| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| dMMR and/or MSI metastatic colorectal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| metastatic colorectal cancer |
|
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052358 |
| E.1.2 | Term | Colorectal cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To assess objective response rates (ORR) at 24 weeks (6 months) using the RECIST 1.1 criteria |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability
- To assess ORR at 24 weeks by iRECIST,
- To assess disease control rate at 12 and 24 weeks by RECIST 1.1 and iRECIST
- To assess duration of response
- To assess progression-free survival by RECIST 1.1 and iRECIST
- To assess overall survival
Exploratory:
- To assess antigen-specific CD4+ T cell immunity as a biomarker of immunotherapy
- To identify immunological and angiogenesis parameters that modulate the specific CD4+ Th1 cells responses
- To analyze ctDNA evolution during treatment
- To centrally confirm the MSI/dMMR status from archive tumor specimens
- To identify circulating tumor biomarkers associated with clinical activity
- To evaluate the efficacy of nivolumab and ipilimumab according to selected tumor tissue biomarkers from archival tumor tissue and fresh biopsy specimen collected at inclusion using NGS and “single-cell” RNA sequencing
-To analyze the gut microbiota composition associated with clinical activity |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated patient informed consent form and willingness to comply with all study procedures and availability for the study duration,
2. Age ≥ 18 years,
3. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1,
4. Histologically confirmed colorectal adenocarcinoma,
5. Documented metastatic disease not suitable for complete surgical resection,
6. At least one measurable lesion as assessed by CT-scan or magnetic resonance imaging (MRI) according to RECIST 1.1 and feasibility of repeated radiological assessments,
7. dMMR and/or MSI tumor status defined by:
- Loss of MMR protein expression using immunohistochemistry with four (anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2) antibodies,
- and/or ≥ two unstable markers by pentaplex polymerase chain reaction (BAT-25, BAT-26, NR-21, NR-24, and NR-27),
NB: In case of loss of expression of only one MMR protein immunohistochemistry, it is necessary to confirm the tumor is MSI using pentaplex PCR.
NB: In cases with two unstable markers, comparison with matching normal tissue is required.
NB: Agreement of the Sponsor (GERCOR) is mandatory to include the patient (the patient’s file will be verified to confirm MSI/dMMR status before inclusion [an anonymized fax] and confirmation of a patient’s allocation will be sent by mail to the Investigator within 24h).
8. Disease progression per iRECIST criteria (i.e., iCPD: immune confirmed PD) during monotherapy with anti-PD1 monoclonal antibody or less than 6 months after the discontinuation of anti-PD1 monoclonal antibody and without any other treatment (immunotherapy, chemotherapy, radiotherapy, surgery…) administrated during this interval,
9. For all patients, a new biopsy must be performed to obtain fresh anti-PD1 resistant tumor tissue prior to study treatment initiation,
10. For all patients, archival formalin-fixed paraffin-embedded tissue (FFPE) blocks and/or FFPE unstained slides (minimum of 30 positively charged slides representative of tumor tissue and non-tumor adjacent prior to anti-PD1 therapy (i.e., primary or metastatic site naïve of immunotherapy) must be submitted to the central laboratory,
11. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 7 days prior inclusion :
- Adequate hematological status:
White blood cell > 2000/µL;
Neutrophils > 1500/µL;
Platelets > 100.000/µL;
Hemoglobin > 10.0 g/dL;
- Adequate renal function:
Serum creatinine level < 120 µM;
Clearance > 50 ml/min (Modification of the Diet in Renal Disease [MDRD] or Cockcroft and Gault,
- Adequate liver function:
Serum bilirubin ≤ 1.5 x upper normal limit (ULN);
Alkaline phosphatase (ALP) ≤ 3.0 x ULN;
Alanine aminotransferase (ALT) ≤ 3.0 x ULN;
Aspartate aminotransferase (AST) ≤ 3.0 x ULN;
- Hemostasis :
Prothrombin time (PT)/International normalized ratio (INR) and activated partial PT (aPTT) ≤ 1.5 x ULN unless participants are receiving anticoagulant therapy and their INR is stable and within the recommended range for the desired level of anticoagulation,
12. Females of childbearing potential must have negative serum pregnancy test within 7 days before starting study treatment,
13. Women of childbearing potential should use effective contraception during treatment and at least 5 months thereafter.
