| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with deficient MMR and/or MSI Metastatic Colorectal Cancer treated with nivolumab and ipilimumab |
|
| E.1.1.1 | Medical condition in easily understood language |
| patients with deficient MMR and/or MSI Metastatic Colorectal Cancer treated with nivolumab and ipilimumab |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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) |
|
| E.2.2 | Secondary objectives of the trial |
- 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 <6 months to the end of adjuvant chemotherapy in order for fluoropyrimidine and oxaliplatin to count as a prior therapy needed for entry.
8. Hematological status: absolute neutrophil count (ANC) ≥1.5x109/L; platelets ≥100x109/L; hemoglobin ≥9g/dL,
9. Adequate renal function: serum creatinine level <150µM,
10. Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alkaline phosphatase <5xULN, alanine aminotransferase (ALAT) and aspartame aminotransferase (ASAT) ≤3.0x ULN (≤5.0x ULN for patients with liver involvement of their cancer),
11. Registration in a National Health Care System (Couverture maladie universelle [CMU] included),
12. Mesurable disease per RECIST 1.1. Subjects with lesions in a previously irradiated field as the sole site of measurable disease will be permitted to enroll provided the lesion(s) have demonstrated clear progression and can be measured accurately,
13. Subject willing to comply to provide primary and metastatic tumor tissue (archival or fresh biopsy specimen), including possible pre-treatment biopsy, for PD-L1 expression analysis and other biomarker correlative studies,
14. At least one target lesion on CT or MRI less than 28 days before the first injection of treatment,
15. No contraindication to Iodine injection during CT.
|
|
| E.4 | Principal 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
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| DCR at 12 weeks by RECIST 1.1 and iRECIST |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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.
|
|
| E.5.2.1 | 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 Baseline, 3 months, 12 months
- Microbiome Analysis - sample at Baseline and 3 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Evaluation of DCR by 2 differents methods of radiological evaluation |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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