An Open-Label Phase I/II Study of GSK2110183 in Combination With Carboplatin and Paclitaxel in Subjects With Platinum-Resistant Ovarian Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Accenture
- 入组人数
- 59
- 试验地点
- 10
- 主要终点
- Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity
研究概览
简要总结
- 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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- Female
- 接受健康志愿者
- 否
入选标准
- •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:
- •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
- •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
排除标准
- •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
研究组 & 干预措施
GSK2110183, carboplatin and paclitaxel
Subjects will be treated with a maximum of six doses of carboplatin + paclitaxel in combination with continuous daily GSK2110183 followed by single agent GSK2110183 at the single-agent MTD of 125 mg or above oral daily.
干预措施: GSK2110183 in combination with carboplatin and paclitaxel (Drug)
结局指标
主要结局
Phase 1: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade Greater Than or Equal to (≥) 3 in Severity
时间窗: Up to Week 3
Phase 1 Safety: Number of Subjects Reporting Adverse Events
时间窗: Up to Week 3
Study Treatment refers to GSK2110183 with or without Carboplatin and/or Paclitaxel. Dose limiting toxicity (DLT): An event is considered a DLT if it had a reasonable causal relationship to study drug \& occurs within first 3 weeks of therapy \& met at least one of the following criteria: * Grade 3 or 4 non-hematologic toxicity as described in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0, 2009 \[NCI, 2009\] with the exceptions of Grade 3 electrolyte disturbances that respond to correction within 24 hours; or Grade 3 rash, diarrhea, nausea, vomiting and mucositis that responded to standard medical supportive care within 48 hours). * Grade 4 neutropenia lasting ≥5 days * Febrile neutropenia * Grade 3 thrombocytopenia with bleeding * Grade 4 thrombocytopenia * Grade 4 anemia * Treatment delay of \>14 days due to unresolved toxicity * Alanine aminotransferase (ALT) \>3 times upper limit of normal (ULN) with bilirubin \>2 times ULN
Phase 1: Maximum Tolerated Dose (MTD) of GSK2110183
时间窗: Up to Week 3
MTD is defined as the highest dose at which 1 or fewer of up to 6 subjects experience a dose limiting toxicity (DLT) during the first 3 weeks of combination therapy. MTD was considered exceeded if 2 or more subjects in a cohort of up to 6 subjects experienced a DLT.
Overall Response Rate (ORR) in Phase 2 Subjects With Recurrent Platinum-resistant Ovarian Cancer (Cohort A)
时间窗: Every 3 weeks up to 6 months
Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST) 1.1 criteria for target lesions and assessed by MRI: Complete Response (CR) is Disappearance of all target lesions and Partial Response (PR) is greater than or equal to (≥) 30% decrease in the sum of the longest diameter of target lesions. Overall Response (OR) = CR + PR.
ORR in Phase 2 Subjects With Recurrent Platinum-refractory Ovarian Cancer (Cohort B)
时间窗: Every 3 weeks up to 6 months
Per RECIST version 1.1 criteria for target lesions and assessed by MRI: Complete Response (CR) is Disappearance of all target lesions and Partial Response (PR) is ≥30% decrease in the sum of the longest diameter of target lesions. Overall Response (OR) = CR + PR.
次要结局
- ORR in Phase 1 Subjects With Recurrent Platinum-resistant Ovarian Cancer(Up to Week 3)
- Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) of Grade ≥3 in Severity(Up to Day 21 (Phase 2))
- Phase 2 Safety: Number of Subjects Reporting Adverse Events(Up to Day 51)
- Phase 2: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125(From Month 1 to 6)
- Progression Free Survival (PFS) by RECIST or Clinical Symptomatic Progression of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A)(From first dose until disease progression or death (approximately 36 months))
- PFS by RECIST of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase 2-Cohort A)(From first dose until disease progression or death (approximately 36 months))