Efficacy Comparison of Nivolumab-Ipilimumab Versus Immune Checkpoint Inhibitor-VEGFR TKI Combinations in Untreated Metastatic Renal Cell Carcinoma
- Trial ID
- 2023-503317-29-00
- Protocol
- 2023/3764
- Sponsor
- Institut Gustave Roussy
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of an immune checkpoint inhibitor combination (ICI-ICI) with nivolumab-ipilimumab (NIVO-IPI) compared to an ICI-VEGFR TKI combination in patients with metastatic renal cell carcinoma (mRCC) who are classified as intermediate and poor risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. The efficacy will be assessed based on PDL1 stratification, with overall survival being the primary endpoint for the PDL1(+) population, and both progression-free survival and overall survival serving as co-primary endpoints for the PDL1(-) population. This is clinically relevant as it aims to optimize first-line treatment strategies for mRCC, potentially improving patient outcomes.
Secondary objectives include: - Progression-free survival according to RECIST 1.1 - Objective Response Rate according to RECIST 1.1 - Quality of Life via questionnaires - Duration of Treatment - Time to treatment discontinuation - Treatment-free survival - Time to subsequent systemic anticancer therapy - Safety - Health Economic evaluation in France and the Netherlands only
Participants
The clinical trial involves a total of **150 participants** diagnosed with **metastatic renal cell carcinoma (mRCC)**. The study population includes both male and female adults aged 18 years and older, with a focus on individuals classified as intermediate or poor risk according to the IMDC classification. Participants were selected based on specific inclusion criteria, including a histologically confirmed diagnosis of metastatic renal cell carcinoma with a clear-cell component and a Karnofsky Performance Status of 70% or higher. The trial population is required to have adequate organ and marrow function and must not include pregnant women. Both male and female participants of childbearing potential are required to adhere to strict contraceptive measures. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial aims to evaluate the efficacy of different treatment combinations in untreated mRCC patients, stratified by PDL1 status.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **immune checkpoint inhibitor** combinations in patients with metastatic renal cell carcinoma (mRCC). This study employs a randomized, double-blind, controlled design to compare the combination of nivolumab and ipilimumab (NIVO-IPI) against a combination of immune checkpoint inhibitors and VEGFR tyrosine kinase inhibitors in patients classified as intermediate or poor risk according to the IMDC criteria. The trial aims to assess overall survival in the PDL1(+) population and both progression-free survival and overall survival in the PDL1(-) population as co-primary endpoints. The trial is expected to commence recruitment in April 2024 and conclude by May 2032.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed mRCC, adequate organ function, and a Karnofsky Performance Status of at least 70%. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, with assessments including overall survival, progression-free survival, and objective response rate according to RECIST 1.1 criteria. The end-of-study visit will occur upon completion of the treatment period or in the event of disease progression or unacceptable toxicity.
The expected duration of participant involvement is contingent upon individual response to treatment, with a maximum treatment period of one year. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial is categorized as a low-intervention study, ensuring that all treatments align with current guidelines and standard care practices, thereby minimizing additional risks to participants.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **CABOMETYX** (cabozantinib) is provided as 40 mg film-coated tablets. The medication is administered orally with a maximum daily dose of 40 mg. The treatment period is limited to one day, and the medication functions as an antineoplastic agent and protein kinase inhibitor. Participant compliance is monitored through standard clinical trial procedures.
**OPDIVO** (nivolumab) is available as a 10 mg/mL concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 3 mg/kg. The treatment period is also limited to one day. Nivolumab is classified as an antibody, and its administration is monitored to ensure adherence to the dosing schedule.
**AXITINIB SANDOZ** (axitinib) is provided in the form of 5 mg film-coated tablets. This medication is administered orally with a maximum daily dose of 10 mg. The treatment period is restricted to one day, and axitinib acts as an antineoplastic agent and protein kinase inhibitor. Compliance is tracked through regular assessments.
**LENVIMA** (lenvatinib) is available as 10 mg hard capsules. The medication is administered orally with a maximum daily dose of 20 mg, and the treatment period is limited to one day. Lenvatinib functions as an antineoplastic agent and protein kinase inhibitor, with compliance monitored through standard trial protocols.
Another formulation of **OPDIVO** (nivolumab) is provided as a 10 mg/mL concentrate for solution for infusion, administered as a solution for infusion with a maximum daily dose of 480 mg. The treatment period is one day, and the medication is classified as an antibody. Administration and compliance are closely monitored.
**KEYTRUDA** (pembrolizumab) is available as a 25 mg/mL concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 400 mg. The treatment period is one day, and pembrolizumab is classified as an antibody. Compliance is ensured through regular monitoring.
**YERVOY** (ipilimumab) is provided as a 5 mg/mL concentrate for solution for infusion. The medication is administered via IV infusion with a maximum daily dose of 1 mg/kg. The treatment period is limited to one day, and ipilimumab is classified as an antibody. Participant adherence to the dosing schedule is monitored throughout the trial.
Efficacy
Efficacy in the clinical trial will be assessed using several primary endpoints, including **Overall Survival (OS)** and **Progression-Free Survival (PFS)** according to RECIST 1.1 criteria. These endpoints will be evaluated in patients with metastatic renal cell carcinoma (mRCC) who are stratified based on PDL1 status. For the PDL1(+) population, the primary endpoint is overall survival, while for the PDL1(-) population, both progression-free survival and overall survival are co-primary endpoints. Additionally, the **Objective Response Rate (ORR)** will be measured according to RECIST 1.1.
Secondary efficacy parameters include the percentage of patients experiencing a deterioration of ≥3 points on the NFKSI-19 score within the first twelve months post-randomization, mean change from baseline in EQ-VAS, and response frequencies for the EQ-5D-5L dimensions. The median treatment duration per treatment, time to subsequent systemic therapy, and health economic evaluation through incremental cost per Quality-adjusted life year (QALY) will also be assessed. The percentage of subjects experiencing grade 3-5 adverse events (AEs) and treatment-related grade 3-5 AEs, as well as the percentage of patients experiencing AE grade ≥2 leading to modification of study drug administration, will be recorded.
Data collection will occur at specified intervals throughout the trial, with efficacy assessments conducted using validated scales and laboratory tests. The trial is designed to optimize treatment in patients with mRCC, and all treatments will be administered according to current guidelines and standard of care. The trial is expected to conclude by May 2032, with recruitment starting in April 2024.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically confirmed metastatic (AJCC Stage IV) renal cell carcinoma with a clear-cell component
- Intermediate- or poor-risk mRCC as defined by IMDC classification.
- Adult male or female patients (≥ 18 years of age at inclusion).
- Karnofsky Performance Status (KPS) ≥70%.
- Adequate organ and marrow function, according to investigator assessment and a.Absolute neutrophil count (ANC) ≥ 1000/μL (≥ 1.5 GI/L) b.Platelets ≥ 100,000/μL (≥ 100 GI/L) c.Hemoglobin ≥ 8 g/dL (≥ 80 g/L) d.Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 xULN. e.Calculated creatinine clearance ≥ 30 mL/min (≥ 0.67 mL/sec) using the CKD-EPI equation
- Patient should understand, sign, and date the written informed consent form prior to anyprotocol-specific procedures performed
- Patient should be able and willing to comply with study visits and procedures as per protocol
- Patients must be affiliated to a social security system or beneficiary of the same
- Female patients must either be of non-reproductive potential or must have a negativeserum pregnancy test within 14 days prior to the administration of study drug.Childbearing potential women must have agreed to use at least one highly effectivecontraceptive method during treatment on this trial and for up to 6 months after the lastdose of study treatment
- Fertile men with a female partner of childbearing potential must agree to use malecondom plus spermicide. Also, it is recommended their women of childbearing potentialpartner use a highly effective method of contraception
- Female subjects of childbearing potential must not be pregnant at screening
Exclusion Criteria
- Prior systemic anticancer therapy for mRCC including investigational agents. Note: One prior systemic adjuvant therapy is allowed for completely resected RCC and ifrecurrence occurred at least 6 months after the last dose of adjuvant therapy.
- Uncontrolled brain metastases (adequately treated with radiotherapy and/orradiosurgery prior to randomization are eligible). Subjects who are neurologicallysymptomatic as a result of their CNS metastasis or are receiving systemic corticosteroidtreatment (prednisone equivalent > 10 mg/day) at the planned time of randomizationare not eligible
- Concomitant oral anti-vitamin K anticoagulation. An exception is the use of LMWH ordirect oral anticoagulants (DOAC), if considered safe by investigator assessment
- The subject has uncontrolled, significant intercurrent or recent illness such as thefollowing conditions: a.Cardiovascular i.Congestive heart failure (CHF) class III or IV as defined by the NewYork Heart Association, unstable angina pectoris, myocardialinfarction, serious cardiac arrhythmias (e.g., ventricular flutter,ventricular fibrillation, Torsades de pointes). ii.Uncontrolled hypertension despite optimal antihypertensive treatment. iii.Stroke, or other symptomatic ischemic event or severe thromboembolicevent (e.g., symptomatic pulmonary embolism [PE], incidental PE isacceptable if deemed safe by the investigator) within 3 months beforerandomization. b.Active GI bleeding or symptomatic Gastrointestinal (GI) tract obstruction c.Clinically significant bleeding including uncontrolled hematuria, hematemesis,or hemoptysis d.Autoimmune disease that has been symptomatic or requiredimmunosuppressive systemic treatment within the past two years from the dateof randomization. Note: Patients with a history of Crohn’s disease or ulcerative colitis are always excluded e.Any condition requiring systemic treatment with either corticosteroids (> 10 mgdaily prednisone equivalent) or other immunosuppressive medications within14 days of randomization. Note: Inhaled, intranasal, intra-articular, or topical steroids are permitted.Adrenal replacement steroid doses > 10 mg daily prednisone equivalent arepermitted. Transient short-term use of systemic corticosteroids for allergicconditions (e.g., contrast allergy) is also allowed. f.Active infection requiring systemic treatment. g.Major surgery (e.g., nephrectomy, GI surgery, removal of brain metastasis)within 4 weeks prior to randomization or serious non-healing wound/ulcer/bonefracture. disorders
- Pregnant or breastfeeding females.
- Any other active malignancy at time of randomization or diagnosis of anothermalignancy within 3 years prior to randomization that requires active treatment, exceptfor locally curable cancers that have been apparently cured
- Persons deprived of their freedom or under guardianship, or for whom it would be impossible to undergo the medical follow-up required by the trial, for geographic, socialor psychological reasons
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 01 Apr 2024 | 15 |
 Belgium | Recruiting | 01 Apr 2024 | 68 |
 Czechia | Recruiting | 01 Apr 2024 | 100 |
 Denmark | Not Yet Recruiting | 01 Apr 2024 | 20 |
 Finland | Recruiting | 01 Apr 2024 | 20 |
 France | Recruiting | 01 Apr 2024 | 450 |
 Germany | Recruiting | 01 Apr 2024 | 100 |
 Greece | Recruiting | 01 Apr 2024 | 80 |
 Italy | Recruiting | 01 Apr 2024 | 150 |
 The Netherlands | Recruiting | 01 Apr 2024 | — |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
YERVOY 5 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 1 | 1 | PRD2341715 |
CABOMETYX 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 40 | 1 | PRD4382703 |
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 3 | 1 | PRD2941375 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 400 | 1 | PRD4323105 |
LENVIMA 10 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 20 | 1 | PRD2958374 |
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 480 | 1 | PRD2941372 |
AXITINIB SANDOZ 5 mg, comprimé pelliculé | Test | COMPRIMÉ PELLICULÉ | ORAL | 10 | 1 | PRD10195545 |