CARE1 Pragmatic Clinical Trial

NCT06364631 | Recruiting Phase 3 DMC

• 2 other identifiers: 2023-503317-29-002023/3764
• Study Type: interventional
• Target: 1,250
• Locations: 4 countries
• Sites: 46

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.

Conditions

Metastatic Kidney Cancer; Metastatic Kidney Carcinoma

Keywords

METASTATIC KIDNEY CANCER; METASTATIC KIDNEY CARCINOMA; PRAGMATIC CLINICAL TRIAL; PDL1

Outcome Measures

Primary Outcomes (1)

• Overall Survival (OS).

  From randomization to time of death

  At end of study, 97 months

Secondary Outcomes (12)

• Progression-free survival according to RECIST 1.1

  At end of study, 97 months

• Objective Response Rate (ORR) according to RECIST 1.1

  At end of treatment, 60 months

• Quality of Life via 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)

  Baseline, Month 3, Month 6, Month 9, Month 12

• Quality of Life via questionnaire Kidney Symptom Index (KSI)

  Baseline, Month 3, Month 6, Month 9, Month 12

Study Arms (2)

Arm A: ICI - ICI Combination

OTHER

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; Drug: Ipilimumab

Arm B: VEGFR-TKI- ICI arm (axitinib + pembrolizumab)

OTHER

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; Drug: Pembrolizumab; Drug: Cabozantinib; Drug: Axitinib; Drug: Lenvatinib

Interventions

Nivolumab DRUG

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.

Also known as: OPDIVO

Arm A: ICI - ICI Combination; Arm B: VEGFR-TKI- ICI arm (axitinib + pembrolizumab)

Ipilimumab DRUG

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.

Also known as: YERVOY

Arm A: ICI - ICI Combination

Pembrolizumab DRUG

Pembrolizumab is to be administered as an approximately 30-minute IV infusion.

Also known as: KEYTRUDA

Arm B: VEGFR-TKI- ICI arm (axitinib + pembrolizumab)

Cabozantinib DRUG

Cabozantinib is a medication that is taken orally every day, once a day away from meals at the initial dose of 40 mg/day.

Also known as: CABOMETYX

Arm B: VEGFR-TKI- ICI arm (axitinib + pembrolizumab)

Axitinib DRUG

Axitinib is a medication that is taken orally every day, 2 times a day continuously, at the starting dose of 5mg x2/day.

Also known as: INLYTA

Arm B: VEGFR-TKI- ICI arm (axitinib + pembrolizumab)

Lenvatinib DRUG

Lenvatinib is a medication that is taken orally every day, once a day at the initial dose of 20mg/day.

Also known as: LENVIMA

Arm B: VEGFR-TKI- ICI arm (axitinib + pembrolizumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed metastatic (AJCC Stage IV) renal cell carcinoma with a clear-cell component.
• Intermediate- or poor-risk mRCC as defined by IMDC classification.
• Karnofsky Performance Status (KPS) ≥70%.
• Adequate organ and marrow function, according to investigator assessment and
• Absolute neutrophil count (ANC) ≥ 1000/μL (≥ 1.5 GI/L)
• Platelets ≥ 100,000/μL (≥ 100 GI/L)
• Hemoglobin ≥ 8 g/dL (≥ 80 g/L)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN.
• 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 any protocol-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 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.
• 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.
• Female subjects of childbearing potential must not be pregnant at screening.

You may not qualify if:

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

Sponsors & Collaborators

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

Study Sites (46)

Medical University of Vienna

Vienna, 1090, Austria

NOT YET RECRUITING

Masarykův onkologický ústav, Masaryk Memorial Cancer Institute (MOU)

Brno, 65653, Czechia

NOT YET RECRUITING

Fakultní nemocnice Hradec Králová, University Hospital Hradec Kralove (FNHK)

Hradec Králové, 50005, Czechia

NOT YET RECRUITING

Fakultní nemocnice Olomouc, University Hospital Olomouc (FNOL)

Olomouc, 77900, Czechia

RECRUITING

Fakultní nemocnice v Motole, University Hospital Motol (MOTOL)

Prague, 15000, Czechia

NOT YET RECRUITING

Institut de Cancérologie de l'Ouest - Angers

Angers, 49055, France

RECRUITING

CHU Angers

Angers, 49933, France

RECRUITING

Institut Sainte Catherine

Avignon, 84000, France

RECRUITING

CH de la Côte Basque

Bayonne, 64100, France

RECRUITING

Hôpital Jean Minjoz

Besançon, 25030, France

RECRUITING

CHU de Bordeaux Hôpital Saint-André

Bordeaux, 33000, France

NOT YET RECRUITING

Centre François Baclesse

Caen, 14076, France

RECRUITING

CH Châlon Sur Saône

Chalon-sur-Saône, 71321, France

NOT YET RECRUITING

Centre Jean Perrin

Clermont-Ferrand, 63011, France

NOT YET RECRUITING

Hôpital Henri Mondor

Créteil, 94000, France

RECRUITING

Centre Georges-François Leclerc

Dijon, 21079, France

RECRUITING

CHU Grenoble

Grenoble, 38043, France

RECRUITING

CHD Vendée

La Roche-sur-Yon, 85925, France

RECRUITING

Centre Oscar Lambret

Lille, 59000, France

NOT YET RECRUITING

Polyclinique de Limoges

Limoges, 87000, France

RECRUITING

Centre Léon Bérard

Lyon, 69008, France

NOT YET RECRUITING

Institut Paoli-Calmettes

Marseille, 13009, France

RECRUITING

Institut Régional du Cancer de Montpellier

Montpellier, 34298, France

RECRUITING

Centre Antoine Lacassagne

Nice, 06189, France

RECRUITING

CHU de Nîmes

Nîmes, 30029, France

RECRUITING

Hôpital de la Pitié Salpêtrière

Paris, 75013, France

NOT YET RECRUITING

Hôpital Bichat - Claude Bernard

Paris, 75018, France

NOT YET RECRUITING

Hôpital Tenon

Paris, 75020, France

RECRUITING

Hôpital Saint-Louis

Paris, 75475, France

RECRUITING

Institut Mutualiste Montsouris

Paris, 75674, France

RECRUITING

CH de Pau

Pau, 64000, France

RECRUITING

Hospices Civils de Lyon

Pierre-Bénite, 69310, France

RECRUITING

CHU Poitiers

Poitiers, 86021, France

RECRUITING

Institut Godinot

Reims, 51100, France

RECRUITING

Centre Eugène Marquis

Rennes, 35042, France

RECRUITING

CHU Saint-Etienne

Saint-Etienne, 42270, France

NOT YET RECRUITING

Institut de Cancérologie de l'Ouest - Saint Herblain

Saint-Herblain, 44806, France

RECRUITING

HIA Bégin

Saint-Mandé, 94160, France

RECRUITING

CHU Sud Réunion

Saint-Pierre, 97448, France

RECRUITING

Institut de cancérologie Strasbourg Europe

Strasbourg, 67200, France

RECRUITING

Hôpital Foch

Suresnes, 92150, France

RECRUITING

Oncopole Claudius Regaud - IUCT-Oncopole

Toulouse, 31059, France

RECRUITING

Hôpital Bretonneau

Tours, 37044, France

RECRUITING

Institut de Cancérologie de Lorraine

Vandœuvre-lès-Nancy, 54519, France

RECRUITING

Gustave Roussy

Villejuif, 94805, France

RECRUITING

Antoni van Leeuwenhoek

Amsterdam, 1066CX, Netherlands

NOT YET RECRUITING

MeSH Terms

Conditions

Kidney Neoplasms; Carcinoma, Renal Cell

Interventions

Nivolumab; Ipilimumab; pembrolizumab; cabozantinib; Axitinib; lenvatinib

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Indazoles; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Laurence ALBIGES, MD, PhD

  Gustave Roussy, Cancer Campus, Grand Paris

  STUDY CHAIR

Central Study Contacts

Laurence ALBIGES, MD, PhD

CONTACT

+33 (0)1 42 11 66 90; laurence.albiges@gustaveroussy.fr

Maia CLAVEAU

CONTACT

+33 (0)1 42 11 53 49; Maia.CLAVEAU@gustaveroussy.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: International, multicenter, open-label, randomized, controlled Phase 3 trial - 2 arms (A and B)

Study Record Dates

• First Submitted: April 4, 2024
• First Posted: April 15, 2024
• Study Start: April 12, 2024
• Primary Completion (Estimated): May 5, 2032
• Study Completion (Estimated): May 5, 2032
• Last Updated: January 16, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1); FR (40); CZ (4); NL (1)