Patients with deficient MMR and/or MSI Metastatic Colorectal Cancer treated with nivolumab and ipilimumab MedDRA version: 20.0 Level: LLT Classification code 10052362 Term: Metastatic colorectal cancer System Organ Class: 100000004864
Conditions
Interventions
Trade Name: YERVOY
Product Name: Ipilimumab
Pharmaceutical Form: Solution for infusion
Trade Name: OPDIVO
Product Name: nivolumab
Pharmaceutical Form: Solution for infusion
Sponsors
GERCOR
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed and dated informed consent, and willing and able to comply with protocol requirements, 2. Histologically proven metastatic adenocarcinoma of the colon and/or rectum, 3. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study, 4. Microsatellite instability expression (Immunohistochemistry and or polymerase chain reaction [PCR]). Agreement of the SPONSOR (GERCOR) will be mandatory to include a patient. GERCOR will check every patient’s file to confirm the dMMR/ MSI-H patient’s status before inclusion (an anonymized fax or scan document in electronic case report form [e-CRF]). The confirmation of a patient’s allocation will be immediately sent by mail to the investigator. Tumor MMR and/or MSI will be assessed per local guidelines: by immunohistochemistry with two (anti-MLH1 and anti-MSH2) or four antibodies (anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2) and/or by polymerase chain reaction (PCR) by the investigators prior to screening. In immunohistochemistry, the extinction of MLH1 (+/-PMS2), or MSH2 (+/- MSH6) or PMS2 alone is necessary for inclusion (dMMR). For PCR, pentaplex panel (BAT25, BAT26, NR21, NR24, and NR27) is recommended. Tumor samples with instability in 0, 1, or =2 markers are identified as microsatellite stable, MSI-low, and MSI-H, respectively. Only patients with tumor samples presenting instability in =2 markers (MSI-H) will be included in the study. 5. Age =18 years, 6. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, 7. Progression during or after treatment, or intolerance to =1 line treatment(s), including at least A fluoropyrimidine, and oxaliplatin or irinotecan, Subjects who received fluoropyrimidines and oxaliplatin in an adjuvant setting should have metastatic relapse within 6 months of completion of adjuvant therapy or =65 years) yes F.1.3.1 Number of subjects for this age range 19
Exclusion criteria
Exclusion criteria: 1. Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy), 2. Treatment with any investigational medicinal product within 28 days prior to study entry, 3. Other serious and uncontrolled non-malignant disease (including active infection), 4. Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for >5 years, 5. Pregnant or breastfeeding women, 6. History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis, Note: History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. Note: Controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible. 7. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest imaging, 8. Human immunodeficiency virus (HIV), 9. Active hepatitis B virus (HBV, defined as having a positive hepatitis B surface antigen [HBsAg] test prior to randomization) or hepatitis C virus (HCV), Note: Patients with past HBV infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen antibody test) are eligible. Note: Patients positive for HCV antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA). 10. Administration of a live, attenuated vaccine within four weeks prior to start of maintenance treatment or anticipation that such a live attenuated vaccine will be required during the remainder of the study, 11. Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents, 12. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within four weeks or five half-lives of the drug, whichever is shorter, prior to start of maintenance treatment. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to start of maintenance treatment, or requirement for systemic immunosuppressive medications during the remainder of the study. Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Note: Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the Medical Monitor
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Secondary Objective: - PFS by iRECIST and PFS by RECIST1.1, - ORR by iRECIST and ORR by RECIST1.1, - OS and Safety ( [NCI CTCAE] v4.0), - Inclusion of DWI MRI and texture analysis in the portfolio of evaluation is questionable. - Lynch versus sporadic (with definition of Lynch and sporadic, with immunochemistry of MMR proteins, and in case of loss of Hmlh1 protein, BRAF status and methylation status); and /or in case of knowledge of somatic mutation, - BRAF mutated versus BRAF wild-type, - PD1 and PDL1 expression: Expression =1% and 5% versus no expression, - CD3, CD8, FOXP3: Expression versus no expression, - Investigation whether immune checkpoints expression (PD-L1, PD-L2, PD-1, CTLA-4, TIM-3, LAG-3, GAL9, and IDO) in tumor samples using no string technology and immunochemistry could be predictive of patients’ response to these molecules.;Main Objective: Comparison of DCR at 12 weeks by RECIST and iRECIST (Central Review) Evaluation of RECIST and iRECIST will be done in each center in order to choose the optimal therapy (Assessment by Investigators). A centralized evaluation of RECIST and iRECIST, will be organized in Saint-Antoine (Pr Yves Menu: central review);Primary end point(s): DCR at 12 weeks by RECIST 1.1 and iRECIST;Timepoint(s) of evaluation of this end point: 12 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - PFS by iRECIST and PFS by RECIST1.1, - ORR by iRECIST and ORR by RECIST1.1, - OS and Safety (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.0), - Inclusion of DWI MRI and texture analysis in the portfolio of evaluation is questionable. These examinations could probably be easily acquired during the same patient’s stay in the imaging facility, however they require local acceptance and organization. These can be an optional proposal for some centers in this study, but are obligatory for patients included at Saint-Antoine Hospital, - Lynch versus sporadic (with definition of Lynch and sporadic, with immunochemistry of MMR proteins, and in case of loss of Hmlh1 protein, BRAF status and methylation status); and /or in case of knowledge of somatic mutation, - BRAF mutated versus BRAF wild-type, - PD1 and PDL1 expression: Expression =1% and 5% versus no expression, - CD3, CD8, FOXP3: Expression versus no expression, - Investigation whether immune checkpoints expression (PD-L1, PD-L2, PD-1, CTLA-4, TIM-3, LAG-3, GAL9, and IDO) in tumor samples using no string technology and immunochemistry could be predictive of patients’ response to these molecules. ;Timepoint(s) of evaluation of this end point: - PFS is defined as time from date of first dose of study treatment to date of first documented PD or death due to any cause determined by the Investigator assessment in accordance to RECIST 1.1 or iRECIST - OS is defined as the time between the date of the first dose of study treatment and the death date. - Patients will be assessed for AEs every visits and evaluations, PD, and treatment discontinuation - Tumor tissue from the primary tumor and/or metastases obtained at the time of the initial diagnosis - Blood samples at baseline for MSI and ctDNA - Assessment of antigen-specific CD4 T cell immunity as a biomarker of anti-PD1/PDL1 immunotherapy in mismatch repair deficient cancers - samples at Ba | — |
Countries
France
Contacts
Public ContactRegualtory affairs
GERCOR
Outcome results
None listed