A Phase I Open-Label Dose Escalation Study of the Focal Adhesion Kinase Inhibitor, GSK2256098, in Subjects With Solid Tumors
- 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
- 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
- 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
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
- 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
- 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,
- 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
- 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
- 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
- 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]
- 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
- 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
- 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
- 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
Additional Exclusion Criteria - Part 4 only:
- Subjects with >/=Grade 1 intracranial hemorrhage