NCT01159418Unknown1 期
A Phase IB Study of the Histone Deacetylase Inhibitor Panobinostat (LBH589) Given Orally in Combination With Carboplatin and Paclitaxel in Patients With Advanced Solid Tumors
Southern Europe New Drug Organization3 个研究点 分布在 1 个国家目标入组 36 人开始时间: 2008年6月最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 36
- 试验地点
- 3
- 主要终点
- Maximum Tolerated Dose (MTD) Recommended Dose (RD)
研究概览
简要总结
The purpose of this study is to determine the Maximum Tolerated Dose (MTD) of Panobinostat (LBH589) when administered in combination with Carboplatin and Paclitaxel in patients with advanced solid malignancies and to identify the Recommended Dose (RD) for a subsequent Phase II study.
详细描述
The combination of Carboplatin (C) and Paclitaxel (PTX) is considered standard treatment in patients with epithelial ovarian cancer and endometrial cancer, in USA and in those in whom anthracyclines are not recommended. In cervical cancer, where very often the renal function is impaired, C represents a convenient substitute of cisplatin in the combination with PTX; in NSCLC the C and PTX regimen is first choice therapy for outpatient treatment first or second line.
LBH is a histone deacetylase (HDAC) inhibitor available also for oral administration.
In combination with platinum agents LBH589 could improve efficacy on DNA by multiple non-exclusive mechanisms (by increasing drug access to chromosomal DNA, interfering with DNA repair, modulating the levels of pro antiapoptotic genes or proliferation/survival genes).
The inclusion of Paclitaxel in the combination of LBH589 and Carboplatin is supported by the results already available with the combination of the HDAC inhibitor Vorinostat (suberoylanilide hydroxamic acid) given orally with carboplatin (AUC 6 mg/ml.h) and paclitaxel (200 mg/m2) in a Phase I study in patients with solid tumors. The regimen proved to be feasible, well tolerated and was associated with promising antitumor activity in patients with NSCLC.
The mechanism of action, and the preliminary preclinical data, suggest that the combination of LBH589, Carboplatin and Paclitaxel could be feasible and worthy of clinical investigation.
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histological/cytological diagnosis of solid tumors in which treatment with Carboplatin and Paclitaxel is indicated, e.g. NSCLC, GY tumors, prostate cancer, unknown primary
- •Progressive disease (also in terms of tumor markers only, like CA 125 for ovary and PSA for prostate).
- •Age 18-75 years
- •Prior chemotherapy of ≤ 1 line for advanced disease
- •ECOG Performance Status < 2
- •Life expectancy of at least 3 months
- •The patient must be able to read, understand and provide written evidence of informed consent
- •Female patients may not be pregnant or lactating and must be willing to practice contraception. The effects of LBH589 on the developing human fetus are unknown. For this reason, women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation.
- •Male patients that are not surgically sterile must be practicing a medically acceptable contraceptive regimen while on study treatment
- •Adequate organ function as defined by the following:
- •ANC > 1500/µL
- •Platelets ≥ 100,000/µL
- •Haemoglobin ≥ 10 g/dl
- •Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 60 ml/min
- •Magnesium, potassium and phosphorus ≥ the lower limit of normal or correctable with supplements
- •Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 x ULN or ≤ 5.0 x ULN if hepatic involvement is present
- •Serum bilirubin ≤ 1.5 x ULN
- •Alkaline phosphatase (ALP) ≤ 2.5 x ULN or ALP > 2.5 x UNL with liver fraction ≤ 2.5 x ULN
排除标准
- •Other chemotherapy treatment < 4 weeks prior to enrolment
- •Hypersensitivity or allergic reactions to platinum compounds or Carboplatin®; hypersensitivity or allergic reactions to Paclitaxel
- •Radiotherapy involving > 30% of the active bone marrow
- •Radiotherapy < 4 weeks prior to enrolment
- •Pre-existing peripheral neuropathy ≥ grade 2
- •Pre-existing CTCAE hearing loss or tinnitus ≥ grade 2
- •Symptomatic pleural effusion
- •Clinically significant third space fluid accumulation (e.g. ascites,..)
- •Symptomatic brain metastasis or meningeal tumors
- •Patients who have not recovered (> grade 1) from the following toxicities of previous regimens before enrolment: fatigue, mucositis, nausea/vomiting, diarrhea
- •Concurrent enrolment, or previous enrolment within 30 days prior to registration in another investigational device or drug trial(s) or is receiving other investigational agent(s)
- •Human immunodeficiency virus (HIV) infection
- •History of bone marrow or major organ transplant
- •Prior high dose treatment with PBSC support
- •Impaired cardiac function, including any one of the followings:
- •Complete Left Bundle Branch Block or obligate use of a cardiac pacemaker or congenital long QT syndrome or history or presence of atrial or ventricular tachyarrhythmias or clinically significant resting bradycardia (< 50 beats per minute) or QTcF > 480 msec on screening ECG or Right Bundle Branch block + left anterior hemiblock (bifascicular block)
- •Angina pectoris or acute MI ≤ 3 months prior to starting study drug
- •Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LBH589 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, malabsorption syndrome, or small bowel resection)
- •Acute or chronic liver or renal disease
- •Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease) that could cause unacceptable safety risks or compromise compliance with the protocol
- •Concomitant use of CYP3A4/5 inhibitors or inducers where the treatment can not be discontinued or switched to a different medication prior to starting study drug (medications listed in Appendix 3). The medications listed in Appendix 3 have a relative risk of prolonging the QT interval or inducing Torsades de Pointes, but do not represent an exclusion criteria
- •Treatment with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GMCSF) ≤ 2 weeks prior to starting study drug.
- •Treatment with therapeutic doses of sodium warfarin (Coumarin ). Low doses of Coumarin (e.g., ≤ 2 mg/day) for line patency is allowable
- •Patients who have received biologic therapy (excluding antiangiogenics) or immunotherapy ≤ 2 weeks prior to starting study treatment or who have not recovered from side effects of such therapy
- •Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
- •Unable or unwilling to comply with all study procedures
- •Current history of alcohol or drug abuse
研究组 & 干预措施
Panobinostat (LBH589), Carboplatin and Paclitaxel
Experimental
干预措施: Panobinostat (LBH589), Carboplatin and Paclitaxel (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) Recommended Dose (RD)
时间窗: 3 weeks after the first drug administration (1 Cycle)
Number of Dose-Limiting Tocixities (DLTs)
次要结局
- Hints of antitumor activity(from first drug administration until tumor progression (every 6 weeks))
- Biomarkers of HDAC(Cycle 1 on day 1, 4, 8, 15 and Cycle 2 on day 1, 8.)
- Safety and tolerability(4 weeks after last drug administration)
研究者
研究点 (3)
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