CARE1 Pragmatic Clinical Trial (CARE1)

January 14, 2025 updated by: Gustave Roussy, Cancer Campus, Grand Paris

First Line Randomised Study Platform to Optimize Treatment in Patients With Metastatic Renal Cell Carcinoma

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Estimated)

1250

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Austria
  • Czechia
      • Brno, Czechia, 65653
        • Not yet recruiting
        • Masarykův onkologický ústav, Masaryk Memorial Cancer Institute (MOU)
        • Contact:
          • Alexandr Poprach, MD, PhD
          • Phone Number: +420 543136831
          • Email: poprach@mou.cz
      • Hradec Kralove, Czechia, 50005
        • Not yet recruiting
        • Fakultní nemocnice Hradec Králová, University Hospital Hradec Kralove (FNHK)
        • Contact:
      • Olomouc, Czechia, 77900
        • Recruiting
        • Fakultní nemocnice Olomouc, University Hospital Olomouc (FNOL)
        • Contact:
      • Praha, Czechia, 15000
        • Not yet recruiting
        • Fakultní nemocnice v Motole, University Hospital Motol (MOTOL)
        • Contact:
  • France
      • Angers, France, 49933
        • Recruiting
        • CHU Angers
        • Contact:
      • Angers, France, 49055
      • Avignon, France, 84000
        • Recruiting
        • Institut Sainte Catherine
        • Contact:
      • Bayonne, France, 64100
      • Besançon, France, 25030
      • Bordeaux, France, 33000
        • Not yet recruiting
        • CHU de Bordeaux Hôpital Saint-André
        • Contact:
      • Caen, France, 14076
      • Chalon Sur Saône, France, 71321
      • Clermont-Ferrand, France, 63011
      • Créteil, France, 94000
      • Dijon, France, 21079
        • Recruiting
        • Centre Georges-Francois Leclerc
        • Contact:
      • Grenoble, France, 38043
      • La Roche-Sur-Yon, France, 85925
      • Lille, France, 59000
        • Not yet recruiting
        • Centre Oscar Lambret
        • Contact:
      • Limoges, France, 87000
        • Recruiting
        • Polyclinique de Limoges
        • Contact:
      • Lyon, France, 69008
      • Marseille, France, 13009
        • Recruiting
        • Institut Paoli-Calmettes
        • Contact:
      • Montpellier, France, 34298
        • Recruiting
        • Institut Régional du Cancer de Montpellier
        • Contact:
      • Nice, France, 06189
      • Nîmes, France, 30029
      • Paris, France, 75475
        • Recruiting
        • Hôpital Saint-Louis
        • Contact:
      • Paris, France, 75013
        • Not yet recruiting
        • Hopital de La Pitie Salpetriere
        • Contact:
      • Paris, France, 75020
        • Recruiting
        • Hopital Tenon
        • Contact:
      • Paris, France, 75018
        • Not yet recruiting
        • Hôpital Bichat - Claude Bernard
        • Contact:
      • Paris, France, 75674
        • Recruiting
        • Institut Mutualiste Montsouris
        • Contact:
      • Pau, France, 64000
      • Pierre-Bénite, France, 69310
      • Poitiers, France, 86021
      • Reims, France, 51100
      • Rennes, France, 35042
      • Saint-Etienne, France, 42270
        • Not yet recruiting
        • CHU Saint-Etienne
        • Contact:
      • Saint-Herblain, France, 44806
        • Recruiting
        • Institut de Cancérologie de l'Ouest - Saint Herblain
        • Contact:
      • Saint-Mandé, France, 94160
      • Saint-Pierre, France, 97448
      • Strasbourg, France, 67200
        • Recruiting
        • Institut de cancérologie Strasbourg Europe
        • Contact:
      • Suresnes, France, 92150
      • Toulouse, France, 31059
      • Tours, France, 37044
        • Recruiting
        • Hopital Bretonneau
        • Contact:
      • Vandoeuvre-les-Nancy, France, 54519
        • Recruiting
        • Institut de Cancérologie de Lorraine
        • Contact:
      • Villejuif, France, 94805
  • Netherlands
      • Amsterdam, Netherlands, 1066CX
        • Not yet recruiting
        • Antoni van Leeuwenhoek
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Arm A: ICI - ICI Combination

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.
Drug: Nivolumab
Briefly, nivolumab is administered as an approximately 30-minute (240mg every 2 weeks) or 60-minute (480mg every 4 weeks) IV infusion. Nivolumab is to be administered first. The nivolumab infusion must be promptly followed by a saline flush to clear the line of nivolumab before starting the ipilimumab infusion.
Other Names:
  • OPDIVO
Drug: Ipilimumab

The second infusion will always be ipilimumab and will start at least 30 minutes after completion of the nivolumab infusion. Ipilimumab is to be administered as an approximately 30-minute IV infusion.

