Primary Efficacy Objectives• To compare the overall survival (OS) in subjects with malignant pleural mesothelioma receiving VS-6063 or placebo.• To compare the progression free survival (PFS) in subjects with malignant pleural mesothelioma receiving…
ID
Source
Brief title
Condition
- Mesotheliomas
- Pleural disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Objectives
• To compare the overall survival (OS) in subjects with malignant pleural
mesothelioma receiving VS-6063 or placebo.
• To compare the progression free survival (PFS) in subjects with malignant
pleural mesothelioma receiving VS-6063 or placebo.
Secondary outcome
Secondary Efficacy Objective
• To assess Quality of Life (QoL) in subjects treated with VS-6063 or placebo
using the Lung Cancer Symptom Scale modified for mesothelioma (LCSS-Meso).
• To determine the objective response rate (ORR) in subjects receiving VS 6063
or placebo.
Exploratory Efficacy Objectives
• To determine the time to new lesion in subjects receiving VS-6063 or placebo.
• To evaluate the relationship of VS-6063 pharmacokinetics and outcome.
• To evaluate the population pharmacokinetics of VS-6063 in subjects with
malignant pleural mesothelioma.
Safety Objectives
• To evaluate the safety and tolerability of VS-6063 in subjects with malignant
pleural mesothelioma
Background summary
This is a phase II, randomized, double-blind, placebo-controlled, multicenter
study of VS-6063 in subjects with malignant pleural mesothelioma who have not
progressed (confirmed PR/SD) following at least 4 cycles of treatment with
pemetrexed/cisplatin or pemetrexed/carboplatin. Approximately 40% of MPM
patients have mutations in the NF-2 gene that lead to low Merlin protein (a
tumor suppression protein) expression. In previous studies Merlinnegative
subjects (subjects with mutations in the neurofibromatosis type 2 gene [NF2]
leading to low Merlin expression) treated with FAK inhibitors had longer median
PFS than did Merlin-positive (subjects with high Merlin protein expression).
In this study it is hypothesized that Merlin-low subjects may respond to
VS-6063 (a FAK inhibitor) better than Merlin-high
subjects. To account for possible differential response, this study will use an
adaptive enrichment design, whereby enrollment may be
restricted to subjects in the Merlin-low stratum after an interim analysis.
Decisions regarding enrichment will be based on an
interim analysis of PFS (a primary efficacy endpoint). In addition, a
subsequent sample size re-estimation for the primary efficacy
endpoint of OS will be performed.
Study objective
Primary Efficacy Objectives
• To compare the overall survival (OS) in subjects with malignant pleural
mesothelioma receiving VS-6063 or placebo.
• To compare the progression free survival (PFS) in subjects with malignant
pleural mesothelioma receiving VS-6063 or placebo.
Secondary Efficacy Objective
• To assess Quality of Life (QoL) in subjects treated with VS-6063 or placebo
using the Lung Cancer Symptom Scale modified for mesothelioma (LCSS-Meso).
• To determine the objective response rate (ORR) in subjects receiving VS 6063
or placebo.
Exploratory Efficacy Objectives
• To determine the time to new lesion in subjects receiving VS-6063 or placebo.
• To evaluate the relationship of VS-6063 pharmacokinetics and outcome.
• To evaluate the population pharmacokinetics of VS-6063 in subjects with
malignant pleural mesothelioma.
Safety Objectives
• To evaluate the safety and tolerability of VS-6063 in subjects with malignant
pleural mesothelioma
Study design
This study is a Phase II, randomized, double-blind, placebocontrolled,
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 >= 4 cycles of treatment with pemetrexed/cisplatin or
pemetrexed/carboplatin.
Prior to entry and randomization to the study, tumor moesin-ezrinradixin-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.
Intervention
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).
Study burden and risks
It is expected that patients will be on the study for a minimum of 3.5 months :
28 day maximum screening period,
Approx.6 weeks of treatment followed by a 30 day follow up period. The answer
on question E6 are based on this period.
From the start of the treatment onwards the patient will take one or two
tablets BID. The patients keeps a dosing diary to write down the times the
tablets were taken. the patient takes the study medication until disease
progression is assessed with use of RECIST criteria.
The following assessments will be done.
For screening:
-informed consent, check in- and exclusion criteria, Merlin assessment, medical
history, demographics, physical exam, Karnofsky score, ECG, vital signs,
pregnancy test, clinical chemistry, hematology, coagulation parameters,
urinalysis, quality of life assessment, disease assessment (CT scan),
concomitant medications, adverse events.
At the start of the treatment:
-check in- and exclusion criteria, physical exam, Karnofsky score, ECG, vital
signs, pregnancy test, clinical chemistry, hematology, coagulation parameters,
urinalysis, quality of life assessment, review dosing diary, concomitant
medications, adverse events.
Then every 3 weeks (week 4, 7, 10, 13, 16, 19, 22, 25):
physical exam, Karnofsky score, ECG, vital signs, clinical chemistry,
hematology, coagulation parameters, urinalysis, quality of life assessment,
review dosing diary, concomitant medications, adverse events.
Then every 4 weeks these same assessments will be repeated.
For the Pharmacokinetics the following blood samples are taken:
In week 4 before intake of the tablets and 1 and 4 hour after that
In week 7 before intake of the tablets and 2 and 6 hour after that
In week 10 before intake of the tablets
In week 13 before intake of the tablets
On day 1, 2 hours after intake of the tablets, an extra ECG will be made.
In week 1 and week 4 blood sampling will be done as well for biomarkers.
At screening and after that every 6 to 8 weeks a CT scan will be made during
the hospital visit. This is used to assess the tumor size. If at end of
treatment it has been longer than 28 days a CT scan was made, it will be
repeated.
At the end of treatment:
physical exam, Karnofsky score, ECG, vital signs, pregnancy test, clinical
chemistry, hemaotlogy, coagulation parameters, urinalysis, quality of life
assessment, review dosing diary, concomitant medications, adverse events.
At 30 days follow-up:
physical exam, Karnofsky score, vital signs, quality of life assessment,
concomitant medications, adverse events.
After this the patient will be called every 2 months until end of study or
death of the patient.
Kendrick Street, Suite 500 117
Needham, Massachusetts 02494
US
Kendrick Street, Suite 500 117
Needham, Massachusetts 02494
US
Listed location countries
Age
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 pemetrexed/cisplatin or pemetrexed/carboplatin therapy within <= 6 weeks of study entry. ;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 chemotherapy induced toxicities must have resolved to grade <= 1 prior to randomization. ;10) Performance status according to Karnofsky Performance Scale >= 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 >= 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] and/or glomerular filtration rate of >= 50mL/min).;14) Adequate hepatic function (total bilirubin <=1.5 x ULN; aspartate transaminase and alanine transaminase <= 2.5x 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
Exclusion Criteria:
1) Currently enrolled in (or completed within 30 days before study drug administration) another investigational drug study.
2) Gastrointestinal (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 (AIDS) (testing not required).
7) Subjects with known infection with hepatitis A, B or C virus (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 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 (NYHA) 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 non-invasive, 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 a focal adhesion kinase (FAK) inhibitor.
16)Women who are pregnant or breastfeeding.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-001033-40-NL |
| ClinicalTrials.gov | NCT01870609 |
| CCMO | NL44213.031.13 |