E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients at high risk of Renal Cell Carcinoma (RCC) recurrence after nephrectomy and select patients with metastatic RCC recurrence who have undergone complete metastasectomy |
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E.1.1.1 | Medical condition in easily understood language |
RCC is a kidney cancer that originates in the lining of the very small tubes in the kidney that transport waste molecules from the blood to the urine |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 11.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10038408 |
E.1.2 | Term | Renal cell carcinomas |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To evaluate the efficacy of adjuvant treatment with atezolizumab in patients at high risk of RCC recurrence as determined by Independent Review Facility (IRF)-assessed disease free survival (DFS) |
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E.2.2 | Secondary objectives of the trial |
• To evaluate other measures of efficacy of adjuvant treatment with atezolizumab • To evaluate the safety and tolerability of atezolizumab in the adjuvant setting • To characterize the Pharmacokinetic (PK) profile of atezolizumab • To evaluate the immune response to atezolizumab • To explore the potential relationship of the immunogenic response and PK profile
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >= 18 years - Eastern Cooperative Oncology Group (ECOG) performance status of <= 1 - Able to comply with the study protocol, in the investigator’s judgment - Pathologically confirmed RCC with a component of either clear cell histology or sarcomatoid histology that has not been previously treated in the adjuvant or neoadjuvant setting. Patients enrolled based on localized disease include those with T2 Grade 4, T3a Grade 3-4, T3b/c any grade, T4 any grade and TxN + any grade are eligible - Patients with pulmonary (treated with sub-lobar or lobar resection), lymph node, or soft-tissue metachronous recurrence of disease occurring greater than 12 months following nephrectomy who undergo complete resection and have no evidence of disease following metastasectomy are also eligible. Patients with resected CNS, bone or adrenal metastasis are not eligible - Patients with synchronous isolated solitary ipsilateral or contralateral adrenal and lung metastases treatable with a sub-lobar or lobar resection within 12 weeks of nephrectomy are eligible - Radical or partial nephrectomy with lymphadenectomy in select patients - Representative formalin-fixed paraffin-embedded resected tumor specimens in paraffin blocks or at least 15 unstained slides, with an associated pathology report, for central testing and determined to be evaluable for tumor programmed death ligand-1 (PD-L1) expression prior to study enrollment - Absence of residual disease and absence of metastasis, as confirmed by a negative baseline computed tomography (CT) of the pelvis, abdomen, and chest no more than 4 weeks prior to randomization. Confirmation of disease-free status will be assessed by an independent central radiologic review of imaging data - Absence of brain metastasis, as confirmed by a negative CT with contrast or magnetic resonance imaging scan of the brain, no more than 4 weeks prior to randomization for those enrolled based upon a metastasectomy - Full recovery from nephrectomy or metastasectomy within 12 weeks from randomization following surgery - Adequate hematologic and end-organ function within 28 days prior to randomization - For women of childbearing potential: agreement to remain abstinent or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period for at least 5 months after the last dose of study drug, and agreement to refrain from donating eggs during this same period |
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E.4 | Principal exclusion criteria |
- Bilateral synchronous tumors with inheritable forms of RCC including von Hippel-Lindau - Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment - Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days or five half-lives of the investigational agent, whichever is longer, prior to enrollment - Central nervous system metastases or leptomeningeal disease - Malignancies other than RCC within 5 years prior to Cycle (C) 1, Day (D) 1. Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of metastasis or death <5% at 5 years) are eligible provided they meet all of the following criteria: Malignancy treated with expected curative intent (e.g., adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ of the breast treated surgically with curative intent). No evidence of recurrence or metastasis by follow-up imaging and any disease-specific tumor markers - Life expectancy of < 24 weeks - Pregnancy or lactation, or intending to become pregnant during the study - Serum albumin < 2.5 g/dL - History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins - Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation - History of autoimmune diseases. Patients with a history of autoimmune-related hypothyroidism and Type 1 diabetes mellitus on a stable dose of hormone or insulin replacement may be eligible for this study. Patients with well controlled, limited autoimmune skin conditions may be eligible. - Patients with prior allogeneic stem cell or solid organ transplantation - History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan - Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class III or greater), myocardial infarction within 3 months prior to initiation of study treatment, unstable arrhythmias, or unstable angina - Patients with a known left ventricular ejection fraction <40%. - Positive test for human immunodeficiency virus - Patients with active hepatitis B and hepatitis C - Active tuberculosis - Severe infections within 4 weeks prior to initiation of study treatment - Receipt of therapeutic oral or intravenous antibiotics within 2 weeks prior to initiation of study treatment - Major surgical procedure within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis - Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study treatment - Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications - Prior treatment with CD137 agonists, anti-CTLA-4, anti-PD−1, or anti−PD-L1 therapeutic antibody or pathway-targeting agents - Treatment with systemic immunostimulatory agents within 6 weeks or five half-lives of the drug, whichever is shorter, prior to initiation of study treatment - Treatment with systemic immunosuppressive medications within 2 weeks prior to initiation of study treatment or anticipated need for systemic immunosuppressive medications during the study
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E.5 End points |
E.5.1 | Primary end point(s) |
• Independent Review Facility (IRF)-assessed disease free survival (DFS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Overall survival 2. Investigator-assessed DFS 3. IRF-assessed DFS in patients with PD-L1 IHC IC 1/2/3 expression 4. Investigator-assessed DFS in patients with IC1/2/3 5. Disease specific survival 6. Distant metastasis-free survival 7. One, two and three year IRF-assessed DFS rate 8. One, two and three investigator-assessed DFS rate 9. Incidence, nature, and severity of adverse events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 10. Changes in vital signs and clinical laboratory results 11. Serum concentration of atezolizumab at specified timepoints 12. Incidence of anti-therapeutic antibodies (ATA) against atezolizumab 13. Relationship between detectable ATA incidence and PK endpoints
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-10. Up to 88 months 11-12. C1D1, C2D1, C3D1, C4D1, C8D1, treatment discontinuation visit 13. Up to 30 days after the last dose of atezolizumab
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability, immune response, health-related quality of life |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 67 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Chile |
Czech Republic |
Denmark |
France |
Germany |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Poland |
Russian Federation |
Serbia |
Spain |
Taiwan |
Thailand |
Turkey |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial 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
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The end of this study is defined as when the required numbers of deaths have been observed for the final analysis of overall survival (OS) in the intent-to-treat (ITT) population. Additionally, the Sponsor may decide to terminate the study at any time. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 4 |