dMMR and/or MSI metastatic colorectal cancer MedDRA version: 21.0 Level: PT Classification code 10052360 Term: Colorectal adenocarcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Opdivo (100 mg/10 ml)
Product Name: NIVOLUMAB
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: NIVOLUMAB
CAS Number: 946414-94-4
Other descriptive name: NIVO
Sponsors
GERCOR
Eligibility
Sex/Gender
All
Inclusion criteria
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, or 2, 4. Histologically or cytologically confirmed colorectal adenocarcinoma, 5. Documented advanced or 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 v1.1 and feasibility of repeated radiological assessments. Participants 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, 7. dMMR and/or MSI tumor status defined by: - Loss of MMR protein expression using immunohistochemistry with two (anti-MLH1 and anti-MSH2 or anti-MSH6, and anti-PMS2) or four (anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2) antibodies, - and/or = two instable markers by pentaplex polymerase chain reaction (BAT-25, BAT-26, NR-21, NR-24, and NR-27), 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. No or one prior line of systemic treatment for metastatic disease: - No prior systemic treatment; if patient received neoadjuvant/adjuvant therapy this therapy should be completed > 6 months prior the diagnosis of metastatic or recurrent disease is made, - Maximum one prior line of systemic treatment; if patient received one prior line of systemic therapy in the metastatic setting and experienced progression or patient received neoadjuvant/adjuvant therapy and experienced recurrence within = 6 months after completion of therapy, 9. Availability of a representative tumor specimen for exploratory translational research; tumor tissue specimens, either formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections (minimum of 30 positively charged slides) from primary or metastatic site must be submitted to the central laboratory, 10. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment: - Hematological status: o White blood cell > 2000/µL; o Neutrophils > 1500/µL; o Platelets > 100.000/µL; o Hemoglobin > 9.0 g/dL; - Adequate renal function: o Serum creatinine level < 150 µM; - Adequate liver function: o Serum bilirubin = 1.5 x upper normal limit (ULN); o Alkaline phosphatase (ALP) = 3 x ULN; o Alanine aminotransferase (ALT) = 3.0 x ULN ; o Aspartame aminotransferase (AST) = 3.0 x ULN; o Prothrombin time (PT)/International normalized ratio (INR) and partial PT (PTT) = 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, 11. Females of childbearing potential must have negative serum pregnancy test within 7 days before starting study treatment, 12. Women of childbearing potential should use effective contraception during treatment and 5 months thereafter. Males should use condoms during treatment and 7 months thereafter, 13. Registration in a national health care system (Protection Universelle Malad
Exclusion criteria
Exclusion criteria: 1. Known brain metastases or leptomeningeal metastases, 2. Persistence of toxicities related to prior chemotherapies grade > 1 (NCI CTCAE v5.0; except alopecia, fatigue, or peripheral sensory neuropathy, which can be grade 2), 3. Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, radiotherapy, immunotherapy), 4. Major surgical procedure within 4 weeks prior to initiation of study treatment, 5. Prior treatment with an anti-PD1, anti-PD-L1, anti-PD-L2, 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, 6. Patients receiving any investigational drug, biological, immunological therapy within the previous 28 days before study treatment, 7. Impossibility of submitting to the medical follow-up of the study for geographical, social or psychic reasons, 8. 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, 9. History of interstitial lung disease or pneumonitis, 10. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses >10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease, 11. 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; 12. 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. 13. Prior allogeneic bone marrow transplantation or prior solid organ transplantation, 14. 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, 15. Known allergy/hypersensitivity to any component of study agents, 16. Administration of a (attenuated) live vaccine within 28 days of planned start of study therapy of known need for this vaccine during treatment, 17. Patient on tutelage or guardianship
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: -To assess the safety (grade 3 or 4 AEs) profile according to NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 of two different combination schemes of nivolumab plus ipilimumab during the first 24 weeks of treatment, - To assess PFS at week 24 for two combination schemes. ;Secondary Objective: - To assess the safety (AEs, treatment-related AEs and immune-related AEs [iAEs]) and tolerability of two combination schemes, - To assess ORR of two combination schemes at weeks 24 and 48, and at 2 years (RECIST v1.1), - To assess PFS of two combination schemes at week 48 and at 2 years (RECIST v1.1), - To assess PFS of two combination schemes at weeks 24 and 48, and at 2 years (iRECIST), - To assess OS of two combination schemes at week 48 and at 2 years (RECIST v1.1), - To evaluate the percentage of patients who received immune modulating concomitant medication (e.g., corticosteroids, infliximab, mycophenolate mofetil), - To evaluate the percentage of patients who received hormonal replacement therapy for immune-related endocrine toxicities, - To assess median time to onset and median time to resolution (grade 3-4) of serious AEs (SAEs) and TRAEs, - To evaluate changes in HRQoL and patient-reported outcomes (EORTC QLQ-C30 and PRO-CTCAE). ;Primary end point(s): - Grade 3 or 4 AEs during the first 24 weeks (NCI CTCAE v5.0), - PFS at week 24 (RECIST v1.1). ;Timepoint(s) of evaluation of this end point: 24 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - AEs (NCI CTCAE v5.0), - Treatment-related AEs and iAEs, - ORR - PFS - PFS and ORR - OS - Percentage of patients who received immune modulating concomitant medication (e.g., corticosteroids, infliximab, mycophenolate mofetil), - Percentage of patients who received hormonal replacement therapy for immune-related endocrine toxicities, - Median time to onset, median time to resolution (grade 3-4) of SAEs and TRAEs, - HRQoL (EORTC QLQ-C30 and NCI-PRO-CTCAE). ;Timepoint(s) of evaluation of this end point: - AEs : at every visit during treatment and at 100 days after treatment ends(NCI-CTCAE version 5.0) - ORR: 24 weeks; 48 weeks and 2 years(RECIST v1.1) - PFS: 24 weeks; 48 weeks and 2 years(RECIST v1.1) - OS: weeks 24 and 48, and at 2 years (RECIST v1.1), - until 108 weeks of the last patient randomized - until 28 days after the last dose | — |
Countries
France
Contacts
Public ContactRegulatory Affairs
GERCOR
Outcome results
None listed