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 |
a type of lung cancer that is called “malignant pleural mesothelioma” (MPM) |
|
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 | 21.0 |
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 |
The objective of this trial is to assess the effect of atezolizumab in terms of PFS and OS when added to standard of care (carboplatin/pemetrexed/bevacizumab), as first-line treatment of advanced MPM. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate secondary measures of clinical efficacy including response rate, disease control rate, time to treatment failure, duration of response.
To assess the safety and tolerability of the treatment.
To evaluate symptom-specific and global quality of life. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histologically confirmed advanced malignant pleural mesothelioma (all histological subtypes are eligible)
- Not amenable for radical surgery based on local standards
- Evaluable disease or measurable disease as assessed according to the mRECIST v1.1
- Availability of tumour tissue for translational research. Either archival tumour or fresh biopsy sample taken >7 days prior to protocol treatment start.
- Age >18 years
- Performance Status 0-1
- Life expectancy >3 months
- Adequate haematological, renal (CrCl >45) and liver function
- Able to understand and give written informed consent and comply with trial procedures
Women of childbearing potential, including woman who had their last menstrual period in the last 2 years, must have a negative serum pregnancy test within 2 weeks before randomisation.
- Baseline QoL form has been completed
- Written Informed Consent for protocol treatment must be signed and dated by the patient and the investigator prior to any trial-related intervention. |
|
E.4 | Principal exclusion criteria |
- Prior treatment for malignant pleural mesothelioma. Prior radiotherapy for symptom control is allowed, but the irradiated lesion cannot be used as target lesion. If the patient has another target lesion, the patient is eligible.
- Treatment with systemic immune-stimulatory agents (including but not limited to interferons, interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to randomisation and during protocol treatment.
- Treatment with systemic immunosuppressive medications (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumour necrosis factor [anti-TNF] agents) within 2 weeks prior to randomisation and during protocol treatment. Patients who have received acute, low-dose (≤10 mg oral prednisone or equivalent), systemic immunosuppressant medications may be enrolled in the trial.
- Previous allogenic tissue/solid organ transplant
- Live vaccines within 4 weeks prior to first dose of protocol treatment
- Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg). Anti-hypersensive therapy to achieve adequate control is allowable.
- Prior history of hypertensive crisis or hypertensive encephalphathy.
- Significant vascular disease (e.g., aortic aneurysm requiring surgical repair of recent peripheral arterial thrombosis) within 6 months prior to randomisation
- History of haemoptysis (≥one-half teaspoon of bright red blood per episode) within 1 month prior to randomisation
- Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
- Current or recent (within 10 days before randomisation) use of aspirin (>325 mg/day) or treatment with dipyridamole, ticlopidine, clopidogrel, and cilostazol
- Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes that has not been stable for >2 weeks prior to randomisation
- Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to the first dose of bevacizumab
- Major surgery or significant traumatic injury within 28 days prior to inclusion.
- Minor surgical procedure within 7 days, or placement of a vascular access device within 2 days of before randomisation.
- History of abdominal or tracheoesophageal fistula or gastrointestinal perforation withn 6 months prior to randomisation
- Clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
- Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
- Serious, non-healing wound, active ulcer, or untreated bone fracture
- Clear signs of tumour infiltration into the thoracic great vessels (on imaging)
- Clear signs of cavitation of pulmonary lesions (on imaging)
- Known history of severe allergic reactions to an platinum-containing compounds or any component of pemetrexed, bevacizumab or atezolizumab
- Grade ≥2 peripheral neuropathy as defined by NCI CTCAE v5.0
- HIV or active hepatitis B or hepatitis C
- Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol.
- 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 6 months after discontinuing protocol treatment.
- Active autoimmune disease that has required systemic treatment in past 2 years
- History of active diverticulitis
- Previous treatment with atezolizumab and/or bevacizumab or parallel participation in other interventional clinical trial with atezolizumab and/or bevacizumab. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Co-Primary endpoints: Progression-free survival (PFS) according to the mRECIST v1.1 and overall-survival (OS) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
-PFS: time from the date of randomisation until documented progression or death
-OS: time from the date of randomisation until death from any cause. |
|
E.5.2 | Secondary end point(s) |
Response rate (OR)
Disease control rate (DC)
Time to treatment failure (TTF)
Duration of response (DoR)
Adverse events according to CTCAE v5.0
Symptom-specific and global quality of life |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
-OR: from the start of protocol treatment across all time points until the end of protocol treatment
-DC: at 24 weeks.
-TTF: time from the date of randomisation to discontinuation of protocol treatment for any reason
-DoR: interval from the date of first documentation of objective response to the date of first documented progression or relapse.
-Adverse events:from the date of signature of informed consent until 90 days after the last dose of protocol treatment, regardless of whether it is considered related to a medication.
-Quality of life: from baseline to 12 weeks after treatment start. |
|
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
Belgium |
France |
Italy |
Spain |
Switzerland |
United Kingdom |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 7 |