Study of a Focal Adhesion Kinase Inhibitor in Subjects With Solid Tumors

NCT01138033 | Completed Phase 1

• 1 other identifier: 113517
• Study Type: interventional
• Target: 74
• Locations: 3 countries
• Sites: 10

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.

Conditions

Cancer

Keywords

pharmacodynamics; cancer; focal adhesion kinase inhibitor; pharmacokinetics; solid tumors; Phase 1

Outcome Measures

Primary Outcomes (1)

• 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.

  Until disease progression

Secondary Outcomes (4)

• To characterize the pharmacokinetics of GSK2256098 in blood after single- and repeat-dose administration

  Until disease progression

• 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

Study Arms (5)

Part 1

EXPERIMENTAL

Part 1 - dose escalation; starting dose 80 mg BID

Drug: GSK2256098

Part 2

EXPERIMENTAL

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

Drug: GSK2256098

Part 3

EXPERIMENTAL

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

Drug: GSK2256098

Part 4

EXPERIMENTAL

Part 4 - Explore further the safety, PK, tolerability and anti-tumor activity of GSK2256098 in subjects with relapsed glioblastoma multiforme (GBM).

Drug: GSK2256098

Part 5

EXPERIMENTAL

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.

Drug: GSK2256098

Interventions

GSK2256098 DRUG

GSK2256098 is a potent focal adhesion kinase inhibitor that will be administered orally as 20, 100 or 250 mg capsules. The starting dose in Part 1 is 80 mg twice daily. The dose will continue to be increased until the maximum tolerated dose is identified.

Part 1; Part 2; Part 3; Part 4; Part 5

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent provided.
• 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:
• Non-child bearing potential (i.e., physiologically incapable of becoming pregnant) including any woman who is characterized by at least one of the following:
• oHas had a hysterectomy oHas had a bilateral oophorectomy (ovariectomy) oHas had a bilateral tubal ligation oIs post-menopausal (total cessation of menses for ≥ 1 year)
• Childbearing potential, has a negative serum pregnancy test at screening, and agrees to one of the following from at least 2 weeks prior to the first dose of study drug and until 21 days after last dose of study medication:
• Use an intrauterine device (IUD) with a documented failure rate of less than 1% per year.
• Have intercourse only with a vasectomized partner who is sterile and is the sole sexual partner for that woman.

You may not qualify if:

• 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).
• 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.
• Primary malignancy of the central nervous system.
• 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.
• Consumption of red wine, Seville oranges, grapefruit or grapefruit juice or kumquats, pummelos, exotic citrus fruit (i.e., star fruit, bitter melon), grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication.
• Any serious and/or unstable pre-existing medical, psychiatric or other condition (including lab abnormalities) that could interfere with subject safety or obtaining informed consent.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (10)

GSK Investigational Site

Heidelberg, Victoria, 3084, Australia

Location

GSK Investigational Site

Nedlands, Western Australia, 6009, Australia

Location

GSK Investigational Site

Caen, 14033, France

Location

GSK Investigational Site

Villejuif, 94805, France

Location

GSK Investigational Site

Glasgow, G61 1BD, United Kingdom

Location

GSK Investigational Site

London, NW1 2BU, United Kingdom

Location

GSK Investigational Site

London, W12 0HS, United Kingdom

Location

GSK Investigational Site

London, W1G 6AD, United Kingdom

Location

GSK Investigational Site

Manchester, M20 4BX, United Kingdom

Location

GSK Investigational Site

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (1)

• Brown NF, Williams M, Arkenau HT, Fleming RA, Tolson J, Yan L, Zhang J, Singh R, Auger KR, Lenox L, Cox D, Lewis Y, Plisson C, Searle G, Saleem A, Blagden S, Mulholland P. A study of the focal adhesion kinase inhibitor GSK2256098 in patients with recurrent glioblastoma with evaluation of tumor penetration of [11C]GSK2256098. Neuro Oncol. 2018 Nov 12;20(12):1634-1642. doi: 10.1093/neuonc/noy078.

  PMID: 29788497 DERIVED

Related Links

• Results for study 113517 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Neoplasms

Interventions

GSK2256098

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 3, 2010
• First Posted: June 7, 2010
• Study Start: July 27, 2010
• Primary Completion: December 21, 2015
• Study Completion: December 21, 2015
• Last Updated: May 11, 2017

Record last verified: 2017-05

Locations

GB (6); AU (2); FR (2)