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Colorectal Cancer MetastaticPhase 2NIPISAFENCT04730544

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

A Phase 2 study testing Nivolumab 480mg + Ipilimumab and Nivolumab 240 mg + Ipilimumab in people with Colorectal Cancer Metastatic and MSI-H Colorectal Cancer, run by GERCOR - Multidisciplinary Oncology Cooperative Group at 19 sites in France.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Nivolumab 480mg + Ipilimumab and Nivolumab 240 mg + Ipilimumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
96 participants
Where
19 sitesFrance
Study dates
21 May 2021to Apr 2028
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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,
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  • 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),
  • 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;
  • Adequate renal function: Serum creatinine level < 150 µM;
  • Adequate liver function: Serum bilirubin ≤ 1.5 x upper normal limit (ULN); Alkaline phosphatase (ALP) ≤ 3 x ULN; Alanine aminotransferase (ALT) ≤ 3.0 x ULN ; Aspartame aminotransferase (AST) ≤ 3.0 x ULN; 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,
  • 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 5 months thereafter. Males should use condoms during treatment and 7 months thereafter,
  • Registration in a national health care system ( "Protection Universelle Maladie" (PUMa) included).

Who cannot join

  • 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,
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  • 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,
  • 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,
  • Administration of a (attenuated) live vaccine within 28 days of planned start of study therapy of known need for this vaccine during treatment,
  • Patient on tutelage or guardianship or under the protection of justice.

Trial locations and contacts

19 sites in 1 country.

19 sites in 1 country

France19 sites

  • Institut Sainte Catherine

    Avignon

  • CHU Jean Minjoz

    Besançon

  • CHU Morvan

    Brest

  • Hôpital Henri Mondor

    Créteil

  • Centre Georges François Leclerc

    Dijon

  • Clinique Victor Hugo-Centre jean Bernard

    Le Mans

  • Hopital Franco-Britannique - Fondation Cognacq-Jay

    Levallois-Perret

  • CHRU Lille

    Lille

  • Centre Léon Bérard

    Lyon

  • Hôpital Privé Jean Mermoz

    Lyon

  • Hôpital de la Timone

    Marseille

  • ICM Val d'Aurelle

    Montpellier

  • CHU Nantes- Hôtel Dieu

    Nantes

  • Hôpital Saint Antoine

    Paris

  • Institut Mutualiste Montsouris

    Paris

  • CHU Bordeaux - Hôpital Haut Lévêque

    Pessac

  • CHU Poitiers

    Poitiers

  • Hôpital Robert Debré

    Reims

  • CHU Toulouse - IUCT Rangueil -Larrey

    Toulouse

Other trials in France

About this study

Official title: 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).

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.

Read the 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).

Being tested
Nivolumab 480mg + Ipilimumab, Nivolumab 240 mg + Ipilimumab

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Nivolumab 480mg + IpilimumabDrug

    Also called Opdivo, Yervoy

    Nivolumab 480 mg q4w + Ipilimumab 1 mg/kg q6w

  • Nivolumab 240 mg + IpilimumabDrug

    Also called Opdivo

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

Study groups in NCT04730544
Study groupRoleWhat they receive
Experimental Arm AExperimentalTreatment 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).
Receives: Drug: Nivolumab 480mg + Ipilimumab
Control Arm BActive comparatorInduction 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).
Receives: Drug: Nivolumab 240 mg + Ipilimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: At week 24

  2. 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.

    Measured: At week 24 for two combination schemes

Secondary outcomes (9)

  1. Number of participants with treatment-related adverse events

    All grade and severe toxicities, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

    Measured: Assessed up to 80 months

  2. Overall response rate (ORR)

    To assess ORR of two combination schemes (RECIST v1.1),

    Measured: At weeks 24 and 48, and at 2 years

  3. PFS of two combination schemes according to RECIST v1.1

    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.

    Measured: At week 48 and at 2 years

  4. PFS of two combination schemes according to Immune Response Evaluation Criteria In Solid Tumors (iRECIST)

    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.

    Measured: At weeks 24 and 48, and at 2 years

  5. Overall survival (OS) of two combination schemes (RECIST v1.1),

    OS is defined as the time between inclusion and death.

    Measured: At week 48 and at 2 years

  6. Percentage of patients who received immune modulating concomitant medication

    To evaluate the percentage of patients who received immune modulating concomitant medication (e.g., corticosteroids, infliximab, mycophenolate mofetil).

    Measured: Until the study treatment end - 48 months

  7. Percentage of patients who received hormonal replacement therapy for immune-related endocrine toxicities

    To evaluate the percentage of patients who received hormonal replacement therapy for immune-related endocrine toxicities.

    Measured: Until the study treatment end - 48 months

  8. Median time to onset, median time to resolution (grade 3-4) of serious adverse event (SAEs) and Treatment-related adverse events (TRAEs),

    To assess median time to onset and median time to resolution of serious AEs (SAEs) and TRAEs (grade 3-4).

    Measured: Up to 80 months

  9. Time to Health-related quality of life (HRQoL) score definitive deterioration (TUDD)

    TUDD is defined as the time interval between randomization and the first occurrence of a decrease in quality of life questionnaire (QLQ)-C30 score ⩾5 points without any further improvement in Quality of life (QoL) score ⩾5 points or any further available QoL data. TUDD will be estimated using the Kaplan-Meier method and the long-rank test. Cox regression analyses will be used to identify HRQoL items influencing TUDD. All analyses will be done on the HRQoL population.

    Measured: assessed up 48 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Jan 2021
  2. Study start21 May 2021
  3. Primary completionApr 2027 (estimated)
  4. Study completionApr 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
96 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04730544
Sponsor's protocol ID
NIPISAFE G-106
Acronym
NIPISAFE
Status last verified
Jun 2025
First submitted
26 Jan 2021
Last updated
13 Jun 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nivolumab 480mg + Ipilimumab and Nivolumab 240 mg + Ipilimumab in people with Colorectal Cancer Metastatic and MSI-H Colorectal Cancer, run by GERCOR - Multidisciplinary Oncology Cooperative Group at 19 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 13 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 19 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of adverse events grade 3 or 4 at week 24 for two combination schemes. (time frame: At week 24). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04730544.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jun 2025.

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