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

• ClinicalTrials.gov Identifier: NCT02610140
• Recruitment Status: Completed
• First Posted: November 20, 2015
• Results First Posted: July 17, 2020
• Last Update Posted: November 4, 2020
• Sponsor: Bayer
• Collaborator: ImmunoGen and MorphoSys
• Information provided by (Responsible Party): Bayer

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Mesothelioma	Drug: Anetumab ravtansine (BAY94-9343); Drug: Vinorelbine	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 248 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: December 3, 2015
• Actual Primary Completion Date: May 31, 2017
• Actual Study Completion Date: September 6, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: BAY94-9343; Drug Anetumab ravtansine given Intravenously (IV)	Drug: Anetumab ravtansine (BAY94-9343); 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.
Active Comparator: Vinorelbine; Drug Vinorelbine given Intravenously	Drug: Vinorelbine; 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.

Outcome Measures

Primary Outcome Measures :

1. Progression-free Survival (PFS), [95% CI] [ Time Frame: From randomization till approximately 117 PFS events observed, up to approx. 30 months (data cut-off: 31-May-2017) ]
   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.

Secondary Outcome Measures :

1. Overall Survival (OS), [95% CI] [ Time Frame: 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. ]
   Overall survival (OS) was defined as time from randomization until death from any cause.
2. Objective Response Rate (ORR) [ Time Frame: up to approx. 30 months (data cut-off: 31-May-2017) - Time from randomization until death from any cause. ]
   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.
3. Disease Control Rate (DCR) [ Time Frame: Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. ]
   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.
4. Duration of Response (DOR) [ Time Frame: Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. ]
   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.
5. Durable Response Rate (DRR) [ Time Frame: Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. ]
   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.
6. Percentage of Participants With Confirmed Improvement of Symptoms Characteristic of Mesothelioma [ Time Frame: up to approx. 30 months (data cut-off: 31-May-2017) ]
   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.
7. Time to Worsening of Symptoms Characteristic of Mesothelioma [ Time Frame: up to approx. 30 months (data cut-off: 31-May-2017) ]
   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.
8. Time to Worsening of Pain [ Time Frame: up to approx. 30 months (data cut-off: 31-May-2017) ]
   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.
9. Percentage of Participants With Confirmed Improvement of Pain [ Time Frame: Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. ]
   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.
10. Percentage of Participant With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: 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). ]
    TEAEs were defined as all AEs starting or worsening within the treatment period.
11. Number of Deaths [ Time Frame: Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. ]
    TEAE(s) associated with a fatal outcome (CTCAE Grade 5) at the time of the data cut-off 06-Apr-2018.
12. Overall Survival (OS) - Addendum [ Time Frame: Up to approx. 55 month (data cut-off: 02-JUL-2019) - Time from randomization until death from any cause ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

La Jolla, California, United States, 92093-1503

United States, Colorado

Aurora, Colorado, United States, 80045

United States, Connecticut

Norwich, Connecticut, United States, 06360

United States, Florida

Tampa, Florida, United States, 33612

United States, Illinois

Chicago, Illinois, United States, 60612

Chicago, Illinois, United States, 60637

United States, Louisiana

New Orleans, Louisiana, United States, 70121

United States, Maryland

Bethesda, Maryland, United States, 20814

United States, Minnesota

Rochester, Minnesota, United States, 55905

United States, New York

Buffalo, New York, United States, 14263-0001

New York, New York, United States, 10016

United States, North Carolina

Durham, North Carolina, United States, 27710

United States, Ohio

Cleveland, Ohio, United States, 44195

United States, Texas

Dallas, Texas, United States, 75251

Houston, Texas, United States, 77030

Australia, New South Wales

St Leonards, New South Wales, Australia, 2065

Australia, Queensland

Woolloogabba, Queensland, Australia, 4102

Australia, South Australia

Adelaide, South Australia, Australia, 5043

Australia, Victoria

Richmond, Victoria, Australia, 3122

Australia, Western Australia

Nedlands, Western Australia, Australia, 6009

Belgium

Bruxelles - Brussel, Belgium, 1200

Edegem, Belgium, 2650

Gent, Belgium, 9000

Leuven, Belgium, 3000

Liege, Belgium, 4000

Sint-niklaas, Belgium, 9100

Canada, Alberta

Calgary, Alberta, Canada, T2N 4N2

Canada, Ontario

Hamilton, Ontario, Canada, L8V 5C2

London, Ontario, Canada, N6A 4L6

Toronto, Ontario, Canada, M5G 2M9

Finland

Helsinki, Finland, 00290

Turku, Finland, 20520

Vaasa, Finland, 65130

France

Bordeaux Cedex, France, 33076

Caen Cedex 5, France, 14076

Lille Cedex, France, 59037

Marseille, France, 13915

Paris, France, 75018

Paris, France, 75020

Pierre Benite, France, 69495

Italy

Pordenone, Friuli-Venezia Giulia, Italy, 33081

Bergamo, Lombardia, Italy, 24125

Milano, Lombardia, Italy, 20089

Milano, Lombardia, Italy, 20133

Monza Brianza, Lombardia, Italy, 20900

Torino, Piemonte, Italy, 10043

Siena, Toscana, Italy, 53100

Korea, Republic of

Seoul, Korea, Republic of, 05505

Seoul, Korea, Republic of, 06351

Netherlands

Amsterdam, Netherlands, 1066 CX

Rotterdam, Netherlands, 3015 CE

Poland

Gdansk, Poland, 80-952

Krakow, Poland, 31-202

Krakow, Poland, 31-501

Szczecin, Poland, 70-891

Russian Federation

Omsk, Russian Federation, 644013

Yekaterinburg, Russian Federation, 620036

Spain

A Coruña, Spain, 15006

Alicante, Spain, 03010

Barcelona, Spain, 08035

Madrid, Spain, 28041

Málaga, Spain, 29010

Turkey

Adana, Turkey, 01330

Ankara, Turkey, 06100

Eskisehir, Turkey, 26480

Istanbul, Turkey, 34899

Malatya, Turkey, 44280

Yenimahalle, Turkey, 06200

United Kingdom

Plymouth, Devon, United Kingdom, PL6 8DH

Maidstone, Kent, United Kingdom, ME16 9QQ

Leicester, Leicestershire, United Kingdom, LE1 5WW

Glasgow, United Kingdom, G12 0YN

London, United Kingdom, SE1 9RT

Manchester, United Kingdom, M23 9LT

Newcastle Upon Tyne, United Kingdom, NE7 7DN

Sponsors and Collaborators

Bayer

ImmunoGen and MorphoSys

Investigators

• Study Director: Bayer Study Director; Bayer

  Study Documents (Full-Text)

Documents provided by Bayer:

Study Protocol  [PDF] March 27, 2018

Statistical Analysis Plan  [PDF] April 18, 2018

More Information

Additional Information:

Click here to find results for studies related to Bayer Healthcare products. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kindler HL, Novello S, Bearz A, Ceresoli GL, Aerts JGJV, Spicer J, Taylor P, Nackaerts K, Greystoke A, Jennens R, Calabrò L, Burgers JA, Santoro A, Cedrés S, Serwatowski P, Ponce S, Van Meerbeeck JP, Nowak AK, Blumenschein G Jr, Siegel JM, Kasten L, Köchert K, Walter AO, Childs BH, Elbi C, Hassan R, Fennell DA. Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial. Lancet Oncol. 2022 Apr;23(4):540-552. doi: 10.1016/S1470-2045(22)00061-4.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT02610140
• Other Study ID Numbers: 15743; 2012-003650-88 ( EudraCT Number )
• First Posted: November 20, 2015
• Results First Posted: July 17, 2020
• Last Update Posted: November 4, 2020
• Last Verified: October 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Mesothelioma; Mesothelioma, Malignant; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases; Vinorelbine; Maytansine; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action