| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Malignant Pleural Mesothelioma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Mesothelioma that has progressed and has spread to other parts of the Body (metastatic) while or after standard treatment. |
|
| 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 | 10035605 |
| E.1.2 | Term | Pleural mesothelioma malignant advanced |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To investigate whether pre-treated mesothelioma patients treated with pembrolizumab have a better outcome in terms of progression-free survival (PFS), as assessed by independent radiological review, compared to standard, institutional-choice chemotherapy (gemcitabine or vinorelbine). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate secondary measures of clinical efficacy including objective response rate (ORR), investigator assessed progression free survival (PFS), overall survival (OS), and time to treatment failure (TTF).
To assess the safety and tolerability of the treatment.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Male and female patients aged 18 years and older
- Histologically confirmed malignant pleural mesothelioma (all subtypes are eligible)
- Progressing after or on previous platinum based chemotherapy.
- Availability of tumour tissue for translational research
- ECOG performance status 0-1 (patients who capable of all self-care)
- Life expectancy of at least 3 months
- Measurable or evaluable disease according to RECIST 1.1 criteria
- Adequate haematological function (Haemoglobin ≥90 g/L or ≥5.6 mmol/L; White Blood Cells ≥1.0 × 109/L; Lymphocytes ≥0.5 g/L; Absolute neutrophils count (ANC) ≥1.5 × 109/L; Platelet count ≥100 × 109/L)
- Adequate renal function (Creatinine ≥1.5 × ULN OR calculated creatinine clearance ≥40 mL/min)
- Adequate liver function (ALT and AST ≤2.5 × ULN; if the patient has liver metastases, ALT and AST must be ≤5 × ULN)
- Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 35 days before randomisation (the test has to be repeated 72 hours before pembrolizumab treatment start).
|
|
| E.4 | Principal exclusion criteria |
- Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
- Prior therapy with gemcitabine or vinorelbine.
- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to randomisation and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to randomisation. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
- Known or suspected hypersensitivity to pembrolizumab or any of its excipients.
- Known unstable or unresolved surgical or chemotherapy-related toxicity that would compromise the patient’s capacity to participate in the trial.
- Previous allogeneic tissue/solid organ transplant.
- Live vaccines within 30 days prior to first dose of pembrolizumab.
- Regular intake of immune-modulating drugs (such as interferon, methotrexate).
- History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease (ILD) or active, non-infectious pneumonitis.
- Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) or topical therapy (e.g., steroids) for psoriasis or eczema is not considered a form of systemic treatment.
- Ongoing clinically serious infections requiring systemic antibiotic or antiviral, antimicrobial, or antifungal therapy.
- HIV infection.
- Known active hepatitis B or hepatitis C.
- Known history of active tuberculosis.
- Patients with diagnosed immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomisation.
- Patients with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical condition that could affect the patient’s capacity to participate in the trial.
- Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the trial or evaluation of the trial results.
- Women who are pregnant or in the period of lactation.
- Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the trial and up to 120 days following cessation of trial treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival according to RECIST 1.1 criteria based on independent radiological review. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time from the date of randomisation until documented progression or death |
|
| E.5.2 | Secondary end point(s) |
• Objective Response (OR) determined by RECIST 1.1 criteria
• Overall survival (OS)
• Time to treatment failure
• Investigator assessed progression-free survival (PFS) determined according to RECIST 1.1 criteria
• Tolerability assessed by adverse events graded according CTCAE v4.0
Correlative endpoints:
• Responses according to PD-L1 expression levels, measured by IHC
• TILs analysis
• Mutation load
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-OR: across all assessment time-points during period from randomisation to termination of trial treatment.
-OS: time from the date of randomisation until death from any cause
- Time to treatement failure: time from the date of randomisation to discontinuation of treatment for any reason
- Investigator assessed PFS: Time from the date of randomisation until documented progression or death
-Tolerability: across all assessment time-points every 3 weeks during period from randomisation to termination of trial treatment |
|
| 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 | 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) | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
|
| 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
|
| Patient accrual is expected to be completed within 19 months including a run-in period of 6 months. The trial treatment phase will continue for a maximum of 2 years from the inclusion of the last patient and the trial is expected to end at all sites approximately 43 months after the inclusion of the first patient. |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
