Standard Chemotherapy vs Immunotherapie in 2nd Line Treatment of MSI Colorectal Mestastatic Cancer

Study Overview
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Brief Summary
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Immune chekpoints (ICI) are evaluated in many digestive cancers. Certain types of cancer appear to be rather refractory to ICI such as colorectal cancers (CRC). However, the MSI CRC representing approximately 15% of the CRCs exhibits a high mutational load which generates many potentially immunogenic neoantigens. In addition, strong expression of PD-L1 was found in the MSI CRCs relative to the CRC (MSS) stages. Localized MSI CRCs have a better prognosis than MSS CRCs, probably due to immunogenic neoantigens associated with a CD8 + T-specific immune response. On the oher hand, in metastatic CRC (mCRC) things are different because i) the MSI frequency is only 4 to 7% and ii) the good prognosis conferred by the MSI status is controversial. Preliminary results suggest that patients with MSI mCRC are highly sensitive to ICI even chemoresistant tumors receiving several lines of chemotherapy. Recently, another anti-PD1 alone or in combination with an anti-CTLA4 (antigen associated with cytotoxic T-lymphocyte 4) was tested in the MSI CRCs and a selection of interesting results in heavily pretreated patients with a disease control rate of 56% for monotherapy and 81% for combinated therapy. Anti-PD1s now have marketing authorization for patients with melanoma and metastatic pulmonary carcinoma , Which are known to have a high level of mutations . ICIs appear to be as promising in MSI CRCs as in other tumors and therefore face the same major challenges. Avalumab is an anti-PD-L1 antibody recently tested in several different types of tumors with promising results and is currently being studied in phase III in gastric cancer. There is no data on the effectiveness of this ICI in the MSI mCRCs. In addition, only anti-PD1 was used in the MSI-mCRC and not the anti-PD-L1, and only in chemoresistance (3rd line or more). The main objective of the SAMCO study is to test the efficacy and tolerance of avelumab in the 2nd line of treatment in patients with a MSI mCRC progression after standard 1st line chemotherapy +/- targeted therapy.

Official Title
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Multicenter Randomized Phase II Study Comparing the Effectiveness and Tolerance of Avelumab Versus Standard 2nd Line Treatment Chemotherapy in Patients With Colorectal Metastatic Cancer With Microsatellite Instability (MSI)

