Malignant Pleural Mesothelioma
Conditions
Keywords
Mesothelioma, adenoma, Neoplasms, Mesothelial, Focal Adhesion Kinase Inhibitor
Brief summary
This is an open label neoadjuvant (treatment with VS-6063 prior to mesothelioma surgery) study in subjects with malignant pleural mesothelioma who are eligible for surgery. Subjects will receive VS-6063 (defactinib) 400 mg twice daily for 12, 21, or 35 days or 100 mg formulation twice daily for 21 days. Pre- and post-treatment biopsies and blood samples will be collected. The purpose of this study is to assess biomarker responses from tumor tissue. The safety, pharmacokinetics, and tumor response rate to VS-6063 (defactinib) will be also be assessed.
Interventions
DRUGVS-6063
Sponsors
Verastem, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed malignant pleural mesothelioma that is not metastatic or unresectable * Eligible to undergo excisional surgery such as pleurectomy/decortication (P/DC) or any other mesothelioma surgery. * Localized disease. The malignancy is confined to one affected hemithorax. Mediastinal N2 lymph nodes via cervical mediastinoscopy or EBUS (endobronchial ultrasound) must be negative in order to be eligible * Grossly normal pulmonary, cardiac function, renal, hepatic hematologic and performance functions * Male or non-pregnant female * Age ≥ 18 years of age * Tissue is required prior to enrollment. If patient was diagnosed outside and tumor tissue is not available, a pleural biopsy for frozen tissue collection is required.
Exclusion criteria
* Participants who have had chemotherapy or radiotherapy any time prior to entering the study or at any prior time for mesothelioma. Patients receiving chemotherapy type drugs for benign conditions can participate in this trial * History of upper gastrointestinal bleeding, ulceration, or perforation within 12 months prior to the first dose of study drug * Known history of Gilbert's Syndrome or any current hyperbilirubinemia of any cause * Known history of stroke or cerebrovascular accident within 6 months prior to the first dose of study drug * Subjects with known infection with human immunodeficiency virus (HIV) or Acquired Immune Deficiency Syndrome (AIDS) * Subjects with confirmed Hepatitis A, B or C * Subjects being actively treated for a secondary malignancy or any malignancy within the last 3 years, with the exception of non-melanomatous skin cancer or localized, definitively treated cervical cancer. Men under observation for local prostate cancer are also eligible if they have had stable disease for at least 1 year. * 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 * Known history of malignant hypertension * Uncontrolled intercurrent illness including symptomatic congestive heart failure, cardiac arrhythmia, or psychiatric illness/social situations which in the opinion of the study investigators would be associated with undue risk of participation in the study * Use of an investigational drug within 28 days or 5 half-lives prior to first dose. * Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of pFAK Inhibition in Tumor Tissue | Cohort 1, From Baseline to Day 12; Cohort 2, From Baseline to Day 35; Cohorts 3, From Baseline to Day 21; Cohorts 3, From Baseline to day 21 day. | percentage VS-6063 (defactinib) |
| Evaluate the Pharmacokinetics of VS-6063 (Defactinib), CMax | 0-24 hours | Maximum observed plasma concentration |
| Evaluate the Pharmacokinetics of VS-6063 (Defactinib), AUC (Area Under the Curve) | 0-8 hours | Area under plasma Concentration (AUC) 0 to t |
| Evaluate the Pharmacokinetics of VS-6063 (Defactinib), Median Tmax (h) | 0-24 hours | Time to Maximum concentration (Tmax) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With at Least One Adverse Event | Cohort 1, 40 days; Cohort 2, 42 days; Cohort 3, 28 days; Cohort 4, 28 days. | Adverse events will be graded by the CTCAE (Common Terminology Criteria for Adverse Events) 4.0 and summarized according to the worst grade observed since the first treatment dose. |
| To Evaluate the Tumor Response to VS-6063 (Defactinib) | Cohort 1, 40 days; Cohort 2, 42 days; Cohort 3, 28 days; Cohort 4, 28 days. | Modified RECIST criteria for assessment of response in malignant pleural mesothelioma Ann Oncol 2004. Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the in the volume of target lesions; Progressive Disease (PD) at least a 20% increase in the volume of target lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Defactinib 400 mg BID for 12 Days | 10 |
| Cohort 2 Defactinib 400 mg BID for 35 Days | 10 |
| Cohort 3 Defactinib 400 mg BID for 21 Days | 10 |
| Cohort 4 Defactinib 100 mg BID for 21 Days | 5 |
| Total | 35 |
Baseline characteristics
| Characteristic | Cohort 1 | Total | Cohort 4 | Cohort 3 | Cohort 2 |
|---|---|---|---|---|---|
| Age, Continuous | 75.9 years STANDARD_DEVIATION 7.69 | 71.9 years STANDARD_DEVIATION 8.44 | 66.6 years STANDARD_DEVIATION 7.5 | 71.7 years STANDARD_DEVIATION 7.29 | 70.6 years STANDARD_DEVIATION 9.83 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 35 Participants | 5 Participants | 10 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 10 Participants | 32 Participants | 5 Participants | 8 Participants | 9 Participants |
| Region of Enrollment United States | 10 participants | 35 participants | 5 participants | 10 participants | 10 participants |
| Sex: Female, Male Female | 2 Participants | 8 Participants | 2 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 8 Participants | 27 Participants | 3 Participants | 8 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 1 / 10 | 1 / 10 | 0 / 5 |
| other Total, other adverse events | 7 / 10 | 8 / 10 | 6 / 10 | 2 / 5 |
| serious Total, serious adverse events | 1 / 10 | 2 / 10 | 2 / 10 | 2 / 5 |
Outcome results
Primary
Evaluate the Pharmacokinetics of VS-6063 (Defactinib), AUC (Area Under the Curve)
