Clinical trial NCT01938443: A Dose Escalation Study to Assess Safety of GSK2256098 (FAK Inhibitor) in Combination With Trametinib (MEK Inhibitor) in Subjects With Advanced Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cancer
Neoplasms
Keywords: pharmacodynamics
MEK inhibitor
Focal adhesion kinase inhibitor
cancer
pharmacokinetic
mesothelioma
Phase 1
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-09-10
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria

Part 1 Subject 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

* Mesotheliomas originating outside of the pleural cavity (e.g., peritoneal mesothelioma) are excluded in the Pharmacodynamic Cohort in Part 1 and Part 2, but are permitted in Dose Escalation Cohorts in Part 1.
* Subjects with leptomeningeal or brain metastases or spinal cord compression.
* Use of an investigational anti-cancer drug within 28 days or five half-lives with a minimum duration of 10 days from prior therapy preceding the first dose of GSK2256098/trametinib OR Chemotherapy within the last 3 weeks (6 weeks for prior nitrosourea or mitomycin C) OR any major surgery, radiotherapy, or immunotherapy within the last 4 weeks. NOTE: Limited palliative radiation (i.e., duration typically \< 15 days) with last dose \>=6 weeks preceding the first dose of combination treatment is acceptable provided subject meets all of the other eligibility criteria and radiotherapy port does not encompass all measurable tumor. In addition, prophylactic radiation therapy to the site of tumor biopsies (as per the standard of care) during the current study to prevent seeding of the needle tract/biopsy is acceptable and does not require dose modification.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2256098 or trametinib.
* Previous treatment with GSK2256098 or trametinib, as well as other MEK or FAK inhibitors.
* Current use of a prohibited medication or requires any of these medications during treatment.
* Current use of warfarin for therapeutic anticoagulation. NOTE: Low molecular weight heparin is permitted. PT/PTT must meet the inclusion criteria.
* Presence of an active gastrointestinal disease, or other condition known to interfere significantly with the absorption, distribution, metabolism, or excretion of drugs.
* History or evidence of cardiovascular risk including any of the following: Left ventricle ejection fraction (LVEF) \< lower limit of normal (LLN) per local institutional practice; A QT interval corrected for heart rate using the Fredericia's formula (QTcF) \>=480 msec;History or evidence of current clinically significant uncontrolled arrhythmias; Exception: Subjects with controlled atrial fibrillation for \>30 days prior to randomization are eligible; History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization; History or evidence of current \>= Class II congestive heart failure as defined by New York Heart Association; Treatment refractory hypertension defined as a blood pressure of systolic\> 140 millimeter of mercury (mmHg) and/or diastolic \> 90 mmHg which cannot be controlled by anti-hypertensive therapy; Patients with intra-cardiac defibrillators or permanent pacemakers; Known cardiac metastases;
* Active interstitial lung disease or pneumonitis.
* History or current evidence / risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): History of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes); Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as: Evidence of new optic disc cupping, Evidence of new visual field defects and Intraocular pressure \> 21 mmHg
* Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted).
* History of another malignancy (excludes non-melanoma skin cancer). Exception: Subjects who have been continuously disease-free for 3 years or who have had complete resection of a non-invasive primary cancer within 3 years of enrollment. Consult GSK Medical Monitor if unsure whether second malignancies meet requirements specified above.
* Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
* Concurrent condition that in the Investigator's opinion would jeopardize compliance with the protocol.
* Nursing female.

