E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients affected by solid tumors other than hematologic malignancies, non small cell lung cancer , triple-negative breast cancer, urothelial bladder cancer, renal cell carcinoma, melanoma, and glioblastoma that are advanced and have progressed following at least one line of prior systemic therapy or for which standard or curative therapy does not exist or is not considered appropriate by the investigator. |
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E.1.1.1 | Medical condition in easily understood language |
Study for evaluation of activity of MPDL3280A in different types of tumors |
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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 |
The main objective is to evaluate the percentage of patients that do not experience progression during the first 18 weeks of treatment with MPDL3280A in patients affected by advanced solid tumors. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate the percentage of patients that do not progress during the first 24 weeks of treatment with MPDL3280A, the percentage of patients that achieve a response, the best response achieved, the duration of response and the progression free survival; these variables will be evaluated according to RECIST criteria v1.1. and according to modified RECIST criteria. Moreover OS will be evaluated as secondary endpoint. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Ability to comply with protocol
2.Male or female, 18 years of age or older
3.Histologically- or cytologically-documented solid tumors that are advanced and have progressed following at least one line of prior systemic therapy or for which standard or curative therapy does not exist or is not considered appropriate by the investigator
4.Representative formalin-fixed paraffin-embedded tumor specimens in paraffin blocks or, in exceptional cases, 15 unstained slides, with an associated pathology report, for central testing. Detection of tumor in the provided block needs to be confirmed by the central pathology laboratory prior to study enrollment. Patients with fewer than 15 unstained slides available at baseline (but no fewer than 10) may be eligible following discussion with the Sponsor
Only tissue from core needle, punch or excisional biopsy sample collection will be accepted. For core-needle biopsy specimens, at least three cores should be submitted for evaluation. Fine-needle aspiration, brushing, bone tissue, and lavage samples are not acceptable
Patients who do not have tissue specimens meeting eligibility requirements must undergo a biopsy during the screening period. Acceptable samples include core needle biopsies for deep tumor tissue (minimum three cores) or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions
5.Measurable disease as defined by RECIST, v1.1. (except for prostate cancer and malignant pleural mesothelioma) and disease-specific criteria for patients with prostate cancer (see Appendix 6) and malignant pleural mesothelioma (see Appendix 7)
6.ECOG Performance Status of 0 or 1
7.Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1):
-Absolute neutrophil count (ANC) ≥ 1500 cells/µL (without granulocyte colony-stimulating factor support within 2 weeks before Cycle 1, Day 1)
-Lymphocyte count ≥ 500/µL
-White blood cell counts > 2500/μL
-Platelet count ≥ 100,000/µL (without transfusion within 2 weeks before Cycle 1, Day 1)
-Hemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoyetic treatment to meet this criterion)
-Serum bilirubin < 1.5 × upper limit of normal (ULN), with the following exception:
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled
-Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions:
Patients with liver involvement: AST and/or ALT ≤ 5 × ULN
Patients with liver or bone metastases: alkaline phosphatase ≤ 5 × ULN
-Serum creatinine ≤ 1.5 × ULN
-International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN. This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low−molecular weight heparin or warfarin) should be on a stable dose
8.Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of study drug
9.For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective 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 |
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E.4 | Principal exclusion criteria |
1.Hematologic malignancies, NSCLC, triple-negative breast cancer, urothelial bladder cancer, renal cell carcinoma, melanoma, and glioblastoma
2.Malignancies other than disease under study 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
3.Uncontrolled tumor-related pain
4.Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
5.Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
6.Active or untreated CNS metastases as determined by CT or MRI evaluation during screening and prior radiographic assessments
7.Leptomeningeal disease
8.Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for ≥ 2 weeks prior to Cycle 1, Day 1
9.Any approved anticancer therapy, including chemotherapy, hormonal therapy or radiotherapy, within 3 weeks prior to initiation of study treatment; however, the following are allowed: hormone-replacement therapy or oral contraceptives and palliative radiotherapy for bone metastases > 2 weeks prior to Cycle 1, Day. Acute toxicities from previous therapy that have not resolved to Grade ≤ 1, except for alopecia
10.Pregnant and lactating women
11.Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease
12.Significant cardiovascular disease, such as New York Heart Association cardiac disease, myocardial infarction within 3 months prior to Cycle 1, Day 1, unstable arrhythmias or unstable angina
13.Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia or severe pneumonia
14.Received oral or IV antibiotics within 2 weeks prior to Cycle 1, Day. Patients receiving prophylactic antibiotics are eligible
15.Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study
16.History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
17.Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or to any component of the MPDL3280A formulation
18.History of autoimmune disease. Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible
19.Prior allogeneic bone marrow transplantation or prior solid organ transplantation
20.History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field is permitted
21.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 complication
22.Positive test for HIV
23.Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C
24.Active tuberculosis
25.Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
26.Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study.
27.Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD1, or anti−PDL1 therapeutic antibodies. Patients who have received prior treatment with anti−CTLA-4 may be enrolled, provided at least 5 half-lives have elapsed from the last dose of anti-CTLA-4 to the first dose of MPDL3280A and there was no history of severe immune-mediated adverse effects from anti−CTLA-4
28.Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug prior to Cycle 1, Day 1
29.Treatment with an investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within five half-lives of the investigational product, whichever is longer)
30.Known tumor PD-L1 expression status from other clinical trials
31.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) |
To evaluate non-progression rate (NPR) at 18 weeks in patients with advanced solid tumors treated with MPDL3280A, defined as the percentage of patients with complete response (CR) partial response (PR) or stable disease (SD) as assessed by the Investigator according to Response Evaluation Criteria In Solid Tumors, Version 1.1 (RECIST, v1.1) (except for prostate cancer and malignant pleural mesothelioma) and disease-specific criteria for patients with prostate cancer and malignant pleural mesothelioma |
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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) |
To evaluate NPR at 24 weeks, overall response rate (ORR), best overall response (BOR), clinical benefit rate (CBR), duration of response (DOR), time to tumor progression (TTP) and progression-free survival (PFS), as assessed by the Investigator using RECIST, v1.1 (except for prostate cancer and malignant pleural mesothelioma) and disease-specific criteria for patients with prostate cancer and malignant pleural mesothelioma
To evaluate NPR at 18 and 24 weeks, ORR, BOR, CBR, DOR, TTP and PFS, as assessed by the Investigator using modified RECIST
To evaluate overall survival (OS)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
NPR at 24 weeks according to RECIST v1.1
NPR at 18 and 24 weeks according to modified RECIST |
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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 | 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 | 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.8.3 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
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 |
Austria |
Brazil |
Canada |
China |
Denmark |
Finland |
France |
Germany |
Ireland |
Italy |
Netherlands |
Norway |
Poland |
Russian Federation |
Spain |
Switzerland |
Turkey |
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 for each cohort will occur when all patients have been followed for survival for a minimum of 24 months after the last patient has been enrolled or until all patients have died, withdrawn consent or are lost to follow up, whichever occurs first. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 2 |