Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Symptoms and General Pathology

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Tissue Adhesions

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Administered orally BID in a 21 day cycle

defactinib (VS-6063)

David E Gerber, M.D.

This is a Phase II, open-label, multicenter, multi cohort, study of VS-6063 (defactinib), a focal adhesion kinase inhibitor, in patients with KRAS mutant non-small cell lung cancer (NSCLC). NSCLC with a KRAS mutation is required for study entry and subjects will be enrolled into 1 of 4 cohorts based on the status of their INK4a/Arf and p53 mutations. The purpose of this study is to demonstrate if VS-6063 (defactinib) improves PFS within each cohort. The safety and tolerability of VS-6063, tumor response rate, progression free survival and overall survival will also be assessed. The pharmacodynamic effects of VS-6063 (defactinib) will be examined in a tumor biopsy and a blood sample.

Eleven subjects will be enrolled into one of four cohorts: Cohort A (KRAS mutation, wild type INK4a/ARF and wildtype p53), Cohort B (KRAS mutation, INK4s/ARF mutation and wild type p53), Cohort C (KRAS mutation, wild type INK4a/ARF and p53 mutation), and Cohort D (KRAS mutation, INK4a/ARF mutation and p53 mutation). If \>/= 4 patients demonstrate PFS at 12 weeks in each cohort, an additional 23 subjects will be enrolled.

Phase II Study of VS-6063 in Patients With KRAS Mutant Non-Small Cell Lung Cancer

Phase II Study of VS-6063, A Focal Adhesion Kinase (FAK) Inhibitor, in Patients With KRAS Mutant Non-Small Cell Lung Cancer

Adverse events (AEs) include the incidences of all treatment-emergent AEs (TEAEs) and all Serious Adverse Events (SAEs); by severity, relationship to study drug, and discontinuation of patients from study therapy due to AEs and due to deaths. Safety endpoints for AEs, clinical laboratory tests, vital signs, ECGs and physical examinations will be summarized using descriptive statistics as determined based on CTCAE (Common Toxicity Criteria for Adverse Effects) 4.03

RR is measured as the best overall response using Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1.

PFS will be estimated in each cohort using Kaplan-Meier product limit estimates.

OS in each cohort will be estimated using Kaplan-Meier product limit estimates.

Verastem, Inc.

Neoplasm Metastasis

Neoplastic Processes

Oral VS-4718 administered BID (QD during first cohort) during a 28 day cycle.

VS-4718

Hagop Youssoufian, MD

This is a Phase I, open-label, multicenter, dose-escalation trial of VS-4718, a focal adhesion kinase inhibitor, in subjects with metastatic non-hematologic malignancies. This clinical study is comprised of 2 parts: Part 1 (Dose Escalation) and Part 2 (Expansion). The purpose of this study is to evaluate the safety (including the recommended Phase II dose), pharmacokinetics (the amount of VS-4718 in your blood) and the anti-cancer activity of VS-4718. The pharmacodynamic effects (genes or proteins that may predict or show how your body may respond to VS-4718) will also be examined in tumor biopsies and blood samples.

Phase I Dose Escalation Study of VS-4718 in Subjects With Metastatic Non-Hematologic Malignancies

A Phase I Study of VS-4718, a Focal Adhesion Kinase Inhibitor, in Subjects With Metastatic Non-Hematologic Malignancies

Serious Adverse events, Adverse events and their frequency, duration and severity, physical examination, laboratory parameters, vital signs and ECGs as determined based on CTCAE (Common Toxicity Criteria for Adverse Effects) V4.03. A Safety monitoring committee will review safety information.

The RP2D will be determined based on the maximum tolerated dose (MTD) of VS-4718 as determined by number of participants with dose limiting toxicities related to VS-4718. Observations related to pharmacokinetics, pharmacodynamics, and any VS-4718 related toxicities may be included in the rationale supporting the RP2D and will not exceed the MTD.

Response rate and progression-free survival as determined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1

PK (pharmacokinetics) parameters, including but not limited to clearance, plasma concentration, AUC (Area Under Curve, 0-24 and 0-t), Cmax, Tmax, and T1/2

Pre and post dose biomarker analysis in serum and tumor samples to identify possible prognostic factors to VS-4718 response

Tumor expression status (pFAK, cancer stem cells, CSC, and other biomarkers) compared with response to VS-4718, as determined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1

Oral defactinib (VS-6063) administered twice a day (BID) during a 21 day cycle.

