| 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 |
| To evaluate the efficacy of MPDL3280A in patients with solid tumors whom, in the opinion of the investigator, based on available clinical data, may benefit from treatment with anti PD-L1 , after investigational imaging (within the trials MPDL3280A-imaging-IST-UMCG, IL2-imaging-IST-UMCG, CD8-imaging), as measured by objective response rate (ORR) according to standard RECIST v1.1 as assessed by the investigator. |
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| E.2.2 | Secondary objectives of the trial |
•Evaluate PFS and DOR according to standard RECIST v1.1 as assessed by investigator
•Evaluate ORR, PFS and DOR according to modified RECIST as assessed by investigator
•Evaluate safety and tolerability of MPDL3280A
•Evaluate safety and tolerability of MPDL3280A while patients get 89Zr-MPDL3280A or 89Zr-CD8 antibody tracer
•Determine number of patients with and without tumor tracer uptake with 89Zr-MPDL3280A, 18F-FB-IL2 or 89Zr-CD8 antibody (as assessed in trials MPDL3280A-img-042015, IL2-img-UMCG-2015 and 89Zr-CD8 antibody imaging), and who also demonstrate response to MPDL3280A therapy
•Correlate PD-L1 biopsy results as assessed in trials MPDL3280A-img-042015, IL2-img-UMCG-2015 or 89Zr-CD8 imaging to response to MPDL3280A therapy
•Evaluate utility of biopsy at the time of apparent disease progression to distinguish apparent increases in tumor volume related to immunomodulatory activity of MPDL3280A (i.e., pseudoprogression/tumor immune infiltration) from true disease progression |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Histologically or cytologically documented locally advanced or metastatic solid tumor whom, in the opinion of the investigator, based on available clinical data, may benefit from treatment with anti PD-L1 immunotherapy
2.Participation within the 18F-IL2 imaging trial (IL2-imaging-IST-UMCG) or 89Zr-MPDL3280A antibody imaging trial (MPDL3280A-imaging-IST-UMCG) or CD8 imaging trial (ZED88082-img-UMCG-2018) before participation in the MPDL3280A treatment trial.
3.Assessment of the PD-L1-tumor status of a fresh tumor biopsy as determined by an IHC assay based on PD-L1 expression on immunocells and/or tumor cells performed by a central laboratory, performed as part of one of the investigational imaging trials.
4.Patients are eligible if disease progression during or following first-line chemotherapy or any subsequent treatment lines for locally advanced or metastatic solid tumor whom, in the opinion of the investigator, based on available clinical data, may benefit from treatment with anti PD-L1 immunotherapy
•Additional criteria for cancer of the urinary tract:
oPatients with disease progression during or following platinum-based adjuvant/neoadjuvant chemotherapy are eligible if ≤ 12 months have elapsed between the last treatment administration and the date of recurrence.
•Additional criteria for NSCLC:
oPatients with disease progression during or following platinum-based adjuvant/neoadjuvant chemotherapy or concurrent chemoradiation for NSCLC are eligible if ≤ 6 months have elapsed between the last treatment administration and the date of recurrence.
oPatients with a known sensitizing mutation in the epidermal growth factor receptor (EGFR) gene must also have experienced disease progression (during or after treatment) or intolerance to treatment with erlotinib, gefitinib, or another EGFR tyrosine kinase inhibitor (TKI).
oPatients with a known Anaplastic Lymphoma Kinase (ALK) fusion oncogene must also have experienced disease progression (during or after treatment) or intolerance to treatment with crizotinib or another ALK inhibitor.
5.Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6.Life expectancy ≥12 weeks.
7.Signed Informed Consent Form.
8.Ability to comply with protocol.
9.Age ≥18 years.
10.Measurable disease, as defined by standard RECIST v1.1. Previously irradiated lesions should not be counted as target lesions.
11.Adequate hematologic and end organ function, defined by the following laboratory results obtained within ≤28days prior to the first full dose of MPDL3280A:
•ANC ≥1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
•WBC counts >2500/μL
•Lymphocyte count ≥500/μL
•Platelet count ≥100,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
•Hemoglobin ≥9.0 g/dL. Patients may be transfused or receive erythropoietic treatment to meet this criterion.
•AST, ALT, and alkaline phosphatase ≤ 2.5× the upper limit of normal (ULN), with the following exceptions:
oPatients with documented liver metastases: AST and/or ALT ≤ 5 × ULN
oPatients with documented liver or bone metastases: alkaline phosphatase ≤ 5 × ULN
•Serum bilirubin ≤ 1.5 × ULN. Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled.