When administered together, nivolumab and ipilimumab will be administered on Day 1 of each 21-day cycle.

Other Names:
  • YERVOY
Other: Arm B: VEGFR-TKI- ICI arm (axitinib + 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)
Drug: Nivolumab
Briefly, nivolumab is administered as an approximately 30-minute (240mg every 2 weeks) or 60-minute (480mg every 4 weeks) IV infusion. Nivolumab is to be administered first. The nivolumab infusion must be promptly followed by a saline flush to clear the line of nivolumab before starting the ipilimumab infusion.
Other Names:
  • OPDIVO
Drug: Pembrolizumab
Pembrolizumab is to be administered as an approximately 30-minute IV infusion.
Other Names:
  • KEYTRUDA
Drug: Cabozantinib
Cabozantinib is a medication that is taken orally every day, once a day away from meals at the initial dose of 40 mg/day.
Other Names:
  • CABOMETYX
Drug: Axitinib
Axitinib is a medication that is taken orally every day, 2 times a day continuously, at the starting dose of 5mg x2/day.
Other Names:
  • INLYTA
Drug: Lenvatinib
Lenvatinib is a medication that is taken orally every day, once a day at the initial dose of 20mg/day.
Other Names:
  • LENVIMA

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival (OS).
Time Frame: At end of study, 97 months
From randomization to time of death
At end of study, 97 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free survival according to RECIST 1.1
Time Frame: At end of study, 97 months
From randomization to progression, also a primary outcome for PDL1(-) population.
At end of study, 97 months
Objective Response Rate (ORR) according to RECIST 1.1
Time Frame: 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.
At end of treatment, 60 months
Quality of Life via questionnaire EQ-5D-5L
Time Frame: Baseline, Month 3, Month 6, Month 9, Month 12
Patient's response to the Quality of Life questionnaire EQ-5D-5L.
Baseline, Month 3, Month 6, Month 9, Month 12
Quality of Life via questionnaire NNCCN/FACT Kidney Cancer Symptom Index (NFKSI)
Time Frame: Baseline, Month 3, Month 6, Month 9, Month 12
Patient's response to the Quality of Life questionnaire NFKSI19.
Baseline, Month 3, Month 6, Month 9, Month 12
Quality of Life via questionnaire Kidney Symptom Index (KSI)
Time Frame: Baseline, Month 3, Month 6, Month 9, Month 12
Patient's response to the Quality of Life questionnaire KSI.
Baseline, Month 3, Month 6, Month 9, Month 12
Duration of Treatment
Time Frame: At end of treatment, 60 months
Duration of protocolar treatment administration.
At end of treatment, 60 months
Time to treatment discontinuation (TTD)
Time Frame: 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.
At end of treatment, 60 months
Treatment-free survival (TFS)
Time Frame: 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.
At end of study, 97 months
Time to subsequent systemic anticancer therapy (TTSST)
Time Frame: At end of study, 97 months
TTSST is defined the time from the date of randomization to the date of next subsequent systemic therapy.
At end of study, 97 months
Incidence of AE's
Time Frame: 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.
At end of treatment, 60 months
Health Economic evaluation: healthcare costs [France & Netherlands only]
Time Frame: At end of study, 97 months
The cost difference between arms in each patient subgroup (comparison of healthcare costs)
At end of study, 97 months
Health Economic evaluation: cost-utility [France & Netherlands only]
Time Frame: At end of study, 97 months
The incremental cost per QALY and the incremental net monetary benefit in each patient subgroup (cost-utility analysis).
At end of study, 97 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gustave Roussy, Cancer Campus, Grand Paris

Collaborators

Medical University of Vienna
University Hospital, Essen
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Queen Mary University of London
Rennes University Hospital
National Cancer Institute, France
The Netherlands Cancer Institute
European Commission
Hospital Universitario 12 de Octubre
Servicio Madrileño de Salud, Madrid, Spain
Fakultní nemocnice Olomouc
CRIS Cancer Foundation
Fundació Privada Institut d'Investigació Oncològica de Vall d'Hebron
International Kidney Cancer Coalition
Association pour la Recherche sur les Tumeurs du Rein
Resilience
PRIMAA

Investigators

  • Study Chair: Laurence ALBIGES, MD, PhD, Gustave Roussy, Cancer Campus, Grand Paris

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 12, 2024

Primary Completion (Estimated)

May 5, 2032

Study Completion (Estimated)

May 5, 2032

Study Registration Dates

First Submitted

April 4, 2024

First Submitted That Met QC Criteria

April 9, 2024

First Posted (Actual)

April 15, 2024

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

January 14, 2025

Last Verified

January 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2023-503317-29-00
  • 2023/3764 (Other Identifier: CSET number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Metastatic Kidney Carcinoma

Clinical Trials on Nivolumab

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Chile

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe