magnesium ≥ lower limit of normal; Calcium ≥ lower limit of normal. Exclusion Criteria: Prior palliative chemotherapy; Prior treatment with EGFR inhibitors; Symptomatic peripheral neuropathy ≥ 2 grade NCIC-CTG criteria; Presence or history of CNS metastasis; Active uncontrolled infections; active disseminated intravascular coagulation; Past or current history of malignancies other than colorectal carcinoma, except for curatively treated basal and squamous cell carcinoma of the skin cancer or in situ carcinoma of the cervix; Clinically significant cardiovascular disease, for example cerebrovascular accidents (CVA) (≤ 6 months before treatment start), myocardial infarction (≤ 6 months before treatment start), unstable angina, NYHA ≥ grade 2 chronic heart failure (CHF), uncontrolled arrhythmia; Fertile women (< 2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception; Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment; History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FOLFOXIRI + Panitumumab<br>PANITUMUMAB 6 mg/Kg i.v. over 1 hour followed by IRINOTECAN 150 mg/sqm i.v. over 1 hour followed by OXALIPLATIN 85 mg/sqm i.v. over 2 hours concomitantly with L-LV 200 mg/sqm over 2 hours followed by 5-FLUOROURACIL 2400 mg/sqm c.i. over 48 hours starting on day 1 repeated every 2 weeks. | Drug: FOLFOXIRI + Panitumumab<br>* PANITUMUMAB 6 mg/Kg i.v. over 1 hour followed by IRINOTECAN 150 mg/sqm i.v. over 1 hour followed by OXALIPLATIN 85 mg/sqm i.v. over 2 hours concomitantly with L-LV 200 mg/sqm over 2 hours followed by 5-FLUOROURACIL* 2400 mg/sqm c.i. over 48 hours starting on day 1 repeated every 2 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Response rate is defined as the fraction of treated patients who achieve a response as defined according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria vers. 1.1. | Up to 3 years (objective response will be evaluated every 8 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression free survival is defined as time from study entry until progression of disease (according to RECIST 1.1) or death from any cause. Patients who are alive without having progressed at the end of the study will be censored at their last radiological assessment. | Up to 3 years | 
| Overall Survival | Overall survival is defined as the time from study entry until death from any cause. Patients who are alive at the end of the study will be censored at that point. | Up to 3 years | 
| Safety Profile | Safety Profile is based on the collection of all the adverse events occurring during the study graded by NCI-CTC criteria. | Up to 3 years | 
| Secondary Radical Surgery on Metastases | Secondary Radical Surgery on Metastases is defined as microscopically margin-free complete surgical removal of all residual disease performed during treatment or after its completion allowed by tumoral shrinkage and or desappearance of one or more lesions. | Up to 3 years | 
| Analyses of Potential Predictive Factors | Exploratory analyses of potential predictive factors and surrogate markers of treatment activity or efficacy. | Up to 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
RAS Wild-Type, BRAF Wild-Type