A PHASE II RANDOMIZED, DOUBLE-BLIND, PLACEBO[?] CONTROLLED, MULTICENTER STUDY OF VS-6063 IN SUBJECTS WITH MALIGNANT PLEURAL MESOTHELIOMA

Summary

This study is a Phase ii, randomized, double-blind, placebo- controlled, multicenter study of VS-6063 in subjects with malignant pleural mesothelioma (MPM) who have not progressed (confirmed Response evaluation Criteria in Solid Tumors [ReCiST] status of PR [partial response] or SD [stable disease]) following [GreaterThanorequalTo] 4 cycles of treatment with pemetrexed/cisplatin or pemetrexed/carboplatin.

Prior to entry and randomization to the study, tumor moesin-ezrin- radixin-like protein (Merlin) status for each subject will be determined by immunohistochemistry performed at a central laboratory.

Subjects will be randomized in a 1:1 ratio to receive oral VS-6063 400 mg twice daily (BiD) 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 ReCiST Version 1.1. Subjects will continue to receive treatment until disease progression or other discontinuation criteria are met. Radiographic progression must be confirmed centrally before removal of subject from the study drug. Removal of subject for clinical progression will be at the discretion of the investigator. Response assessments will be performed every 6 weeks for the first 25 weeks. after 25 weeks of treatment, response assessments will be performed every 8 weeks. The same method of assessment should be used throughout the study.

Following documentation of non-fatal disease progression, all subjects will be followed for survival by telephone contact every 2 months until death or the close of the study.

Blinding
VS-6063 is formulated as a white to off-white oval tablet for oral administration and supplied in single unit dose strength of 200 mg. a matched placebo control will also be provided.
The placebo will be similar in color, shape and composition but will contain no active ingredients.

Randomization
Study drug will be administered in a double-blind manner. Randomization will be performed centrally using an interactive Web Response System (iWRS), and subjects will be randomized to receive VS-6063 or a matched placebo with equal allocation between the 2 study arms. The randomization will be stratified by tumor Merlin status (high versus low) as determined by immunohistochemistry performed at a central lab. The randomization process will provide balance between treatment groups within each of the stratification categories. The total number of subjects enrolled within a randomization stratum will not be restricted overall or by site.


The overall purpose of this study is to support the development of oral VS-6063 for treatment of patients with MPM. VS-6063 is a highly potent, selective, and pharmacologically active inhibitor of FaK. The compound has demonstrated efficacy as a single agent in nonclinical tumor models, and the research literature supports the potential for application of FaK inhibitors alone or in combination with existing chemotherapeutics in MPM.

Participant Eligibility

Subjects eligible for inclusion in this trial must fulfill all of the following 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. Refer to
Appendix D for additional guidance.
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.