Area under plasma Concentration (AUC) 0 to t
Time frame: 0-8 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Evaluate the Pharmacokinetics of VS-6063 (Defactinib), AUC (Area Under the Curve) | 5280 ng*h/mL | Geometric Coefficient of Variation 136 |
| Cohort 2 | Evaluate the Pharmacokinetics of VS-6063 (Defactinib), AUC (Area Under the Curve) | 5280 ng*h/mL | Geometric Coefficient of Variation 136 |
| Cohort 3 | Evaluate the Pharmacokinetics of VS-6063 (Defactinib), AUC (Area Under the Curve) | 2753 ng*h/mL | Geometric Coefficient of Variation 198 |
| Cohort 4 | Evaluate the Pharmacokinetics of VS-6063 (Defactinib), AUC (Area Under the Curve) | 1891 ng*h/mL | Geometric Coefficient of Variation 69 |
Primary
Evaluate the Pharmacokinetics of VS-6063 (Defactinib), CMax
Maximum observed plasma concentration
Time frame: 0-24 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Evaluate the Pharmacokinetics of VS-6063 (Defactinib), CMax | 1052 ng/mL | Geometric Coefficient of Variation 126 |
| Cohort 2 | Evaluate the Pharmacokinetics of VS-6063 (Defactinib), CMax | 1052 ng/mL | Geometric Coefficient of Variation 126 |
| Cohort 3 | Evaluate the Pharmacokinetics of VS-6063 (Defactinib), CMax | 513 ng/mL | Geometric Coefficient of Variation 180 |
| Cohort 4 | Evaluate the Pharmacokinetics of VS-6063 (Defactinib), CMax | 517 ng/mL | Geometric Coefficient of Variation 76 |
Primary
Evaluate the Pharmacokinetics of VS-6063 (Defactinib), Median Tmax (h)
Time to Maximum concentration (Tmax)
Time frame: 0-24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Evaluate the Pharmacokinetics of VS-6063 (Defactinib), Median Tmax (h) | 1 hour |
| Cohort 2 | Evaluate the Pharmacokinetics of VS-6063 (Defactinib), Median Tmax (h) | 1 hour |
| Cohort 3 | Evaluate the Pharmacokinetics of VS-6063 (Defactinib), Median Tmax (h) | 4 hour |
| Cohort 4 | Evaluate the Pharmacokinetics of VS-6063 (Defactinib), Median Tmax (h) | 1 hour |
Primary
Percentage of pFAK Inhibition in Tumor Tissue
percentage VS-6063 (defactinib)
Time frame: Cohort 1, From Baseline to Day 12; Cohort 2, From Baseline to Day 35; Cohorts 3, From Baseline to Day 21; Cohorts 3, From Baseline to day 21 day.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Percentage of pFAK Inhibition in Tumor Tissue | NA percentage of pFAK inhibition in a tumor |
| Cohort 2 | Percentage of pFAK Inhibition in Tumor Tissue | NA percentage of pFAK inhibition in a tumor |
| Cohort 3 | Percentage of pFAK Inhibition in Tumor Tissue | 85.6 percentage of pFAK inhibition in a tumor |
| Cohort 4 | Percentage of pFAK Inhibition in Tumor Tissue | NA percentage of pFAK inhibition in a tumor |
Secondary
Number of Patients With at Least One Adverse Event
Adverse events will be graded by the CTCAE (Common Terminology Criteria for Adverse Events) 4.0 and summarized according to the worst grade observed since the first treatment dose.
Time frame: Cohort 1, 40 days; Cohort 2, 42 days; Cohort 3, 28 days; Cohort 4, 28 days.
Population: Patients with at least one treatment-related treatment-emergent adverse events
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Patients With at Least One Adverse Event | 10 Participants |
| Cohort 2 | Number of Patients With at Least One Adverse Event | 10 Participants |
| Cohort 3 | Number of Patients With at Least One Adverse Event | 10 Participants |
| Cohort 4 | Number of Patients With at Least One Adverse Event | 5 Participants |
Secondary
To Evaluate the Tumor Response to VS-6063 (Defactinib)
Modified RECIST criteria for assessment of response in malignant pleural mesothelioma Ann Oncol 2004. Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the in the volume of target lesions; Progressive Disease (PD) at least a 20% increase in the volume of target lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter.
Time frame: Cohort 1, 40 days; Cohort 2, 42 days; Cohort 3, 28 days; Cohort 4, 28 days.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Progressive Disease | 0 Participants |
| Cohort 1 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Partial Response | 1 Participants |
| Cohort 1 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Non-Evaluable | 0 Participants |
| Cohort 1 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Stable Disease | 9 Participants |
| Cohort 1 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Complete Response | 0 Participants |
| Cohort 2 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Stable Disease | 4 Participants |
| Cohort 2 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Progressive Disease | 3 Participants |
| Cohort 2 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Non-Evaluable | 1 Participants |
| Cohort 2 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Partial Response | 2 Participants |
| Cohort 2 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Complete Response | 0 Participants |
| Cohort 3 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Stable Disease | 7 Participants |
| Cohort 3 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Complete Response | 0 Participants |
| Cohort 3 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Partial Response | 1 Participants |
| Cohort 3 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Progressive Disease | 2 Participants |
| Cohort 3 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Non-Evaluable | 0 Participants |
| Cohort 4 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Progressive Disease | 3 Participants |
| Cohort 4 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Partial Response | 0 Participants |
| Cohort 4 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Complete Response | 0 Participants |
| Cohort 4 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Stable Disease | 2 Participants |
| Cohort 4 | To Evaluate the Tumor Response to VS-6063 (Defactinib) | Non-Evaluable | 0 Participants |