Evaluation study of a treatement with Nivolumab and Ipilimumab or tKi according to molecular group in naïve metastatic Kidney cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Artic

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-01-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Bristol-Myers Squibb

External identifiers

EU CT number

2024-520045-23-00

EudraCT number

2016-003099-28

ClinicalTrials.gov

NCT02960906

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the ORR according to molecular subgroups (ccRCC1 to 4)and assigned treatment (nivolumab monotherapy, nivolumab combined with ipilimumab, or TKI: sunitinib or pazopanib), based on Investigator assessments.

Secondary objectives 20

1. To evaluate PFS in subjects with previously untreated mRCC according to their molecular group and assigned treatment, based on both Investigator radiological assessments.
2. To evaluate the OS in subjects with previously untreated mRCC according to their molecular group (1&4 vs 2&3) and assigned treatment. Percentages of patients alive at 1 year and 2 year will be evaluated.
3. To evaluate objective response rate at 22 weeks as a surrogate of other endpoints according to their molecular group (1&4 vs 2&3) and assigned treatment.
4. To evaluate the duration of treatment (DOT) of nivolumab combined with ipilimumab or nivolumab alone or TKI (sunitinib or pazopanib) in subjects with previously untreated mRCC according to their molecular group (1&4 vs 2&3) and assigned treatment.
5. To evaluate the duration of response (DOR) of nivolumab combined with ipilimumab or nivolumab alone or TKI (sunitinib or pazopanib) in subjects with previously untreated mRCC according to their molecular group (1&4 vs 2&3) and assigned treatment.
6. To determine the incidence of AEs associated with nivolumab combined with ipilimumab or nivolumab alone or TKI (sunitinib or pazopanib) in all treated subjects with previously untreated mRCC.
7. To assess gene expression of immune population markers in the primary tumor as well as in the metastases before beginning treatment, and at progression if safely achievable.
8. Gene expression analysis will be performed from frozen and FFPE tumor tissue in order to compare the two methods.
9. To assess the density and phenotype of selected immune populations (CD8, CD3/CD20, PD-1, TIM-3, LAG3, FoxP3) as well as the phenotype of tumor cells (PD-L1, PD-L2) by immunohistochemistry (IHC) in the primary tumor and metastases, before treatment initiation and at progression if safely achievable
10. Explorer l'association entre biomarqueurs tissulaires et circulants et les résultats (ORR, ORR à 22 semaines, OS et PFS).
11. To assess the functional status of peripheral blood lymphocytes (PBL) by flow cytometry, before treatment initiation, during treatment, and at progression
12. To identify genetic and epigenetic alterations associated with either response or resistance to immune checkpoint inhibitors and tyrosine kinase inhibitors.
13. To evaluate the association between immune cells composing tumor microenvironment and response and/or resistance to immune checkpoint inhibitors or tyrosine kinase inhibitors.
14. To evaluate additional genetic and epigenetic tumor alterations at resistance/progression or after resection of residual mass.
15. Discover new imaging biomarkers using radiomics to predict response to immunotherapy in patients with metastatic clear cell renal cell carcinoma (ccRCC).
16. Evaluate the benefit of immunotherapy with centralized iRECIST review of all tumour assessments (CT-scans/MRI) of all patients.
17. To quantify plasmatic angiogenesis-related (i.e. VEGF-A, VEGF-C its soluble receptors VEGFR-1 and 2 and co-receptors neuropilin 1 and 2, angiopoietins, SDF-1, PDGFs…)) and endothelial cell-derived molecules (i.e. endoglin, VE-cadherin) before treatment initiation, during treatment, and at progression.
18. To correlate plasmatic angiogenesis-related molecules with tumor vascularization studied by immunofluorescence (IF) and a multi-spectral analyzer (Vectra technology) on tumor tissue
19. To investigate a predictive role of the response of CXCL7 and sCD146 to TKI, nivolumab and/or nivolumab+ipilimumab.
20. To determine whether the mutation and methylation analysis of circulating tumor DNA can be used as predictive biomarker of response, resistance to treatment and progression.

Conditions and MedDRA coding

Kidney cancer

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Histological confirmation of RCC with a clear-cell component. Patients with TFE3 or TFEB translocation proven by cytogenetic analysis or by fluorescence in situ hybridization (FISH) are eligible.
2. Metastatic (American Joint Committee on Cancer [AJCC] Stage IV) RCC
3. No prior systemic therapy for mRCC (patients with relapse >1 year after adjuvant treatment discontinuation are eligible)
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2
5. Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
6. Frozen tumor samples or fresh tumor samples immediately stored in "RNA later" medium (primary tumor and/or metastasis biopsies) must be available and received by the central laboratory (Cordelier Research Center) to determine molecular groups. (Note: fine needle aspiration [FNA] and bone metastases samples are not acceptable for submission).
7. Formalin-fixed, paraffin-embedded (FFPE) tumor tissue available for biomarker (gene expression and immunohistochemistry (IHC)) analysis
8. Molecular group has to be determined prior to randomization.

Exclusion criteria 28

1. Any untreated CNS metastases. Patients with CNS metastases will be eligible if they are: asymptomatic, without significant edema, not on corticosteroids, not eligible for radiation therapy/surgery or have already received radiation therapy.
2. Prior systemic treatment with VEGF or VEGF receptor-targeted therapy (including, but not limited to, sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab) except in an adjuvant setting with a free interval of more than 1 year.
3. Prior treatment with an anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
4. Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (>10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type 1 diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.
5. Any condition requiring systemic treatment with corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of SD. Inhaled steroids and adrenal replacement steroid doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
6. Uncontrolled adrenal insufficiency
7. Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as >450 msec for males and >470 msec for females, where QTcF = QT / 3√RR.
8. Poorly controlled hypertension (defined as SBP of >150 mmHg or DBP of >90 mmHg), despite antihypertensive therapy
9. History of any of the following CV conditions within 12m of enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the NYHA.
10. History of cerebrovascular accident including transient ischemic attack within the past 12 months.
11. History of DVT unless adequately treated with low molecular weight heparin
12. History of pulmonary embolism within the past 6m unless stable, asymptomatic, and treated with low molecular weight heparin for at least 6 weeks
13. Known history of COPD
14. Known history of uveitis or complaint of double vision
15. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.
16. Serious, non-healing wound or ulcer
17. Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days.
18. Any requirement for anti-coagulation, except for low molecular weight heparin
19. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
20. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
21. Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
22. Known medical condition (e.g., a condition associated with diarrhea or acute diverticulitis) that, in the Investigator’s opinion, would increase the risk associated with study participation or study drug administration, or interfere with the interpretation of safety results
23. Known history of hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory, neuropathy, and polyneuropathy
24. Major surgery (e.g., nephrectomy) less than 35 days prior to the first dose of study drug
25. Focal radiation therapy less than 14 days prior to the first dose of study drug.
26. Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors
27. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of TKI (e.g., malabsorptive disorder, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection).
28. Any of the following laboratory test findings: a) WBC <2,000/mm3 b) Hemoglobin ≤9.0 g/dL c) Neutrophils <1,500/mm3 d) Platelets <100,000/mm3 e) AST or ALT >3 x ULN (>5 x ULN if liver metastases are present) f) Lipase and amylase > 1.5 ULN g) Total Bilirubin >1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin <3.0 mg/dL) h) Serum creatinine >1.5 x ULN or creatinine clearance <40 mL/min (measured or calculated by Cockroft-Gault formula) i) Proteinuria: patients with ≥2+ protein on urine dipstick at baseline must undergo a 24-hour urine collection for protein then if > 1.0 g of protein patient will not be included.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Investigator-assessed ORR is defined as the proportion of randomized subjects who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) using RECIST 1.1 criteria based on Investigator assessments.

Secondary endpoints 6

1. Progression-free Survival The primary definition of PFS is specified as the time between randomization to the first date of documented progression, based on Investigator radiological assessments (as per RECIST 1.1 criteria), or death due to any cause, whichever occurs first. Subjects who die without a reported progression will be considered to have progressed on the date of their death.
2. Overall Survival OS is defined as the time from randomization to the date of death from any cause. For subjects that are alive, their survival time will be censored at the date of last contact (“last known alive date”).
3. Objective response rate at 22 weeks ORR at 22 weeks as defined as percentage of patients with an objective response (decrease of SLD by at least 30%) at second CT or MRI after treatment initiation.
4. Duration of treatment Duration of treatment (DOT) is defined as the time between treatment initiation and discontinuation for any reason or End of study.
5. Duration of response Duration of response (DOR) is defined as the time between response to treatment and discontinuation for any reason or End of study.
6. AE Incidence Rate The AE incident rate is defined as the proportion of subjects with any-grade AEs among subjects in each treatment arm. Events reported from the first dose, up to and including 100 days following the last dose of study treatment will be included in calculating this incidence rate

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Artic

Sponsor organisation

ARTIC

Address

20 Rue Leblanc

City

Paris

Postcode

75015

Country

France

Scientific contact point

Organisation

ARTIC

Contact name

Professor

Public contact point

Organisation

ARTIC

Contact name

Clinical Project Manager

Locations

1 EU/EEA country · 16 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 13 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