E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Urothelial Carcinoma, locally advanced or metastatic |
|
E.1.1.1 | Medical condition in easily understood language |
Urothelial cancer is a type of cancer that affects the urinary tract. It includes cancer of the bladder, ureters, and renal pelvis |
|
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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064467 |
E.1.2 | Term | Urothelial carcinoma |
E.1.2 | System Organ Class | 100000004864 |
|
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 efficacy of atezolizumab (Atez) plus platinum-based chemotherapy vs. placebo plus platinum-based chemotherapy based on progression-free survival (PFS) and overall survival (OS) • To evaluate efficacy of Atez monotherapy compared vs. placebo plus platinum-based chemotherapy on the basis of OS
|
|
E.2.2 | Secondary objectives of the trial |
• To evaluate efficacy of Atez given as either monotherapy or in combination with platinum-based chemotherapy vs. placebo in combination with platinum-based chemotherapy based on objective response rate (ORR), duration of response (DOR), OS rate, PFS rate, time to deterioration in global health status and in physical function as measured by European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life (QLQ) Questionnaire Core 30 • Investigator-assessed PFS for Atez monotherapy vs. placebo plus platinum-based chemotherapy • To evaluate safety and tolerability of Atez given as either monotherapy or in combination with platinum-based chemotherapy vs. placebo plus platinum-based chemotherapy • To characterize pharmacokinetics (PK) of Atez when administered as monotherapy or in combination with platinum-based chemotherapy in patients who are treatment-naive • To evaluate immune response to Atez as monotherapy and in combination with platinum-based chemotherapy
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >= 18 years - Considered to be eligible to receive platinum-based chemotherapy, in the investigator’s judgment - Eastern Cooperative Oncology Group performance status of <= 2 - Histologically documented, locally advanced (T [tumor] 4b, any N [nodes]; or any T, N 2−3) or metastatic urothelial carcinoma (mUC) (M [metastasized] 1, Stage IV) - Representative formalin-fixed paraffin-embedded tumor specimens in paraffin blocks or at least 15 unstained slides - No prior chemotherapy for inoperable locally advanced or mUC - Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 - Adequate hematologic and end-organ function - For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of carboplatin, cisplatin, or gemcitabine or for 5 months after the last dose of Atez - For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm that together result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of carboplatin and or gemcitabine, and/or cisplatin
|
|
E.4 | Principal exclusion criteria |
Cancer-Specific Exclusions: - 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 prior to enrollment - Active or untreated central nervous system metastases as determined by computed tomography or magnetic resonance imaging evaluation during screening and prior radiographic assessments - Leptomeningeal disease - Uncontrolled hypercalcemia, tumor-related pain, pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures - Malignancies other than urothelial carcinoma within 5 years prior to Cycle 1, Day 1 General Medical Exclusions: - Life expectancy of < 12 weeks - Pregnant or lactating, or intending to become pregnant during the study - Serum albumin < 25 gram per liter Exclusion Criteria Related to Atez: - History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins - History of autoimmune disease - 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 - Significant cardiovascular disease - Known left ventricular ejection fraction < 40% - Positive test for HIV - Active hepatitis B or hepatitis C, tuberculosis - Severe infections within 4 weeks prior to randomization - Therapeutic oral or intravenous antibiotics within 2 weeks prior to randomization - Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 - Prior treatment with Cluster of Differentiation (CD) 137 agonists, anti- cytotoxic T-lymphocyte-associated protein (CTLA)-4, anti− programmed cell death protein (PD)-1, or anti−PD-L1 therapeutic antibody or pathway-targeting agents - Treatment with systemic immunostimulatory agents, systemic corticosteroids or other systemic immunosuppressive medications Exclusion Criteria Related to Gemcitabine: - Known hypersensitivity to gemcitabine Exclusion Criteria Related to Carboplatin: - History of severe allergic reactions to cisplatin or other platinum-containing compounds - Severe bone marrow depression or significant bleeding Exclusion Criteria Related to Cisplatin: - Patients with preexisting renal impairment - Patients with myelosuppresion or hearing impairment - History of allergic reactions to cisplatin or other platinum-containing compounds
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. PFS as assessed by the investigator using RECIST v1.1 (Atez plus chemotherapy vs. placebo plus chemotherapy arms only) 2. OS (Atez plus chemotherapy vs. placebo plus chemotherapy arms only) 3. OS (Atez monotherapy vs. placebo plus platinum-based chemotherapy)
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1. Objective Response Rate (ORR) 2. Duration of Response (DOR) 3. Investigator assessed PFS using RECIST v1.1 (Atez monotherapy vs. placebo plus platinum-based chemotherapy) 4. OS rate 5. PFS rate 6. Time to deterioration in global health status and physical function as measured by the EORTC QLQ-C30 Safety 7. Incidence, nature and severity of adverse events 8. Changes in vital signs and clinical laboratory results Pharmacokinetic 9. Maximum and minimum serum concentration of Atez Immunogenicity 10. Incidence of anti-therapeutic antibodies (ATAs) during the study relative to the prevalence of ATAs at baseline |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. Up to 44 months 4-5. 1 year 6-8. Up to 44 months 9-10. Pre-dose Cycle (C) 1 Day (D) 1, D1 of C2, C3, C4, and C8, at treatment discontinuation, 120 days (+/- 30 days) after last dose of Atez |
|
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 |
|
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 | Yes |
E.8.1.7.1 | Other trial design description |
a third treatment arm was added (open-label atezolizumab monotherapy) |
|
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 | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
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 |
Australia |
Belgium |
Brazil |
Chile |
China |
Czech Republic |
Estonia |
Finland |
Greece |
Hong Kong |
Italy |
Korea, Republic of |
Mexico |
Netherlands |
Poland |
Portugal |
Romania |
Russian Federation |
Serbia |
Slovenia |
South Africa |
Spain |
Taiwan |
Thailand |
Turkey |
Ukraine |
United Kingdom |
United States |
|
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
|
The end of this study is defined as the date when the required number of deaths has been observed for the final analysis of OS in the global study’s intend-to-treat population or when the required number of OS events in patients enrolled in China has occurred, whichever is later. Additionally, the Sponsor may decide to terminate the study at any time. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 8 |