Patients with advanced or metastatic malignant pleural mesothelioma overexpressing mesothelin MedDRA version: 20.0 Level: LLT Classification code 10035605 Term: Pleural mesothelioma malignant advanced System Organ Class: 100000004864
Conditions
Sponsors
Bayer AG
Eligibility
Sex/Gender
All
Inclusion criteria
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. 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 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 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 RECIST 1.1. This will be confirmed by central review of images before the patient can be randomized into the study. Note: In case the only site of disease was previously treated with radiotherapy, there should be evidence of unequivocal PD in this site: measurable pleural disease should be assessed on a contrast enhanced CT/MRI done at the minimum 4 weeks after the end of radiotherapy and compared with previous imaging; unequivocal progression should be judged by the investigator as per mRECIST per MPM 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 4 months after the last study drug administration. Men being treated with vinorelbine are advised not to father a child during and up to 6 months after treatment; for all male patients, prior to treatment with either study drug, advice should be sought for conserving sperm due to the chance of irreversible infertility as a consequence of treatment (22).The investigator or a designated associate is
Exclusion criteria
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 re
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS); Secondary Objective: • 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 ;Primary end point(s): Primary endpoint is progression free survival.; Timepoint(s) of evaluation of this end point: Assuming true median PFS of 3.6 months under vinorelbine treatment and constant hazards, the study primary hypothesis test is designed to detect a 100% prolongation of true PFS (median 7.2 months) in the anetumab ravtansine arm in comparison to the comparator arm (hazard ratio 0.5) with 90% power with a 1-sided significance level of 0.0125. The final primary endpoint analysis will be performed after approximately 117 PFS events have been observed. The 210 randomized patients are estimated to be accrued in approximately 19.8 months. Data for final PFS analysis are estimated to mature in 21.2 months. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary endpoint is overall survival. ;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. An interim OS analysis will be performed at the time of the final PFS analysis at an estimated 22 months from first patient randomized, when an estimated 80 OS events will have been observed. If the study is not stopped for superiority at the OS IA, the final OS analysis will occur after approximately159 OS events have been observed, at approximately 41.3 months from first patient randomized | — |
Countries
Australia, Belgium, Canada, Finland, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Poland, Russian Federation, Spain, Turkey, United Kingdom, United States
Contacts
Public ContactBayer Clinical Trials Contact
Bayer AG
Outcome results
None listed