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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01138033




Registration number
NCT01138033
Ethics application status
Date submitted
3/06/2010
Date registered
7/06/2010
Date last updated
11/05/2017

Titles & IDs
Public title
Study of a Focal Adhesion Kinase Inhibitor in Subjects With Solid Tumors
Scientific title
A Phase I Open-Label Dose Escalation Study of the Focal Adhesion Kinase Inhibitor, GSK2256098, in Subjects With Solid Tumors
Secondary ID [1] 0 0
113517
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 0 0
Condition category
Condition code
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - GSK2256098

Experimental: Part 1 - Part 1 - dose escalation; starting dose 80 mg BID

Experimental: 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

Experimental: 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

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

Experimental: 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.


Treatment: Drugs: GSK2256098
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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
Until disease progression
Secondary outcome [1] 0 0
To characterize the pharmacokinetics of GSK2256098 in blood after single- and repeat-dose administration
Timepoint [1] 0 0
Until disease progression
Secondary outcome [2] 0 0
To identify a range of biologically active doses
Timepoint [2] 0 0
Until disease progression
Secondary outcome [3] 0 0
To explore anti-tumor activity after treatment with GSK2256098
Timepoint [3] 0 0
Until disease progression
Secondary outcome [4] 0 0
To explore relationships between GSK2256098 PK, PD and clinical endpoints
Timepoint [4] 0 0
Until disease progression

Eligibility
Key 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:

- 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.

- Complete abstinence from sexual intercourse.

- Use double barrier contraception defined as condom with 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.

NOTE: Oral contraceptives are not reliable due to potential for drug-drug interaction.

- Adequate organ system function

- Paraffin-embedded, archival tumor tissue available for testing. If archival tissue is
available but it is not feasible to obtain within the screening period, subjects may
enroll and enter the study prior to these specimens being received for analyses. In
situations that archival tumor specimens are not available, (i.e. insufficient
archival tumor specimens or a local hospital refuses to release a tissue block or
specimen for the purposes of the study), only subjects for Part 1 would be eligible
under such circumstances if there is documentation to explain why this tissue is not
available

Inclusion Criteria Part 2 and Part 3

- Confirmed cancers of the breast, esophagus, ovary, head and neck, colon, rectum,
stomach, liver, endometrium, cervix, oral epithelium, thyroid, lung, prostate, sarcoma
and other tumors reported in medical literature to overexpress FAK that are not
responsive to accepted standard therapies or for which there is no standard or
curative therapy.

- Subjects enrolled in Part 3 must have solid tumors that are amenable to biopsy.

Inclusion Criteria Part 4

- Subjects with glioblastoma multiforme at first or second recurrence defined as one or
two progressions as Grade 4 astrocytic tumor since original diagnosis of any grade
glioma.

- Subjects with prior treatment with bevacizumab (approximately 10 evaluable subjects)
and subjects without prior treatment with anti-angiogenic therapy (includes
bevacizumab and VEGFR inhibitors) will be allowed to enroll (approximately 10
evaluable subjects). For subjects with prior bevacizumab treatment, they should have
progressed while receiving bevacizumab as defined by the RANO criteria. [WEN PY, 2010]

- Recurrent or refractory disease must meet all of the following criteria:

- Received prior chemoradiotherapy that incorporated temozolomide

- Confirmed true progressive disease (rather than pseudoprogression) according to the
proposed RANO criteria [Wen PY, 2010]

- Progressive disease occurring within the first 12 weeks after completion of
chemoradiotherapy must be radiographically documented (i.e., new area of enhancement)
as being clearly outside the radiation field or must be pathologically confirmed

- Progressive disease occurring at = 12 weeks after completion of chemoradiotherapy
should include at least one of the following: -New contrast-enhancing lesion on
decreasing, stable, or increasing doses of corticosteroids (new contrast- enhancing
nonmeasurable disease is permitted) OR

- Increase of 25% in the sum of the products of perpendicular diameters of the
contrast-enhancing lesions compared to baseline (e.g., 1st postradiotherapy scan) or
best response after initiation of therapy while on stable or increasing doses of
corticosteroids OR

- Significant increase in T2/FLAIR nonenhancing lesion (for subjects receiving
antiangiogenic therapy) compared to baseline (e.g., 1st postradiotherapy scan) or best
response after initiation of therapy on stable, or increasing doses of corticosteroids
OR

- Clear radiographic progression of nonmeasurable lesions NOTE: An increase in
corticosteroid dose or clinical deterioration not attributable to concurrent
medication or comorbid conditions alone is not sufficient to indicate progressive
disease for the purpose of entry onto the study.

- Documented radiographic presence of at least one measurable or non-measurable lesion
as defined by the RANO criteria [Wen PY, 2010]

- If recent resection or biopsy of tumor has taken place, then all of the following must
apply:

- Planned first dose of GSK2256098 must be > 28 days after surgery (or > 7 days after
core needle biopsy)

- Subject has recovered from the effects of surgery

- Subject has at least one non-measurable residual lesion following surgery as defined
by the RANO criteria [WEN PY, 2010]
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

- 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.

Additional Exclusion Criteria - Part 4 only:

- Subjects with >/=Grade 1 intracranial hemorrhage

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
27/07/2010
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
21/12/2015
Sample size
Target
Accrual to date
Final
74
Recruitment in Australia
Recruitment state(s)
VIC,WA
Recruitment hospital [1] 0 0
GSK Investigational Site - Heidelberg
Recruitment hospital [2] 0 0
GSK Investigational Site - Nedlands
Recruitment postcode(s) [1] 0 0
3084 - Heidelberg
Recruitment postcode(s) [2] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
France
State/province [1] 0 0
Caen Cedex 9
Country [2] 0 0
France
State/province [2] 0 0
Villejuif
Country [3] 0 0
United Kingdom
State/province [3] 0 0
Glasgow
Country [4] 0 0
United Kingdom
State/province [4] 0 0
London
Country [5] 0 0
United Kingdom
State/province [5] 0 0
Manchester
Country [6] 0 0
United Kingdom
State/province [6] 0 0
Newcastle upon Tyne

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT01138033
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT01138033