Uptake and Biodistribution of 89Zirconium-labeled Ipilimumab in Ipilimumab Treated Patients With Metastatic Melanoma
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 29
- 试验地点
- 2
- 主要终点
- The detection of 89Zr-ipilimumab in tumor lesions
研究概览
简要总结
Rationale:
Ipilimumab, a monoclonal antibody targeting CTLA-4, is approved for the treatment of metastatic melanoma and significantly increases median overall survival. However, use of this drug is associated with immune related adverse events (IRAEs) like colitis, hepatitis, dermatitis, alveolitis and hypophysitis in 10-40% of the patients. In general IRAEs are manageable by cessation of ipilimumab in combination with treatment with corticosteroids or TNF-alpha blockade but they can be severe or even life-threatening. In addition, treatment with ipilimumab is expensive. Because of the high costs and the potential serious toxicity of ipilimumab, it is of great importance to identify biomarkers that correlate with clinical activity and can be used to select patients that will benefit from CTLA-4 blockade therapy.
The investigators hypothesize that differences in response to treatment with ipilimumab are due to variability in the pharmacodynamics and -kinetics of the antibody. It is hypothesized that patients who do not respond to treatment with ipilimumab have lower drug levels in tumor tissues as compared to patients with a good response to therapy. In addition, the investigators hypothesize that IRAEs are associated with high drug levels in the affected tissue.
To visualize molecular interactions a novel technique is used in which positron emission tomography (PET) is combined with labeled monoclonal antibodies. Because ipilimumab induces activation of T-lymphocytes it is hypothesized that uptake of 89Zr-ipilimumab in tumor lesions and normal tissue is different (i.e. higher) after the second administration of ipilimumab (3 weeks after first injection). Therefore immuno-PET scans will be performed after the first and after the second injection of ipilimumab.
Objective:
Part one: The primary objective is:
1. To assess uptake (visual and quantitative) of 89Zr-ipilimumab in tumor lesions and biodistribution at two timepoints (at start of ipilimumab therapy and after the second injection 3 weeks later).
The secondary objectives are:
- To determine the correlation between tumor targeting of ipilimumab and response to therapy.
- To assess uptake (visual and quantitative) of 89Zr-ipilimumab in normal tissues.
- To determine de correlation between organ targeting and toxicity
详细描述
see above
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Diagnostic
- 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
- •Advanced/metastatic melanoma.
- •Scheduled for treatment with ipilimumab.
- •Age ≥ 18 years.
- •Histological or cytological documentation of cancer is required.
- •WHO Performance Status of 0 or
- •At least 1 measurable lesion.
- •Signed informed consent must be obtained prior to any study procedures.
- •Patients must be able to adhere to the study appointments and other protocol requirements.
排除标准
- •Previous exposure to ipilimumab.
- •Pregnant or breast-feeding subjects. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start treatment. Both men and women enrolled in this trial must agree to use adequate barrier birth control measures (e.g. cervical cap, condom and diaphragm) during the course of the trial. Oral birth control methods alone will not be considered adequate on this study, because of the potential pharmacokinetic interaction between study drug and oral contraceptives. Concomitant use of oral and barrier contraceptives is advised. Contraception is necessary for at least 6 months after receiving study drug.
- •Concurrent anticancer chemotherapy, immunotherapy or investigational drug therapy during the study or within 4 weeks after starting the study drug.
- •Radiotherapy of target lesions during study or within 4 weeks after starting the study drug. Palliative radiotherapy will be allowed.
- •Major surgery within 28 days of start of study drug.
- •Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results.
- •Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study.
结局指标
主要结局
The detection of 89Zr-ipilimumab in tumor lesions
时间窗: 3 weeks
The detection (visual and quantitative) of 89Zr-ipilimumab in tumor lesions (the short axis diameter of a measurable tumor lesion is ≥1 cm. The five largest lesions will be used for evaluation).
次要结局
- The quantitative detection of 89Zr-ipilimumab in normal tissue(3 weeks)
- The visual detection of 89Zr-ipilimumab in normal tissue(3 weeks)
- Comparison between uptake of 89Zr-ipilimumab(3 weeks)
- Clinical outcome (survival)(Through study completion, an average of 1 year)
- Side effects(Until 30 days after the last immuno-PET scan)
- Clinical outcome (response)(Every 12 weeks, from date of starting therapy until the date of first documented progression or date of death from any cause, whichever came first. Assessed through study completion, an average of 1 year)
- CTLA-4+CD4+ expression of PBMCs(Before start of ipilimumab and during treatment, up to 11 weeks)
- Pharmacokinetics of 89Zr-ipilimumab(144 hours after first injection of 89Zr-ipilimumab)
- Immunohistochemical analysis(3 weeks)
研究者
A.J.M. van den Eertwegh
Principal Investigator
Amsterdam UMC, location VUmc