Phase II Anetumab Ravtansine as 2nd Line Treatment for Malignant Pleural Mesothelioma (MPM)

Study Overview
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Brief Summary
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The main purpose of the 15743 study is to assess efficacy and safety of anetumab ravtansine versus vinorelbine in progression free survival in patients with stage IV mesothelin overexpressing malignant pleural mesothelioma (MPM). 210 eligible patients will be randomized to receive either anetumab ravtansine every three weeks or weekly vinorelbine. Treatment will continue until centrally confirmed disease progression or until another criterion is met for withdrawal from the study. Patients will enter follow up phase to capture safety and endpoint data as required. Efficacy will be measured by evaluating progression free survival from randomization. Radiological tumor assessments will be performed at defined time points until the patient's disease progresses. Blood samples will be collected for safety, pharmacokinetic and biomarker analysis. Archival or fresh biopsy tissue may also be collected for central pathology review and biomarkers.

Official Title
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A Randomized, Open-label, Active-controlled, Phase II Study of Intravenous Anetumab Ravtansine (BAY 94-9343) or Vinorelbine in Patients With Advanced or Metastatic Malignant Pleural Mesothelioma Overexpressing Mesothelin and Progressed on First Line Platinum/Pemetrexed-based Chemotherapy

Conditions
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Mesothelioma

Intervention / Treatment
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* Drug: Anetumab ravtansine (BAY94-9343)
* Drug: Vinorelbine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological documentation of malignant pleural mesothelioma (MPM) overexpressing mesothelin Unresectable locally advanced or metastatic MPM after locally confirmed progression on 1st line treatment with platinum in combination with pemetrexed. Patients must have measurable disease Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 Life expectancy of at least 3 months. Adequate bone marrow, liver and renal function Left ventricular ejection fraction (LVEF) ≥ 50% or the lower limit of normal (LLN) according to local institution ranges of normality. Exclusion Criteria: More than 1 previous systemic anti-cancer therapy line 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. Brain metastases, meningeal tumours or other metastases in the central nervous system Evidence of history of bleeding diathesis. Ongoing or active infection (bacterial, fungal, or viral) of National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 Grade > 2. Pre-existing cardiac conditions

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BAY94-9343<br>Drug Anetumab ravtansine given Intravenously (IV) | Drug: Anetumab ravtansine (BAY94-9343)<br>* Starting dose: 6.5 mg/kg administered as IV infusion over 1 h every 3 weeks until disease progression or treatment withdrawal for any reason. Dose reductions are permitted.<br>|
| Active Comparator: Vinorelbine<br>Drug Vinorelbine given Intravenously | Drug: Vinorelbine<br>* Starting dose: 30mg/m^2 administered as an IV infusion over 6 to 10 min every week until disease progression or treatment withdrawal for any reason. Dose reductions are permitted per standard practise.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS), [95% CI] | Progression-free survival (PFS), defined as time from randomization until disease progression according to mRECIST (Modified Response Evaluation Criteria in Solid Tumors) for Malignant pleural mesothelioma (MPM) per blinded central radiology review, or death. Only descriptive analysis of OS was repeated in the follow-up period. | From randomization till approximately 117 PFS events observed, up to approx. 30 months (data cut-off: 31-May-2017) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS), [95% CI] | Overall survival (OS) was defined as time from randomization until death from any cause. | Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause; one-sided log-rank test stratified by time to progression (TTP) on first line treatment. | 
| Objective Response Rate (ORR) | A patient is a responder if the patient has a confirmed best tumor response on-study of CR (Complete response) or PR (Partial response), as determined by the central radiological reviewer per mRECIST criteria. ORR in each treatment arm was defined as the number of responders divided by the number of randomized patients. A responder was a patient who had a confirmed best tumor response on-study of CR or PR, as determined by the central radiological reviewer per mRECIST criteria. | up to approx. 30 months (data cut-off: 31-May-2017) - Time from randomization until death from any cause. | 
| Disease Control Rate (DCR) | A patient has disease control if the patient has a best tumor response on-study of CR, PR, or SD (Stable disease). DCR was defined as a percentage of patients achieving CR, PR, or SD per mRECIST criteria, as determined by the central radiological reviewer. DCR was calculated in each treatment arm as the number of patients with disease control (a best tumor response on-study of CR, PR, or SD) divided by the number of randomized patients. | Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. | 
| Duration of Response (DOR) | DOR was defined in responders as the time from central documentation of tumor response date of first response in the confirmation sequence) to the earlier of disease progression as determined by the central radiological reviewer, or death without centrally documented progression. A responder was a patient who had a confirmed best tumor response on-study of CR or PR, as determined by the central radiological reviewer per mRECIST criteria. | Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. | 
| Durable Response Rate (DRR) | A durable responder was a responder (i.e. confirmed best tumor response on study of CR or PR) with duration of response of 180 days or more. | Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. | 
| Percentage of Participants With Confirmed Improvement of Symptoms Characteristic of Mesothelioma | Improvement rate of symptoms characteristic of mesothelioma was defined as the number of patients with confirmed improvement of symptoms characteristic of mesothelioma (based on the MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma, MDASI-MPM), divided by the number of patients evaluable for improvement of symptoms characteristic of mesothelioma. | up to approx. 30 months (data cut-off: 31-May-2017) | 
| Time to Worsening of Symptoms Characteristic of Mesothelioma | Time to worsening of symptoms characteristic of mesothelioma (TTWS) was defined in patients evaluable for assessing worsening of symptoms, as the time from randomization until the first worsening of symptoms characteristic of mesothelioma. Patients who died, were lost to follow-up, or ended (MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma) MDASI-MPM assessments without confirmed worsening of symptoms were censored at the date of their last MDASI-MPM assessment with a non-missing (Composite Symptom Score) CSS. | up to approx. 30 months (data cut-off: 31-May-2017) | 
| Time to Worsening of Pain | Time to worsening of pain (TTWP) was defined in patients evaluable for assessing worsening of pain, as time from randomization until the first worsening of pain. Patients who died, were lost to follow-up, or ended (MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma) MDASI-MPM assessments without confirmed worsening of pain were censored at the date of their last MDASI-MPM assessment with a non-missing pain score. | up to approx. 30 months (data cut-off: 31-May-2017) | 
| Percentage of Participants With Confirmed Improvement of Pain | Improvement rate of pain was defined as the number of patients with confirmed improvement of pain (based on the pain at its worst item of MDASI-MPM), divided by the number of patients evaluable for improvement of pain. | Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. | 
| Percentage of Participant With Treatment-emergent Adverse Events (TEAEs) | TEAEs were defined as all AEs starting or worsening within the treatment period. | Up to approx. 55 months (data cut-off: 02-Jul-2019) - Time from randomization until 30 days after last treatment (general AEs), or further until death from any cause (selected AEs). | 
| Number of Deaths | TEAE(s) associated with a fatal outcome (CTCAE Grade 5) at the time of the data cut-off 06-Apr-2018. | Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. | 
| Overall Survival (OS) - Addendum | Overall survival (OS) was defined as time from randomization until death from any cause; Only descriptive analyses of OS were repeated in with the data as of the 02 JUL 2019. | Up to approx. 55 month (data cut-off: 02-JUL-2019) - Time from randomization until death from any cause |