Placebo Controlled Study of VS-6063 in Subjects With Malignant Pleural Mesothelioma

Phase 2

Terminated

• Conditions: Malignant Pleural Mesothelioma
• Interventions: Drug: Placebo; Drug: defactinib (VS-6063)

• Registration Number: NCT01870609
• Lead Sponsor: Verastem, Inc.

Brief Summary

This study is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study of defactinib (VS-6063) in subjects with malignant pleural mesothelioma (MPM) who have not progressed (confirmed partial response or stable disease) following ≥ 4 cycles of treatment with pemetrexed/cisplatin or pemetrexed/carboplatin. Prior to entry and randomization to the study, each subject must have tumor Merlin status(high or low) established by immunohistochemistry performed at a central laboratory. Subjects will be randomized in a 1:1 ratio to receive oral VS-6063 400 mg twice per day, or matched placebo. Randomization will be stratified by tumor Merlin status (high versus low). Progression will be assessed both locally and by central review using the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1. Subjects will continue to receive treatment until disease progression or other discontinuation criteria are met. Following documentation of nonfatal disease progression, all subjects will be followed for overall survival by telephone contact every 2 months until end of life or the close of the study.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2013-05-29
• Study First Submitted QC: 2013-06-03
• Study First Posted: 2013-06-06
• Study Start: 2013-09
• Primary Completion: 2016-01
• Study Completion: 2016-01
• Status Verified: 2016-03
• Disposition First Submitted: 2016-03-31
• Disposition First Submitted QC: 2016-03-31
• Disposition First Posted: 2016-05-02
• Last Update Submitted: 2017-01-26
• Last Update Posted: 2017-01-30

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 344

Inclusion Criteria

• 1. Able to understand and give written informed consent and comply with study procedures.
• 2. Histologically proven diagnosis of MPM. All subjects must have biopsy material (archival tissue is acceptable) available for immunohistochemistry determination of Merlin status prior to enrollment.
• 3. Evaluable disease, or measurable disease as assessed by RECIST version 1.1.
• 4. Received only one prior chemotherapy regimen consisting of ≥ 4 cycles of pemetrexed/cisplatin or pemetrexed/carboplatin; subjects must have documentation of an ongoing response (confirmed PR or SD) following completion of this regimen. Subjects changing from cisplatin to carboplatin or vice versa within the same course of treatment because of platinum toxicity will be considered to have had first-line chemotherapy. Note: Subjects may have undergone previous surgical resection of their disease providing it was completed prior to initiation of chemotherapy.
• 5. Received last dose of prior chemotherapy within ≤ 6 weeks of first dose of VS-6063.
• 6. Have completed baseline quality of life evaluation as assessed by LCSS modified for mesothelioma
• 7. Age ≥18 years.
• 8. Life expectancy ≥3 months.
• 9. All prior cytotoxic toxicities must have resolved to grade ≤ 1 prior to randomization.
• 10. Performance status according to the Karnofsky Scale of ≥ 70% (after palliative measures such as pleural drainage).
• 11. Corrected QT interval (QTc) < 470 ms (as calculated by the Fridericia correction formula).
• 12. Adequate bone marrow function (hemoglobin ≥ 9.0 g/dL; platelets ≥ 100 x 109/L; absolute neutrophil count [ANC] ≥ 1.5 x 109/L) without the use of hematopoietic growth factors.
• 13. Adequate renal function (creatinine ≤ 1.5 x ULN [upper limit of normal] or glomerular filtration rate of ≥ 50mL/min).
• 14. Adequate hepatic function (total bilirubin ≤ 1.5 x ULN for the institution; aspartate transaminase [AST] and alanine transaminase [ALT] ≤ 2.5 x ULN).
• 15. Men and women of childbearing potential must agree to use adequate contraception(double barrier birth control) for the duration of study therapy and for 3 months after the last dose of VS-6063.

