| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with advanced or metastatic malignant pleural mesothelioma overexpressing mesothelin |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced or metastatic malignant pleural mesothelioma |
|
| 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 |
| Test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
• Test overall survival
• Evaluate pulmonary function
• Evaluate patient-reported outcomes – symptom burden and health-related quality of life (QoL)
• Evaluate other indicators of treatment efficacy
• Evaluate safety
The other objectives of this study are to evaluate the:
• Pharmacokinetics and immunogenicity
• Biomarkers
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Eligibility criteria for mesothelin expression testing:
1. Written informed consent for mesothelin expression testing.
2. Unresectable locally advanced or metastatic MPM, confirmed by histology.
3. Availability of archival or fresh tissue for testing of mesothelin expression level.
Note: Archival tissue is preferred and fresh biopsy should only be obtained if no archival tissue is available and if in the investigator’s judgement, there is no additional risk for the patient’s safety. Patients with a sarcomatoid histology are not expected to have mesothelin overexpression and should not be enrolled in the study.
4. Age ≥ 18 years (age limit may be higher if legally required in a country e.g. in Japan adult age is considered ≥ 20 years).
5. ECOG PS of 0 or 1 (specified in Section 16.1).
6. Life expectancy of at least 3 months.
7. No prior treatment with anetumab ravtansine or vinorelbine.
8. No prior use of targeted agents, experimental therapy or systemic anti-cancer treatment other than ongoing or completed 1st line platinum/pemetrexed (with or without bevacizumab).
Eligibility criteria for study treatment
1. Written informed consent for full study.
2. Histological documentation of MPM overexpressing mesothelin at the moderate and stronger membrane staining level in at least 30% of viable tumor cells as determined by centrally performed IHC.
3. Unresectable locally advanced or metastatic MPM after progression on 1st line treatment with platinum in combination with pemetrexed. Last dose of previous therapy must be at least 28 days before start of study treatment.
Note: Patients progressed on 1st line treatment with platinum plus pemetrexed in combination bevacizumab are allowed
4. Patients must have at least 1 measurable lesion according to mRECIST for mesothelioma i.e. pleural lesion(s) measured using mRECIST or extra-pleural lesion(s) measurable per RECIST1.1. This will be confirmed by central review of images before the patient can be randomized into the study
5. ECOG PS of 0 or 1
6. Life expectancy of at least 3 months
7. Women of childbearing potential (WOCBP) and fertile men must agree to use adequate contraception from signing of the ICF for full study until at least 4 months after the last study drug administration. The investigator or a designated associate is requested to advise the patient how to achieve an adequate birth control. Highly effective (failure rate of less than 1% per year) contraception methods to be used (combined hormonal contraception, IUD, bilateral tubal occlusion or vasectomised partner or sexual abstinence).
Male patients with a female partner of childbearing potential must use a condom and ensure that an additional form of contraception is also used during treatment and until 4 months after last study drug administration.
8. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days before starting study treatment:
• Total bilirubin < 1.5 x the upper limit of normal (ULN). Documented Gilbert syndrome is allowed if total bilirubin is mildly elevated (< 6 mg/dL).
• ALT and AST < 3 x ULN (< 5 x ULN for patients with liver involvement of their cancer).
• ALP limit < 2.5 x ULN (< 5 x ULN for patients with liver involvement of their cancer).
• Amylase and lipase < 1.5 x ULN.
• Serum creatinine < 1.5 x ULN
• Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula
• Adequate coagulation, as assessed by the following laboratory test results:
o International normalized ratio (INR) or prothrombin time (PT) < 1.5 x ULN (CTCAE Grade < 1)
o Partial thromboplastin time (PTT) or activated PTT (aPTT) < 1.5 x ULN (CTCAE Grade < 1)
Note: Patients on anti-coagulation therapy will be allowed to participate if INR / PT and PTT / aPTT test results are compatible with the acceptable benefit-risk ratio at the investigator’s discretion
• Platelet (PLT) count > 100000/mm3 , without PLT transfusion within 3 weeks before the start of study treatment
• Hemoglobin (Hb) > 9 g/dL, without blood transfusion or erythropoietin within 6 weeks before the start of study treatment
• Absolute neutrophil count (ANC) > 1500/mm3, without biologic response modifiers, such as G-CSF, within 6 weeks before the start of study treatment
9. Left ventricular ejection fraction (LVEF) ≥ 50% of the lower limit of normal (LLN) according to local institution ranges of normality.
|
|
| E.4 | Principal exclusion criteria |
1. Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.
