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
Overview
- Phase
- Phase 1
- Intervention
- GSK2256098
- Conditions
- Cancer
- Sponsor
- GlaxoSmithKline
- Enrollment
- 34
- Locations
- 1
- Primary Endpoint
- Part 2: Long term safety assessment as assessed by AEs and SAEs
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects with measurable tumors that may benefit from treatment with GSK2256098 and trametinib. This includes mesothelioma along with tumors with a high likelihood of MAPK pathway activation as reported in the medical literature.
- •Part 2 Subject Inclusion Criteria:
- •Histologically- or cytologically- confirmed diagnosis of recurrent or progressive, unresectable MPM with measurable lesion.
- •Part 1 and Part 2 Subject Inclusion Criteria:
- •Written informed consent provided.
- •Males and females \>=18 years of age (at the time consent is obtained).
- •Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
- •Able to swallow and retain orally administered study treatment.
- •Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment and agree to use effective contraception as per study protocol specification. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as as per study protocol specification.
- •Adequate organ system functions as defined in the protocol
Exclusion Criteria
- Not provided
Arms & Interventions
Part 1
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.
Intervention: GSK2256098
Part 1
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.
Intervention: Trametinib
Part 2
Based on determination of combination dose regimen in Part 1, dose expansion cohorts for Part 2 will be opened.
Intervention: GSK2256098
Part 2
Based on determination of combination dose regimen in Part 1, dose expansion cohorts for Part 2 will be opened.
Intervention: Trametinib
Outcomes
Primary Outcomes
Part 2: Long term safety assessment as assessed by AEs and SAEs
Time Frame: From Day 1 till post study visit (approximately 21 days from last dose)
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.
Part 2: Long term safety assessment as assessed by eye examination
Time Frame: Screening and as clinically warranted
A standard ophthalmic exam will be performed by an ophthalmologist.
Part 1: Safety assessment as assessed by echocardiogram
Time Frame: Screening, Day 28 and Day 1 of Weeks 13, 21, 33, then every 12 weeks.
Echocardiograms will be performed to assess cardiac ejection fraction.
Part 2: Long term safety assessment as assessed by UPC ratio
Time Frame: From Day 1 till post study visit (approximately 21 days from last dose)
Urine samples will be collected for the analyses of UPC ratio.
Part 1: Safety assessment as assessed by vital signs
Time Frame: From Day 1 till post study visit (approximately 21 days from last dose)
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, and temperature
Part 1: Safety assessment as assessed by eye examination
Time Frame: Screening and as clinically warranted
A standard ophthalmic exam will be performed by an ophthalmologist.
Part 2: Long term safety assessed as change from baseline in laboratory values
Time Frame: From Day 1 till post study visit (approximately 21 days from last dose)
Clinical laboratory assessments will include hematology, clinical chemistry, routine urinalysis and additional parameters
Part 1: Safety assessment as assessed by 12-lead electrocardiogram (ECG)
Time Frame: Screening, Day 1, Day 15, Day 22, and every 8 weeks from first dose till post study visit (approximately 21 days from last dose)
Twelve lead ECGs will be obtained to determine the MTD and RP2D combination of GSK2256098 and trametinib.
Part 1: Safety assessment as assessed by change from baseline in laboratory values
Time Frame: From Day 1 till post study visit (approximately 21 days from last dose)
Clinical laboratory assessments will include hematology, clinical chemistry, routine urinalysis and additional parameters
Part 2: Long term safety assessment as assessed by vital signs
Time Frame: From Day 1 till post study visit (approximately 21 days from last dose)
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, and temperature
Part 1: Safety assessment as assessed by adverse events (AEs) and serious adverse events (SAEs)
Time Frame: From Day 1 till post study visit (approximately 21 days from last dose)
AEs and SAEs will be assessed to determine the MTD and RP2D combination of GSK2256098 and trametinib.
Part 1: Safety assessment as assessed by urine protein to creatinine (UPC) ratio
Time Frame: From Day 1 till post study visit (approximately 21 days from last dose)
Urine samples will be collected for the analyses of UPC ratio.
Part 2: Long term safety assessment as assessed by 12-lead ECG
Time Frame: Screening, Day 1, Day 15, Day 22, and every 8 weeks from first dose till post study visit (approximately 21 days from last dose)
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
Part 2: Long term safety assessment as assessed by echocardiogram
Time Frame: Screening, Day 28 and Day 1 of Weeks 13, 21, 33, then every 12 weeks.
Echocardiograms will be performed to assess cardiac ejection fraction.
Secondary Outcomes
- Part 1: Tumor response and analysis of change from baseline levels of PD markers including pFAK/FAK, and pERK/ERK measured in tumor biopsies(Screening (before the first dose on Day 1), Day 15 and 22)
- Part 2: Change from baseline in forced vital capacity(Screening, Every 8 weeks from first dose and at progression and post study (approximately 21 days from last dose))
- Part 2: Exploratory analysis between PK parameters, change from baseline levels of PD markers including pFAK/FAK, pERK/ERK measured in tumor biopsies, and tumor response(Day 8, 15, 22, 29, and 57)
- Part 2: Tumor response as measured by modified Response Evaluation Criteria In Solid Tumors (RECIST) for mesothelioma(Screening, Every 8 weeks from first dose and at progression and post study (approximately 21 days from last dose))
- Part 2: Progression-free survival (PFS)(Day 1 up to disease progression or death due to any cause)
- Part 2: Change from baseline in patient reported components of the LCSS-mesothelioma(Baseline and every 8 weeks from first dose till disease progression and post study (21 days from last dose))
- Part 2: Change from baseline in observer assessed components of the Lung cancer symptom scale (LCSS)-mesothelioma(Screening, Every 8 weeks from first dose and at progression and post study (approximately 21 days from last dose))
- Part 1: GSK2256098 and trametinib PK assessment following repeat-dose (Day 15) administration of GSK2256098 and trametinib(Day 15 (pre-dose, 1, 1.5, 2, 4, 6, 8 hours))
- Part 2: GSK2256098 and trametinib PK parameters following repeat-dose (Day 22) administration of GSK2256098 and trametinib(Day 8 (pre-dose), 15 (pre-dose),22 (pre-dose, 1, 1.5,2,4,6 and 8 hrs), 29 and 57)
- Part 1 and 2: GSK2256098 dried blood spot (DBS) and whole blood PK parameter following repeat-dose (Day15 and 22) administration of GSK2256098 and trametinib(Day 15 and 22)