Exclusion Criteria

• 1. Currently enrolled in (or completed within 30 days before study drug administration)another investigational drug study.
• 2. GI condition that could interfere with the swallowing or absorption of study drug.
• 3. History of upper GI bleeding, ulceration, or perforation within 12 months prior to the first dose of study drug.
• 4. Known history of Gilbert's Syndrome.
• 5. Known history of stroke or cerebrovascular accident within 6 months prior to the first dose of study drug.
• 6. Subjects with known infection with human immunodeficiency virus or Acquired Immune Deficiency Syndrome (testing not required).
• 7. Subjects with known infection with hepatitis A, B or C (testing not required).
• 8. Any evidence of serious active infections.
• 9. Major surgery within 28 days prior to the first dose of study drug.
• 10. Uncontrolled or severe concurrent medical condition (including uncontrolled brain metastases). Stable brain metastases either previously treated or being treated with a stable dose of steroids and/or anticonvulsants (no dose change within 28 days prior to the first dose of study drug) will be allowed.
• 11. Uncontrolled or severe cardiovascular disease, including myocardial infarct or unstable angina within 6 months prior to study treatment, New York Heart Association Class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, or cardiac amyloidosis.
• 12 Known history of malignant hypertension.
• 13. Psychiatric illness or social situations that would limit compliance with study requirements.
• 14. History of another invasive malignancy in the last 5 years. Adequately treated noninvasive,non-melanoma skin cancers as well as in situ carcinoma of the cervix within the last 5 years will be allowed.
• 15. Prior treatment with drugs an FAK inhibitor.
• 16. Women who are pregnant or breastfeeding.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	2 placebo tablets, administered orally, twice daily
defactinib (VS-6063)	defactinib (VS-6063)	2 x 200 mg defactinib (VS-6063) tablets, administered orally, twice daily

Primary Outcome Measures

Name	Time	Method
Compare the overall survival (OS) in subjects with malignant pleural mesothelioma receiving defactinib (VS-6063) or placebo	From randomization to end of life, an expected average of 12 months	The median duration of OS will be estimated based on the 50th percentile of the Kaplan-Meier distribution
Compare the progression free survival (PFS) in subjects with malignant pleural mesothelioma receiving defactinib (VS-6063) or placebo	From date of randomization to earliest documented date of progression, an expected average of 4 months	PFS will be calculated based on the stratified log-rank test, and will use Kaplan-Meier estimation methods for estimation of summary statistics

Secondary Outcome Measures

Name	Time	Method
To assess Quality of Life (QoL) in subjects treated with defactinib (VS-6063) or placebo using the Lung Cancer Symptom Scale modified for mesothelioma (LCSS-Meso)	Every 3-4 weeks from baseline through end of treatment, an expected average of 4 months	QoL will be assessed using the LCSS-Meso. The LCSS-Meso total score will be analyzed through a comparison of median area under the curve (AUC) between the 2 treatment groups using a Wilcoxon test.
To determine the objective response rate (ORR) in subjects receiving defactinib (VS-6063) or placebo.	Every 6-8 weeks from baseline through end of treatment, an expected average of 4 months	ORR is measured as the best overall response assessed by central review using Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1.

Trial Locations

Locations (73)

University of California San Francisco Medical Center; 🇺🇸 San Francisco, California, United States

Gustave Roussy; 🇫🇷 Villejuif, France

Royal Surrey County Hospital; 🇬🇧 Guildford, United Kingdom

Kent Oncology Centre, Maidstone Hospital; 🇬🇧 Kent, United Kingdom

Guys Hospital; 🇬🇧 London, United Kingdom

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Cleveland Clinic Florida; 🇺🇸 Weston, Florida, United States

University of Chicago Medical Center; 🇺🇸 Chicago, Illinois, United States

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Roswell Park Cancer Institute; 🇺🇸 Buffalo, New York, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

Abramson Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States

Sarah Cannon Research Institute; 🇺🇸 Nashville, Tennessee, United States

Sir Charles Gairdner Hospital; 🇦🇺 Perth, Western Australia, Australia

Chris O'Brien Lifehouse at RPA; 🇦🇺 Camperdown, Australia

Epworth Hospital; 🇦🇺 Melbourne, Australia

Monash Cancer Center; 🇦🇺 East Bentlrigh, Australia

Northern Cancer Institute; 🇦🇺 Sydney, Australia

Calvary Mater Newcastle; 🇦🇺 Waratah, Australia

Princess Alexandra Hospital +61(0)7 3176 5054; 🇦🇺 Woolloongabba, Australia

UCL - St. Luc; 🇧🇪 Brussel, Belgium

Universitaire Ziekenhuizen Leuven (University Hospitals Leuven); 🇧🇪 Leuven, Belgium