•INR and aPTT ≤ 1.5 × ULN. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
•Creatinine clearance ≥ 30 mL/min
12.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 6 months after the last dose of MPDL3280A. |
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| E.4 | Principal exclusion criteria |
1.Any approved anti-cancer therapy, including chemotherapy or hormonal therapy within ≤21 days prior to first full dose MPDL3280A
2.Treatment with any other investigational agent, other than investigational tracer 89Zr-MPDL3280A, 18F-FB-IL2 or 89Zr-CD8-imaging, or participation in another trial with therapeutic intent within 28 days prior to first full dose MPDL3280A
3.Unstable brain metastases
4.Unstable leptomeningeal disease
5.Uncontrolled tumor-related pain
6.Uncontrolled pleural effusion, pericardial effusion, ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX) are allowed
7.Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or calcium >12 mg/dL or corrected serum calcium >ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
8. A second malignancy within 5 years prior to Cycle 1 Day 1, with exception of those with negligible risk of metastasis or death treated with expected curative outcome (adequately treated carcinoma in situ of cervix, basal or squamous cell skin cancer, localized prostate cancer treated with curative intent, ductal carcinoma in situ treated surgically with curative intent)
9.Pregnant and lactating women
10.History of severe allergic, anaphylactic, other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
11.Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cell products or any component of MPDL3280A formulation
12.History of autoimmune disease, including but not limited to 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, or glomerulonephritis.
• history of autoimmune-related hypothyroidism on stable dose of thyroid replacement hormone may be eligible
• controlled Type I diabetes mellitus on a stable dose of insulin regimen may be eligible
• eczema, psoriasis, lichen simplex chronicus, vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided they meet following conditions:
o Rash must cover less than 10% BSA
o Disease well controlled at baseline and only requiring low potency topical steroids
o No acute exacerbation of underlying condition within the previous 12 months (not requiring PUVA, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency or oral steroids)
13.History of idiopathic pulmonary fibrosis, organizing pneumonia (bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
14.Serum albumin < 2.5 g/dL
15.Positive test for HIV
16.Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C
17.Active tuberculosis
18.Severe infections within 4 weeks prior to first full dose MPDL3280A, including but not limited to hospitalization for complications of infection, bacteremia, severe pneumonia
19.Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
20.Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
21.Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, unstable angina
22.Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1 or anticipation of need for major surgical procedure during course of study
23.Prior allogeneic bone marrow transplantation or solid organ transplant
24.Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1or anticipation that such a live attenuated vaccine will be required during study
25.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
26.Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD-1, anti−PD-L1 therapeutic antibodies.
27.Treatment with systemic immunostimulatory agents (including but not limited to IFNs,IL-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to first full dose MPDL3280A
28.Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, anti−tumor necrosis factor agents) within 2 weeks prior to Cycle 1, Day 1 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Response to MPDL3280A therapy as measured by ORR according to standard RECIST v1.1, defined as the proportion of patients whose best overall response is either a partial response (PR) or complete response (CR), as assessed by the investigator. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis of the primary endpoint will be performed after a minimum of 6 months follow-up. |
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| E.5.2 | Secondary end point(s) |
• Evaluation of ORR, PFS and DOR according to modified RECIST, as assessed by the investigator.
o ORR is defined as the proportion of patients whose best overall response is either a PR or CR, as assessed by the investigator.
o PFS is defined as the time from the first full treatment dose of MPDL3280A to time of disease progression per modified RECIST as determined by the investigator or death due to any cause, whichever occurs first.
o DOR will be analyzed for the subset of patients, who achieved an objective response assessed by the investigator per modified RECIST. DOR is defined as the time from the initial occurrence of documented CR or PR until documented disease progression as determined by the investigator or death due to any cause, whichever occurs first.
• Evaluation of PFS and DOR according to standard RECIST v1.1, as assessed by the investigator.
o PFS is defined as the time from the first full treatment dose of MPDL3280A to time of disease progression per standard RECIST v1.1 as determined by the investigator or death due to any cause, whichever occurs first.
o DOR will be analyzed for the subset of patients, who achieved an objective response assessed by the investigator per standard RECIST v1.1. DOR is defined as the time from the initial occurrence of documented CR or PR until documented disease progression as determined by the investigator or death due to any cause, whichever occurs first.
• Safety assessment through:
o Incidence, nature and severity of adverse events, including protocol-defined events of special interest, graded according to NCI CTCAE4.0
o Changes in laboratory test results, vital signs and physical findings.
• 89Zr-MPDL3280A, 18F-FB-IL2 or CD8 imaging tumor uptake, as defined and assessed in the investigational imaging protocols MPDL3280A-img-042015 and IL2-img-UMCG-2015.
•Number of patients with and patients without tumor tracer uptake with 89Zr-MPDL3280A, 18F-FB-IL2 or 89Zr-CD8 antibody study, who demonstrate response to MPDL3280A therapy.
•Pathological PD-L1 assessment, as defined and evaluated in the investigational imaging protocols MPDL3280A-imaging-IST-UMCGimg-042015 and IL2-imaging-IST-UMCGimg-UMCG-2015.
•Status of tumor-infiltrating immune cells in biopsy specimen collected at the first evidence of radiographic disease progression according to standard RECIST v1.1.
• The fecal microbiome will be analysed in related to antitumor effect. Feces sampling will be performed before treatment and at cycle three. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | 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 | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 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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| 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 | |
| E.8.9.1 | In the Member State concerned days | |
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