Irinotecan/Cetuximab Followed by XELOX/Cetuximab vs the Reverse Sequence in Metastatic CRC

Study Overview
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Brief Summary
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This phase II study will evaluate which is the best way to administer cetuximab after recurrence in 1st line irinotecan+bevacizumab based treatment and to obtain results of the efficacy of the oxaliplatin+cetuximab combination as 2nd line treatment.

Detailed Description
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Because of the recent advances in the field of systemic chemotherapy for mCRC, like irinotecan, oxaliplatin, capecitabine, and targeted agents (Cetuximab, Bevacizumab) mCRC patients have an overall survival that in some cases reaches 25 months.Irinotecan is an inhibitor of the DNA enzyme topoisomerase I, with use in clinical practice for the last 10 years.In a phase II study with mCRC patients resistant to irinotecan based therapy the combination of irinotecan and Cetuximab (an IgG1 anti-EGFR antibody) yielded a response rate of 22.5%.Capecitabine was shown to have improved tolerability and response rate compared with bolus 5-FU, with comparable time to progression and survival.Oxaliplatin has been approved by the FDA for 2nd line treatment in the metastatic CRC setting as a number of trials have shown promising data for response rates, disease stabilization rates,median progression free survival (PFS) and overall survival (OS).KRAS is a predictive marker for clinical benefit from EGFR-based antibody treatment. KRAS is the first molecular marker for selection of a targeted therapy in combination with a standard chemotherapy regimen. Patients with KRAS wild-type tumors have a strong benefit from the administration of cetuximab with better PFS and objective responses.

Official Title
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A Parallel Phase II Study With Irinotecan/Cetuximab (Until PD) Followed by XELOX/Cetuximab (Until PD) vs the Reverse Sequence in Metastatic CRC With Previous Benefit on Irinotecan/Bevacizumab Based Therapy

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Irinotecan
* Drug: Capecitabine
* Drug: Cetuximab
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed locally advanced or metastatic colorectal cancer Measurable or evaluable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) ECOG performance status ≤ 2 Age 18 - 72 years Patients who have had a CR, PR or SD after 1st line therapy based on Irinotecan+Bevacizumab Paraffin block from the primary tumor in order to perform tha mutational analysis of the KRAS gene Adequate liver (Bilirubin ≤ 1.5 upper normal limit, SGOT/SGPT ≤ 4 upper normal limit, ALP ≤ 2.5 upper normal limit),renal (Creatinine ≤ 1.5 upper normal limit) and bone marrow (ANC ≥ 1,500/mm3, PLT ≥100,000/mm3) function Patients must be able to understand the nature of this study Written informed consent Exclusion Criteria: Presence of central nervous system or brain metastases Pregnant or lactating woman Life expectancy < 3 months Previous radiotherapy within the last 4 weeks or > 25% of bone marrow or in the field where the treatment target is located Peripheral neuropathy grade ≥2 Known hypersensitivity to Erbitux Metastatic infiltration of the liver >50% Patients with chronic diarrhea (at least for 3 months) or partial bowel obstruction or total colectomy Active infection Second primary malignancy, except for non-melanoma skin cancer and in situ cervical cancer Psychiatric illness or social situation that would preclude study compliance

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 72 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Irinotecan+Erbitux -> XELOX+Erbitux | Drug: Irinotecan<br>* Irinotecan (IV) 150 mg/m2 on day 1 every two weeks until progression<br>* Other names: Campto;Drug: Capecitabine<br>* Capecitabine (p.o) 2000 mg/m2 (1000 mg/m2 x 2) on day 1-7 every 2 weeks until progression<br>* Other names: Xeloda;Drug: Cetuximab<br>* Cetuximab(IV) 500 mg/m2 on day 1 every two weeks until progression<br>* Other names: Erbitux;Drug: Oxaliplatin<br>* Oxaliplatin (I.V) 85 mg/m2 on day 1 every two weeks until progression<br>* Other names: LoHP;|
| Experimental: 2<br>XELOX+Erbitux ->Irinotecan+Erbitux | Drug: Irinotecan<br>* Irinotecan (IV) 150 mg/m2 on day 1 every two weeks until progression<br>* Other names: Campto;Drug: Capecitabine<br>* Capecitabine (p.o) 2000 mg/m2 (1000 mg/m2 x 2) on day 1-7 every 2 weeks until progression<br>* Other names: Xeloda;Drug: Cetuximab<br>* Cetuximab(IV) 500 mg/m2 on day 1 every two weeks until progression<br>* Other names: Erbitux;Drug: Oxaliplatin<br>* Oxaliplatin (I.V) 85 mg/m2 on day 1 every two weeks until progression<br>* Other names: LoHP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time To Progression |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate |  | Objective responses confirmed by CT or MRI (on 3rd and 6th cycle) | 
| Toxicity profile |  | Toxicity assessment on each chemotherapy cycle | 
| 1 year Survival and Overall Survival |  | Probability of 1-year survival (%) | 
| Correlation of the molecular characteristics of the tumor with the clinical outcome |  | Corralation after the end of chemotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic colorectal cancer, Second line, Irinotecan, Cetuximab (Erbitux), Capecitabine (Xeloda)