Phase I Study of the Combination of Axitinib (AX) Plus Everolimus (EV) in Patients With Malignant Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 19
- 试验地点
- 4
- 主要终点
- Proportion of patients with DLT (dose limiting toxicity) during the first cycle (first 28 days of the combination of both study compounds), per dose level explored
研究概览
简要总结
The aim of the study is to determine the MTD of the combination of everolimus plus axitinib in solid tumors, especially RCC.
详细描述
Phase I study of the combination of axitinib (AX) plus everolimus (EV) in patients with malignant advanced solid tumors.
- To determine the recommended dose for phase II study of the combination of AX + EV
- To determine the safety profile and predictive factors for toxicity, pharmacokinetics (PK), and efficacy in adult solid tumors.
- To assess functional vascular imaging (FVI) as surrogate marker of activity, biomarkers predictive of activity and preliminary efficacy data in metastatic RCC, untreated with antiangiogenics.
Phase I, multicentre, open-label, non-randomized, sequential algorithm based dose-finding (3+3), clinical study in successive cohorts of patients.
Patients will take both drugs orally, every day, without planned rest period (AX bid and EV once a day). By convention one cycle is 28 days. At the first cycle patients will take one week of AX single agent before starting EV. Patients will be treated at increasing dose levels (DLs) in successive cohorts of 3-6 patients according to the number of patients with dose limiting toxicities (DLT) until the maximum tolerated dose (MTD; i.e. the DL at which <= 1/6 patient experiences a DLT during the first cycle). All decision concerning qualification for DLT, dose escalation, study termination, inclusion of additional patients, will be taken by a Trial Monitoring Committee..
The MTD will not be higher than the recommended dose of each single agent. Six additional patients will be entered at the MTD to confirm the feasibility of the dose and preliminarily assess the efficacy of the combination in patients with RCC untreated with antiangiogenics.
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
- •Histologically proven advanced adult solid tumors, with the exception of Hodgkin and non Hodgkin lymphoma. Patients with hepatocellular carcinomas (HCC) may be enrolled without histological documentation if they meet the consensus non-invasive diagnostic criteria.
- •Failure or contra-indication of all standard therapies, except for the patients with advanced renal cell carcinoma, enrolled at the recommended dose who will be naïve of previous lines of therapy while metastatic.
- •Age > 18 years
- •ECOG Performance status (PS) 0-1
- •Life expectancy > 3 months
- •Measurable/evaluable disease according to RECIST CRITERIA version 1.0
- •Acceptable biological values: Hemoglobin > 10g /dL; neutrophils > 1.5 x 109/L; platelets > 100 x 109/L, AST and ALT < 2.5 x the upper normal limits (UNL), or < 5 x UNL in case of liver metastases, GGT < 3 x the upper normal limits (UNL), PAL < 2.5 x the upper normal limits (UNL), or < 5 x UNL in case of liver metastases, serum bilirubin < 1.5 x ULN, creatinine clearance (Cockroft & Gault formula) > 60 mL/min.
- •24 hours proteinuria ≤ 1 g/24 h
- •Albumin > 30 g/l
- •Amylase and lipase ≤ 1.5 UNL
- •Electrolytes (calcium, sodium, potassium, chlore, magnesium, phosphate) in the normal range. Supplementation could be possible before study entry.
- •Total cholesterol ≤ 2.5 UNL
- •Triglycerides ≤ 2.5 UNL
- •BP < 140/90
- •Washout period from last anticancer therapy, including radiation and surgery > 3 weeks and recovery of toxicities to NCI-CTC grade <
- •Written informed Consent.
- •Use of effective contraceptive method (Intrauterine device, oral combined contraceptive) for women of child-bearing age or whose partner is included in the trial.
- •Patient with french social security.
- •Additional inclusion criteria before the association axitinib plus everolimus period
- •No toxicity with NCI-CTC grade > 2 at the end of axitinib alone period just before starting axitinib and everolimus (cycle 1)
- •BP < 140/ 90
排除标准
- •Brain metastasis
- •Severe underlying cardiovascular disease, even medically controlled, such as angina pectoris, myocardial infarction, cardiac insufficiency, cardiac failure, cerebral strokes, lower limb ischemic disease, thromboembolic disease, and any patient, who, in the investigator's opinion is at high risk for arterial or venous thromboembolism.
- •Hepatitis B or C carrier or at a chronic state
- •Uncontrolled hypertension, or diabetes mellitus despite medical treatment.
- •Inability to swallow pills
- •Unresolved pneumopathy, no need for antibiotherapy
- •Any medical or social condition, which; in the investigator's opinion, would jeopardize patient's safety, patient's compliance to the protocol, or the interpretation of study results. These conditions include (but are not limited to): severe infection, cardiac failure, chronic gastrointestinal disease compromising oral drug absorption, psychiatric illnesses, foreseeable poor treatment compliance with oral medications, patients living far away from the investigational centers, etc…
- •Hypersensitivity to Axitinib or Everolimus
- •Participation to another clinical trial, or use of an unapproved medication within 4 weeks prior to study treatment initiation.
- •Pregnant or lactating women.
研究组 & 干预措施
Axitinib plus everolimus
干预措施: Axitinib plus everolimus (Drug)
结局指标
主要结局
Proportion of patients with DLT (dose limiting toxicity) during the first cycle (first 28 days of the combination of both study compounds), per dose level explored
时间窗: during cycle 1
A DLT will be one of the following adverse events, with a possible relationship to the study medications * Febrile, related bleeding or any grade 4 neutropenia or thrombocytopenia, * grade 3 non-hematological toxicity, unless adequately treated with usual symptomatic therapy * grade 4 non-hematological toxicity * study treatment interruption \> 2 weeks, inability to deliver at least 80% of the intended doses of axitinib and/or everolimus between day 8 and 35 due to toxicity.
次要结局
- Adverse event (AE) will be graded according to NCI-CTC criteria V3(After each cycle of treatement)
- Rate of non-tumor progression at 16 weeks(at 16 weeks)
- Progression-free Survival (PFS) defined as the time between study treatment initiation and either tumor progression or death, regardless of the cause, whichever occurs first and PFS at 1 year(1 year)
- Comparison of PK parameters(day 1 (axitinib alone) and day 15 (everolimus combined with axitinib))
- Best response rate will be assessed according to RECIST criteria, during the follow-up(Every other cycle of treatment)