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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Association Gercor

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Decision date (initial)

2025-01-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518138-10-00

EudraCT number

2020-004366-19

ClinicalTrials.gov

NCT04730544

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

- To assess the safety (grade 3 or 4 TRAEs) profile according to NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 of two different combination schemes of nivolumab plus ipilimumab during the first 24 weeks of treatment,
- To assess PFS at week 24 for two combination schemes.

Secondary objectives 9

1. To assess the safety (AEs, treatment-related AEs and iAEs) and tolerability of two combination schemes
2. To assess ORR of two combination schemes at 24 weeks and 48, and at 2 years (RECIST v1.1)
3. To assess PFS of two combination schemes at week 48 and at 2 years (RECIST v1.1)
4. To assess PFS of two combination schemes at 24 weeks and 48, and at 2 years (iRECIST)
5. To assess OS of two combination schemes at week 48 and at 2 years (RECIST v1.1)
6. To evaluate the percentage of patients who received immune modulating concomitant medication (e.g., corticosteroids, infliximab, mycophenolate mofetil)
7. To evaluate the percentage of patients who received hormonal replacement therapy for immune-related endocrine toxicities
8. To assess median time to onset and median time to resolution of serious AEs (SAEs) and TRAEs (grade 3-4)
9. To evaluate changes in HRQoL and patient-reported outcomes using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; Appendix 19.2) and NCI-Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (NCI-PRO-CTCAE) questionnaire.

Conditions and MedDRA coding

Patients with DMMR and/or MSI metastatic colorectal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Signed and dated patient informed consent form (ICF) and willingness to comply with all study procedures and availability for the study duration
2. Age ≥ 18 years
3. 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. 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, NB: if loss of only one protein, necessary to have 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 7 days prior to initiation of study treatment: - Hematological status: White blood cell > 2000/μL; o Neutrophils > 1500/μL; o Platelets > 100.000/μL; o Hemoglobin > 9.0 g/dL; - Adequate renal function: o Serum creatinine level < 150 μM; - Adequate liver function: o Serum bilirubin ≤ 1.5 x upper normal limit (ULN); o Alkaline phosphatase (ALP) ≤ 3 x ULN; o Alanine aminotransferase (ALT) ≤ 3.0 x ULN; o Aspartame aminotransferase (AST) ≤ 3.0 x ULN; o 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 urine or 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 17

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-PD-L1, anti-PD-L2, 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
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The co-primary endpoint of this study is Grade 3 or 4 TRAEs during the first 24 weeks (NCI CTCAE v5.0) and PFS at week 24

Secondary endpoints 10

1. AEs (NCI CTCAE v5.0)
2. Treatment and iAEs
3. Percentage of patients who received immune modulating concomitant medication (e.g., corticosteroids, infliximab, mycophenolate mofetil)
4. Percentage of patients who received hormonal replacement therapy for immune-related endocrine toxicities
5. Median time to onset, median time to resolution of SAEs and TRAEs (grade 3-4)
6. Score changes in EORTC QLQ-C30 and NCI-PRO-CTCAE scales
7. ORR at weeks 24 and 48, and at 2 years (RECIST v1.1)
8. PFS at week 48 and at 2 years (RECIST v1.1)
9. PFS and ORR at weeks 24 and 48, and at 2 years (iRECIST)
10. OS at weeks 24 and 48, and at 2 years

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Association Gercor

Sponsor organisation

Association Gercor

Address

151 Rue Du Faubourg Saint Antoine

City

Paris

Postcode

75011

Country

France

Scientific contact point

Organisation

Association Gercor

Contact name

Dr GARCIA-LARNICOL

Public contact point

Organisation

Association Gercor

Contact name

Dr GARCIA-LARNICOL

Locations

1 EU/EEA country · 19 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications