A Phase I Open-Label Dose Escalation Study of the Focal Adhesion Kinase Inhibitor, GSK2256098, in Subjects With Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- GSK2256098
- Conditions
- Cancer
- Sponsor
- GlaxoSmithKline
- Enrollment
- 74
- Locations
- 1
- Primary Endpoint
- To evaluate the Maximum tolerated dose, identify the recommended Phase 2 dose(s), dose limiting toxicities, safety and tolerability of GSK2256098 given orally on consecutive days.
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
This study is a Phase I dose escalation study in subjects with solid tumors. Part 1 will identify the maximum tolerated dose (MTD) using a dose-escalation procedure. Following identification of the MTD, enrollment into Parts 2, 3, 4 and 5 may be concurrent. Part 2 will explore further the safety, PK, tolerability, and anti-tumor activity of GSK2256098 in subjects with tumors known to overexpress focal adhesion kinase (FAK). Part 3 will characterize the range of biologically effective doses by assessing pharmacodynamic (PD) markers in hair, skin and tumor tissue at doses that will not go lower than 80 mg or above the MTD dose levels tested during the Phase 1 dose escalation. Part 4 will explore further the safety, PK, tolerability and anti-tumor activity of GSK2256098 in subjects with relapsed glioblastoma multiforme (GBM). The primary objective of this study is to determine the safety, tolerability, and MTD of GSK2256098. Secondary objectives are to characterize the pharmacokinetics (PK) of GSK2256098; to identify a range of biologically active doses; to explore the anti-tumor activity of GSK2256098, and to explore relationships between GSK2256098 PK, PD and clinical endpoints. Part 5 will investigate the time course, the extent of an apparent change in the PK of GSK2256098 following repeated dosing, and screen for potential CYP3A induction as a possible mechanism of reduced systemic exposure of GSK2256098 at Day 15 and later time points. The primary objective of this study is to determine the safety, tolerability, and MTD of GSK2256098.
Detailed Description
This study is a Phase I dose escalation study in subjects with solid tumors. Part 1 will identify the maximum tolerated dose (MTD) using a dose-escalation procedure. Following identification of the MTD, enrollment into Parts 2, 3, 4, and 5 may be concurrent. Part 2 will explore further the safety, PK, tolerability, and anti-tumor activity of GSK2256098 in subjects with tumors known to overexpress focal adhesion kinase (FAK). Part 3 will characterize the range of biologically effective doses by assessing pharmacodynamic (PD) markers in hair, skin and tumor tissue at doses that will not go lower than 80 mg or above the MTD dose levels tested during the Phase 1 dose escalation. Part 4 will explore further the safety, PK, tolerability and anti-tumor activity of GSK2256098 in subjects with relapsed glioblastoma multiforme (GBM). The primary objective of this study is to determine the safety, tolerability, and MTD of GSK2256098. Secondary objectives are to characterize the pharmacokinetics (PK) of GSK2256098; to identify a range of biologically active doses; to explore the anti-tumor activity of GSK2256098, and to explore relationships between GSK2256098 PK, PD and clinical endpoints. Subjects with solid tumors will receive GSK2256098 orally without interruption on consecutive days. The planned starting dose in Part 1 will be a total daily dose of 160 mg administered as 80 mg twice daily (BID) during the repeat dose phase of the study. In the first cohort, administration of study drug will be initiated as a single dose (80 mg) on Day 1 that will be followed by collection of PK samples. Subjects may then begin repeat dosing (80 mg BID) on Day 2 following the collection of the 24-h PK sample. In subsequent cohorts, administration of study drug will be given as a single dose (half the total daily dose) on Day 1 followed by collection of PK samples. Subjects may begin repeat dosing on Day 2 following collection of the 24-h PK sample. During dose escalation (Part 1), a modified accelerated dose titration design will be followed by a standard 3+3 dose escalation design until the MTD is established. After the MTD is established approximately 30 additional subjects with tumors reported to have FAK over-expression will be enrolled to further explore the safety, tolerability and clinical activity of GSK2256098 (Part 2). Additional cohorts below the MTD may be expanded to further explore and characterize the range of biologically effective doses (Part 3). Part 4 will further explore the safety, PK, tolerability and anti-tumor activity of GSK2256098 in subjects with relapsed glioblastoma multiforme (GBM). Part 5 will investigate the time course, the extent of an apparent change in the PK of GSK2256098 following repeated dosing, and screen for potential CYP3A induction as a possible mechanism of reduced systemic exposure of GSK2256098 at Day 15 and later time points. The primary objective of this study is to determine the safety, tolerability, and MTD of GSK2256098.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Written informed consent provided.
- •18 years old or older.
- •Confirmed diagnosis of a solid tumor malignancy that is not responsive to accepted standard therapies or for which there is no standard or curative therapy. Subjects with malignancies related to HIV infection or organ transplantation are excluded.
- •Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group scale
- •Able to swallow and retain oral medication
- •A male is eligible to enter and participate in the study if he either:
- •agrees to abstain from sexual intercourse from the first dose of study drug and until 21 days after last dose of study medication, or
- •agrees to use a condom and occlusive cap (diaphragm or cervical/vault cap) with spermicidal foam/gel/film/cream/suppository from the first dose of study drug and until 21 days after last dose of study medication,
- •or is surgically sterile. NOTE: Male subjects must use contraception to prevent pregnancy in a female partner and prevent exposure of any partner to semen by any means (refer to Section 8.1).
- •A female is eligible to enroll in the study if she is of:
Exclusion Criteria
- •Use of an investigational anti-cancer drug within 28 days or 5 half-lives with a minimum duration of 10 days from prior therapy preceding the first dose of GSK2256098 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.
- •Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug. (To date there are no known approved drugs chemically related to GSK2256098.)
- •Current use of a prohibited medication or requires any of these medications during treatment with GSK2256098 (Section 9.2).
- •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 OR prior resection of small intestine.
- •Unresolved toxicity greater than Grade 1 from previous anti-cancer therapy except alopecia.
- •QTc interval \> 450 msecs in males, 470 msec in women or congenital long QT syndrome. QTc calculation to be calculated by Fridericia formula. (Section 7.2.3)
- •History of acute coronary syndromes (including unstable angina and myocardial infarction), atrial fibrillation, coronary angioplasty, or stenting within the past 24 weeks.
- •Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
- •Symptomatic or untreated leptomeningeal or brain metastases. Subjects previously treated for these conditions who are asymptomatic and have not received corticosteroid and P450-inducing anti-epileptic medication for at least 2 months are permitted.
Arms & Interventions
Part 2
Part 2 - Dose expansion phase of the study at the maximum tolerated dose and schedule identified in Part 1 in patients with tumors known to over express FAK
Intervention: GSK2256098
Part 1
Part 1 - dose escalation; starting dose 80 mg BID
Intervention: GSK2256098
Part 3
Part 3 - Characterize the biologically active dose range by analysis of PD markers in skin, hair and in tumor tissue in subjects with solid tumors amendable to biopsy and know to over express FAK
Intervention: GSK2256098
Part 4
Part 4 - Explore further the safety, PK, tolerability and anti-tumor activity of GSK2256098 in subjects with relapsed glioblastoma multiforme (GBM).
Intervention: GSK2256098
Part 5
Part 5 will investigate the time course, the extent of an apparent change in the PK of GSK2256098 following repeated dosing, and screen for potential CYP3A induction as a possible mechanism of reduced systemic exposure of GSK2256098 at Day 15 and later time points.
Intervention: GSK2256098
Outcomes
Primary Outcomes
To evaluate the Maximum tolerated dose, identify the recommended Phase 2 dose(s), dose limiting toxicities, safety and tolerability of GSK2256098 given orally on consecutive days.
Time Frame: Until disease progression
Secondary Outcomes
- To identify a range of biologically active doses(Until disease progression)
- To explore anti-tumor activity after treatment with GSK2256098(Until disease progression)
- To explore relationships between GSK2256098 PK, PD and clinical endpoints(Until disease progression)
- To characterize the pharmacokinetics of GSK2256098 in blood after single- and repeat-dose administration(Until disease progression)