E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 |
Evaluated the efficacy of MPDL3280A in patients with locally advanced or metastatic urothelial bladder cancer as measured by independent review facility assessed ORR using RECIST v1.1 and investigator assess ORR according to modified RECIST |
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E.2.2 | Secondary objectives of the trial |
To evaluate PFS, DOR by RECIST v1.1 as assessed by independent review; to evaluate PFS and DOR according to modified RECIST as assessed by investigators; to evaluate ORR, DOR, and PFS according to RECIST v1.1 as assessed by the investigator; to evaluate OS and 1-year OS; to characterize the safety and tolerability of MPDL3280A; to characterize the pharmacokinetics of MPDL3280A; and to evaluate the incidence and tiers of anti-therapeutic antibodies against MPDL3280A |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Ability to comply with protocol
•Age > 18 years
•Histologically or cytologically documented locally advanced (T4b, any N; or any T, N 2−3) or metastatic (M1, Stage IV) TCC (also termed urothelial cell carcinoma) of the urothelium (including renal pelvis, ureters, urinary bladder, urethra)
•Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks preferred) or at least 15 unstained slides, with an associated pathology report, for central testing and determined to have sufficient viable tumor content prior to study enrollment; tumor specimens will be evaluated for PD-L1 expression; patients with fewer than 15 unstained slides available at baseline (but no fewer than 10) may be eligible following discussion with Medical Monitor.
•Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Patients with ECOG 2 are allowed in Cohort 1.
•Life expectancy > 12 weeks
•Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions should not be counted as target lesions.
•Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:
•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 treatment period and for at least 90 after the last dose of atezolizumab.
Cohort 1-Specific Inclusion Criteria
•No prior chemotherapy for inoperable locally advanced or metastatic or recurrent UBC
•Ineligible (“unfit”) for cisplatin-based chemotherapy as defined by any one of the following criteria:
Impaired renal function (glomerular filtration rate [GFR] > 30 but < 60 mL/min). GFR should be assessed by direct measurement (i.e., creatinine clearance or ethyldediaminetetra-acetate) or, if not available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula) A hearing loss (measured by audiometry) of 25 dB at two contiguous frequencies Grade 2 or greater peripheral neuropathy (i.e., sensory alteration or parasthesis including tingling)
ECOG performance score of 2
Cohort 2-Specific Inclusion Criteria
•Disease progression during or following treatment with at least one platinum-containing regimen (e.g., gemcitabine and cisplatin [GC], methotrexate, vinblastine, doxorubicin, and cisplatin [MVAC], CarboGem, etc.) for inoperable locally advanced or metastatic urothelial carcinoma or disease recurrence
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E.4 | Principal exclusion criteria |
Cancer Specific Exclusion Criteria
•Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment; the following exceptions are allowed:
•Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrollment
•Active or untreated central nervous system (CNS) metastases as determined by CT or MRI evaluation during screening and prior radiographic assessments
•Leptomeningeal disease
•Uncontrolled tumor-related pain
•Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
•Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
•Malignancies other than UBC within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome
General Medical Exclusion Criteria
•Pregnant and lactating women
•History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
•Known hypersensitivity to Chinese hamster ovary cell products or any component of the MPDL3280A formulation
•History of autoimmune disease
•History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
•Serum albumin <2.5 g/dL
•Positive test for HIV
Medication-Related Exclusion Criteria:
•Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
•Treatment with systemic immunostimulatory agents within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
•Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial
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E.5 End points |
E.5.1 | Primary end point(s) |
IRF-assessed ORR according to RECIST v1.1 and investigator-assessed ORR according to modified RECIST criteria |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluated radiographically every 9 weeks following C1D1 for 1 year, then every 12 weeks. Analysis will be performed approximately 6 months after the last patient is enrolled into the study. |
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E.5.2 | Secondary end point(s) |
DOR and PFS assessed by the IRF and investigator assessed per RECIST v1.1, OS, and 1-year OS; DOR and PFS per modified RECIST |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluated radiographically every 9 weeks following C1D1 for 1 year, then every 12 weeks. Analysis will be performed approximately 6 months after the last patient is enrolled into the study. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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 |
immune- and bladder specific biomarkers predictive for response; PD-L1 IHC. |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 42 |
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 |
Canada |
France |
Germany |
Italy |
Netherlands |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 study is defined as the date of the last follow-up visit of the last patient
enrolled and is expected to occur approximately 12 months after the last patient enrolls in the study. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |