A Phase I/II Trial of Hsp 90 Inhibitor AUY-922 in Patients With Lung Adenocarcinoma With "Acquired Resistance" to EGFR Tyrosine Kinase Inhibitors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 38
- 试验地点
- 2
- 主要终点
- Maximally Tolerated Dose (MTD) of AUY922 and Erlotinib Treatment Combination (Phase I)
研究概览
简要总结
Hsp90 inhibitor AUY922 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase I/II trial is studying the side effects and best dose of Hsp90 inhibitor AUY922 when given together with erlotinib hydrochloride and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer.
详细描述
This is a phase I, dose-escalation study of Hsp90 inhibitor AUY922 followed by a phase II study. Patients receive Hsp90 inhibitor AUY922 IV over 1 hour once weekly and oral erlotinib hydrochloride once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.
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
- All
- 接受健康志愿者
- 否
入选标准
- •All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q)
- •Radiographic progression by RECIST during treatment with erlotinib/gefitinib
- •Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time
- •Measurable (RECIST) indicator lesion not previously irradiated
- •Must have undergone a biopsy after the development of acquired resistance
- •Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1
- •Signed informed consent
- •Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months
- •Total bilirubin =< 1.5 x Upper Limit of Normal (ULN)
- •AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present
- •Absolute neutrophil count (ANC) >= 1.5 x10^9/L
- •Hemoglobin (Hgb) >= 9g/dL
- •Platelets (plts) >= 100 x 10^9/L
- •Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min
排除标准
- •Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids
- •Prior treatment with any HSP90 inhibitor compounds
- •Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed)
- •Palliative radiation within 2 weeks
- •Unresolved diarrhea >= CTCAE grade 2
- •Pregnant or lactating women
- •Women of childbearing potential (WCBP) (i.e. women able to become pregnant) not using double-barrier methods of contraception (abstinence, oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly, or surgically sterile); male patients whose partners are 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 randomization or who have not recovered from such therapy
- •History (or family history) of long QT syndrome
- •Mean QTc >= 450 msec on baseline ECG
- •History of clinically manifested ischemic heart disease =< 6 months prior to study start
- •History of heart failure or left ventricular (LV) dysfunction (LVEF =< 45%) by MUGA or ECG
- •Clinically significant resting bradycardia (< 50 beats per minute)
- •Clinically significant ECG abnormalities including 1 or more of the following: left bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior hemi-block (LAHB); ST segment elevation or depression > 1mm, or 2nd (Mobitz II), or 3rd degree AV block
- •History ventricular tachycardia
- •Other clinically significant heart disease including congestive heart failure (New York Heart Association class III/IV) or uncontrolled hypertension (> 160/90 despite intensive medical management)
- •Patients who are currently receiving treatment with any medication which has a relative risk of prolonging the QTcF interval and cannot be switched or discontinued to an alternative drug prior to commencing AUY922
- •Known diagnosis of 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 who are receiving warfarin (Coumadin®) will be excluded unless =< 2 mg/d, with an INR < 1.5
- •Patients with known disorders due to a deficiency in bilirubin glucuronidation (e.g. Gilbert's syndrome)
研究组 & 干预措施
Arm I
Patients receive Hsp90 inhibitor AUY922 IV over 1 hour once weekly and oral erlotinib hydrochloride once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: erlotinib hydrochloride (Drug)
Arm I
Patients receive Hsp90 inhibitor AUY922 IV over 1 hour once weekly and oral erlotinib hydrochloride once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Hsp90 inhibitor AUY922 (Drug)
Arm I
Patients receive Hsp90 inhibitor AUY922 IV over 1 hour once weekly and oral erlotinib hydrochloride once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: mutation analysis (Genetic)
Arm I
Patients receive Hsp90 inhibitor AUY922 IV over 1 hour once weekly and oral erlotinib hydrochloride once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: laboratory biomarker analysis (Other)
Arm I
Patients receive Hsp90 inhibitor AUY922 IV over 1 hour once weekly and oral erlotinib hydrochloride once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: needle biopsy (Procedure)
Arm I
Patients receive Hsp90 inhibitor AUY922 IV over 1 hour once weekly and oral erlotinib hydrochloride once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: pharmacological study (Other)
结局指标
主要结局
Maximally Tolerated Dose (MTD) of AUY922 and Erlotinib Treatment Combination (Phase I)
时间窗: During the first 4 weeks of treatment for each patient.
To determine the maximally tolerated dose (MTD), and recommended phase II dose of AUY922 when given in combination with erlotinib for patients with acquired resistance to erlotinib. (Phase I) Escalation of dose will be in a 3+3 design. If no dose limiting toxicities (DLTs) are seen in 3 patients enrolled at that dose level, then dose will be escalated to the next dose level and the next 3 patients will be enrolled at that dose. Alternatively, if 1 DLT is seen in 3 patients at that dose level, 3 more patients will be added at that same dose level. If 1 DLT is seen in 6 patients at that dose level, MTD will be determined to be at that dose. If more than 1 DLT is seen at that dose level, then the prior lower dose level will be the considered the MTD. DLT is defined as any of the following related to the investigational agent: Death and grade 3 and 4 specific hematological and non-hematological toxicities defined in the protocol.
Overall Response Rate (ORR), Defined as Complete Response(CR) + Partial Response (PR) Using the Modified RECIST 1.1 Criteria for All Patients Treated at Dose of 70mg/m2 AUG922
时间窗: At 8 weeks from treatment initiation
Overall response rate (ORR) will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan or MRI: Complete response (CR) defined as disappearance of all target lesions. Partial Response (PR), defined as \>=30% decrease in the sum of the longest diameter of target lesions. Stable Disease (SD) defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions
次要结局
- Progression-free Survival (Phase II)(From the time of first treatment with AUY922 to disease progression for up to 2 years post treatment)
- Toxicity as Assessed by NCI CTCAE Version 4.00 When AUG922 Administered at Its MTD (Phase I and II)(At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment for up to 2 years and half years)
- Overall Survival (Phase II)(From the time of first treatment with AUY922 to death, followed up to 2 years post treatment)
- Incidence of Reported Adverse Events in Phase I(At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment, for up to 2 years and half years)
- Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II)(From the time of first treatment with AUY922 to death, followed for up to 2 years)