E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
T2-T4N0M0 transitional cell carcinoma of the bladder |
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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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066752 |
E.1.2 | Term | Bladder transitional cell carcinoma stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066754 |
E.1.2 | Term | Bladder transitional cell carcinoma stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066753 |
E.1.2 | Term | Bladder transitional cell carcinoma stage II |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 determine MPDL3280A's ability to reduce the size of bladder cancer before surgery (measured as pathological complete response rate), and assess the impact of the drug on the body's immune system. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are as follows: - Assess the safety and tolerability of MPDL3280A in this patient population by collecting information about adverse events and surgical complications. - Assess the anti-tumour effect of MPDL3280A by examining the radiological response (looking at pre- and post-treatment MRI/CT scan images) and “disease free survival” rates. - Assess the effect of MPDL3280A on overall patient survival. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Willing and able to provide written informed consent -Ability to comply with the protocol -Age ≥ 18 years -Histopathologically confirmed transitional cell carcinoma (T2-T4a) of the bladder. Patients with mixed histologies are required to have a dominant transitional cell pattern. -Residual disease after TURBT (surgical opinion, cystoscopy or radiological presence). -Fit and planned for cystectomy (according to local guidelines). -N0 or M0 disease CT or MRI (within 4 weeks of registration) -Representative formalin-fixed paraffin embedded (FFPE) bladder tumour samples with an associated pathology report that are determined to be available and sufficient for central testing. -Patients who refuse neoadjuvant cisplatin based chemotherapy or in whom neoadjuvant cisplatin based therapy is not appropriate. -Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 -Negative pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential. -For female patients of childbearing potential to use a highly effecting form(s) of contraception (i.e. one that results in a low failure rate [<1% per year] when used consistently and correctly) and to continue its use for 90 days after the last dose of MPDL3280A. -Adequate hematologic and end-organ function within 4 weeks prior to the first study treatment defined by the following: a) ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1) b) WBC counts > 2500/μL c)Lymphocyte count ≥ 500/μL d) Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1) e) Haemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic treatment to meet this criterion). f) AST or ALT, and alkaline phosphatase ≤ 2.5 times the institutional upper limit of normal (ULN) (patients with known Gilbert disease who have serum bilirubin level ≤ 3 × the institutional ULN may be enrolled). g) INR and aPTT ≤ 1.5 × the institutional ULN. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. h) Calculated creatinine clearance ≥ 20 mL/min (Cockcroft-Gault formula) |
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E.4 | Principal exclusion criteria |
-Pregnant and lactating female patients -Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis -Previous intravenous chemotherapy for bladder cancer -Patients with prior allogeneic stem cell or solid organ transplantation -Prior treatment with CD137 agonists, anti-CTLA-4, anti−programmed death−1 (PD-1), or anti−PD-L1 therapeutic antibody or pathway-targeting agents -Patients must not have had oral/IV steroids for 14 days prior to study entry. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids and mineralocorticoids is allowed. -Received therapeutic oral or intravenous antibiotics within 2 weeks prior to enrolment. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible -Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study -Treatment with systemic immunostimulatory agents (e.g. interferons or interleukin [IL]−2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment -Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrolment -Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome) -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 and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatment naive) -Severe infections within 4 weeks prior to enrolment in the study (e.g. hospitalization for complications of infection, bacteraemia, severe pneumonia) -Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrolment, unstable arrhythmias, or unstable angina -History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted) -Patients with uncontrolled Type 1 diabetes mellitus. Patients with Type 1 diabetes controlled on a stable insulin regimen are eligible. -Patients with active hepatitis infection (positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA -Positive test for HIV -Patients with active tuberculosis -History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug -Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serum calcium > the institutional ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab. Patients who are receiving bisphosphonate therapy or denosumab to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible. Patients receiving denosumab prior to enrollment must be willing and eligible to receive bisphosphonate instead while on study -History of autoimmune disease including myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, glomerulonephritis -Patients with a history of autoimmune-related hypothyroidism, unless on a stable dose of thyroid-replacement hormone -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 MPDL3280A formulation |
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E.5 End points |
E.5.1 | Primary end point(s) |
Clinical: Pathological complete response rate (pCRR) defined as ≥20% decrease in residual disease of the bladder, based on histological evaluation of the resected bladder specimen collected during cystectomy (post–treatment).
Biological: Dynamic changes in T cell subpopulations (CD8 and/or CD3) measured in tumour samples collected pre- and post-treatment with MPDL3280A. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Clinical: pCR rate will be based on histological evaluation of the resected bladder specimen collected during cystectomy (after 1-2 cycles of MPDL3280A treatment).
Biological: The change in T cell expression will be measured in tumour biopsy samples collected before and after treatment with MPDL3280A (an archival sample and a sample taken at cystectomy or post- treatment biopsy). |
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E.5.2 | Secondary end point(s) |
• Incidence, nature and severity of adverse events graded according to NCI-CTCAE v4.03 collected during and after MPDL3280A treatment. • Surgical complications as assessed by the Clavien-Dindo scoring system. • Radiological response, defined as a >30% decrease in tumour diameter from the baseline scan based on local investigator assessments • Disease-free survival, defined as time between the date of enrolment to first evidence of disease progression based on local investigator assessments or death, whichever occurs first. • Overall survival, defined as the time between the date of enrolment and death due to any cause. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Adverse events will be recorded during treatment and up to 24 weeks post cystectomy (AEs are recorded up to 4 weeks post-cystectomy, and unresolved AEs monitored until resolved or until 24 weeks post-cystectomy). Surgical complications will be assessed by the Clavien-Dindo scoring system post-cystectomy. • Radiological response will be assessed before and after treatment with MPDL3280A (baseline and pre-cystectomy). • Disease free survival will be recorded from enrolment until first evidence of disease recurrence or death; patients are followed up for 2 years after cystectomy. • Overall survival is defined as time from enrolment to death due to any cause. Patients are followed for 2 years after cystectomy; data will be collected until this time point. |
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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 | No |
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 | No |
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 | No |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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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 | 3 |
E.8.9.1 | In the Member State concerned days | 1 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 1 |