Analysis of the Efficacy and Safety of Two Combination Treatment Regimens of Nivolumab and Ipilimumab in Patients With dMMR and / or MSI Metastatic Colorectal Cancer: A GERCOR Open-label, Randomized, Non-comparative, Two-stage Phase II Trial (NIPISAFE).
Overview
- Phase
- Phase 2
- Status
- Active, not recruiting
- Sponsor
- GERCOR - Multidisciplinary Oncology Cooperative Group
- Enrollment
- 96
- Locations
- 19
- Primary Endpoint
- Number of adverse events grade 3 or 4 at week 24 for two combination schemes.
Overview
Brief Summary
NIPISAFE is open-label, phase II study to identify a combination scheme of nivolumab and ipilimumab with a high level of clinical activity, but with a lower toxicity in MSI/dMMR metastatic colorectal cancer patients.
Detailed Description
This is a randomized non-comparative two-stage phase II study with a co-primary endpoint (toxicity and progression-free survival) to evaluate two different schemes of the nivolumab and ipilimumab combination in terms of the toxicity and efficacy in MSI/dMMR metastatic colorectal cancer patients in order to identify a combination scheme with a higher level of clinical activity and a lower toxicity.
Patients will be randomized in a 2:1 ratio to receive one of the following treatments:
Experimental ARM A: Nivolumab 480 mg every 4 weeks and ipilimumab 1 mg/kg every 6 weeks for a total of 24 months of treatment Control ARM B: Nivolumab 240 mg and ipilimumab 1 mg/kg every 3 weeks for 4 dosing cycles.
Maintenance of 96 weeks: Nivolumab 480 mg every 4 weeks for 24 dosing cycles for a total of 24 months of treatment (or less in case of RECIST PD or limiting toxicity, whichever occurs first).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Signed and dated patient informed consent form and willingness to comply with all study procedures and availability for the study duration,
- •Age ≥ 18 years,
- •Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1, or 2,
- •Histologically or cytologically confirmed colorectal adenocarcinoma,
- •Documented advanced or metastatic disease not suitable for complete surgical resection,
- •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,
- •Deficient mismatch repair (dMMR) and/or Microsatellite instability (MSI) tumor status defined by:
- •Loss of MMR protein expression using immunohistochemistry with four (anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2) antibodies Nota Bene (NB): if loss of only one protein, necessary to have Polymerase Chain Reaction (PCR)
- •and/or ≥ two instable markers by pentaplex polymerase chain reaction (BAT-25, BAT-26, NR-21, NR-24, and NR-27), NB: if two instable markers in the pentaplex panel, it is required to present confirmation of the dMMR status by immunohistochemistry or a comparison of the tumor PCR test with matched normal tissue.
- •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),
Exclusion Criteria
- •Known brain metastases or leptomeningeal metastases,
- •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),
- •Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, radiotherapy, immunotherapy),
- •Major surgical procedure within 4 weeks prior to initiation of study treatment,
- •Prior treatment with an anti-PD1, anti-programmed death (PD)-L1, anti-PD-L2, anti-cytotoxic T-lymphocyte-associated (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,
- •Patients receiving any investigational drug, biological, immunological therapy within the previous 28 days before study treatment,
- •Impossibility of submitting to the medical follow-up of the study for geographical, social or psychic reasons,
- •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,
- •History of interstitial lung disease or pneumonitis,
- •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,
Arms & Interventions
Experimental Arm A
Treatment for 108 weeks (one cycle = 12 weeks; 9 cycles):
Nivolumab 480 mg every 4 weeks (27 infusions) and ipilimumab 1 mg/kg every 6 weeks (18 infusions) for a total of 24 months of treatment (or less in case of RECIST progression (PD) or limiting toxicity, whichever occurs first).
Intervention: Nivolumab 480mg + Ipilimumab (Drug)
Control Arm B
Induction of 12 weeks (one cycle = 3 weeks; 4 cycles):
Nivolumab 240 mg and ipilimumab 1 mg/kg every 3 weeks for 4 dosing cycles (4 infusions of nivolumab and ipilimumab), Maintenance of 96 weeks (one cycle = 4 weeks; 24 cycles): Nivolumab 480 mg every 4 weeks for 24 dosing cycles (24 infusions) for a total of 24 months of treatment (or less in case of RECIST progression (PD) or limiting toxicity, whichever occurs first).
Intervention: Nivolumab 240 mg + Ipilimumab (Drug)
Outcomes
Primary Outcomes
Number of adverse events grade 3 or 4 at week 24 for two combination schemes.
Time Frame: At week 24
According to NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
Progression-free survival (PFS) at week 24 for two combination schemes.
Time Frame: At week 24 for two combination schemes
PFS is defined as time from inclusion to the first documented PD determined by the Investigator assessment in accordance to RECIST v1.1 or death due to any cause, whichever occurs first. Alive patients without progression will be censored at the last tumor assessment, either during study treatment period or during follow-up period.
Secondary Outcomes
- Number of participants with treatment-related adverse events(Assessed up to 80 months)
- Overall response rate (ORR)(At weeks 24 and 48, and at 2 years)
- PFS of two combination schemes according to Immune Response Evaluation Criteria In Solid Tumors (iRECIST)(At weeks 24 and 48, and at 2 years)
- Overall survival (OS) of two combination schemes (RECIST v1.1),(At week 48 and at 2 years)
- Percentage of patients who received immune modulating concomitant medication(Until the study treatment end - 48 months)
- Percentage of patients who received hormonal replacement therapy for immune-related endocrine toxicities(Until the study treatment end - 48 months)
- Median time to onset, median time to resolution (grade 3-4) of serious adverse event (SAEs) and Treatment-related adverse events (TRAEs),(Up to 80 months)
- PFS of two combination schemes according to RECIST v1.1(At week 48 and at 2 years)
- Time to Health-related quality of life (HRQoL) score definitive deterioration (TUDD)(assessed up 48 months)