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

Malignant Pleural Mesothelioma Clinical Trial

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Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01870609
• Other study ID #: VS-6063-202
• Status: Terminated
• Phase: Phase 2
• First received: May 29, 2013
• Last updated: January 26, 2017
• Start date: September 2013
• Est. completion date: January 2016

Study information

• Verified date: March 2016
• Source: Verastem, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 344
• Est. completion date: January 2016
• Est. primary completion date: January 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Malignant Pleural Mesothelioma
• Mesothelioma

Intervention

Drug:
• defactinib (VS-6063)

• Placebo
Sugar pill manufactured to mimic defactinib tablet

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Verastem, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Italy,  Japan,  Netherlands,  New Zealand,  Norway,  Poland,  South Africa,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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
Primary	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	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
Secondary	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