Primary outcomes:
measure: Part 1: Safety assessment as assessed by adverse events (AEs) and serious adverse events (SAEs)
timeFrame: From Day 1 till post study visit (approximately 21 days from last dose)
measure: Part 1: Safety assessment as assessed by 12-lead electrocardiogram (ECG)
timeFrame: Screening, Day 1, Day 15, Day 22, and every 8 weeks from first dose till post study visit (approximately 21 days from last dose)
measure: Part 1: Safety assessment as assessed by vital signs
timeFrame: From Day 1 till post study visit (approximately 21 days from last dose)
measure: Part 1: Safety assessment as assessed by change from baseline in laboratory values
timeFrame: From Day 1 till post study visit (approximately 21 days from last dose)
measure: Part 1: Safety assessment as assessed by echocardiogram
timeFrame: Screening, Day 28 and Day 1 of Weeks 13, 21, 33, then every 12 weeks.
measure: Part 1: Safety assessment as assessed by eye examination
timeFrame: Screening and as clinically warranted
measure: Part 1: Safety assessment as assessed by urine protein to creatinine (UPC) ratio
timeFrame: From Day 1 till post study visit (approximately 21 days from last dose)
measure: Part 2: Long term safety assessment as assessed by AEs and SAEs
timeFrame: From Day 1 till post study visit (approximately 21 days from last dose)
measure: Part 2: Long term safety assessment as assessed by 12-lead ECG
timeFrame: Screening, Day 1, Day 15, Day 22, and every 8 weeks from first dose till post study visit (approximately 21 days from last dose)
measure: Part 2: Long term safety assessment as assessed by vital signs
timeFrame: From Day 1 till post study visit (approximately 21 days from last dose)
measure: Part 2: Long term safety assessed as change from baseline in laboratory values
timeFrame: From Day 1 till post study visit (approximately 21 days from last dose)
measure: Part 2: Long term safety assessment as assessed by echocardiogram
timeFrame: Screening, Day 28 and Day 1 of Weeks 13, 21, 33, then every 12 weeks.
measure: Part 2: Long term safety assessment as assessed by eye examination
timeFrame: Screening and as clinically warranted
measure: Part 2: Long term safety assessment as assessed by UPC ratio
timeFrame: From Day 1 till post study visit (approximately 21 days from last dose)
Secondary outcomes:
measure: Part 1: GSK2256098 and trametinib PK assessment following repeat-dose (Day 15) administration of GSK2256098 and trametinib
timeFrame: Day 15 (pre-dose, 1, 1.5, 2, 4, 6, 8 hours)
measure: Part 1: Tumor response and analysis of change from baseline levels of PD markers including pFAK/FAK, and pERK/ERK measured in tumor biopsies
timeFrame: Screening (before the first dose on Day 1), Day 15 and 22
measure: Part 2: Tumor response as measured by modified Response Evaluation Criteria In Solid Tumors (RECIST) for mesothelioma
timeFrame: Screening, Every 8 weeks from first dose and at progression and post study (approximately 21 days from last dose)
measure: Part 2: Change from baseline in observer assessed components of the Lung cancer symptom scale (LCSS)-mesothelioma
timeFrame: Screening, Every 8 weeks from first dose and at progression and post study (approximately 21 days from last dose)
measure: Part 2: Change from baseline in forced vital capacity
timeFrame: Screening, Every 8 weeks from first dose and at progression and post study (approximately 21 days from last dose)
measure: Part 2: Progression-free survival (PFS)
timeFrame: Day 1 up to disease progression or death due to any cause
measure: Part 2: Change from baseline in patient reported components of the LCSS-mesothelioma
timeFrame: Baseline and every 8 weeks from first dose till disease progression and post study (21 days from last dose)
measure: Part 2: GSK2256098 and trametinib PK parameters following repeat-dose (Day 22) administration of GSK2256098 and trametinib
timeFrame: Day 8 (pre-dose), 15 (pre-dose),22 (pre-dose, 1, 1.5,2,4,6 and 8 hrs), 29 and 57
measure: 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
timeFrame: Day 8, 15, 22, 29, and 57
measure: 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
timeFrame: Day 15 and 22
Other outcomes:
Locations:
city: Villejuif Cedex
country: France
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Newcastle upon Tyne
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Mak G, Soria JC, Blagden SP, Plummer R, Fleming RA, Nebot N, Zhang J, Mazumdar J, Rogan D, Gazzah A, Rizzuto I, Greystoke A, Yan L, Tolson J, Auger KR, Arkenau HT. A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours. Br J Cancer. 2019 May;120(10):975-981. doi: 10.1038/s41416-019-0452-3. Epub 2019 Apr 17.