Phase I Open-Label, Dose-Escalation Study of GSK1059615 in Patients With Solid Tumors or Lymphoma

A Phase I Open-Label, Dose-Escalation Study of the Phosphoinositide 3-Kinase Inhibitor GSK1059615 in Patients With Solid Tumors or Lymphoma

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.

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.