NCT01610570终止1 期
Phase I/II Trial of Mithramycin in Children and Adults With Refractory Extracranial Solid Tumors (Phase I) or Ewing Sarcoma and EWSFLI1 Fusion Transcript (Phase II)
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of Mithramycin
研究概览
简要总结
Background:
- Mithramycin is a drug that was first tested as a cancer therapy in the 1960s. It acted against some forms of cancer, but was never accepted as a treatment. Research suggests that it may be useful against some solid tumors, particularly Ewing sarcoma. Researchers want to see if mithramycin can be used to treat solid tumors in children and adults. It will be tested in different groups of people, including those with a type of Ewing sarcoma that contains a chemical called Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1).
Objectives:
- To see if mithramycin is safe and effective against solid tumors and Ewing sarcoma in children and adults.
Eligibility:
- Children and young adults between 1 and 17 years of age with solid tumors that have not responded to standard treatment.
- Adults at least 18 years of age with EWS-FLI1 Ewing sarcoma that has not responded to standard treatment.
- Children and young adults between 1 and 17 years of age with EWS-FLI1 Ewing sarcoma that has not responded to standard treatment.
Design:
- Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and tumor tissue samples will be used to monitor the cancer before treatment. Individuals with solid brain tumors will not be eligible.
- Participants will receive mithramycin every day for 7 days, followed by 14 days without treatment. Each 28-day round of treatment is called a cycle.
- Treatment will be monitored with frequent blood tests and imaging studies.
- Participants will continue to take the drug for as long as the side effects are not severe and the tumor responds to treatment.
详细描述
BACKGROUND:
- Mithramycin, an anti-tumor antibiotic, underwent broad clinical evaluation in solid tumors and leukemias in the 1960s and demonstrated activity in some leukemias, lymphomas, and solid tumors. In particular, mithramycin was found to have activity against testicular cancers and was briefly used in the clinic for this tumor prior to the development of the currently used treatment regimen.
- The Ewing Sarcoma Family of Tumors (ESFT) is the second most common malignant bone tumor of childhood. There has been very little improvement in overall patient survival in past years, particularly for patients with high risk metastatic or relapsed disease. Therefore, there is a need for effective novel agents for the treatment of this disease.
- Multiple studies have shown that suppressing the expression of EWS-FLI1 effectively limits the tumorigenicity of ESFT cells. Laboratory studies have shown that mithramycin effectively suppresses the activity of EWS-FLI1 both in vitro and in vivo.
OBJECTIVES (PRIMARY):
- Phase I portion of this study is to: determine the tolerability, toxicity, and the recommended phase II dose of mithramycin in children and adolescents with refractory extracranial solid tumors.
- Phase II portion of this trial is to: determine the objective response rate (complete response (CR) and partial response (PR)) of Ewing sarcoma to mithramycin in children and adults using Response Evaluation Criteria in Solid Tumors (RECIST) criteria when administered at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression.
- Phase II portion of this trial to: evaluate if mithramycin inhibits NR0B1 in tumor tissue and determine changes in gene expression signature pre-treatment and at steady state on day +4 of treatment in patients greater than or equal to 18 years old with Ewing sarcoma and EWS/FLI1 fusion transcript with disease amenable to percutaneous biopsy.
ELIGIBILITY:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Phase I Dose Level -1
Experimental
Dose Escalation Phase 9.0 mcg/kg.dose
干预措施: Mithramycin (Drug)
Phase I Dose Level 1
Experimental
Dose Escalation Phase 13.0 mcg/kg.dose
干预措施: Mithramycin (Drug)
Phase I Dose Level 2
Experimental
Dose Escalation Phase 17.5 mcg/kg.dose
干预措施: Mithramycin (Drug)
Phase II - Expansion Phase
Experimental
Expansion phase 17.5 mcg/kg.dose
干预措施: Mithramycin (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Mithramycin
时间窗: Cycle 1 of therapy (or 28 days)
The MTD will be the maximum dose at which fewer than one-third of patients experience Dose Limiting Toxicity (DLT) (i.e., non-hematologic toxicity and hematologic toxicity) during cycle 1 (or 28 days) of therapy.
Number of Participants With Serious and Non-serious Adverse Events
时间窗: 95 days
Here is the number of participants with serious and non-serious adverse events. For a detailed list of serious and non-serious adverse events see the adverse event module.
次要结局
- Maximum Plasma Concentration (Cmax) of Mithramycin Using Non-Compartmental Methods(Prior to dose 1, 3hrs after dose 1 infusion, prior to end of 6hr infusion, 0.25, 0.5, 1,2,3,4,5, & 7hr post infusion, & between 9 & 12hr completion of 1st dose infusion. Trough & end of infusion samples obtained w/day 2,4,&7 doses & 24hr after day 7 dose)
- Objective Response Rate (Complete Response (CR) + Partial Response (PR))(1-2 months)
- Time to Progression (TTP)(At date of progression, an average of 56 days)
- Count of Participants With NR0B1 Expression in Tumor Biopsies(Pre-treatment and day 4 (+/- 1 day))
- Number of Participants With a Change in Tumor Burden Measured by the Response Evaluation Criteria in Solid Tumors (RECIST)(≥4 weeks from baseline)
- Number of Participants With a Change in Tumor Burden Measured by the World Health Organization (WHO) Criteria(≥4 weeks from baseline)
- Half-Life (HL) of Mithramycin(Prior to dose 1, 3hrs after dose 1 infusion, prior to end of 6hr infusion, 0.25, 0.5, 1,2,3,4,5, & 7hr post infusion, & between 9 & 12hr completion of 1st dose infusion. Trough & end of infusion samples obtained w/day 2,4,&7 doses & 24hr after day 7 dose)
- Area Under the Curve Extrapolated to Infinity (AUCinf)(Prior to dose 1, 3hrs after dose 1 infusion, prior to end of 6hr infusion, 0.25, 0.5, 1,2,3,4,5, & 7hr post infusion, & between 9 & 12hr completion of 1st dose infusion. Trough & end of infusion samples obtained w/day 2,4,&7 doses & 24hr after day 7 dose)
- Area Under the Curve for the Dosing Interval (AUCtau)(Prior to dose 1, 3hrs after dose 1 infusion, prior to end of 6hr infusion, 0.25, 0.5, 1,2,3,4,5, & 7hr post infusion, & between 9 & 12hr completion of 1st dose infusion. Trough & end of infusion samples obtained w/day 2,4,&7 doses & 24hr after day 7 dose)
- Clearance at Steady State (CLss)(Prior to dose 1, 3hrs after dose 1 infusion, prior to end of 6hr infusion, 0.25, 0.5, 1,2,3,4,5, & 7hr post infusion, & between 9 & 12hr completion of 1st dose infusion. Trough & end of infusion samples obtained w/day 2,4,&7 doses & 24hr after day 7 dose)
- Volume of Distribution at Steady State (Vss)(Prior to dose 1, 3hrs after dose 1 infusion, prior to end of 6hr infusion, 0.25, 0.5, 1,2,3,4,5, & 7hr post infusion, & between 9 & 12hr completion of 1st dose infusion. Trough & end of infusion samples obtained w/day 2,4,&7 doses & 24hr after day 7 dose)
研究者
Brigitte Widemann, M.D.
Principal Investigator
National Institutes of Health Clinical Center (CC)
研究点 (1)
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