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

A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of VS-6063 in Subjects With Malignant Pleural Mesothelioma

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.

Study Overview

• Status: Terminated
• Conditions: Malignant Pleural Mesothelioma
• Intervention / Treatment: Drug: defactinib (VS-6063); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 344
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Camperdown, Australia
    • Chris O'Brien Lifehouse at RPA
  • East Bentlrigh, Australia, 3165
    • Monash Cancer Center
  • Melbourne, Australia
    • Epworth Hospital
  • Sydney, Australia
    • Northern Cancer Institute
  • Waratah, Australia
    • Calvary Mater Newcastle
  • Woolloongabba, Australia, QLD 4102
    • Princess Alexandra Hospital +61(0)7 3176 5054
  • Victoria
    • Frankston, Victoria, Australia
      • Peninsula Oncology Centre
  • Western Australia
    • Perth, Western Australia, Australia
      • Sir Charles Gairdner Hospital
• Belgium
  • Brussel, Belgium
    • UCL - St. Luc
  • Edegem, Belgium
    • Antwerp University Hospital
  • Ghent, Belgium
    • University Hopsital Ghent
  • Leuven, Belgium
    • Universitaire Ziekenhuizen Leuven (University Hospitals Leuven)
  • Liege, Belgium
    • CHU Liège - Sart Tilman
• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • Princess Margaret Hospital
• France
  • Lille, France
    • CHRU, Lille
  • Marseille, France
    • Hôpitaux de Marseille
  • Villejuif, France
    • Gustave Roussy
• Italy
  • Bergamo, Italy
    • Cliniche Humanitas Gavazzeni
  • Padova, Italy
    • Istituto Oncologico Veneto
• Japan
  • Fukuoka, Japan
    • Kyushu Cancer Center
  • Hiroshima, Japan
    • Hiroshima University Hospital
  • Hyogo, Japan
    • Hyogo College of Medicine
  • Okayama, Japan
    • Okayama Rousai Hospital
  • Osaka, Japan
    • Kinki University Hospital
  • Tokyo, Japan
    • Juntendo University
• Netherlands
  • Amsterdam, Netherlands
    • Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis
  • Enschede, Netherlands
    • Medisch Spectrum Twente, Enschede
  • Heerlen, Netherlands
    • Atrium MC
  • Rotterdam, Netherlands
    • Erasmus MC
• New Zealand
  • Auckland, New Zealand
    • Auckland Oncology Research Centre
  • Christchurch, New Zealand
    • Canterbury Regional Cancer & Haematology Service
• Norway
  • Oslo, Norway
    • Norwegian Radium Hospital
• Poland
  • Bystra, Poland
    • Centrum Pulmonologii Ii Torakochirurgii w Bystrej
• South Africa
  • Johannesburg, South Africa
    • The Medical Oncology Centre of Rosebank
  • Pretoria, South Africa
    • Mary Potter Oncology Center, Little Company of Mary Hospital
  • Free State
    • Bloemfontein, Free State, South Africa
      • Iatros International / Bloemfontein Medi-Clinic
• Spain
  • Barcelona, Spain
    • Institut Oncològic del Vallés Consorci Hospitalari Parc Tauli
  • Barcelona, Spain
    • Vall d'Hebron University Hospital
  • Madrid, Spain
    • Ensayos Clínicos Oncología
  • Madrid, Spain
    • Hospital Madrid Norte- Sanchinarro, Centro Integral Oncológico Clara Campal (CIOCC)
• Sweden
  • Lund, Sweden
    • Skane University Hospital
  • Stockholm, Sweden
    • Karolinska University Hospital
  • Uppsala, Sweden
    • University Hospital
• United Kingdom
  • Bristol, United Kingdom
    • Southmead Hospital
  • Cambridge, United Kingdom
    • Addenbrooke's Hospital
  • Cardiff, United Kingdom
    • Velindre Hospital Cardiff
  • Chelmsford, United Kingdom, CM1 7ET
    • Broomfield Hospital
  • Dundee, United Kingdom
    • Tayside Cancer Centre
  • Glasgow, United Kingdom
    • Beatson Oncology Centre
  • Guildford, United Kingdom
    • Royal Surrey County Hospital
  • Hull, United Kingdom
    • Castle Hill Hospital
  • Kent, United Kingdom
    • Kent Oncology Centre, Maidstone Hospital
  • Leicester, United Kingdom
    • University of Leicester
  • London, United Kingdom
    • Guys Hospital
  • London, United Kingdom
    • St. Bartholomew's Hospital
  • Manchester, United Kingdom
    • Wythenshawe Hospital
  • Newcastle, United Kingdom
    • Freeman Hospital
  • Plymouth, United Kingdom
    • Derriford Hospital
  • Sheffield, United Kingdom, S10 2SJ
    • Weston Park Hospital
  • Southampton, United Kingdom
    • Southampton General Hospital
  • Wirral
    • Bebington, Wirral, United Kingdom
      • Clatterbridge Cancer Centre
• United States
  • California
    • San Francisco, California, United States
      • University of California San Francisco Medical Center
  • Florida
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Illinois
    • Chicago, Illinois, United States
      • University of Chicago Medical Center
  • Maryland
    • Baltimore, Maryland, United States
      • Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States
      • Mayo Clinic
  • New York
    • Bronx, New York, United States, 10461
      • Jacobi Medical Center
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Ohio
    • Cleveland, Ohio, United States
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Abramson Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States
      • Sarah Cannon Research Institute
  • Texas
    • Dallas, Texas, United States
      • UT Southwestern

