Clinical trial NCT01870609: Placebo Controlled Study of VS-6063 in Subjects With Malignant Pleural Mesothelioma
Official title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of VS-6063 in Subjects With Malignant Pleural Mesothelioma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Malignant Pleural Mesothelioma
Lead sponsor: Verastem, Inc.
Sponsor class: INDUSTRY
First posted: 2013-06-06
Enrollment: 344
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Compare the overall survival (OS) in subjects with malignant pleural mesothelioma receiving defactinib (VS-6063) or placebo
timeFrame: From randomization to end of life, an expected average of 12 months
measure: Compare the progression free survival (PFS) in subjects with malignant pleural mesothelioma receiving defactinib (VS-6063) or placebo
timeFrame: From date of randomization to earliest documented date of progression, an expected average of 4 months
Secondary outcomes:
measure: 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)
timeFrame: Every 3-4 weeks from baseline through end of treatment, an expected average of 4 months
measure: To determine the objective response rate (ORR) in subjects receiving defactinib (VS-6063) or placebo.
timeFrame: Every 6-8 weeks from baseline through end of treatment, an expected average of 4 months
Other outcomes:
measure: Determine the time to new lesion in subjects receiving defactinib (VS-6063) or placebo
timeFrame: Every 6-8 weeks from baseline until end of treatment, an expected average of 4 months
measure: Evaluate the relationship of defactinib (VS-6063) pharmacokinetics (PK) and outcome
timeFrame: Time points at Week 4, Week 7, Week 10 and Week 13
measure: Evaluate the population pharmacokinetics of defactinib (VS-6063) in subjects with malignant pleural mesothelioma
timeFrame: Time points at Week 4, Week 7, Week 10 and Week 13
measure: Evaluate the safety and tolerability of defactinib (VS-6063) in subjects with malignant pleural mesothelioma
timeFrame: From start of treatment to end of treatment, an expected average of 4 months
measure: To collect EuroQol 5-Dimensional Health Questionnaire (EQ-5D) for health economics purposes
timeFrame: Every 3-4 weeks from baseline through end of treatment, an expected average of 4 months
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center
state: California
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Bronx
country: United States
facility: Jacobi Medical Center
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: Abramson Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern
state: Texas
city: Frankston
country: Australia
facility: Peninsula Oncology Centre
state: Victoria
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse at RPA
city: East Bentlrigh
country: Australia
facility: Monash Cancer Center
city: Melbourne
country: Australia
facility: Epworth Hospital
city: Sydney
country: Australia
facility: Northern Cancer Institute
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital +61(0)7 3176 5054
city: Brussel
country: Belgium
facility: UCL - St. Luc
city: Edegem
country: Belgium
facility: Antwerp University Hospital
city: Ghent
country: Belgium
facility: University Hopsital Ghent
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven (University Hospitals Leuven)
city: Liege
country: Belgium
facility: CHU Liege - Sart Tilman
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Lille
country: France
facility: CHRU, Lille
city: Marseille
country: France
facility: Hôpitaux de Marseille
city: Villejuif
country: France
facility: Gustave Roussy
city: Bergamo
country: Italy
facility: Cliniche Humanitas Gavazzeni
city: Padova
country: Italy
facility: Istituto Oncologico Veneto
city: Fukuoka
country: Japan
facility: Kyushu Cancer Center
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital
city: Hyogo
country: Japan
facility: Hyogo College of Medicine
city: Okayama
country: Japan
facility: Okayama Rousai Hospital
city: Osaka
country: Japan
facility: Kinki University Hospital
city: Tokyo
country: Japan
facility: Juntendo University
city: Amsterdam
country: Netherlands
facility: Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente, Enschede
city: Heerlen
country: Netherlands
facility: Atrium MC
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Auckland
country: New Zealand
facility: Auckland Oncology Research Centre
city: Christchurch
country: New Zealand
facility: Canterbury Regional Cancer & Haematology Service
city: Oslo
country: Norway
facility: Norwegian Radium Hospital
city: Bystra
country: Poland
facility: Centrum Pulmonologii Ii Torakochirurgii w Bystrej
city: Bloemfontein
country: South Africa
facility: Iatros International / Bloemfontein Medi-Clinic
state: Free State
city: Johannesburg
country: South Africa
facility: The Medical Oncology Centre of Rosebank
city: Pretoria
country: South Africa
facility: Mary Potter Oncology Center, Little Company of Mary Hospital
city: Barcelona
country: Spain
facility: Institut Oncològic del Vallés Consorci Hospitalari Parc Tauli
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital
city: Madrid
country: Spain
facility: Ensayos Clínicos Oncología
city: Madrid
country: Spain
facility: Hospital Madrid Norte- Sanchinarro, Centro Integral Oncológico Clara Campal (CIOCC)
city: Lund
country: Sweden
facility: Skane University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Uppsala
country: Sweden
facility: University Hospital
city: Bebington
country: United Kingdom
facility: Clatterbridge Cancer Centre
state: Wirral
city: Bristol
country: United Kingdom
facility: Southmead Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Cardiff
country: United Kingdom
facility: Velindre Hospital Cardiff
city: Chelmsford
country: United Kingdom
facility: Broomfield Hospital
city: Dundee
country: United Kingdom
facility: Tayside Cancer Centre
city: Glasgow
country: United Kingdom
facility: Beatson Oncology Centre
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital
city: Hull
country: United Kingdom
facility: Castle Hill Hospital
city: Kent
country: United Kingdom
facility: Kent Oncology Centre, Maidstone Hospital
city: Leicester
country: United Kingdom
facility: University of Leicester
city: London
country: United Kingdom
facility: Guys Hospital
city: London
country: United Kingdom
facility: St. Bartholomew's Hospital
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
Study officials:
affiliation: Verastem, Inc.
name: Hagop Youssoufian
role: STUDY_CHAIR
References:
citation: 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.