Clinical trial NCT06364631: CARE1 Pragmatic Clinical Trial
Official title: First Line Randomised Study Platform to Optimize Treatment in Patients With Metastatic Renal Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Metastatic Kidney Cancer
Metastatic Kidney Carcinoma
Keywords: METASTATIC KIDNEY CANCER
METASTATIC KIDNEY CARCINOMA
PRAGMATIC CLINICAL TRIAL
PDL1
Lead sponsor: Gustave Roussy, Cancer Campus, Grand Paris
Sponsor class: OTHER
Collaborators: name: European Commission
name: CRIS Cancer Foundation
name: National Cancer Institute, France
name: Rennes University Hospital
name: University Hospital, Essen
name: Fundació Privada Institut d'Investigació Oncològica de Vall d'Hebron
name: The Netherlands Cancer Institute
name: Servicio Madrileño de Salud, Madrid, Spain
name: Hospital Universitario 12 de Octubre
name: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
name: Medical University of Vienna
name: FAKULTNI NEMOCNICE OLOMOUC
name: International Kidney Cancer Coalition
name: Association pour la Recherche sur les Tumeurs du Rein
name: Resilience
name: PRIMAA
name: Queen Mary University of London
First posted: 2024-04-15
Enrollment: 1250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: International, multicenter, open-label, randomized, controlled Phase 3 trial - 2 arms (A and B)
Primary purpose: TREATMENT

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'.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Survival (OS).
timeFrame: At end of study, 97 months
Secondary outcomes:
measure: Progression-free survival according to RECIST 1.1
timeFrame: At end of study, 97 months
measure: Objective Response Rate (ORR) according to RECIST 1.1
timeFrame: At end of treatment, 60 months
measure: Quality of Life via questionnaire EQ-5D-5L
timeFrame: Baseline, Month 3, Month 6, Month 9, Month 12
measure: Quality of Life via questionnaire NNCCN/FACT Kidney Cancer Symptom Index (NFKSI)
timeFrame: Baseline, Month 3, Month 6, Month 9, Month 12
measure: Quality of Life via questionnaire Kidney Symptom Index (KSI)
timeFrame: Baseline, Month 3, Month 6, Month 9, Month 12
measure: Duration of Treatment
timeFrame: At end of treatment, 60 months
measure: Time to treatment discontinuation (TTD)
timeFrame: At end of treatment, 60 months
measure: Treatment-free survival (TFS)
timeFrame: At end of study, 97 months
measure: Time to subsequent systemic anticancer therapy (TTSST)
timeFrame: At end of study, 97 months
measure: Incidence of AE's
timeFrame: At end of treatment, 60 months
measure: Health Economic evaluation: healthcare costs [France & Netherlands only]
timeFrame: At end of study, 97 months
measure: Health Economic evaluation: cost-utility [France & Netherlands only]
timeFrame: At end of study, 97 months
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Brno
country: Czechia
facility: Masarykův onkologický ústav, Masaryk Memorial Cancer Institute (MOU)
city: Hradec Kralove
country: Czechia
facility: Fakultní nemocnice Hradec Králová, University Hospital Hradec Kralove (FNHK)
city: Olomouc
country: Czechia
facility: Fakultní nemocnice Olomouc, University Hospital Olomouc (FNOL)
city: Praha
country: Czechia
facility: Fakultní nemocnice v Motole, University Hospital Motol (MOTOL)
city: Angers
country: France
facility: Institut de Cancérologie de l'Ouest - Angers
city: Angers
country: France
facility: CHU Angers
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Bayonne
country: France
facility: CH de la Côte Basque
city: Besançon
country: France
facility: Hôpital Jean Minjoz
city: Bordeaux
country: France
facility: CHU de Bordeaux Hôpital Saint-André
city: Caen
country: France
facility: Centre François Baclesse
city: Chalon Sur Saône
country: France
facility: CH Châlon Sur Saône
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: Centre Georges-François Leclerc
city: Grenoble
country: France
facility: CHU Grenoble
city: La Roche-Sur-Yon
country: France
facility: CHD Vendée
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: Polyclinique de Limoges
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Montpellier
country: France
facility: Institut Régional du Cancer de Montpellier
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nîmes
country: France
facility: CHU de Nîmes
city: Paris
country: France
facility: Hôpital de la Pitié Salpêtrière
city: Paris
country: France
facility: Hôpital Bichat - Claude Bernard
city: Paris
country: France
facility: Hôpital Tenon
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Paris
country: France
facility: Institut Mutualiste Montsouris
city: Pau
country: France
facility: CH de Pau
city: Pierre-Bénite
country: France
facility: Hospices Civils de Lyon
city: Poitiers
country: France
facility: CHU Poitiers
city: Reims
country: France
facility: Institut Godinot
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Saint-Etienne
country: France
facility: CHU Saint-Etienne
city: Saint-Herblain
country: France
facility: Institut de Cancérologie de l'Ouest - Saint Herblain
city: Saint-Mandé
country: France
facility: HIA Bégin
city: Saint-Pierre
country: France
facility: CHU Sud Réunion
city: Strasbourg
country: France
facility: Institut de cancérologie Strasbourg Europe
city: Suresnes
country: France
facility: Hôpital Foch
city: Toulouse
country: France
facility: Oncopole Claudius Regaud - IUCT-Oncopole
city: Tours
country: France
facility: Hôpital Bretonneau
city: Vandoeuvre-les-Nancy
country: France
facility: Institut de Cancérologie de Lorraine
city: Villejuif
country: France
facility: Gustave Roussy
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek
Study officials:
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Laurence ALBIGES, MD, PhD
role: STUDY_CHAIR
References: