Two Combination Treatment Regimens of Nivolumab and Ipilimumab in Patients With dMMR and / or MSI mCRC.

NCT04730544 | Active Not Recruiting Phase 2

• 1 other identifier: NIPISAFE G-106
• Study Type: interventional
• Target: 96
• Locations: 1 country
• Sites: 19

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.

Conditions

Colorectal Cancer Metastatic; MSI-H Colorectal Cancer

Outcome Measures

Primary Outcomes (2)

• Number of adverse events grade 3 or 4 at week 24 for two combination schemes.

  According to NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0

  At week 24

• Progression-free survival (PFS) 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.

  At week 24 for two combination schemes

Secondary Outcomes (9)

• 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 RECIST v1.1

  At week 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

Study Arms (2)

Experimental Arm A

EXPERIMENTAL

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).

Drug: Nivolumab 480mg + Ipilimumab

Control Arm B

ACTIVE COMPARATOR

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).

Drug: Nivolumab 240 mg + Ipilimumab

Interventions

Nivolumab 480mg + Ipilimumab DRUG

Nivolumab 480 mg q4w + Ipilimumab 1 mg/kg q6w

Also known as: Opdivo, Yervoy

Experimental Arm A

Nivolumab 240 mg + Ipilimumab DRUG

induction phase : Nivolumab 240 mg q3w + Ipilimumab 1 mg/kg q3w and then maintenance : Nivolumab 480 mg q4w

Also known as: Opdivo

Control Arm B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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,
• 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,
• 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: White blood cell \> 2000/µL; Neutrophils \> 1500/µL; Platelets \> 100.000/µL; Hemoglobin \> 9.0 g/dL;

You may not qualify if:

• 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,
• 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;
• 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.
• Prior allogeneic bone marrow transplantation or prior solid organ transplantation,

Sponsors & Collaborators

• GERCOR - Multidisciplinary Oncology Cooperative Group: lead
• Bristol-Myers Squibb: collaborator

Study Sites (19)

Institut Sainte Catherine

Avignon, France

Location

CHU Jean Minjoz

Besançon, France

Location

CHU Morvan

Brest, France

Location

Hôpital Henri Mondor

Créteil, France

Location

Centre Georges François Leclerc

Dijon, France

Location

Clinique Victor Hugo-Centre jean Bernard

Le Mans, France

Location

Hopital Franco-Britannique - Fondation Cognacq-Jay

Levallois-Perret, France

Location

CHRU Lille

Lille, France

Location

Centre Léon Bérard

Lyon, France

Location

Hôpital Privé Jean Mermoz

Lyon, France

Location

Hôpital de la Timone

Marseille, France

Location

ICM Val d'Aurelle

Montpellier, France

Location

CHU Nantes- Hôtel Dieu

Nantes, France

Location

Hôpital Saint Antoine

Paris, France

Location

Institut Mutualiste Montsouris

Paris, France

Location

CHU Bordeaux - Hôpital Haut Lévêque

Pessac, France

Location

CHU Poitiers

Poitiers, France

Location

Hôpital Robert Debré

Reims, France

Location

CHU Toulouse - IUCT Rangueil -Larrey

Toulouse, France

Location

MeSH Terms

Interventions

Nivolumab; Ipilimumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Romain COHEN, MD

  Saint Antoine Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 26, 2021
• First Posted: January 29, 2021
• Study Start: May 21, 2021
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2028
• Last Updated: June 13, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

FR (19)