CARE1 Pragmatic Clinical Trial

Phase 3

Recruiting

• Conditions: Metastatic Kidney Cancer; Metastatic Kidney Carcinoma
• Interventions: Drug: Nivolumab; Drug: Ipilimumab; Drug: Pembrolizumab; Drug: Cabozantinib; Drug: Axitinib; Drug: Lenvatinib

• Registration Number: NCT06364631
• Lead Sponsor: Gustave Roussy, Cancer Campus, Grand Paris

Brief Summary

Systemic therapy for renal cell carcinoma (RCC) relies on 2 classes of agents: anti-angiogenic targeted therapy (Vascular endothelial growth factor Tyrosine Kinase Inhibitor- VEGFR TKI) and immune checkpoint inhibitor (ICI), targeting either PD1/PDL1 axis or CTLA4. Combination therapy is SOC for clear cell RCC in all guidelines with either ICI-ICI or ICI-VEGFR TKI. However, no head-to-head comparison have been performed between the 2 approaches and patients are treated based on physician decision without clinical /biomarker factors to guide treatment selection. PDL1 staining is, to date, the biomarker that has demonstrated its ability to enrich for overall survival benefit favoring ICI-ICI strategy in PDL1(+) and ICI-VEGFR TKI in PDL1(-) patients.

Study design has been developed to demonstrate that ICI-ICI is superior to ICI-VEGFR TKI in prolonging Overall Survival (OS) for PDL1(+) patients and to demonstrate that ICI-VEGFR TKI is superior to ICI-ICI in prolonging Progression Free Survival (PFS) and OS for PDL1(-) patients.

Detailed Description

In 2020, there were an estimated 431 288 new cases of kidney cancer (Renal Cell Carcinoma, RCC) globally with 138 611 cases in Europe, leading to 179 368 deaths worldwide, including 54 054 deaths in Europe (source: IARC/Globocan). To define high priority topics in academic research and launch dedicated trials, European RCC academic physicians have gathered into a European initiative - the CARE group.

Systemic therapy for RCC relies on two classes of agents: anti-angiogenic targeted therapy (Vascular endothelial growth factor Tyrosine Kinase Inhibitor- VEGFR TKI) and immune checkpoint inhibitor (ICI), targeting either PD-1/PD-L1 axis or CTLA-4. Combination therapy is standard of care (SOC) for clear cell RCC in all guidelines with either ICI-ICI or ICI-VEGFR TKI. However, no head-to-head comparison have been performed between the two approaches and patients are treated based on physician decision without clinical or biomarker factors to guide treatment selection. PD-L1 staining is, to date, the biomarker that has demonstrated its ability to enrich for overall survival benefit favoring ICI-ICI strategy in PD-L1(+) and ICI-VEGFR TKI in PD-L1(-) patients.

CARE1 PCT is a prospective randomize phase III study, in first line setting for patients with metastatic clear cell RCC comparing ICI-ICI vs ICI-VEGFR TKI approaches stratified on PD-L1 by local determination. Primary endpoint is overall survival (OS). The trial will enroll 1250 patients over 4 years across eight European countries (France, Spain, Netherlands, Czech Republic, Austria, Germany, Italy, UK) that are part of the CARE consortium. Study Sponsor is Gustave Roussy institute within the GETUG network for France, co-sponsor is developed through main academic networks (eg. SOGUG in Spain) and main institutions across Europe (eg. Cancer Core Europe - CCE). Study design has been develop to demonstrate that ICI-ICI is superior to ICI-VEGFR TKI in prolonging OS for PD-L1(+) patients and that ICI-VEGFR TKI is superior to ICI-ICI in prolonging OS for PD-L1(-) patients. CARE1 PCT has been designed and will be conducted with patient advocacy group representatives (ARTuR and IKCC) input.

CARE1 is an academic phase III study designed to define the optimal combination using a pragmatic routinely implementable biomarker. Therefore, CARE1 will inform practice and has the potential to change treatment guidelines. Taken all together, CARE1 is a unique opportunity to build a large-scale platform to define new biomarker based therapy guidelines as well as to investigate quality of life, patient reported outcome and Health-Economic in front line setting, as well as pathological and blood biobank collection for further translational work. This action is part of the Cancer Mission cluster of projects on 'Diagnosis and treatment'.