Defactinib

Hagop Youssoufian, m

This is a phase I, open-label, dose-escalation trial of defactinib (VS-6063), a focal adhesion kinase inhibitor, in Japanese patients with non-hematologic malignancies. The purpose of this study is to assess the safety (including the recommended phase 2 dose), the pharmacokinetics, and the anti-cancer activity of defactinib (VS-6063).

Phase I Dose Escalation Study of VS-6063 in Japanese Subjects With Non-Hematologic Malignancies

A Phase I Dose Escalation Study to Evaluate the Safety and Pharmacokinetics of VS-6063, a Focal Adhesion Kinase Inhibitor, in Japanese Subjects With Non-Hematologic Malignancies

A composite by dose level to include incidence of AEs, SAEs, dose interruptions and dose reductions as a measure of safety and tolerability. Abnormal Clinical significant laboratory results, ECG measurements, vital signs measurement, physical examination findings, and ECOG performance status were captured as adverse events.

The severity of AEs were evaluated according to CTCAE (Common Toxicity Criteria for Adverse Effects) 4.03

The RP2D will be determined based on the MTD of defactinib (VS-6063) as determined by number of participants with dose limiting toxicities (DLTs) related to defactinib.

PK parameters, including but not limited to plasma concentration, AUC (Area Under Curve) 0-t, Cmax, Tmax, and T1/2. Total 24-hour urine output will be collected in conjunction with PK sampling to assess the elimination of defactinib (VS-6063) and its potential metabolites.

Response rate and progression-free survival, as determined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1

The systematic method was through regular investigator assessment and regular laboratory testing.

Defactinib 200 mg Bid

Defactinib 400 mg Bid

Defactinib 600 mg Bid

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Lou Vaickus, MD, FACP/Chief Medical Officer

At least 1 TEAE (treatment emergent AE)

At least 1 TEAE related to study drug

Non-Lab TEAE with Severity ≥ Grade 3

Lab TEAE with Severity ≥ Grade 3

At least 1 Serious TEAE

Dose Interruptions

Dose Reductions

Assess the Safety and Tolerability of Defactinib (VS-6063) in Japanese Subjects With Non-hematologic Malignancies

Define the Maximum Tolerated Dose (MTD), if Achieved, and Establish the Recommended Phase 2 Dose (RP2D) of Defactinib (VS-6063) in Japanese Subjects.

Assess the Pharmacokinetics, Metabolism and Elimination of Defactinib (VS-6063) in Plasma and Urine.

Evaluate the Efficacy (Response Rate and Progression-free Survival) of Subjects Treated With Defactinib (VS-6063).

200 mg bid (twice a day) po (by mouth) defactinib

Overall Study

Rare Diseases

Mesothelioma

Mesothelioma, Malignant

Malignant Mesothelioma

Antineoplastic Agents

All Drugs and Chemicals

Trametinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Part 1 will determine the MTD and RP2D based on the safety and tolerability of GSK2256098 administered with trametinib. Subject will be administered starting dose of 1.0 mg OD trametinib combined with 500 mg BID GSK2256098. Dose escalation will continue until the MTD is established.

Based on determination of combination dose regimen in Part 1, dose expansion cohorts for Part 2 will be opened.

GSK2256098 250 mg will be supplied as white to off-white, round, biconvex tablets with no markings. GSK2256098 will be administered 30 minutes after a light meal with approximately 240 milliliter of water.

GSK2256098

Trametinib 0.5 mg will be supplied as capsules with no identifying markings. Trametinib will be administered orally under fasting conditions two hours after a meal.

GSK Clinical Trials

The purpose of this study is to assess the safety of combination treatment of GSK2256098 and trametinib in mesothelioma subjects and subjects with other selected tumor types. Also, the study will identify a maximum tolerated combination dose of GSK2256098 and trametinib. This study is a Phase I, open-label, dose-escalation study to determine maximal tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) and regimens for oral MEK inhibitor trametinib (once daily \[OD\]dosing) and the oral FAK inhibitor GSK2256098 (twice daily \[BID\] dosing). The synergy of the combination was observed over a wide range of concentrations and results in several-fold reduction in compound concentration to achieve equivalent biological responses compared to either single agent. The dose and schedule of dosing may be modified based on emerging safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. The study will be conducted in two parts; Part 1 Dose Escalation to determine the MTD and RP2D and Part 2 Expansion Cohort to further evaluate the safety and tolerability of trametinib and GSK2256098 at the RP2D and determine clinical activity. Additionally, in Part 1 Dose Escalation, additional subjects with malignant pleural mesothelioma (MPM) will be recruited at doses that are considered tolerable in order to assess PD in MPM subjects at each dose (the Pharmacodynamic Cohort). The Expansion Cohort will be limited to subjects with MPM who have progressed or are intolerant to first-line therapy.

