Safety and Efficacy of RO4929097 in Combination With Temsirolimus: A Pharmacokinetic and Pharmacodynamic Phase I Study in Patients With Advanced Solid Tumours With an Expansion of Cohort With Patients With Recurrent/Metastatic Endometrial and Renal Cell Cancers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 2
- 主要终点
- Recommended phase II dose defined as the dose level at which less than or equal to 1 of 6 patients experienced DLT assessed using NCI CTCAE version 4.0
研究概览
简要总结
This phase I trial is studying the side effects and best dose of giving gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temsirolimus together in treating patients with advanced solid tumors. Gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
详细描述
PRIMARY OBJECTIVES:
I. To determine the recommended phase II dose (RP2D) and safety profile of temsirolimus in combination with RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) in patients with advanced solid tumors.
SECONDARY OBJECTIVES:
I. To obtain pharmacokinetic (PK) profiles for both drugs when administered in combination in order to quantify the expected interactive effects in PK between these two agents.
II. To evaluate pharmacodynamic (PD) effects of both drugs when administered in combination, with the goal of identifying potential predictive and PD markers that need further exploration and validation in future trials.
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
- •Meets one of the following sets of criteria:
- •Dose-escalation group:
- •Histologically and/or cytologically confirmed solid malignancy
- •Metastatic or unresectable disease
- •Disease for which standard curative or palliative measures do not exist or are no longer effective
- •Expansion group:
- •Histologically and/or cytologically confirmed endometrial (endometrioid, uterine papillary serious carcinoma, or carcinosarcoma) or renal cell cancer
- •Metastatic or unresectable disease
- •Disease for which standard curative or palliative measures do not exist or are no longer effective
- •Measurable or non-measurable disease
- •Measurable disease is defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan
- •No known brain metastases
- •ECOG performance status (PS) 0-1 (Karnofsky PS 70-100%)
- •Life expectancy > 12 weeks
- •Leukocytes ≥ 3,000/mm^3
- •ANC ≥ 1,500/mm^3
- •Platelet count ≥ 100,000/mm^3
- •Hemoglobin ≥ 90 g/L (or ≥ 9 g/dL)
- •Total bilirubin normal
- •AST/ALT ≤ 2.5 times upper limit of normal
- •Serum creatinine normal OR creatine clearance ≥ 60 mL/min
- •Fasting cholesterol ≤ 350 mg/dL (9.0 mmol/L)
- •Fasting triglycerides ≤ 400 mg/dL (4.56 mmol/L)
- •No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation
- •Note: it is acceptable to use corrected calcium when interpreting calcium levels
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use two effective forms of contraception (i.e., barrier contraception and one other method of contraception) for ≥ 4 weeks before, during, and for ≥ 12 months after completion of study therapy
- •Able to swallow medication
- •No malabsorption syndrome or other condition that would interfere with intestinal absorption
- •No diarrhea ≥ grade 2 that is not under control with standard anti-diarrhea medications
- •No uncontrolled concurrent illness including, but not limited to, any of the following:
- •Ongoing or active infection
- •Symptomatic congestive heart failure
- •Unstable anginal pectoris
- •Cardiac arrhythmia other than chronic, stable atrial fibrillation
- •Psychiatric illness or social situations that would limit compliance with study medications
- •QTc ≤ 450 msec in males and a QTc ≤ 470 msec in females, as measured by ECG using Bazett formula
- •No history of risk factors for QT interval prolongation including, but not limited to, a family or personal history of any of the following:
- •Long QT syndrome
- •Torsades de pointes
- •Recurrent syncope without known etiology
- •Sudden unexpected death
- •No pre-existing significant pulmonary infiltrates of unknown origin
- •No serologic positivity for hepatitis A, B, or C or history of liver disease or other forms of hepatitis or cirrhosis
- •No HIV-positive patients on combination antiretroviral therapy
- •No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 or temsirolimus
- •Female patients may not donate ova during or after study treatment
- •Male patients may not donate sperm during and for ≥ 12 months after completion of study treatment
- •Patients may not donate blood during and for ≥ 12 months after completion of study treatment
- 另有 12 项未显示
排除标准
- 未提供
研究组 & 干预措施
Treatment (temsirolimus and RO4929097)
Patients receive temsirolimus IV over 30 minutes on day -6 (course 1 only). Patients then receive temsirolimus IV or PO on days 1, 8, and 15 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: temsirolimus (Drug)
Treatment (temsirolimus and RO4929097)
Patients receive temsirolimus IV over 30 minutes on day -6 (course 1 only). Patients then receive temsirolimus IV or PO on days 1, 8, and 15 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: gamma-secretase/Notch signalling pathway inhibitor RO4929097 (Drug)
Treatment (temsirolimus and RO4929097)
Patients receive temsirolimus IV over 30 minutes on day -6 (course 1 only). Patients then receive temsirolimus IV or PO on days 1, 8, and 15 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: laboratory biomarker analysis (Other)
Treatment (temsirolimus and RO4929097)
Patients receive temsirolimus IV over 30 minutes on day -6 (course 1 only). Patients then receive temsirolimus IV or PO on days 1, 8, and 15 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: pharmacological study (Other)
结局指标
主要结局
Recommended phase II dose defined as the dose level at which less than or equal to 1 of 6 patients experienced DLT assessed using NCI CTCAE version 4.0
时间窗: 21 days
Safety profile assessed using NCI CTCAE version 4.0
时间窗: Up to 4 weeks post-treatment
Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Attempts to model associations between pharmacokinetic data with toxicity profiles will be performed primarily using descriptive statistics, however, logistic regression may be used if warranted.
次要结局
- Objective response to treatment assessed using the RECIST criteria 1.1(Up to 4 weeks post-treatment)
- Pharmacokinetic profiles(Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours)
- Pharmacodynamic effects(Up to 4 weeks post-treatment)