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

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.

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.