Participation Criteria

Eligibility Criteria

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

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: defactinib (VS-6063); 2 x 200 mg defactinib (VS-6063) tablets, administered orally, twice daily	Drug: defactinib (VS-6063)
Placebo Comparator: Placebo; 2 placebo tablets, administered orally, twice daily	Drug: Placebo; Sugar pill manufactured to mimic defactinib tablet

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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.	Every 3-4 weeks from baseline through end of treatment, an expected average of 4 months
To determine the objective response rate (ORR) in subjects receiving defactinib (VS-6063) or placebo.	ORR is measured as the best overall response assessed by central review using Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1.	Every 6-8 weeks from baseline through end of treatment, an expected average of 4 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the time to new lesion in subjects receiving defactinib (VS-6063) or placebo	Time to new lesion will be calculated from the date of randomization to the time of CT scan documenting a new lesion or date of other unambiguous indicator of new lesion development.	Every 6-8 weeks from baseline until end of treatment, an expected average of 4 months
Evaluate the relationship of defactinib (VS-6063) pharmacokinetics (PK) and outcome	PK parameters, including but not limited to plasma concentration, AUC (Area Under Curve) 0-t, Cmax, Tmax, and T1/2, compared with outcome	Time points at Week 4, Week 7, Week 10 and Week 13
Evaluate the population pharmacokinetics of defactinib (VS-6063) in subjects with malignant pleural mesothelioma	PK parameters, including but not limited to plasma concentration, AUC (Area Under Curve) 0-t, Cmax, Tmax, and T1/2	Time points at Week 4, Week 7, Week 10 and Week 13
Evaluate the safety and tolerability of defactinib (VS-6063) in subjects with malignant pleural mesothelioma	Adverse events and their frequency, duration and severity, physical examination, laboratory parameters, vital signs and ECG change monitoring as determined based on CTCAE (Common Toxicity Criteria for Adverse Effects) 4.03	From start of treatment to end of treatment, an expected average of 4 months
To collect EuroQol 5-Dimensional Health Questionnaire (EQ-5D) for health economics purposes		Every 3-4 weeks from baseline through end of treatment, an expected average of 4 months

Collaborators and Investigators

• Sponsor: Verastem, Inc.
• Investigators: Study Chair: Hagop Youssoufian, Verastem, Inc.

Publications and helpful links

General Publications

• Fennell DA, Baas P, Taylor P, Nowak AK, Gilligan D, Nakano T, Pachter JA, Weaver DT, Scherpereel A, Pavlakis N, van Meerbeeck JP, Cedres S, Nolan L, Kindler H, Aerts JGJV. Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma: COMMAND-A Double-Blind, Randomized, Phase II Study. J Clin Oncol. 2019 Apr 1;37(10):790-798. doi: 10.1200/JCO.2018.79.0543. Epub 2019 Feb 20.

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: May 29, 2013
• First Submitted That Met QC Criteria: June 3, 2013
• First Posted (Estimate): June 6, 2013

Study Record Updates

• Last Update Posted (Estimate): January 30, 2017
• Last Update Submitted That Met QC Criteria: January 26, 2017
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Mesothelioma; Mesothelioma, Malignant
• Other Study ID Numbers: VS-6063-202