CHRU, Lille; 🇫🇷 Lille, France

CHU Liege - Sart Tilman; 🇧🇪 Liege, Belgium

Antwerp University Hospital; 🇧🇪 Edegem, Belgium

Princess Margaret Hospital; 🇨🇦 Toronto, Ontario, Canada

Hôpitaux de Marseille; 🇫🇷 Marseille, France

Cliniche Humanitas Gavazzeni; 🇮🇹 Bergamo, Italy

Istituto Oncologico Veneto; 🇮🇹 Padova, Italy

Juntendo University; 🇯🇵 Tokyo, Japan

Kinki University Hospital; 🇯🇵 Osaka, Japan

Kyushu Cancer Center; 🇯🇵 Fukuoka, Japan

Hiroshima University Hospital; 🇯🇵 Hiroshima, Japan

Okayama Rousai Hospital; 🇯🇵 Okayama, Japan

Medisch Spectrum Twente, Enschede; 🇳🇱 Enschede, Netherlands

Hyogo College of Medicine; 🇯🇵 Hyogo, Japan

Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis; 🇳🇱 Amsterdam, Netherlands

Atrium MC; 🇳🇱 Heerlen, Netherlands

Auckland Oncology Research Centre; 🇳🇿 Auckland, New Zealand

Erasmus MC; 🇳🇱 Rotterdam, Netherlands

Norwegian Radium Hospital; 🇳🇴 Oslo, Norway

Canterbury Regional Cancer & Haematology Service; 🇳🇿 Christchurch, New Zealand

Centrum Pulmonologii Ii Torakochirurgii w Bystrej; 🇵🇱 Bystra, Poland

Institut Oncològic del Vallés Consorci Hospitalari Parc Tauli; 🇪🇸 Barcelona, Spain

The Medical Oncology Centre of Rosebank; 🇿🇦 Johannesburg, South Africa

Iatros International / Bloemfontein Medi-Clinic; 🇿🇦 Bloemfontein, Free State, South Africa

Mary Potter Oncology Center, Little Company of Mary Hospital; 🇿🇦 Pretoria, South Africa

Ensayos Clínicos Oncología; 🇪🇸 Madrid, Spain

Hospital Madrid Norte- Sanchinarro, Centro Integral Oncológico Clara Campal (CIOCC); 🇪🇸 Madrid, Spain

Karolinska University Hospital; 🇸🇪 Stockholm, Sweden

Clatterbridge Cancer Centre; 🇬🇧 Bebington, Wirral, United Kingdom

Skane University Hospital; 🇸🇪 Lund, Sweden

Southmead Hospital; 🇬🇧 Bristol, United Kingdom

University Hospital; 🇸🇪 Uppsala, Sweden

Beatson Oncology Centre; 🇬🇧 Glasgow, United Kingdom

Addenbrooke's Hospital; 🇬🇧 Cambridge, United Kingdom

Broomfield Hospital; 🇬🇧 Chelmsford, United Kingdom

Velindre Hospital Cardiff; 🇬🇧 Cardiff, United Kingdom

Tayside Cancer Centre; 🇬🇧 Dundee, United Kingdom

University of Leicester; 🇬🇧 Leicester, United Kingdom

Wythenshawe Hospital; 🇬🇧 Manchester, United Kingdom

St. Bartholomew's Hospital; 🇬🇧 London, United Kingdom

Freeman Hospital; 🇬🇧 Newcastle, United Kingdom

Derriford Hospital; 🇬🇧 Plymouth, United Kingdom

Weston Park Hospital; 🇬🇧 Sheffield, United Kingdom

Southampton General Hospital; 🇬🇧 Southampton, United Kingdom

UT Southwestern; 🇺🇸 Dallas, Texas, United States

Peninsula Oncology Centre; 🇦🇺 Frankston, Victoria, Australia

Vall d'Hebron University Hospital; 🇪🇸 Barcelona, Spain

Jacobi Medical Center; 🇺🇸 Bronx, New York, United States

University Hopsital Ghent; 🇧🇪 Ghent, Belgium

Castle Hill Hospital; 🇬🇧 Hull, United Kingdom