Nivolumab and Ipilimumab in Anti-PD1-Resistant dMMR/MSI mCRC

NCT05310643 | Recruiting Phase 2

• 1 other identifier: NIPIRESCUE G-113
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 9

Brief Summary

NIPIRESCUE evaluates nivolumab and ipilimumab in patients with MSI/dMMR mCRC resistant to anti-PD1 monotherapy and previously treated with fluoropyrimidine, oxaliplatine, irinotecan, and anti- vascular endothelial growth factor (VEGF) or anti- epidermal growth factor receptor (EGFR) therapy.

Conditions

Metastatic Colorectal Cancer

Keywords

dMMR; MSI

Outcome Measures

Primary Outcomes (1)

• Objective response rate (ORR) by RECIST 1.1

  ORR defined as the number of patients with partial or complete response from the beginning of the treatment divided by the total of number of patients evaluable for the primary endpoint analysis.

  At week 24 (6 months)

Secondary Outcomes (5)

• Number of participants with treatment-related adverse events

  Up to 100 days after the last dose

• Disease control rate (DCR)

  At 24 week

• Duration of response

  From the time of the first response observed (PR or CR) until documented tumor progression or death, assessed up to 3 years from inclusion

• Progression-free survival (PFS)

  From beginning of treatment to progression or death due to any cause, whichever occurs first, assessed up to 3 years from inclusion

• Overall survival (OS)

  From beginning of treatment to death from any cause, assessed up to 3 years from inclusion

Study Arms (1)

Treatment phase

EXPERIMENTAL

Induction therapy: Nivolumab 240 mg + ipilimumab 1 mg/kg every 3 weeks for 4 dosing cycles (4 infusions of nivolumab and ipilimumab). Maintenance therapy: Nivolumab 480 mg every 4 weeks (21 infusions).

Drug: Nivolumab; Drug: Ipilimumab

Interventions

Nivolumab DRUG

Induction therapy with nivolumab 240 mg; 4 infusions, every 3 weeks. Maintenance therapy with nivolumab 480 mg; 21 infusions, every 4 weeks.

Also known as: Opdivo

Treatment phase

Ipilimumab DRUG

Induction therapy with ipilimumab 1 mg/kg; 4 infusions, every 3 weeks.

Also known as: Yervoy

Treatment phase

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, and 2,
• Histologically confirmed colorectal adenocarcinoma,
• Documented metastatic disease not suitable for complete surgical resection,
• 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
• Disease progression during, after, or patients who are intolerant or have contraindications to approved standard therapies for the metastatic disease, which must include at least: • Fluoropyrimidine, oxaliplatin, and irinotecan, • Anti-EGFR therapy if wild-type RAS, • Anti-VEGF therapy,
• 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,
• 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.
• For all patients, a new biopsy must be performed to obtain fresh anti-PD1 resistant tumor tissue prior to study treatment initiation,
• 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,
• Females of childbearing potential must have negative serum pregnancy test within 7 days before starting study treatment,
• Women of childbearing potential should use effective contraception during treatment and at least 5 months thereafter.
• Registration in a national health care system (Protection Universelle Maladie \[PUMa\] included)

You may not qualify if:

• Known brain metastases or leptomeningeal metastases,
• 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),
• Discontinuation of anti-PD1 treatment due to treatment-related adverse event (AE) grade \> 2 (NCI CTCAE v 5.0),
• 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,
• Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, radiotherapy, immunotherapy),
• Major surgical procedure within 4 weeks prior to initiation of study treatment,
• Patients receiving any investigational drug, biological, immunological therapy within the previous 21 days before study treatment,
• 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,
• NB : Exceptions to this criterion: - Inhaled or topical steroids, and adrenal replacement steroid doses \>10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease, - Systemic corticosteroids at physiologic doses not exceeding strictly 10 mg/day of prednisone or its equivalent,
• 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,
• 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,
• Known allergy/hypersensitivity to any component of study agents,

Sponsors & Collaborators

• GERCOR - Multidisciplinary Oncology Cooperative Group: lead

Study Sites (9)

CHU Jean Minjoz

Besançon, France

RECRUITING

Institute Bergonie

Bordeaux, France

RECRUITING

CHRU Lille

Lille, France

RECRUITING

CHU Dupuytren

Limoges, France

RECRUITING

Centre Léon Bérard

Lyon, France

RECRUITING

ICM Val d'Aurelle

Montpellier, France

RECRUITING

Centre Antoine Lacassagne

Nice, France

RECRUITING

Hôpital Saint Antoine

Paris, France

RECRUITING

CHU Poitiers

Poitiers, France

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

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

Central Study Contacts

Marie Line GARCIA LARNICOL, MD

CONTACT

01 40 29 85 00; marie-line.garcia-larnicol@gercor.com.fr

Study Design

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

Study Record Dates

• First Submitted: January 28, 2022
• First Posted: April 5, 2022
• Study Start: May 5, 2022
• Primary Completion: September 1, 2025
• Study Completion (Estimated): September 1, 2027
• Last Updated: July 1, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

FR (9)