A Phase I, Open-Label, Dose-Escalation, First Time in Human Study to Evaluate the Safety Profile, Pharmacokinetics, and Pharmacodynamics of GSK923295 in Subjects With Refractory Cancers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 39
- 试验地点
- 1
- 主要终点
- Safety: - physical exam
研究概览
简要总结
This is a Phase I, open-label, first time in human study of GSK923295, in adult subjects with cancers that do not respond to standard therapy. This study will be conducted in two stages; a dose-escalation stage (Stage 1) and an expansion cohort stage (Stage 2).
详细描述
Centromere-associated protein E (CENP-E) is a protein that is required for correct chromosomal alignment in mitosis. Loss of CENP-E activity, due to microinjection of antibodies, ablation of gene expression with siRNA or antisense oligonucleotides, or inhibition of enzymatic activity by small molecule inhibitors, causes aberrant cell cycle arrest in mitosis, characterized by a bipolar mitotic spindle with misaligned chromosomes. Studies with small molecule inhibitors have demonstrated that this aberrant cell cycle arrest can result in apoptosis and cell death. CENP-E has been shown to be abundantly expressed in a variety of human tumors. GSK923295 is a potent and selective CENP-E inhibitor which has demonstrated potent and broad spectrum antitumor activity against solid and hematologic malignancies in vitro. GSK923295 is intended for use either as a monotherapy or in combination with existing anti-cancer therapies.
A drug targeting CENP-E may prove as efficacious as the taxanes and vinca alkaloids, without the potential for neurotoxicity or other side-effects associated with interference of tubulin function in non-dividing cells. Similar to many other anti-proliferative drugs, CENP-E inhibitors are expected to have manageable dose-limiting toxicities resulting from action on normal proliferating tissues (e.g., myelosuppression and gastrointestinal epithelial cell damage). The opportunity for inhibitors of CENP-E lies in the potential for broad efficacy. The absence of broad clinical experience with anti-mitotic cancer therapies acting on targets other than tubulin complicates prediction of additional benefits, beyond the lack of neurotoxicity that might accrue from a drug targeting CENPE.
The purpose of this Phase I, first time in human (FTIH) study in subjects with refractory cancers is to determine the maximally tolerated dose (MTD) (or recommended dose based on available safety, pharmacokinetic (PK) and response data), dose-limiting toxicities (DLTs), PK, pharmacodynamics (PD), and preliminary clinical activity of GSK923295, an inhibitor of CENP-E.
The primary objectives in Stage 1 (Dose Escalation) are:
• To determine the MTD (or recommended dose based on available safety, PK, and response data), DLTs, safety, and PK of GSK923295 administered to subjects with advanced, refractory malignancies.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed, written informed consent provided.
- •a) Stage 1 Subjects: Histologically or cytologically confirmed diagnosis of solid tumor malignancy that is not responsive to accepted standard therapies, or for which there is no standard therapy.
- •b) Stage 2 Subjects: Histologically or cytologically confirmed diagnosis of solid tumor malignancy, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia that is not responsive to accepted standard therapies, or for which there is no standard therapy.
- •Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
- •18 years old or older.
- •Male or female
- •A female is eligible to enroll in the study if she is of:
- •Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) including any woman who:
- •Has had a hysterectomy, or
- •Has had a bilateral oophorectomy (ovariectomy), or
- •Has had a bilateral tubal ligation, or
- •Is post-menopausal (demonstrate total cessation of menses for greater than or equal to one year).
- •Childbearing potential, has a negative serum pregnancy test at screening, and agrees to one of the following from at least two weeks prior to study enrolment until completion of the Post Study procedures:
- •An intrauterine device (IUD) with a documented failure rate of less than 1% per year.
- •Vasectomized partner who is sterile and is the sole sexual partner for that woman.
- •Complete abstinence from sexual intercourse.
- •Double barrier contraception defined as condom with spermicidal jelly, foam, suppository, or film; OR diaphragm with spermicide; OR male condom and diaphragm.
- •A male is eligible to enter and participate in the study if he either agrees to abstain from sexual intercourse or use a condom and occlusive cap (diaphragm or cervical/vault cap) with spermicidal foam/gel/film/cream/suppository from the first dose administered until completion of the Post-Treatment procedures; or is surgically sterile.
- •Adequate organ systems function as defined in the protocol.
- •Subjects may have measurable lesions according to RECIST criteria in Stage
- •It is required in Stage 2 that subjects with solid tumors have measurable lesions according to RECIST criteria.
- •Paraffin-embedded archival tumor tissue available for testing.
- •At least one target tumor accessible to serial core needle biopsies at study entry (screening) and one additional time point post-dose Cycle
- •Note: optional for Stage 1 (Dose Escalation); it is mandatory for Stage 2 (Expansion Cohort)
排除标准
- •A subject will not be eligible for inclusion in this study if any of the following criteria apply:
- •Any major surgery OR prior anti-cancer therapy including but not limited to chemotherapy, radiotherapy, immunotherapy, biological therapy, or investigational therapy within the past 28 days (42 days for prior nitrosureas or mitomycin C).
- •Prior allogeneic or autologous bone marrow transplant.
- •Greater than 30% bone marrow irradiated.
- •Unresolved toxicity ≥ Grade 2 from previous anti-cancer therapy (except alopecia).
- •History of hemolytic anemia (either congenital or acquired) OR current laboratory evidence of hemolysis (Grade 1CTCAE or greater) that includes at least one of the following:
- •Decrease in serum haptoglobin (outside normal institutional laboratory values)
- •Increase in indirect bilirubin (outside normal institutional laboratory values)
- •Peripheral blood smear consistent with hemolysis (presence of schistocytes)
- •Pre-existing peripheral neuropathy or other neurological toxicity ≥ Grade
- •Female subjects who are pregnant or lactating.
- •Any serious or unstable pre-existing medical, psychiatric, active infection or other condition (including lab abnormalities) that could interfere with subject safety or obtaining informed consent.
- •Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
- •QTc prolongation defined as a QTc interval greater than or equal to 450 msecs.
- •Other significant ECG abnormalities including 2nd or 3rd degree AV block or bradycardia (ventricular rate less than 50 beats/min).
- •History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty and/or stenting within the past 6 months.
- •For subjects with a history of myocardial infarction, congestive heart failure, abnormal left ventricular ejection fraction (LVEF), or prior anthracycline exposure, LVEF must be assessed within 28 days of the first dose of study drug by one of the following methods: MUGA or ECHO. An LVEF measurement of < 50% will exclude the subject from participation in the study.
- •Class III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
- •Current use of warfarin ≥ 4 mg per day. NOTE: Low molecular weight heparin and prophylactic low-dose warfarin are permitted. PT/PTT must meet the inclusion criteria.
- •Current use of prohibited medications in accordance with the guidelines detailed in the protocol in the "Prohibited Medications" section.
- •Current use of drugs with risk of torsade de pointes as described in the protocol.
- •Evidence of symptomatic or untreated central nervous system involvement (i.e., brain metastases, leptomeningeal disease, cord compression).
研究组 & 干预措施
GSK923295
anti-mitotic compound under study
干预措施: GSK923295 (Drug)
结局指标
主要结局
Safety: - physical exam
时间窗: at screen & Day(D) 1 of each cycle and follow-up(F/U)
- vital signs and lab tests
时间窗: at screen & D1, 8, 15, & 22 for each cycle & F/U
continuous monitoring of adverse events
时间窗: each visit
- ECGs
时间窗: at screen and D1, 8 & 15 for each cycle & F/U
次要结局
- Plasma samples of GSK923295 taken at:(- Day 1 of each cycle for Stage 2)