14. Registration in a national health care system (Protection Universelle Maladie [PUMa] included)
|
|
| E.4 | Principal exclusion criteria |
1. Known brain metastases or leptomeningeal metastases,
2. Persistence of toxicities related to prior treatments (chemotherapies or anti-P1 therapies) grade > 1 (NCI CTCAE v 5.0; except dysthyroidism, adrenal gland deficiency, alopecia, fatigue or oxaliplatin-induced peripheral sensory neuropathy which can be ≥ grade 2),
3. Discontinuation of anti-PD1 treatment due to treatment-related adverse event (AE) grade > 2 (NCI CTCAE v 5.0),
4. Anticancer treatment after PD with anti-PD1 monotherapy,
5. Prior treatment with an anti-LAG-3, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents, except anti-PD1 antibodies,
6. Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, radiotherapy, immunotherapy),
7. Major surgical procedure within 4 weeks prior to initiation of study treatment,
8. Patients receiving any investigational drug, biological, immunological therapy within the previous 21 days before study treatment,
9. Patients with an active, known, or suspected autoimmune disease. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to be enrolled,
10. History of interstitial lung disease or pneumonitis,
11. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of inclusion. Inhaled or topical steroids, and adrenal replacement steroid doses >10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease,
12. Prior malignancy active within the previous 3 years, except for:
- Locally curable cancers that have been apparently cured (e.g. squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast),
- Lynch syndrome-related non-colorectal cancer in complete remission for > 1 year,
13. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test prior to randomization) virus (HBV) or hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection. 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. Patients positive for HCV antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid.
14. Prior allogeneic bone marrow transplantation or prior solid organ transplantation,
15. Any serious or uncontrolled medical disorder that, in the opinion of Investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the participant to receive protocol therapy, or interfere with the interpretation of study results,
16. Known allergy/hypersensitivity to any component of study agents,
17. Administration of a (attenuated) live vaccine within 28 days of planned start of study therapy of known need for this vaccine during treatment,
18. Patient under a legal protection regime (guardianship, curatorship, judicial safeguard) or administrative decision or incapable of giving his/her consent,
19. Impossibility of submitting to the medical follow-up of the study for geographical, social, or psychiatric illness.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rates (ORR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
24 weeks (6 months) from the beginning of the treatment evaluated by RECIST 1.1
|
|
| E.5.2 | Secondary end point(s) |
- AEs (NCI Common Terminology Criteria for Adverse Event [NCI CTCAE] v 5.0),
- ORR at 24 weeks by iRECIST,
- DCR at 24 weeks by RECIST 1.1 and iRECIST,
- Duration of response,
- PFS by RECIST 1.1 and iRECIST,
- OS.
Exploratory :
- Biopsy : Baseline
- Blood Samples
- Microbiota |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- AEs at every visit during treatment and until 100 days after last treatment (NCI-CTCAE version 5.0)
- ORR at 24 weeks by iRECIST,
- DCR at 24 weeks by RECIST 1.1 and iRECIST,
- Duration of response, is measured from the time of the first response observed (PR or CR) until documented tumor progression or death (max 5 years)
- PFS by RECIST 1.1 and iRECIST is defined as time from beginning of treatment to progression or death due to any cause, whichever occurs first (max 5years)
- OS is defined as the time between beginning of treatment and death from any cause. Survival data will be censored at the last follow-up (max 5 years)
Exploratory :
- Biopsy : Baseline
- Blood Samples for immunomonitoring, plasma and ctDNA : Baseline, Week 3 and week 6
- Microbiota : Baseline and week 6 |
|
| 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 | Yes |
| 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 |
| Ancillary studies (tumor/biopsy, bllod samples for PBMC, plasma, ctDNA, microbiota) |
|
| 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 | 6 |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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