A Dose Escalation Study to Assess Safety of GSK2256098 (FAK Inhibitor) in Combination With Trametinib (MEK Inhibitor) in Subjects With Advanced Solid Tumors

A Phase 1b, Multi-center, Open-label, Dose Escalation Study of GSK2256098 (FAK Inhibitor) in Combination With Trametinib (MEK Inhibitor) in Subjects With Advanced Solid Tumors

IPD for this study will be made available via the Clinical Study Data Request site.

AEs and SAEs will be assessed to determine the MTD and RP2D combination of GSK2256098 and trametinib.

Twelve lead ECGs will be obtained to determine the MTD and RP2D combination of GSK2256098 and trametinib.

Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, and temperature

Clinical laboratory assessments will include hematology, clinical chemistry, routine urinalysis and additional parameters

Echocardiograms will be performed to assess cardiac ejection fraction.

A standard ophthalmic exam will be performed by an ophthalmologist.

Urine samples will be collected for the analyses of UPC ratio.

AEs and SAEs will be recorded to assess longer term safety of the GSK2256098/trametinib combination at the RP2D in a larger cohort of subjects with MPM.

Twelve lead ECGs will be obtained to assess longer term safety of the GSK2256098/trametinib combination at the RP2D in a larger cohort of subjects with MPM

Blood sample will be collected for measurements of GSK2256098 and trametinib PK parameters including AUC(0-tau), Ctau, Cmax, and tmax.

PD markers pFAK/FAK, and pERK/ERK levels will be analyzed in fresh tumor tissue to assess the level of target inhibition by GSK2256098 and trametinib, respectively. Tumor tissue will be collected at screening (before the first dose on Day 1) and between 1 and 6 hours after GSK2256098 dosing on a day between Day 15 and Day 22, inclusive.

The LCSS- mesothelioma is a disease- and site-specific quality of life instrument to measure physical and functional dimensions in patients with lung cancer. The LCSS- mesothelioma will be completed by the investigator at each scheduled disease assessment and at progression.

Forced vital capacity will be measured at each scheduled disease assessment using standard methods.

PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause by investigator assessment.

The LCSS- mesothelioma is a disease- and site-specific quality of life instrument to measure physical and functional dimensions in patients with lung cancer. The LCSS- mesothelioma will be completed by the by the subjects with mesothelioma at each scheduled disease assessment and at progression.

Blood samples will be collected to analyze the PK parameters including AUC (0 tau), Ctau, Cmax, and tmax . If data permitting, population PK parameters, such as oral clearance (CL/F) and oral volume of distribution (Vz/F) of GSK2256098 and trametinib may be determined.

The relationship between GSK2256098 and trametinib PK, PD and clinical endpoints in subjects with MPM will be assessed.

Blood samples will be collected to analyses PK parameters includes area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments \[AUC(0-tau)\], maximum observed plasma concentration (Cmax), time to Cmax (tmax), and trough concentration (Ctau) of GSK2256098 DBS and whole blood following repeat-dose (Day15 and 22) administration of GSK2256098 and trametinib.

GlaxoSmithKline

Adenoma

Neoplasms, Mesothelial

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Pleural Neoplasms

Administered orally (BID) for 12, 21 or 35 days (+/- 2 days)

VS-6063

Raphael Bueno, M.D.

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.

Window of Opportunity Study of VS-6063 (Defactinib) in Surgical Resectable Malignant Pleural Mesothelioma Participants

An Open Label Window of Opportunity Phase II Study of the FAK Inhibitor Defactinib VS-6063 in Participants With Surgical Resectable Malignant Pleural Mesothelioma.

Area under plasma Concentration (AUC) 0 to t

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.

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.

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Ethnicity (NIH/OMB)

United States

Region of Enrollment

Clinical Trials

Percentage of pFAK Inhibition in Tumor Tissue

Cohort 1: Defactinib 400 mg BID for 12 days

Cohort 2: Defactinib 400 mg BID for 35 days

Cohort 3 (Fed)

Cohort 4 (Fasted)

Evaluate the Pharmacokinetics of VS-6063 (Defactinib), CMax

Cohort 2 (Fasted)

Evaluate the Pharmacokinetics of VS-6063 (Defactinib), AUC (Area Under the Curve)

Cohort 1: Defactinib 400 mg BID for 12 days Cohort 2: Defactinib 400 mg BID for 35 days

Evaluate the Pharmacokinetics of VS-6063 (Defactinib), Median Tmax (h)

Patients with at least one treatment-related treatment-emergent adverse events

Number of Patients With at Least One Adverse Event

Complete Response

Partial Response

Stable Disease

Progressive Disease

Non-Evaluable

To Evaluate the Tumor Response to VS-6063 (Defactinib)

Cohort 1 VS-6063 (Defactinib)

single dose administration escalating doses starting at 20 mg and continue escalation; the highest dose in this study will not exceed the mean Day 1 exposure in male dogs at the NOAEL dose (6 mg/kg/day).

