CAPRI 2 GOIM Study: Investigate the Efficacy and Safety of a Bio-marker Driven Cetuximab-based Treatment Regimen

Study Overview
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Brief Summary
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This clinical program aims to evaluate the activity and efficacy of cetuximab continuation of treatment for three lines of therapy with rotation of chemotherapy (FOLFIRI, FOLFOX, irinotecan) in mCRC patients, whose tumors remain RAS/BRAF WT. The study will also evaluate the activity and efficacy of cetuximab re-introduction in combination with irinotecan as third line therapy in the concept of re-challenge for those patients that will be treated in second line with chemotherapy plus anti-angiogenic drugs (FOLFOX plus bevacizumab), having a RAS or BRAF mutant disease at the time of progression after FOLFIRI plus cetuximab first line treatment. A novel characteristic of this program is that the therapeutic algorithm will be defined at each treatment decision (first line, second line and third line) in a prospective fashion in each patient by liquid biopsy assessment of RAS/BRAF status.

Detailed Description
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Based on dynamic and longitudinal liquid biopsy assessment of RAS/BRAF status, that will be prospectively performed before each line of treatment, mCRC patients will be treated with cetuximab in combination with chemotherapy throughout three lines of therapy, as follows: FOLFIRI plus cetuximab (first line); FOLFOX plus cetuximab (second line); irinotecan plus cetuximab (third line) in case of RAS/BRAF WT at each time point of progression. If at progression after the first line, the liquid biopsy assessment indicates RAS and or BRAF mutant status, patients will be treated with FOLFOX plus bevacizumab as the second line of therapy. If at progression after the second line, the liquid biopsy assessment indicates RAS and or BRAF mutant status, patients will be treated with regorafenib or trifluridine-tipiracil (investigator's choice), as third line of therapy. Each treatment will be administered using standard doses and schedules until progression of disease or unacceptable toxicity. This study will also evaluate the activity and efficacy of cetuximab re-introduction in combination with irinotecan as third line therapy in the concept of re-challenge for those patients that will be treated in second line with FOLFOX plus bevacizumab, having a RAS or BRAF mutant disease at the time of progression after FOLFIRI plus cetuximab first line treatment. A novel characteristic of this program is that the therapeutic algorithm will be defined at each treatment decision (first line, second line and third line) in a prospective fashion in each patient by liquid biopsy assessment of RAS/BRAF status

Official Title
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CAPRI 2 GOIM Study: Investigate the Efficacy and Safety of a Bio- Marker-driven Cetuximab-based Treatment Regimen Over 3 Treatment Lines in mCRC Patients With RAS/BRAF wt Tumors at Start of First Line

Conditions
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Metastatic Colorectal Adenocarcinoma

Intervention / Treatment
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* Drug: Cetuximab
* Drug: FOLFIRI
* Drug: FOLFOX regimen
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven diagnosis of colorectal adenocarcinoma Diagnosis of metastatic disease RAS and BRAF wild-type status of FFPE analysis of primary colorectal cancer and/or related metastasis Measurable disease according to Response Evaluation Criteria in Solid Tumors RECIST criteria, vers.1.1) Male or female patients ≥ 18 years of age ECOG Performance Status 0,1 Adequate bone marrow, liver and renal function assessed within 14 days before starting study treatment as defined by the following parameters: Bone marrow: Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L Hemoglobin (Hgb) ≥ 9 g/dL Platelets ≥ 100 x 109/L Liver function: • Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and ALT (SGPT) ≤ 2.5 x ULN, except in patients with tumor involvement of the liver who must have AST and ALT ≤ 5 x ULN Renal function: • Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min If female and of childbearing potential, have a negative result on a pregnancy test performed a maximum of 7 days before initiation of study treatment If female and of childbearing potential, or if male, agreement to use adequate contraception (e.g., abstinence, intrauterine device, oral contraceptive, or double-barrier method), during the study and until at least 3 months after last dose of study treatment administration, based on the judgment of the Investigator or a designated associate Signed informed consent obtained before screening. Exclusion Criteria: Any contraindication to the use of cetuximab, Irinotecan, 5-FU, oxaliplatin, folinic acid,bevacizumab, trifluridine-tipiracil, regorafenib Active uncontrolled infections, active disseminated intravascular coagulation or history of interstitial lung disease 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 Pregnancy (exclusion to be ascertained by a beta hCG test) Breastfeeding Fertile women (<2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception• Myocardial infarction, unstable angina pectoris, balloon angioplasty (PTCA) with or without stenting within the past 12 months before inclusion in the study, Grade III or IV heart failure (NYHA classification) Cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta blockers or digoxin Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study Previous chemotherapy for the colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before entering the study Participation in a clinical study or experimental drug treatment within 30 days prior to study inclusion or during participation in the study Known or clinically suspected brain metastases History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea Severe, non-healing wounds, ulcers or bone fractures Uncontrolled hypertension Marked proteinuria (nephrotic syndrome) Known DPD deficiency (specific screening not required) Known history of alcohol or drug abuse A significant concomitant disease which, in the investigating physician's opinion, rules out the patient's participation in the study Absent or restricted legal capacity

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Interventional Model Description: 3 treatment lines in mCRC patients with RAS/BRAF wt tumors at start of first line.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single arm<br>This is an open-label phase II study investigating the efficacy and safety of a bio-marker-driven cetuximab-based treatment regimen over 3 treatment lines in mCRC patients with RAS/BRAF wt tumors at start of first line. Based on dynamic and longitudinal liquid biopsy assessment of RAS/BRAF status, that will be prospectively performed before each line of treatment, mCRC patients will be treated with cetuximab in combination with chemotherapy throughout three lines of therapy, as follows: FOLFIRI plus cetuximab (first line); FOLFOX plus cetuximab (second line); irinotecan plus cetuximab (third line). If at progression after the first line or after the second line, the liquid biopsy assessment indicates RAS and or BRAF mutant status, patients will be treated with FOLFOX plus bevacizumab as second line of therapy, or with regorafenib or with trifluridine-tipiracil (investigator's choice) as third line therapy. | Drug: Cetuximab<br>* I LINE: - FOLFIRI + cetuximab FOLFIRI: 200 mg L-folinic acid with 180 mg/ m² irinotecan over 1.30 h IV infusion, followed by a 400 mg/ m² IV bolus of fluorouracil followed by 2400 mg/ m² fluorouracil IV infusion over 46 h every 14 days. Cetuximab: 400 mg/m2 initial dose (120-minute IV infusion on cycle 1 day 1), then 250 mg/m2 once weekly thereafter II LINE: - FOLFOX + cetuximab FOLFOX: 200 mg L-folinic acid given concurrently with 85 mg/ m² oxaliplatin over 2 h IV infusion, followed by a 400 mg/ m² IV bolus of fluorouracil followed by 2400 mg/ m² fluorouracil IV infusion over 46 h every 14 days. Cetuximab: as I line THIRD LINE: - Irinotecan + cetuximab Irinotecan: 180 mg/ m² irinotecan over 1.30 h, IV infusion every 2 weeks. Cetuximab: as I line<br>* Other names: Erbitux;Drug: FOLFIRI<br>* I LINE: - FOLFIRI + cetuximab FOLFIRI: 200 mg L-folinic acid given concurrently with 180 mg/ m² irinotecan over 1.30 h IV infusion, followed by a 400 mg/ m² IV bolus of fluorouracil followed by 2400 mg/ m² fluorouracil IV infusion over 46 h every 14 days. Cetuximab: 400 mg/m2 initial dose (120-minute IV infusion on cycle 1 day 1), then 250 mg/m2 once weekly thereafter<br>Drug: FOLFOX regimen<br>* II LINE: - FOLFOX + cetuximab FOLFOX: 200 mg L-folinic acid given concurrently with 85 mg/ m² oxaliplatin over 2 h IV infusion, followed by a 400 mg/ m² IV bolus of fluorouracil followed by 2400 mg/ m² fluorouracil IV infusion over 46 h every 14 days. Cetuximab: as I line<br>* Other names: FOLFOX;Drug: Irinotecan<br>* III LINE: - Irinotecan + cetuximab Irinotecan: 180 mg/ m² irinotecan over 1.30 h, IV infusion every 2 weeks. Cetuximab: as I line<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RR | Response rate (RR) for each line of treatment according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in patients with RAS/BRAF wild type (WT) mCRCregimen over 3 treatment lines in patients with RAS/BRAF wild type (WT) mCRC at start of first line therapy | up to 59 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | Progression free survival (PFS) for each line | from 8 weeks to 59 months (from the start of therapy until the first observation of disease progression or death due to any cause) | 
| OS | Overall Survival | up to 59 months | 
| AE | Safety: Adverse events graded according NCI CTCAE v 5.0 | from screening up to 59 months | 
| EORTC Core Quality of Life questionnaire EORTC QLQ C30 | The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) is designed to measure cancer patients' physical, psychological and social functions. The questionnaire is composed of multi-item scales and single items | At screening, for each line of therapy at Week 4, at Week 25 of treatment start and at progression | 
| DERMATOLOGY LIFE QUALITY INDEX (DLQI) | The DLQI consists of 10 questions concerning patients' perception of the impact of skin diseases on different aspects of their health-related quality of life over the last week. | at screening, for each line of therapy at Week 4, at Week 25 of treatment start and at progression |