E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
MPM is a rare but aggressive tumor of the serosal surfaces (specifically
the pleura and peritoneum) that is highly invasive and progresses
rapidly. The main risk factor is exposure to carcinogenic silicate fibers
found in asbestos, although genetic factors may also contribute. VS-
6063 is being studied as a maintenance treatment in subjects with MPM
whose disease has not progressed (confirmed PR or SD) after adequate
first-line treatment with pemetrexed plus platinum based chemotherapy. |
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E.1.1.1 | Medical condition in easily understood language |
Malignant pleural mesothelioma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059518 |
E.1.2 | Term | Pleural mesothelioma malignant |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• 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.
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E.2.2 | Secondary objectives of the trial |
• 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) and time to new lesion in subjects receiving VS 6063 or placebo.
Exploratory 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.
• To collect EuroQol 5-Dimensional Health Questionnaire (EQ-5D) for health economics purposes.
Safety Objectives
• To evaluate the safety and tolerability of VS 6063 in subjects with malignant pleural mesothelioma |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. 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 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. |
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E.4 | Principal 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.
14) Prior treatment with a focal adhesion kinase (FAK) inhibitor.
15) Women who are pregnant or breastfeeding. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoints:
1) Overall Survival
For all subjects, OS will be calculated from the date of randomization to the date of death. Subjects who are still alive at the time point of analyses, or who dropout prior to study end, will be censored at the day they were last known to be alive. If the sample is not enriched, the HR and 95% CI for treatment group will be estimated from a stratified Cox proportional hazards model overall and within randomization strata. In the case of enrichment, the HR and 95% CI for treatment group will be estimated from a Cox proportional hazards model including Merlin-negative subjects only. The adequacy of the model will be evaluated, including an assessment of the proportional hazards assumption.
2) Progression free survival
For all subjects, PFS will be calculated from the date of randomization to the earliest date of CT scan with a central reading documenting relapse, date of other unambiguous indicator of disease development, or date of death. The primary analysis of PFS will be based on the stratified log-rank test, and will use Kaplan-Meier estimation methods for estimation of summary statistics. P-values will be computed by combining results from the initial and primary PFS analysis as described in Section 11.2.3. of the Protocol. Subjects who have no documented relapse and are still alive prior to the final efficacy analyses, who dropout prior to study completion, or who have nonevaluable disease will be censored at the date of the last radiological evidence documenting absence of relapse. The HR with respect to relapse or death will also be calculated using Cox’s proportional hazard model, stratified by randomization strata. Additional exploratory Cox models will be used to determine the effect of other potential prognostic factors, including at least gender, age, histology, and prior surgery. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Subjects will be treated until disease progression (as confirmed by central review) or other discontinuation criteria are met.
Each subject’s active participation in this study will last a minimum of approximately 3.5 months, including:
• Up to 28 day screening period.
• At least 6 weeks of study treatment. However, subjects may continue to receive additional study treatment until disease progression has been documented or other discontinuation criteria have been met.
• Follow-up visit performed 30 days after the last dose of study drug.
Following documentation of non-death related progression, all subjects will be followed for survival by telephone contact every 2 months until death or the close of the study. |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
1) Quality of Life using the Lung Cancer Symptom Scale (LCSS) modified for mesothelioma
2) Objective Response Rate
Exploratory Endpoints:
1) Time to New Lesion
2) EQ-5D Health Assessment Questionnaire |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Subjects will be treated until disease progression (as confirmed by central review) or other discontinuation criteria are met.
Each subject’s active participation in this study will last a minimum of approximately 3.5 months, including:
• Up to 28 day screening period.
• At least 6 weeks of study treatment. However, subjects may continue to receive additional study treatment until disease progression has been documented or other discontinuation criteria have been met.
• Follow-up visit performed 30 days after the last dose of study drug.
Following documentation of non-death related progression, all subjects will be followed for survival by telephone contact every 2 months until death or the close of the study. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Canada |
France |
Italy |
Japan |
Netherlands |
New Zealand |
Poland |
South Africa |
Spain |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |