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Efficacy and Safety of Two Combination Treatment Regimens of Nivolumab and Ipilimumab in Patients With dMMR and / or MSI Metastatic Colorectal Cancer (NIPISAFE)

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ClinicalTrials.gov Identifier: NCT04730544
Recruitment Status : Recruiting
First Posted : January 29, 2021
Last Update Posted : April 8, 2021
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
GERCOR - Multidisciplinary Oncology Cooperative Group

Tracking Information
First Submitted Date  ICMJE January 26, 2021
First Posted Date  ICMJE January 29, 2021
Last Update Posted Date April 8, 2021
Actual Study Start Date  ICMJE April 1, 2021
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 6, 2021)
  • Number of adverse events grade 3 or 4 [ Time Frame: At week 24 for two combination schemes ]
    According to NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
  • Progression free survival (PFS) [ Time Frame: At week 24 for two combination schemes ]
Original Primary Outcome Measures  ICMJE
 (submitted: January 26, 2021)
  • Number of adverse events grade 3 or 4 [ Time Frame: At week 24 for two combination schemes ]
    According to NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
  • Prgression free survival (PFS) [ Time Frame: At week 24 for two combination schemes ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 6, 2021)
  • Number of participants with treatment-related adverse events [ Time Frame: Assessed up to 80 months ]
    All grade and severe toxicities, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0
  • Overall response rate (ORR) [ Time Frame: At weeks 24 and 48, and at 2 years ]
    To assess ORR of two combination schemes (RECIST v1.1),
  • PFS of two combination schemes according to RECIST v1.1 [ Time Frame: at week 48 and at 2 years ]
  • PFS of two combination schemes according to Immune Response Evaluation Criteria In Solid Tumors (iRECIST) [ Time Frame: at weeks 24 and 48, and at 2 years ]
  • Overall survival (OS) of two combination schemes (RECIST v1.1), [ Time Frame: at week 48 and at 2 years ]
  • Percentage of patients who received immune modulating concomitant medication [ Time Frame: until the end of the study treatment - 48 months ]
  • Percentage of patients who received hormonal replacement therapy for immune-related endocrine toxicities [ Time Frame: until the end of the study treatment - 48 months ]
  • Median time to onset, median time to resolution (grade 3-4) of Serious adverse event (SAEs) and Treatment-related adverse events (TRAEs), [ Time Frame: Assessed up to 80 months ]
  • Time to Health-related quality of life (HRQoL) score definitive deterioration (TUDD) [ Time Frame: assessed up 48 months ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 26, 2021)
  • Number of participants with treatment-related adverse events [ Time Frame: Assessed up to 80 months ]
    All grade and severe toxicities, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0
  • Overall response rate (ORR) [ Time Frame: At weeks 24 and 48, and at 2 years ]
    To assess ORR of two combination schemes (RECIST v1.1),
  • PFS of two combination schemes according to RECIST v1.1 [ Time Frame: at week 48 and at 2 years ]
  • PFS of two combination schemes according to iRECIST [ Time Frame: at weeks 24 and 48, and at 2 years ]
  • Overall survival (OS) of two combination schemes (RECIST v1.1), [ Time Frame: at week 48 and at 2 years ]
  • Percentage of patients who received immune modulating concomitant medication [ Time Frame: until the end of the study treatment - 48 months ]
  • Percentage of patients who received hormonal replacement therapy for immune-related endocrine toxicities [ Time Frame: until the end of the study treatment - 48 months ]
  • Median time to onset, median time to resolution (grade 3-4) of SAEs and TRAEs, [ Time Frame: Assessed up to 80 months ]
  • Time to HRQoL score definitive deterioration (TUDD) [ Time Frame: assessed up 48 months ]
    TUDD is defined as the time interval between randomization and the first occurrence of a decrease in QLQ-C30 score ⩾5 points without any further improvement in 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Two Combination Treatment Regimens of Nivolumab and Ipilimumab in Patients With dMMR and / or MSI Metastatic Colorectal Cancer
Official Title  ICMJE 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)
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 (mCRC) patients.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Colorectal Cancer Metastatic
  • MSI-H Colorectal Cancer
Intervention  ICMJE
  • Drug: Nivolumab
    480 mg
  • Drug: Ipilimumab
    1 mg/kg
  • Drug: Nivolumab
    induction phase : 240 mg and then maintenance : 480 mg
Study Arms  ICMJE
  • Experimental: 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).

    Interventions:
    • Drug: Nivolumab
    • Drug: Ipilimumab
  • Active Comparator: 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).

    Interventions:
    • Drug: Ipilimumab
    • Drug: Nivolumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 26, 2021)
96
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2028
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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. 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),

  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: 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,

  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 Maladie" (PUMa) included).

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-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,
  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 or under the protection of justice.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Romain COHEN, MD 01 40 29 85 00 romain.cohen@aphp.fr
Contact: Marie Line GARCIA LARNICOL, MD 01 40 29 85 00 marie-line.garcia-larnicol@gercor.com.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04730544
Other Study ID Numbers  ICMJE NIPISAFE G-106
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party GERCOR - Multidisciplinary Oncology Cooperative Group
Study Sponsor  ICMJE GERCOR - Multidisciplinary Oncology Cooperative Group
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Romain COHEN, MD hôpital Saint Antoine
PRS Account GERCOR - Multidisciplinary Oncology Cooperative Group
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP