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    Summary
    EudraCT Number:2020-000502-29
    Sponsor's Protocol Code Number:WO41994
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-08-10
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2020-000502-29
    A.3Full title of the trial
    A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ATEZOLIZUMAB GIVEN IN COMBINATION WITH CABOZANTINIB VERSUS CABOZANTINIB ALONE IN PATIENTS WITH INOPERABLE, LOCALLY ADVANCED, OR METASTATIC RENAL CELL CARCINOMA WHO EXPERIENCED RADIOGRAPHIC TUMOR PROGRESSION DURING OR AFTER IMMUNE CHECKPOINT INHIBITOR TREATMENT
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate the Efficacy and Safety of Atezolizumab Given in Combination with Cabozantinib Versus Cabozantinib Alone in Patients with Inoperable, Locally Advanced, or Metastatic Renal Cell Carcinoma who Experienced Radiographic Tumor Progression During or After Immune Checkpoint Inhibitor Treatment
    A.4.1Sponsor's protocol code numberWO41994
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffman-La Roche Ltd.
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffman-La Roche Ltd.
    B.4.2CountrySwitzerland
    B.4.1Name of organisation providing supportExelisis, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd.
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobal.rochegenentechtrials@roche.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tecentriq
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAtezolizumab
    D.3.2Product code RO5541267
    D.3.4Pharmaceutical form Concentrate for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNATEZOLIZUMAB
    D.3.9.2Current sponsor codeRO5541267
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCabozantinib
    D.3.2Product code RO7047650
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCaboznatinib
    D.3.9.2Current sponsor codeRO7047650
    D.3.9.3Other descriptive nameCabozantinib S-malate
    D.3.9.4EV Substance CodeSUB176318
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Renal cell carcinoma (RCC)
    E.1.1.1Medical condition in easily understood language
    RCC is the most common type of kidney cancer in adults (responsible for approximately 90-95% of cases)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10038395
    E.1.2Term Renal carcinoma
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10038400
    E.1.2Term Renal carcinoma stage IV
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10050076
    E.1.2Term Metastatic renal carcinoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of atezolizumab in combination with cabozantinib (i.e. atezolizumab + cabozantinib arm) compared with cabozantinib alone (cabozantinib arm) in the intention-to-treat population
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of atezolizumab in combination with cabozantinib compared with cabozantinib alone in the intent-to-treat population
    • To evaluate the safety of atezolizumab in combination with cabozantinib compared with cabozantinib alone in the intent-to-treat population
    • To characterize the pharmacokinetics profile of atezolizumab and cabozantinib administered in combination
    • To evaluate the immune response to atezolizumab (for atezolizumab+ cabozantinib arm)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age >= 18 years
    • Histologically confirmed locally advanced or metastatic clear cell or non-clear cell RCC (RCC with sarcomatoid features is allowed)
    • Radiographic disease progression during or following treatment with immune checkpoint inhibitors (ICI) for locally advanced or metastatic RCC either in first- or second-line treatment. Only patients for whom the immediate preceding line of therapy was an ICI are allowed. ICI is defined by antiPD-L1 or antiPD1 antibody including atezolizumab, avelumab, pembrolizumab, or nivolumab. Ipilimumab monotherapy is not considered an antiPD L1 or antiPD1 therapy.
    • Measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1
    • Evaluable International Metastatic Renal Cell Carcinoma Database Consortium risk score
    • Two representative pretreatment tumor specimen for exploratory biomarker research: archival tumor specimen, and pretreatment tumor tissue from fresh biopsy at screening, if clinically feasible.