2. Previous (within 5 drug half-lifes – if drug half-life in subjects is known – or 28 days, whichever is shorther, before the start of study treatment) or concomitant participation in another clinical study with investigational medicinal product(s).
3. Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site).
4. More than 1 previous systemic anti-cancer therapy line for MPM (even if therapy used as neoadjuvant or adjuvant treatment).
Note: Patients pre-treated with systemic therapy other than platinum, pemetrexed, bevacizumab (e.g. other cytotoxic drugs, immunotherapy, targeted therapy, hormonal therapy, or any other experimental or approved therapy or device) are not to be enrolled.
5. Patients with corneal epitheliopathy or any eye disorder that may predispose the patients to this condition at the discretion of the investigator in consultation with the ophthalmologist/optometrist.
Note: Low grades of superficial punctate keratitis, within the range seen in the normal population, should not lead to the exclusion of the patient.
6. Previous or concurrent cancer that is distinct in primary site or histology from mesothelioma within 5 years before randomization.
Exceptions: curatively treated
• Cervical cancer in situ.
• Non-melanoma skin cancer.
• Superficial bladder tumors [Ta (Non-invasive tumor), Tis (Carcinoma in situ) and T1 (Tumor invades lamina propria)].
7. Major surgery, open biopsy or significant traumatic injury within 28 days before the start of study treatment.
8. Pregnant or breast-feeding patients. WOCBP must have a serum pregnancy test performed a maximum of 7 days before the start of study treatment, and a negative result must be documented before the start of study treatment.
9. Pre-existing cardiac conditions as outlined below:
• Congestive heart failure > New York Heart Association (NYHA) class 2
• Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before the start of study treatment.
• Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
10. Clinically significant uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
11. Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or venous pulmonary embolism within 6 months before the start of study treatment; venous thrombotic events as deep vein thrombosis within 3 months before the start of study treatment.
12. Ongoing or active infection (bacterial, fungal, or viral) of NCI-CTCAE version 4.03 Grade > 2.
13. Known history of human immunodeficiency virus (HIV) infection.
14. Known history of chronic hepatitis B or C.
15. Patients with seizure disorder requiring medication.
16. Brain metastases or meningeal tumors or other metastases in the central nervous system (CNS). Patients with neurological symptoms must undergo a contrast CT scan or MRI of the brain and/or other areas of the CNS as applicable within 28 days before the start of study treatment to exclude metastatic disease in the CNS.
17. History of organ allograft, stem cells or bone marrow transplant.
18. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > CTCAE Grade 3 within 4 weeks before the start of study treatment.
19. Non-healing wound, ulcer, or bone fracture.
20. Renal failure requiring peritoneal or hemodialysis.
21. Known hypersensitivity to anetumab ravtansine or vinorelbine, study drug classes or excipients in the formulation.
22. Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study.
23. Unresolved toxicity higher than NCI-CTCAE version 4.03 Grade 1 attributed to any prior therapy/procedure excluding anemia Grade 2 and alopecia of any Grade.
24. Any prohibited prior or concomitant therapy
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary endpoint is progression free survival. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Assuming median PFS of 3.6 months under vinorelbine treatment and constant hazards and a 2:1 treatment:comparator randomization, a 100% prolongation of PFS in the anetumab ravtansine arm in comparison to the comparator arm can be detected at a 1-sided significance level of 0.0125 with 90% power, with a single-stage trial with approximately 117 PFS events (hazard ratio 0.5). Assuming a maximum accrual rate of 12.5 patients/month (20.83 patients/month screened with 40% overall screening failure rate) with 6-month linear accrual ramp-up, and a 3.4%/month dropout (loss to follow-up and unevaluable for tumor assessment) rate, 210 patients be will accrued in approximately 19.8 months and reach endpoint maturation of 117 events in approximately 22.0 months. |
|
| E.5.2 | Secondary end point(s) |
| The secondary endpoint is overall survival. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Assuming true median OS of 9.6 months under vinorelbine treatment and constant hazards, a 60% prolongation of true OS (median 15.4 months) in the anetumab ravtansine arm in comparison to the comparator arm (median 9.6 months) can be detected with an overall 80% power and an overall 1-sided significance level of 0.025 (hazard ratio 0.625), with a 2-stage group sequential test with a total of 159 events. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Finland |
| France |
| Germany |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
For each participating EU country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last patient for all centers in the respective country has occurred.
As for this study, important data will be collected after LPLV, the end of the study as a whole will be the date when the clean database is available. |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 16 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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