Conditions
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MSI, Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: FOLFOX regimen
* Drug: FOLFIRI Protocol
* Drug: Avelumab
* Drug: Panitumumab
* Drug: Cetuximab
* Drug: Bevacizumab
* Drug: Aflibercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven colorectal adenocarcinoma with metastasis(es) non-resectable MSI-H determined by immunohistochemistry (loss of expression of MLH1, MSH2, MSH6 and/or PMS2) or by molecular biology At least one measurable target (primary tumor or metastasis) according to RECIST v1.1 Mutational status RAS and BRAF Age ≥ 18 OMS ≤ 2 Life expectancy < 3 months Patient failure (progression or unacceptable toxicity) of chemotherapy containing fluoropyrimidine (capecitabine or 5FU) +/- irinotecan +/- oxaliplatin with or without cetuximab, bevacizumab and panitumumab (patients in progression during or within 3 months after discontinuation of adjuvant chemotherapy are eligible) PNN > 1500/mm3, platelets > 100 000/mm3, Hb > 9 g/dL Total bilirubin < 25 µmol/L, ASAT < 5x LSN, ALAT < 5 x LSN, PT > 60%, , PAL<2.5 x LSN ( < 5 x LSN in case of hepatic metastasis) Creatinine clearance > 50 ml/min according to MDRD formula (≥ 30 ml/min according to the Cockcroft-Gault formula) Patient belonging to a social security scheme Patient information and signature of the informed consent Exclusion Criteria: Patient immediately eligible for a curative therapy (surgical and/or percutaneous) after discussion in CPR Patient treated with FOLFIRINOX or FOLFOXIRI in 1st line Cerebral metastasis Previous treatment with anti-PD1 or anti-PDL1 Autoimmune disease that might be aggravated during treatment with an immuno-stimulating agent (patients with type I diabetes, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible) Immunosuppressive long-term treatment (patients necessitating a corticotherapy are eligible if they are administered in doses < or = to the equivalent of 10 mg of prednisone daily, administration of steroids by a route resulting in minimal systemic exposure (local, intra-anal, intraocular or inhalation) are eligible). Transplant patients (including stem cell transplants), HIV positive or other immune deficiency syndromes Active infection by HBV or HCV Known severe hypersensitivity to monoclonal antibodies or history of anaphylactic shock, or uncontrolled asthma Any known specific contraindication or allergy to the treatments used in the study Persistence of toxicities related to 1st line chemotherapy grade > 2 (NCI-CTC v4.0) (except alopecia and neuropathy sequelae of oxaliplatin) Vaccination during the 4 weeks preceding the start of treatment Known deficit in DPD QT/QTc interval > 450 msec for men and > 470 msec for women K+ < LIN, Mg2+ < LIN, Ca2+ < LIN Following alterations in the 6 months prior to inclusion: myocardial infarction, angina, severe/unstable angina, coronary artery bypass surgery, congestive heart failure NYHA class II, III or IV, stroke or transient ischemic attack Any progressive pathology not stabilised over the past 6 months: hepatic failure, renal failure, respiratory failure Patient with interstitial pneumonitis or pulmonary fibrosis History of chronic diarrhea or inflammatory disease of the colon or rectum, or unresolved occlusion or sub-occlusion in symptomatic treatment History of malignant pathologies during the past 5 years except basocellular skin carcinoma or in situ cervical carcinoma, properly treated Patient already included in another clinical trial during treatment with an experimental molecule for L2 Lack of effective contraception in patients (men and/or women) of childbearing age, pregnant or breastfeeding women, women of childbearing age not having had a pregnancy test Persons deprived of liberty or under supervision Impossibility of undergoing medical monitoring during the trial for geographic, social or psychological reasons

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A Chemotherapy (standard treatment)<br>FOLFOX or FOLFIRI +/- targeted therapy | Drug: FOLFOX regimen<br>* A course of treatment every 14 days Oxaliplatin: 85 mg/m² IV over 2 hours Folinic acid: 400 mg/m² (or 200 mg/m² if Elvorine) IV over 2 hours 5FU bolus: 400 mg/m² IV bolus over 10 minutes in 100 ml 0.9% NaCl 5FU continuous: 2,400 mg/m² in NaCl 0.9% in IV over 46 hours<br>Drug: FOLFIRI Protocol<br>* A course of treatment every 14 days Irinotecan: 180 mg/m² IV over 1H30 Folinic acid: 400 mg/m² (or 200 mg/m² if Elvorine) IV over 2 hours 5FU bolus: 400 mg/m² IV bolus over 10 minutes in 100 ml 0.9% NaCl 5FU continuous: 2,400 mg/m² in NaCl 0.9% in IV over 46 hours<br>Drug: Panitumumab<br>* Administered at 6 mg/Kg<br>Drug: Cetuximab<br>* Administered at 500 mg/m²<br>Drug: Bevacizumab<br>* Administered at 5 mg/Kg<br>Drug: Aflibercept<br>* Administered at 4 mg/Kg<br>|
| Experimental: Arm B - Immunotherapy (experimental arm)<br>Avelumab | Drug: Avelumab<br>* A course of treatment every 14 days. Premedication obligatory with antihistamines and paracetamol (example: 25-50 mg diphenhydramine and 500-650 mg paracetamol) IV, approximately 30 to 60 minutes before each dose of avelumab. Then: Avelumab: 10 mg/kg IV in 1 hour diluted with 0.9% saline solution; alternatively a 0.45% saline solution can be used if needed<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) according to the investigator | Progression is defined as RECIST v1.1 criteria. Death is also considered as an event | up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Defined as death due to all causes | up to 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunotherapy, second line