| 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 | 19.0 |
| 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 |
| 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 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 malignant pleural mesothelioma
overexpressing mesothelin at the 2+ and 3+ level in at least 30% of
tumor cells as determined by centrally performed IHC.
Note: Patients with a sarcomatoid histology are not expected to have
mesothelin overexpression and should not be enrolled in the study.
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 least28 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. This will be confirmed by central review of images
before the patient can be randomized into the study
Note: Patients with non-pleural disease as the only relapse site after a
pleural surgery (e.g. subcutaneous lesions, nodal lesions, lung lesions
etc.) will be eligible if at least 1 measurable lesion according to RECIST
1.1 is present
5. Age ≥ 18 years (age limit may be higher if legally required in a
country e.g. in Japan adult age is considered > 20 years)
6. ECOG PS of 0 or 1
7. Life expectancy of at least 3 months
8. Women of childbearing potential (WOCBP) and men must agree to use
adequate contraception from signing of the ICF for full study until at
least 3 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.9. 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
10. 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 metastastic 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 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 73%
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 | 5 |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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