Solid Tumours
Conditions
Keywords
Phosphoinositide 3-kinase inhibitor, solid tumors
Brief summary
This is an open-label, multi-center Phase I study conducted to define the recommended Phase 2 dose, toxicity profile, pharmacokinetics and biologically active dose range of GSK1059615.
Interventions
DRUGGSK1059615
GSK1059615 is dosed orally once daily for 21 days of a 28-day cycle. Patients continue treatment for subsequent cycles as long as eligible and receiving benefit.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent provided. * 18 years old or older. * Histologically- or cytologically- confirmed diagnosis of solid tumor malignancy or lymphoma that is not responsive to accepted standard therapies or for which there is no standard or curative therapy. * Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale. * A life expectancy of \> 12 weeks. * 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 patients must use contraception to prevent pregnancy in a female partner and prevent exposure of any partner to semen by any means (refer to protocol). * 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: * Has had a hysterectomy * Has had a bilateral oophorectomy (ovariectomy) * Has had a bilateral tubal ligation * Is 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 * spermicidal jelly, foam, suppository, or film; OR diaphragm with * spermicide; OR male condom and diaphragm. NOTE: Oral contraceptives are not reliable due to potential for drug-drug interaction. * Adequate organ system function as defined in the protocol.
Exclusion criteria
* Use of an investigational anti-cancer drug within 28 days or 5 half-lives preceding the first dose of GSK1059615. * Chemotherapy within the last 3 weeks (6 weeks for prior nitrosourea or mitomycin C). Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity are permitted with approval of the GSK medical monitor if administered at least 2 weeks prior to the first dose of study drug. * Trastuzumab within the last 4 weeks. * Any major surgery, radiotherapy, or immunotherapy within the last 4 weeks. * Prior use of any PI3K inhibitor. * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug. (To date there are no known FDA approved drugs chemically related to GSK1059615). * Current use of a prohibited medication or requires any of these medications during treatment with GSK1059615 as per protocol. * Current use of warfarin for therapeutic anticoagulation. * NOTE: Low molecular weight heparin and prophylactic low-dose warfarin are permitted. PT/PTT must meet the inclusion criteria. Patients taking warfarin must have their INR followed closely. * Presence of an active gastrointestinal disease or other condition known to interfere significantly with the absorption, distribution, metabolism, or excretion of drugs. * Unresolved toxicity greater than Grade 1 from previous anti-cancer therapy except alopecia. Patients with stable Grade 2 neuropathy can be enrolled with approval by the GSK Medical Monitor. * QTc interval ≥ 480 msecs. * 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. Patients previously treated for these conditions who are asymptomatic and off of 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Adverse events (AEs) and changes in laboratory values and vital signs as per protocol. | 21 days |
Secondary
| Measure | Time frame |
|---|---|
| time to maximum observed plasma drug concentration, and half-life of GSK1059615. | 21 days |
| Metabolic profiling in plasma and urine, and amount excreted in urine (subset of patients). | 21 days |
| Pharmacokinetic parameter values for GSK1059615 following single and repeated dosing, including area under the plasma drug concentration curve (AUC), maximum observed plasma drug concentration (Cmax) | 21 days |
| Change from baseline in protein markers in tumor and/or blood. | 28 days |
| Blood glucose and insulin levels. | Daily for 28 days |
| Tumor response as defined by RECIST in the protocol. | 56 days |
Countries
United States
Outcome results
None listed