Dose to be selected based on emerging safety and PK data; subjects will be given FDA standard high fat meal followed by single dose of study drug.

focal adhesion kinase inhibitor given as a single dose

Placebo to be used as comparator for GSK2256098

Placebo

The purpose of this study is to test the safety of a new drug and to look at how the drug is handled by your body. This is the first time the drug will be given to people, the drug has been safely given to animals over many days at higher doses than will be given in the study. The study will be done in healthy men and woman to determine what effects, good or bad, it has on thier health. This study will find out:

If the drug has any side effects after one dose of the drug is given? How much of the drug gets into the bloodstream, and how long does the body take to get rid of it? If the drug causes any changes to a substance that is in skin, hair or blood.

This study represents the first administration of the focal adhesion kinase (FAK) inhibitor GSK2256098 to humans to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary food effect following single oral doses in adult healthy subjects before proceeding to studies in subjects with cancer that will be given at higher doses over an extended period of time. FAK is a protein in the body that is important in cancer development. Objectives of the study will be to characterize the safety of single doses of GSK2256098; to characterize the single dose PK of GSK2256098 in the presence and absence of food; to examine the dose proportionality of GSK2256098 PK parameters following single dose administration; and to characterize the effect of single doses of GSK2256098 on phospho-FAK (pFAK) tyrosine 397 (Y397) levels in skin and hair follicles. Dose- and concentration-effect relationships for various safety parameters will be explored as appropriate.

Phase I Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of GSK2256098 in Healthy Volunteers

A Phase I, Randomized, Single-Blind, Placebo-Controlled Dose-Escalation Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Food Effect Following Single Oral Doses of the Focal Adhesion Kinase Inhibitor, GSK2256098, in Healthy Subjects

Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase II Study of VS-6063 in Patients With KRAS Mutant Non-Small Cell Lung Cancer	NCT01951690	Non Small Cell ... Lung Cancer	defactinib (VS-...	18 Years -	Verastem, Inc.
Phase I Dose Escalation Study of VS-4718 in Subjects With Metastatic Non-Hematologic Malignancies	NCT01849744	Non Hematologic... Metastatic Canc...	VS-4718	18 Years -	Verastem, Inc.
Phase I Dose Escalation Study of VS-6063 in Japanese Subjects With Non-Hematologic Malignancies	NCT01943292	Non Hematologic...	Defactinib	20 Years -	Verastem, Inc.
Phase I Dose Escalation Study of VS-4718 in Subjects With Metastatic Non-Hematologic Malignancies	NCT01849744	Non Hematologic... Metastatic Canc...	VS-4718	18 Years -	Verastem, Inc.
A Dose Escalation Study to Assess Safety of GSK2256098 (FAK Inhibitor) in Combination With Trametinib (MEK Inhibitor) in Subjects With Advanced Solid Tumors	NCT01938443	Cancer Neoplasms	GSK2256098 Trametinib	18 Years -	GlaxoSmithKline
A Dose Escalation Study to Assess Safety of GSK2256098 (FAK Inhibitor) in Combination With Trametinib (MEK Inhibitor) in Subjects With Advanced Solid Tumors	NCT01938443	Cancer Neoplasms	GSK2256098 Trametinib	18 Years -	GlaxoSmithKline
Window of Opportunity Study of VS-6063 (Defactinib) in Surgical Resectable Malignant Pleural Mesothelioma Participants	NCT02004028	Malignant Pleur...	VS-6063	18 Years -	Verastem, Inc.
Phase I Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of GSK2256098 in Healthy Volunteers	NCT00996671	Cancer	GSK2256098 Placebo	18 Years - 65 Years	GlaxoSmithKline
Phase I Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of GSK2256098 in Healthy Volunteers	NCT00996671	Cancer	GSK2256098 Placebo	18 Years - 65 Years	GlaxoSmithKline
Phase I Dose Escalation Study of VS-6063 in Japanese Subjects With Non-Hematologic Malignancies	NCT01943292	Non Hematologic...	Defactinib	20 Years -	Verastem, Inc.

Spots Global Cancer Trial Database for focal adhesion kinase inhibitor