Phase I Trial of Pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex (LPX) in Subjects With Advanced Ewing's Sarcoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 7
- 试验地点
- 4
- 主要终点
- Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE v4.0
研究概览
简要总结
The purpose of this study is to determine the safety and the maximum tolerated dose of of pbi-shRNA™ EWS/FLI1 Type 1 lipoplex in patients with advanced Ewing's sarcoma.
详细描述
Eligible participants with advanced Ewing's sarcoma will be accrued in 3-subject dose escalation cohorts using the following escalation schema (50%→33%→25%→25%→25%) at a starting IV dose of 0.04 mg/kg and up to a dose of 0.156mg/kg.
For this first in class study of pbi-shRNA™ EWS/FLI1 Type 1 lipoplex, Dose Limiting Toxicity (DLT) will be defined as any ≥ Grade 3 toxicity reported within the four weeks following the first administration of the investigational product, regardless of attribution. Any other ≥ Grade 3 toxicity encountered after the first four weeks post Dose 1 on Cycle 1 will be reported according to the CTCAE Version 4.0 but not defined as DLTs.
If 1 of 3 subjects within a dose cohort experiences a DLT, that dose cohort will be expanded to six subjects provided no further subjects experience a DLT. If no further subjects experience a DLT, dose-escalation may continue. If ≥2 subjects within a dose cohort experiences a DLT, this will define the DLT dose level and the Maximum Tolerated Dose (MTD) will have been exceeded.
The preceding dose level will be expanded to a total of 6 subjects and, if ≤1 subject experiences a DLT, that dose level will be considered the MTD. If no further subjects experience a DLT, dose-escalation may resume per escalation schema. Once the presumptive MTD is reached, an additional 6 subjects will be treated at that dose, designated the expanded MTD dose cohort.
Participants who experience an unrelated Grade ≥3 toxicity that normalizes within 1 week may continue study treatment when the adverse event returns to Grade 1 or better at 50% of their assigned cohort dose. Delay in dosing of >24 hours will require that the next dose is skipped.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 8 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed Ewing's Sarcoma Family of Tumors (ESFT).
- •Age ≥8 years.
- •Evidence of EWS translocation fusion by FISH or RT-PCR or NGS.
- •Evidence of Type 1 fusion by molecular diagnostics.
- •Refractory or intolerant to standard of care. Subjects must have failed surgery (if resectable), radiation (if no function-preserving surgical approach at primary site, unresectable primary following induction chemotherapy, residual microscopic or gross disease after surgery or inadequate margins), and the following chemotherapy agents: doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide.
- •ECOG performance status (PS) = 0-2, or Karnofsky PS ≥60% or Lansky PS ≥60%.
- •Normal organ and marrow function as defined below:
- •Absolute granulocyte count ≥1,000/mm3 Absolute lymphocyte count ≥400/mm3 Platelets ≥100,000/mm3 Total bilirubin ≤ institutional upper limit of normal AST(SGOT)/ALT(SGPT) ≤2x institutional upper limit of normal Creatinine <1.5 mg/dL
- •Normal pulmonary function as defined as FEV1/FVC greater than 70% in adults or greater than 80% in individuals between 8 and 18 years of age.
- •Subject has recovered to CTCAE Grade 1 or better from all adverse events associated with prior therapy or surgery. Pre-existing motor or sensory neurologic pathology or symptoms must be recovered to CTCAE Grade 2 or better.
- •If female of childbearing potential, has a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a negative serum test will be required for study entry.
- •Ability to understand and the willingness to sign a written informed protocol specific consent. Pediatric patients must sign an assent with a parent or legal guardian sign a written informed consent, per institutional guidelines.
- •Subjects will NOT be eligible for study registration and enrollment if meeting any of the following criteria:
排除标准
- •Anti-cancer chemotherapy, biologic therapy or immunotherapy within 3 weeks or radiation therapy within 2 weeks of first infusion.
- •Known history of other malignancy unless having undergone curative intent therapy without evidence of that disease for ≥ 3 years except cutaneous squamous cell and basal cell skin cancer, superficial bladder cancer, in situ cervical cancer or other in situ cancers are allowed if definitively resected.
- •Patients with PET avid disease only will be excluded.
- •Brain metastases unless treated with curative intent (gamma knife or surgical resection) and without evidence of progression for ≥ 2 months.
- •History of or current evidence of thrombosis.
- •History of or current evidence of any condition (including medical, psychiatric or substance abuse disorder), therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the Investigator.
- •Known HIV or chronic Hepatitis B or C infection.
- •Have signs and symptoms consistent with an active infection.
- •Live vaccination for the prevention of infectious disease administered <30 days prior to the start of study therapy or inactivated vaccination <14 days prior to the start of study therapy.
结局指标
主要结局
Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE v4.0
时间窗: From first dose and up to 60 days following the last treatment, up to approximately 13 months.
Adverse events(AEs) will be recorded for the duration of the participant's study treatment (following the first dose of the investigational product), and for up to 60 days following the last study treatment. AEs will be graded and reported using the Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03. The relationship of each event to the investigational product will be assessed by the Treating Physician.
Determine the maximum tolerated dose of intravenous administration of lipoplex
时间窗: From first subject, first dose and after an additional 6 subjects have been treated at the MTD, up to 4 weeks.
By observing the Dose Limiting Toxicities, including ≥ Grade 3 toxicity encountered within the four weeks following the first administration of the investigational product the MTD will be determined.
次要结局
- To assess disease response for different cohorts following pbi-shRNA™ EWS/FLI1 Type 1 lipoplex administration at different dose(s).(From Baseline and quarterly thereafter until progressive disease is noted, up to approximately 12 months.)
- To assess ctDNA (EWSR-FLI1) levels and compare to tumor burden and disease response prior to and following pbi-shRNA™ EWS/FLI1 Type 1 lipoplex administration.(From Cycle 1 Week 1 Day 1 and until the last even cycle where product was administered, up to approximately 1 year.)
- To assess the pharmacokinetics of pbi-shRNA™ EWS/FLI1 Type 1 plasmid.(From Cycle 1 Week 1 Day 1 and until Cycle 2 Week 1 Day 1, approximately 8 weeks.)