| 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 |
|
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase II:
• To evaluate whether pembrolizumab, alone or given to patients receiving standard chemotherapy, improves progression-free survival (RECIST 1.1) in malignant pleural mesothelioma (MPM) compared to standard chemotherapy.
Phase III:
• To evaluate whether pembrolizumab improves overall survival when added to standard chemotherapy in malignant pleural mesothelioma (MPM). |
|
| E.2.2 | Secondary objectives of the trial |
Phase II/III:
• To evaluate the tolerability of pembrolizumab, alone or given to patients receiving standard chemotherapy.
• To assess antitumour activity of pembrolizumab, alone or given to patients receiving standard chemotherapy including response rate (complete and partial response), using RECIST 1.1.
• To evaluate the quality of life impact of pembrolizumab, alone or given to patients receiving standard chemotherapy as measured by time from randomization to first deterioration in the three common MPM Quality of Life scales.
• To evaluate whether pembrolizumab improves progression-free survival (RECIST 1.1) when added to standard chemotherapy in malignant pleural mesothelioma (MPM).
• To explore the predictive and prognostic value of PD-L1 expression and presence of inflammatory cell subsets within the tumour microenvironment.
Phase III:
• To evaluate the incremental cost effectiveness and cost utility ratios between arms. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must have histologically confirmed malignant pleural mesothelioma. Patients must be eligible to receive standard chemotherapy with pemetrexed and cisplatin and have no contraindications to standard chemotherapy.
2. Patients must have unresectable advanced and/or metastatic disease, incurable by standard therapies.
3. All patients must have a cellular tumour block from their primary or metastatic tumour available and consent to release the block/recently cut slides for correlative analyses.
4. Presence of radiologically documented disease. At least one site of disease must be unidimensionally measurable by mRECIST or RECIST 1.1.
5. Age ≥ 18 years.
6. ECOG performance status 0 or 1.
7. Previous Therapy
Cytotoxic Chemotherapy:
• Patients must not have received prior chemotherapy for any stage of advanced/metastatic disease.
• Patients who received previous (neo)adjuvant cisplatin-based systemic chemotherapy must have received the last dose of chemotherapy at least 12 months before registration.
Other Anti-Cancer Therapy:
• Patients may not have received targeted small molecule therapy, immunotherapies and viral therapies, biologic therapies and angiogenesis inhibitors for advanced/metastatic disease, or any prior immunotherapy for any stage of disease.
Radiation:
Patients may have had prior radiation therapy, but NOT to the thorax unless clear disease progression has been demonstrated and confirmed with CCTG. A minimum of 28 days must have elapsed between the end of radiotherapy and registration onto the study. Radiation must have involved < 30% of functioning bone marrow and there must be measurable disease outside the previously irradiated area (patients whose sole site of disease (for example pleural rind) is in a previously irradiated area are ineligible UNLESS there is evidence of progression, or new lesions have been documented, in the irradiated field). Please call the CCTG at 613-533-6430 PRIOR to registration if questions arise about the interpretation of this criterion). Patients must have recovered from any acute toxic effects from radiation prior to registration.
Previous Surgery:
Previous major surgery is permitted provided that it has been at least 28 days prior to patient registration and that wound healing has occurred.
8. Laboratory Requirements : Absolute neutrophils ≥ 1.5 x 109/L ; Platelets ≥ 100 x 109/L ; Hemoglobin ≥ 90 g/L ; Bilirubin ≤ 1.5 x ULN ; AST and ALT ≤ 2.5 x ULN ; Serum creatinine < 1.25 x ULN or Creatinine clearance ≥ 50 mL/min.
9. Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements.
10. Patients must be accessible for treatment, response assessment and follow-up.
11. Protocol treatment is to begin within 2 working days of patient randomization.
12. Women/men of childbearing potential must have agreed to use two highly effective contraceptive methods during the study and for six months after discontinuation.
13. Patient must be able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires.
|
|
| E.4 | Principal exclusion criteria |
1. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at doses more than 10 mg prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first and any dose of trial treatment.
2. Has active autoimmune disease that has required systemic treatment in the past 3 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) or history of allogeneic transplantation. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
3. Must not have received a live vaccine within 30 days of planned start of study therapy.
4. Patients with known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment 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 trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
5. Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction within the previous year or cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects). Patients with a significant cardiac history, even if controlled, should have a LVEF ≥ 50%.
6. Patients with a history of other malignancies unless having undergone curative therapy (i.e. resection, radiation, etc.) and do not require concurrent anticancer therapy.
7. History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab or any of the other chemotherapy agents.
8. Concurrent treatment with other investigational drugs or anti-cancer therapy.
9. Patients with serious illness or medical condition that would not permit the patient to be managed according to the protocol including, but not limited to:
• History of significant neurologic or psychiatric disorder which would impair the ability to obtain consent or limit compliance with study requirements.
• Active infection requiring systemic therapy; (including any patient known to have active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) [note: testing in asymptomatic patients is not required] or tuberculosis).
Known history of, or any evidence of active, non-infectious pneumonitis.
• Any other medical conditions that might be aggravated by treatment.
• Serious or non-healing wound, ulcer, or bone fracture.
10. Patients with evidence of interstitial lung disease.
11. Patients with severe/ uncontrollable tumor pain that requires radiation prior to starting on systemic therapy.
12. Pregnant or lactating women. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| During treatment period and post-treatment with follow-up every 12 weeks until progression, then every 24 weeks until death |
|
| E.5.2 | Secondary end point(s) |
Phase II/III:
• To evaluate the tolerability of pembrolizumab, alone or given to patients receiving standard chemotherapy.
• To assess antitumour activity of pembrolizumab, alone or given to patients receiving standard chemotherapy including response rate (complete and partial response), using RECIST 1.1.
• To evaluate the quality of life impact of pembrolizumab, alone or given to patients receiving standard chemotherapy as measured by time from randomization to first deterioration in the three common MPM Quality of Life scales.
• To evaluate whether pembrolizumab improves progression-free survival (RECIST 1.1) when added to standard chemotherapy in malignant pleural mesothelioma (MPM).
• To explore the predictive and prognostic value of PD-L1 expression and presence of inflammatory cell subsets within the tumour microenvironment.
Phase III:
• To evaluate the incremental cost effectiveness and cost utility ratios between arms. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| According to protocol schedules |
|
| 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 | No |
| 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 | 27 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 | 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
|
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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