Avelumab Combined With Cetuximab and Irinotecan for Treatment Refractory Metastatic Colorectal Microsatellite Stable Cancer

Study Overview
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Brief Summary
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Cancer immunotherapy with immunostimulatory antibodies targeting the CTLA-4 or PD-1/PD-L1 pathways has demonstrated its efficacy in variable proportions of cancer. For metastatic colorectal cancer (mCRC) it appeared that only the small subgroup of patients with MSI-H tumors (microsatellite instability-high phenotype) had a clinically meaningful response to the anti-PD-1- L1 antibodies. In the majority group of non-MSI-H CRC (90-95% of patients), current research expect that additional means would be able to render the tumor immunogenic (like MSI-H CRC) and increase the intratumoral immune infiltrate which is the prerequisite to observe a benefit from PD1-PD-L1 inhibitors. Combinations of immune checkpoint inhibitors and procedures that increase intratumoral immune responses, such as targeted therapy, are actively explored.

Official Title
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Avelumab Combined With Cetuximab and Irinotecan for Treatment Refractory Metastatic Colorectal Microsatellite Stable Cancer - A Proof of Concept, Open Label Non-randomized Phase IIa Study. The AVETUXIRI Trial

Conditions
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Colorectal Neoplasms, Malignant

Intervention / Treatment
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* Drug: Avelumab
* Drug: Cetuximab Injection
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 and over, Performance status: ECOG 0-1 Histologically proven metastatic colorectal adenocarcinoma, refractory to standard chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan) and anti-EGFR treatment (only for RAS WT tumor) Measurable disease (RECIST 1.1) Metastasis accessible for sequential biopsies Patient consent for metastasis biopsies in the study protocol BRAF V600E wild-type and MSS tumors Adequate normal organ and marrow function (see adequate section of the full protocol for definition) Life expectancy of at least 4 months Exclusion Criteria: Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy that are not indicated in the study protocol Systemic autoimmune disease, Chronic treatment with corticoids or other immunosuppressive treatment Clinically significant cardiac, lung or general disease despite optimal treatment Non-progressive disease following irinotecan-based treatment. For RAS WT, non-progressive disease following anti-EGFR treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Avelumab, Cetuximab, Irinotecan<br>Avelumab : administrated at a fixed dose of 10 mg/kg once every 2- week. Cetuximab: administered at 400 mg/m2 loading dose week 1, 250 mg/m2 from week 2 followed by 500 mg/m2 from week 3. Irinotecan: administrated every 2 weeks (180 mg/m2). | Drug: Avelumab<br>* Avelumab will be administered at a fixed dose of 10 mg/kg once every 2- week<br>Drug: Cetuximab Injection<br>* Cetuximab will be administered at 400 mg/m2 loading dose week 1, 250 mg/m2 from week 2 followed by 500 mg/m2 from week 3 and irinotecan administered every 2 weeks (180 mg/m2).<br>Drug: Irinotecan<br>* Irinotecan will be administered every 2 weeks (180 mg/m2)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response rate | The overall tumor response rate (ORR) defined as the proportion of all included patient with a confirmed best overall tumor response of PR or CR according to irRECIST 1.1 occuring until 19 weeks after study treatment start. | Up to 19 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Safety will be controlled | Up to 19 weeks |