dose-finding study in platinum-resistant ovarian cancer

Conditions: Recurrent Platinum-resistant Ovarian Cancer

Summary: * dose-finding study of gsk2110183 administered in combination with carboplatin and paclitaxel to any subject with recurrent ovarian cancer. * safety and efficacy study of gsk2110183 administered in combination with carboplatin and paclitaxel to subjects with platinum-resistant ovarian cancer.

pkb116611 is an open-label phase i/ii study of the investigational drug gsk2110183 given in combination with carboplatin and paclitaxel to subjects with recurrent ovarian cancer. phase i is a dose escalation evaluation of daily oral doses of gsk2110183 administered in combination with every 3 week carboplatin and paclitaxel to any subject with recurrent ovarian cancer. phase ii is a single arm evaluation of the clinical efficacy of the combination identified in phase i to subjects with platinum-resistant ovarian cancer.

Eligibility criteria:
phase i inclusion criteria: * female, 18 years of age as of signing the informed consent form, capable of giving/complying with written informed consent * histologically or cytologically confirmed serous ovarian cancer (includes primary peritoneal and fallopian tube) * negative serum pregnancy test in women of childbearing potential within 14 days of first dose of treatment, agree to use effective contraception during/after (6 months post dose of paclitaxel or 30 days post dose gsk2110183 whichever is longer) * performance status score of 0-2 according to the ecog scale. * able to swallow and retain oral medication * subjects diagnosed previously with type 2 diabetes must have been diagnosed ≥ 6 months prior to enrollment * prior treatment-related toxicities (except for alopecia) must be ≤ grade 1 according to nci-ctcae (version 4.0 \[nci, 2009\]) at the time of treatment allocation or ≤ grade 2 and stable for 4 weeks or longer at the time of screening evaluation. exception: subjects with peripheral neuropathy \>/= grade 2 will not be eligible * adequate organ system function phase ii inclusion criteria: cohort a * phase i criteria * documented complete or partial response by recist to at least 1 prior platinum-based therapy * progression defined by either (1) recist v1.1 criteria or (2) gcig ca 125 criteria associated with symptoms necessitating treatment between 1 and 6 months of prior platinum-based therapy either in adjuvant or metastatic setting * subjects allowed to have a maximum of one non-platinum-based therapy between the onset of platinum resistance * must have radiologically measurable disease i.e. presenting with at least one measurable lesion per recist 1.1 cohort b * phase i criteria * documented complete or partial response by recist to at least 1 prior platinum-based therapy * progression defined by either (1) recist v1.1 criteria or (2) gcig ca 125 criteria associated with symptoms necessitating treatment while being treated with a regimen containing carboplatin and paclitaxel (or within 4 weeks of completing treatment) * subjects will be required to start on treatment within 8 weeks after the last infusion of chemotherapy and may not have had any other anti-cancer therapy in the intervening time * must have radiologically measurable disease i.e. presenting with at least one measurable lesion per recist 1.1 * additional restrictions on number of prior therapies may be added to eligibility criteria based on emerging data exclusion criteria: * history of another malignancy (some exceptions may apply) * serious and/or unstable pre-existing medical or psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures * current use of prohibited medication during treatment. * chemotherapy, immunotherapy, or other anti-cancer therapy within 14 days prior to the first dose study drug * radiotherapy prior to initiation of therapy (some exceptions may apply) * contraindications (identified by the investigator) to the doses of carboplatin and/or paclitaxel * history of reduction in standard of care paclitaxel dose for peripheral neuropathy * no known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs similar or related to gsk2110183 * no known delayed hypersensitivity reaction or idiosyncratic reaction to drugs similar to carboplatin or paclitaxel (some exceptions may apply) * prior use of a drug that targets akt including perifosine * history of type 1 diabetes * gastrointestinal disease or other condition that could affect absorption or predispose subject to gastrointestinal ulceration * mucosal or internal bleeding * major surgery within the last four weeks * infection requiring parenteral or oral anti-infective treatment * severe or uncontrolled systemic diseases * brain metastases and/or leptomeningeal disease * qtcf interval ≥ 470 msecs * bundle branch block, pacemaker or clinically significant ecg abnormalities including 2nd degree (type ii) or 3rd degree atrioventricular (av) block * history of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty,stenting or bypass grafting within six months of screening * class ii, iii or iv heart failure as defined by the nyha functional classification system * pregnant or lactating female * malignancies related to hiv or solid organ transplant; history of known hiv, history of know hbv surface antigen positivity (subjects with documented laboratory evidence of hbv clearance may be enrolled) or positive hcv antibody

Keywords: cancer ovarian platinum-resistant