A Phase I Dose Escalation, Single Center, Open-Label Study of AUY922 Administered IV on a Once-Weekly Schedule in Adult Patients 75 Years of Age or Older With Advanced Solid Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- MTD of Hsp90 inhibitor AUY922
研究概览
简要总结
This phase I trial studies the side effects and best dose of Hsp90 inhibitor AUY922 in treating older patients with advanced solid malignancies. Hsp90 inhibitor AUY922 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth
详细描述
PRIMARY OBJECTIVES:
I. The primary objective is to determine the maximally tolerated dose (MTD) of AUY922 (Hsp90 inhibitor AUY922) as a single agent when administered intravenously (IV) on a once-weekly schedule to adult patients 75 years of age or older with advanced solid tumors whose disease has progressed despite standard therapy or for whom no standard therapy exists.
SECONDARY OBJECTIVES:
I. To characterize the safety and tolerability of treatment with AUY922. II. To characterize the pharmacokinetic profiles of AUY922, including the parent drug and any potential metabolites.
III. To determine the efficacy of AUY922 in elderly patients with measurable disease.
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
- 75 Years 至 —（Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have a histologically proven solid tumor malignancy which is refractory to standard therapy and for which no curative therapy is available
- •Patients must have at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST); irradiated lesions are only evaluable for disease progression
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of =< 1
- •Life expectancy of >= 12 weeks
- •Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
- •Hemoglobin (Hgb) >= 9 g/dl
- •Platelets (plt) >= 100 x 10^9/L
- •Potassium within normal limits or correctable with supplements
- •Total calcium (corrected for serum albumin) and phosphorus within normal limits
- •Magnesium above lower limit of normal (LLN) or correctable with supplements
- •Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) =< 2.5 x upper limit of normal (ULN) if no liver metastases are present
- •AST/SGOT and ALT/SGPT =< 5 x ULN if liver metastases are present
- •Serum bilirubin =< 1.5 x ULN
- •Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 ml/min
- •Patients must be able to understand and voluntarily sign written informed consent
- •Male participants with partners who are of child bearing potential must:
- •Agree to use double barrier method of birth control 28 days prior to study entry, during course of study and for 28 days following the last dose of AUY922
- •OR have history of a vasectomy
排除标准
- •Patients with central nervous system (CNS) metastasis which are:
- •Symptomatic or
- •Require treatment for symptom control and/or
- •Growing Note: Patients without clinical signs or symptoms of CNS involvement are not required to have a computed tomography (CT)/magnetic resonance imaging (MRI) of the brain
- •Prior treatment with any heat shock protein (HSP)90 or histone deacetylase (HDAC) inhibitor compounds
- •Patients who received systemic anti-cancer treatment prior to the first dose of AUY922 within the following time frames:
- •Radiotherapy or conventional chemotherapy: within 4 weeks
- •Palliative radiotherapy: within 2 weeks
- •Nitrosoureas, mitomycin, or monoclonal antibodies, such as trastuzumab, within 6 weeks
- •Any systemic anti-cancer treatment for which the elimination period is not known, or investigational drugs (i.e. targeted agents) within a duration of =< 5 half lives of the agent and their active metabolites (if any)
- •Treatment with therapeutic doses of coumadin-type anticoagulants (maximum daily dose of 2 mg, for line patency permitted)
- •Unresolved diarrhea >= Common Terminology Criteria for Adverse Events (CTCAE) grade 1, despite treatment with antidiarrheal agents
- •Patients with malignant ascites that require invasive treatment
- •Male patients whose partners are women of child-bearing potential (WCBP) not using double-barrier methods of contraception
- •Acute or chronic liver or renal disease
- •Other concurrent severe and/or uncontrolled medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol
- •Major surgery =< 2 weeks prior to Cycle 1, Day 1 or who have not recovered from such therapy; (placement of a venous access device within 2 weeks is permitted)
- •Impaired cardiac function, including any one of the following:
- •History (or family history) of long QT syndrome
- •Mean corrected QT interval (QTc) >= 450 msec on baseline electrocardiogram (ECG)
- •History of clinically manifested ischemic heart disease =< 6 months prior to study start
- •History of heart failure or left ventricular (LV) dysfunction (left ventricular ejection fraction [LVEF] =< 45%) by multigated acquisition scan (MUGA) or echocardiogram (ECHO)
- •Clinically significant ECG abnormalities including 1 or more of the following: left bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior hemiblock (LAHB); ST segment elevation or depression > 1mm, or 2nd (Mobitz II), or 3rd degree atrioventricular (AV) block
- •History or presence of atrial fibrillation, atrial flutter or ventricular arrhythmias including ventricular tachycardia or Torsades de Pointes
- •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)
- •Clinically significant resting bradycardia (< 50 beats per minute)
- •Patients who are currently receiving treatment with any medication which has a relative risk of prolonging the corrected QT using Bazett's formula (QTcB) interval or inducing Torsades de Pointes and cannot be switched or discontinued to an alternative drug prior to commencing AUY922
- •Patients who are dependent on a pacemaker due to cardiac conduction dysfunction; known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
- •Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
- •Patients unwilling or unable to comply with the protocol
研究组 & 干预措施
Treatment (enzyme inhibitor therapy)
Patients receive Hsp90 inhibitor AUY922 IV over 1 hour on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Hsp90 inhibitor AUY922 (Drug)
Treatment (enzyme inhibitor therapy)
Patients receive Hsp90 inhibitor AUY922 IV over 1 hour on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: pharmacological study (Other)
Treatment (enzyme inhibitor therapy)
Patients receive Hsp90 inhibitor AUY922 IV over 1 hour on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
MTD of Hsp90 inhibitor AUY922
时间窗: at 28 days
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as clinically relevant, and occurs \< 28 days following the first dose of AUY922. Toxicity will be measured by CTCAE criteria (Version 4.02). The MTD will be determined using a standard design.
次要结局
- Toxicity by CTCAE (v 4.02)(at 28 days)
- Pharmacokinetic parameters, including area under the curve (AUC), clearance, volume of distribution (VD), time to the maximum concentration (Tmax), maximum plasma concentration (Cmax), and elimination half-life(at baseline and at 28 days (first cycle))
- Tumor response will be measured by RECIST criteria (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD], overall response [OR], response rate [RR])(at baseline and at end of cycle 2 (8 weeks))
- Geriatric assessment will be made including Mini Mental Exam, Get up and Go, assessment of comorbidity, and Geriatric Depression Scale(at baseline and at end of cycle 2 (8 weeks))
- Evaluation of responses to a bioethics questionnaire will be used to assess patient factors influencing enrollment in this elderly-specific phase I trial(Baseline)
- Number of Circulating Tumor Cells (CTC) at baseline and after treatment with Hsp90 inhibitor AUY922(at baseline and end of treatment)
- Level of HSP70 at baseline and after treatment with Hsp90 inhibitor AUY922(at baseline and at 28 days (first cycle))
- Level of M30 and M65 at baseline and following therapy with Hsp90 inhibitor AUY922(at baseline and at 28 days (first cycle))
研究者
Dale Shepard, MD, PhD
Principal Investigator
Case Comprehensive Cancer Center