    • Karnofsky Performance Status score of >= 70
    • Adequate hematologic and end-organ function
    • Negative hepatitis B testing at screening
    • Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening
    • Negative HIV test at screening
    • For women of childbearing potential: agreement to remain abstinent or use contraception and agree to refrain from donating eggs for 4 months after the final dose of cabozantinib and for 5 months after the final dose of atezolizumab
    • For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm for 4 months after the final dose of cabozantinib to avoid exposing the embryo
    E.4Principal exclusion criteria
    •Treatment with anti-cancer therapy within 28 d prior to initiation of study treatment
    •Patients received cabozantinib (Cabo) at any time prior to screening
    •Patients who received more than 1 regimen of ICIs
    •Patients who received more than 2 prior lines of therapy in the advanced or metastatic setting
    •Patients who received ICI in the adjuvant setting
    •Patients who have received a mammalian target of rapamycin inhibitor in the advanced or metastatic setting
    •Symptomatic, untreated, or actively progressing CNS metastases
    •History of leptomeningeal disease
    •Uncontrolled tumor-related pain, pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures, uncontrolled or symptomatic hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
    •History of malignancy other than renal carcinoma within 5 years prior to screening
    •Radiotherapy for RCC within 14 d prior to Day 1 of Cycle 1
    •Active tuberculosis
    •Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
    •Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of atezolizumab (Atezo) and 4 months after the final dose of Cabo
    •Severe infection within 4 weeks prior to initiation of study treatment
    •Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during Atezo treatment or within 5 months after the final dose of Atezo
    •Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives prior to initiation of study treatment
    •Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment
    •Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
    •Prior allogeneic stem cell or solid organ transplantation
    •Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
    •Current treatment with anti-viral therapy for HBV or HCV
    •Active or history of autoimmune disease or immune deficiency
    •History of idiopathic pulmonary fibrosis, organizing pneumonia drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
    •Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
    •Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mmHg systolic or > 90 mmHg diastolic despite optimal antihypertensive treatment
    •Stroke, myocardial infarction (MI), or other symptomatic ischemic event, or thromboembolic event within 6 months before first dose
    •Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
    •History of clinically significant ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease, coronary heart disease, clinically significant electrolyte abnormalities, or family history of sudden unexplained death or long QT syndrome
    •History of congenital QT syndrome
    •History or presence of an abnormal ECG that is clinically significant in the investigator's opinion
    •QT interval corrected through use of Fridericia's formula > 480 ms per ECG within 14 d before randomization
    •Significant vascular disease within 6 months prior to Day 1 of Cycle 1
    •Evidence of bleeding diathesis or significant coagulopathy
    •History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6 months prior to Day 1 of Cycle 1
    •Concomitant anticoagulation with coumarin agents, direct thrombin inhibitor dabigatran, direct factor Xa inhibitor betrixaban, or platelet inhibitors
    •Clinical signs or symptoms of GI obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
    •Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
    •Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
    •Prior history of hypertensive crisis or hypertensive encephalopathy
    •Known hypersensitivity to Chinese hamster ovary cell products or to any component of the Atezo formulation
    •History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
    •Known allergy or hypersensitivity to any component of the Cabo formulation
    •Patients who are not able to swallow a tablet
    E.5 End points
    E.5.1Primary end point(s)
    1. Progression-free survival as assessed by Independent Review Facility (IRF)
    2. Overall survival
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Approximately 55 months
    E.5.2Secondary end point(s)
    1. Progression-free survival as assessed by investigators
    2. Investigator- and IRF-assessed objective response rate
    3. Investigator- and IRF-assessed duration of objective response
    4. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0
    5. Change from baseline in targeted vital signs
    6. Change from baseline in targeted clinical laboratory test results
    7. Atezolizumab concentrations at specified timepoints (for atezolizumab+ cabozantinib arm)
    8. Cabozantinib concentrations at specified timepoints
    9. Prevalence of anti-drug antibodies (ADAs) to atezolizumab at baseline and incidence of ADAs to atezolizumab during the study (for atezolizumab+ cabozantinib arm)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-4. Approximately 55 months
    5-6. From baseline (Day-28 to -1) to 55 months
    7. Day 1 of Cycle 1-4, 8, 12, 16 and at treatment discontinuation visit (for atezolizumab+ cabozantinib arm)
    8. Day 1 of Cycle 2-4, and at treatment discontinuation visit
    9. Day 1 of Cycle 1-4, 8, 12, 16 and at treatment discontinuation visit (for atezolizumab+ cabozantinib arm)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned12
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA87
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Canada
    Denmark
    France
    Germany
    Greece
    Italy
    Japan
    Korea, Republic of
    Poland
    Russian Federation
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of this study is defined as the date when the required numbers of events for the final analysis of OS in the ITT population has occurred.
    In addition, the Sponsor may decide to terminate the study at any time.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months55
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months55
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 275
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 225
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state65
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 257
    F.4.2.2In the whole clinical trial 500
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The Sponsor will offer continued access to study treatment (atezolizumab and cabozantinib) free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-09-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-08
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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