Study Timeline

• Study First Submitted: 2024-04-04
• Study First Submitted QC: 2024-04-09
• Study Start: 2024-04-12
• Study First Posted: 2024-04-15
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-14
• Last Update Posted: 2025-01-16
• Primary Completion: 2032-05-05
• Study Completion: 2032-05-05

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1250

Inclusion Criteria

1. Histologically confirmed metastatic (AJCC Stage IV) renal cell carcinoma with a clear-cell component.

2. Intermediate- or poor-risk mRCC as defined by IMDC classification.

3. Adult male or female patients (≥ 18 years of age at inclusion).

4. Karnofsky Performance Status (KPS) ≥70%.

5. Adequate organ and marrow function, according to investigator assessment and

   1. Absolute neutrophil count (ANC) ≥ 1000/μL (≥ 1.5 GI/L)
   2. Platelets ≥ 100,000/μL (≥ 100 GI/L)
   3. Hemoglobin ≥ 8 g/dL (≥ 80 g/L)
   4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN.
   5. Calculated creatinine clearance ≥ 30 mL/min (≥ 0.67 mL/sec) using the CKD- EPI equation

6. Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed.

7. Patient should be able and willing to comply with study visits and procedures as per protocol

8. Patients must be affiliated to a social security system or beneficiary of the same

9. Female patients must either be of non-reproductive potential or must have a negative serum pregnancy test within 14 days prior to the administration of study drug. Childbearing potential women must have agreed to use one barrier method of contraception, such as condom, plus an additional highly effective method of contraception during treatment on this trial and for up to 5 months after the last dose of study treatment.

10. Fertile men with a female partner of childbearing potential must agree to use one barrier method of contraception, such as condom, during treatment on this trial and for up to 4 months after the last dose of treatment. Their women of childbearing potential partner must agree to use a highly effective method of contraception during the same period.

11. Female subjects of childbearing potential must not be pregnant at screening.

Exclusion Criteria

1. Prior systemic anticancer therapy for mRCC including investigational agents. Note: One prior systemic adjuvant therapy is allowed for completely resected RCC and if recurrence occurred at least 6 months after the last dose of adjuvant therapy.

2. Uncontrolled brain metastases (adequately treated with radiotherapy and/or radiosurgery prior to randomization are eligible). Subjects who are neurologically symptomatic as a result of their CNS metastasis or are receiving systemic corticosteroid treatment (prednisone equivalent > 10 mg/day) at the planned time of randomization are not eligible.

3. Concomitant oral anti-vitamin K anticoagulation. An exception is the use of LMWH or direct oral anticoagulants (DOAC), if considered safe by investigator assessment.

4. The subject has uncontrolled, significant intercurrent or recent illness such as the following conditions:

   a. Cardiovascular disorders:

   i. Congestive heart failure (CHF) class III or IV as defined by the New York Heart Association, unstable angina pectoris, myocardial infarction, 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 thromboembolic event (e.g., symptomatic pulmonary embolism [PE], incidental PE is acceptable if deemed safe by the investigator) within 3 months before randomization.

   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 required immunosuppressive systemic treatment within the past two years from the date of 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 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization.

   Note: Inhaled, intranasal, intra-articular, or topical steroids are permitted. Adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted. Transient short-term use of systemic corticosteroids for allergic conditions (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/bone fracture.

5. Pregnant or breastfeeding females.

6. Any other active malignancy at time of randomization or diagnosis of another malignancy within 3 years prior to randomization that requires active treatment, except for locally curable cancers that have been apparently cured.

7. Hypersensitivity to any of the active substances or to any of the excipients administered during the study

8. Use of live vaccines within 28 days before randomization

9. 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, social or psychological reasons.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B: VEGFR-TKI- ICI arm (axitinib + pembrolizumab)	Cabozantinib	Investigator's choice between: * Axitinib (5 mg oral twice a day) + pembrolizumab (200 mg flat IV every 3 weeks or 400 mg flat IV every 6 weeks). * Cabozantinib (40 mg oral, once a day away from meals) + nivolumab infusion (480 mg flat dose every 4 weeks) * Lenvatinib (20 mg oral, once a day) + pembrolizumab (200 mg flat IV every 3 weeks or 400 mg flat IV every 6 weeks)
Arm A: ICI - ICI Combination	Nivolumab	Nivolumab (3 mg/kg infusion, every 3 weeks) x 4 doses + ipilimumab (1 mg/kg infusion, every 3 weeks) x 4 doses. At the end of the 4 injections carried out 21 days apart and in the absence of limiting side effects or progression justifying the cessation of the treatment according to the investigating doctor, maintenance treatment with nivolumab will be continued, at a rate of one injection every 2 weeks at a dose of 240 mg or every 4 weeks at a dose of 480 mg depending on the choice of the investigating doctor. Nivolumab will be administered for a maximum of 2 years. Patients are required to receive all four doses of NIVO+IPI before beginning NIVO monotherapy except for ipilimumab-induced toxicity compatible with nivolumab maintenance.
Arm A: ICI - ICI Combination	Ipilimumab	Nivolumab (3 mg/kg infusion, every 3 weeks) x 4 doses + ipilimumab (1 mg/kg infusion, every 3 weeks) x 4 doses. At the end of the 4 injections carried out 21 days apart and in the absence of limiting side effects or progression justifying the cessation of the treatment according to the investigating doctor, maintenance treatment with nivolumab will be continued, at a rate of one injection every 2 weeks at a dose of 240 mg or every 4 weeks at a dose of 480 mg depending on the choice of the investigating doctor. Nivolumab will be administered for a maximum of 2 years. Patients are required to receive all four doses of NIVO+IPI before beginning NIVO monotherapy except for ipilimumab-induced toxicity compatible with nivolumab maintenance.
Arm B: VEGFR-TKI- ICI arm (axitinib + pembrolizumab)	Nivolumab	Investigator's choice between: * Axitinib (5 mg oral twice a day) + pembrolizumab (200 mg flat IV every 3 weeks or 400 mg flat IV every 6 weeks). * Cabozantinib (40 mg oral, once a day away from meals) + nivolumab infusion (480 mg flat dose every 4 weeks) * Lenvatinib (20 mg oral, once a day) + pembrolizumab (200 mg flat IV every 3 weeks or 400 mg flat IV every 6 weeks)
Arm B: VEGFR-TKI- ICI arm (axitinib + pembrolizumab)	Pembrolizumab	Investigator's choice between: * Axitinib (5 mg oral twice a day) + pembrolizumab (200 mg flat IV every 3 weeks or 400 mg flat IV every 6 weeks). * Cabozantinib (40 mg oral, once a day away from meals) + nivolumab infusion (480 mg flat dose every 4 weeks) * Lenvatinib (20 mg oral, once a day) + pembrolizumab (200 mg flat IV every 3 weeks or 400 mg flat IV every 6 weeks)
Arm B: VEGFR-TKI- ICI arm (axitinib + pembrolizumab)	Axitinib	Investigator's choice between: * Axitinib (5 mg oral twice a day) + pembrolizumab (200 mg flat IV every 3 weeks or 400 mg flat IV every 6 weeks). * Cabozantinib (40 mg oral, once a day away from meals) + nivolumab infusion (480 mg flat dose every 4 weeks) * Lenvatinib (20 mg oral, once a day) + pembrolizumab (200 mg flat IV every 3 weeks or 400 mg flat IV every 6 weeks)
Arm B: VEGFR-TKI- ICI arm (axitinib + pembrolizumab)	Lenvatinib	Investigator's choice between: * Axitinib (5 mg oral twice a day) + pembrolizumab (200 mg flat IV every 3 weeks or 400 mg flat IV every 6 weeks). * Cabozantinib (40 mg oral, once a day away from meals) + nivolumab infusion (480 mg flat dose every 4 weeks) * Lenvatinib (20 mg oral, once a day) + pembrolizumab (200 mg flat IV every 3 weeks or 400 mg flat IV every 6 weeks)

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS).	At end of study, 97 months	From randomization to time of death

Secondary Outcome Measures

Name	Time	Method
Progression-free survival according to RECIST 1.1	At end of study, 97 months	From randomization to progression, also a primary outcome for PDL1(-) population.
Objective Response Rate (ORR) according to RECIST 1.1	At end of treatment, 60 months	ORR (estimand 3) is defined as the percentage of randomised participants (ITT set) who achieve a best response of complete response (CR) or partial response (PR) over the treatment observation period based on Investigators assessments.
Quality of Life via questionnaire EQ-5D-5L	Baseline, Month 3, Month 6, Month 9, Month 12	Patient's response to the Quality of Life questionnaire EQ-5D-5L.
Quality of Life via questionnaire NNCCN/FACT Kidney Cancer Symptom Index (NFKSI)	Baseline, Month 3, Month 6, Month 9, Month 12	Patient's response to the Quality of Life questionnaire NFKSI19.
Quality of Life via questionnaire Kidney Symptom Index (KSI)	Baseline, Month 3, Month 6, Month 9, Month 12	Patient's response to the Quality of Life questionnaire KSI.
Duration of Treatment	At end of treatment, 60 months	Duration of protocolar treatment administration.
Time to treatment discontinuation (TTD)	At end of treatment, 60 months	TTD is defined as the time from the date of treatment initiation to the date of last treatment dose.
Treatment-free survival (TFS)	At end of study, 97 months	TFS is defined as the date from protocol therapy cessation (whatever the reason) to the date of subsequent systemic therapy initiation or death.
Time to subsequent systemic anticancer therapy (TTSST)	At end of study, 97 months	TTSST is defined the time from the date of randomization to the date of next subsequent systemic therapy.
Incidence of AE's	At end of treatment, 60 months	Incidence of AEs will be summarized by system organ class and preferred term according to MedDRA coding, and will be presented by treatment groups and overall.
Health Economic evaluation: healthcare costs [France & Netherlands only]	At end of study, 97 months	The cost difference between arms in each patient subgroup (comparison of healthcare costs)
Health Economic evaluation: cost-utility [France & Netherlands only]	At end of study, 97 months	The incremental cost per QALY and the incremental net monetary benefit in each patient subgroup (cost-utility analysis).

Trial Locations

Locations (46)

Medical University of Vienna; 🇦🇹 Vienna, Austria

Masarykův onkologický ústav, Masaryk Memorial Cancer Institute (MOU); 🇨🇿 Brno, Czechia

Fakultní nemocnice Hradec Králová, University Hospital Hradec Kralove (FNHK); 🇨🇿 Hradec Kralove, Czechia

Fakultní nemocnice Olomouc, University Hospital Olomouc (FNOL); 🇨🇿 Olomouc, Czechia

Fakultní nemocnice v Motole, University Hospital Motol (MOTOL); 🇨🇿 Praha, Czechia

Institut de Cancérologie de l'Ouest - Angers; 🇫🇷 Angers, France

CHU Angers; 🇫🇷 Angers, France

Institut Sainte Catherine; 🇫🇷 Avignon, France

CH de la Côte Basque; 🇫🇷 Bayonne, France

Hôpital Jean Minjoz; 🇫🇷 Besançon, France

CHU de Bordeaux Hôpital Saint-André; 🇫🇷 Bordeaux, France

Centre François Baclesse; 🇫🇷 Caen, France

CH Châlon Sur Saône; 🇫🇷 Chalon Sur Saône, France

Centre Jean Perrin; 🇫🇷 Clermont-Ferrand, France

Hôpital Henri Mondor; 🇫🇷 Créteil, France

Centre Georges-François Leclerc; 🇫🇷 Dijon, France

CHU Grenoble; 🇫🇷 Grenoble, France

CHD Vendée; 🇫🇷 La Roche-Sur-Yon, France

Centre Oscar Lambret; 🇫🇷 Lille, France

Polyclinique de Limoges; 🇫🇷 Limoges, France

Centre Léon Bérard; 🇫🇷 Lyon, France

Institut Paoli-Calmettes; 🇫🇷 Marseille, France

Institut Régional du Cancer de Montpellier; 🇫🇷 Montpellier, France

Centre Antoine Lacassagne; 🇫🇷 Nice, France

CHU de Nîmes; 🇫🇷 Nîmes, France

Hôpital de la Pitié Salpêtrière; 🇫🇷 Paris, France

Hôpital Bichat - Claude Bernard; 🇫🇷 Paris, France

Hôpital Tenon; 🇫🇷 Paris, France

Hôpital Saint-Louis; 🇫🇷 Paris, France

Institut Mutualiste Montsouris; 🇫🇷 Paris, France

CH de Pau; 🇫🇷 Pau, France

Hospices Civils de Lyon; 🇫🇷 Pierre-Bénite, France

CHU Poitiers; 🇫🇷 Poitiers, France

Institut Godinot; 🇫🇷 Reims, France

Centre Eugène Marquis; 🇫🇷 Rennes, France

CHU Saint-Etienne; 🇫🇷 Saint-Etienne, France

Institut de Cancérologie de l'Ouest - Saint Herblain; 🇫🇷 Saint-Herblain, France

HIA Bégin; 🇫🇷 Saint-Mandé, France

CHU Sud Réunion; 🇫🇷 Saint-Pierre, France

Institut de cancérologie Strasbourg Europe; 🇫🇷 Strasbourg, France

Hôpital Foch; 🇫🇷 Suresnes, France

Oncopole Claudius Regaud - IUCT-Oncopole; 🇫🇷 Toulouse, France

Hôpital Bretonneau; 🇫🇷 Tours, France

Institut de Cancérologie de Lorraine; 🇫🇷 Vandoeuvre-les-Nancy, France

Gustave Roussy; 🇫🇷 Villejuif, France

Antoni van Leeuwenhoek; 🇳🇱 Amsterdam, Netherlands