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Nivolumab in Relapsed Pediatric Solid Tumors

2016年9月14日 更新者:Hadassah Medical Organization

A Phase I/II Clinical Trial of Nivolumab in Progressive/Relapsed Pediatric Solid Tumors

patients with progressive/relapsed solid tumors who failed first line therapy , will be treated biweekly with the anti PD1- Nivolumab. at least one month after treatment initiation low dose cyclophosphamide will be started .

patients on trial will submit tissue and blood tests for whole exome an immune genomic signature. patients will also undergo repeated immunophenotype as part of follow up.

研究概览

详细说明

Programmed cell death 1 (PD-1) is an inhibitory receptor that prevents immune activation. PD-1 blockade can mediate reactivation of immune mediated tumor killing leading to tumor regression . Another mechanism of tumor associated immune inactivation is elevation of rates of T regulatory cells. This process may be prevented by treatment with low dose cyclophosphamide.

Objective:

This study will evaluate safety and tolerability of the anti PD1 antibody Nivolumab combined with other immunomodulating treatments, in pediatric patients with relapsed/progressive solid tumors

Method:

Patients will be treated with IV Nivolumab 3mg/kg over 60 minutes on day 1 and 15 of each cycle of 28 days.

  1. Dose finding phase:

    1. Six patients will be accrued for the first cohort and treated for 1 month
    2. If an adverse event >grade 2 will occur in>2 patients, study medication dose will be reduced by 25% and another cohort of 6 patients will be accrued on the reduced dose.
    3. Dose finding cohorts will be accrued until determination of a dose with allowed DLT
  2. Expansion phase

    1. Following dose determination patients will be accrued, to the final number of 30 patients
    2. Cyclophosphamide at the dose of 50 mg/dayx7days every 14 days (one week on one week off ) will be started . immunophenotype will be done every 28 days and dose of cyclophosphamide will be elevated by 25mg /day every month until highest ratio of CD8/CD25FOXP3 cells will be reached for every child
    3. All patients will be treated for 1 year or until imaging proven disease progression.
  3. Required follow up

    1. All patients will undergo tumor bed imaging (CT/MRI-based on tumor location) with metastatic evaluation (according to standar follow up) every 4 months
    2. Tumor response will be measured based on RECIST criteria
    3. Toxicity assessment will be done according to the CTCAE v. 4.03

c. Collateral studies:

  1. Immunohistochemical analysis for PD1 and PDL1 will be done on pretreatment paraffin embedded tissue to estimate it's ability to predict response.
  2. Immune profile of peripheral blood lymphocytes including CD3+, CD4+, CD8+ FOX P3+ cells and it's correlation to objective response to therapy.
  3. Exome sequencing of the tumor and peripheral blood will be done for every patient.

Exome will be evaluated for driver mutations and immunologic genomic signature.

研究类型

介入性

注册 (预期的)

30

阶段

  • 阶段2
  • 阶段1

联系人和位置

本节提供了进行研究的人员的详细联系信息,以及有关进行该研究的地点的信息。

参与标准

研究人员寻找符合特定描述的人,称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。

资格标准

适合学习的年龄

1年 至 21年 (孩子、成人)

接受健康志愿者

有资格学习的性别

全部

描述

Inclusion Criteria:

  1. Ages Eligible for Study: 12 Months and older
  2. Patients must have had histologic verification of malignancy at original diagnosis or relapse

    Eligible pathologies:

    1. neuroblastoma following lack of complete response to at least two lines of therapy
    2. rhabdomyosarcoma following progression after first line therapy
    3. Ewing sarcoma following progression after second line of therpy
    4. Osteosarcoma following progression after first line of therapy all other pathologies will be discussed with PI
  3. Patients must have measurable disease
  4. Patient's current disease state must be one for which there is no known curative therapy
  5. Karnofsky >= 50 for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  6. Patients must have fully recovered from the acute toxic effects of all prior anti-cancer treatment

    1. At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
    2. At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines
    3. at least 56 days must have elapsed after transplant or stem cell infusion; patients with prior allogeneic transplants are not eligible
  7. Blood counts recovery including ANC >= 750/mm^3 and Platelet count >= 50,000/mm^3
  8. Creatinine clearance ≤ 1.5 ULN
  9. liver function:Total bilirubin ≤ 2 ULN, ALT or AST ≤ 2.5 ULN (or < 5 in case of liver impairment)
  10. Life expectancy of at least 4 months
  11. Pregnancy:

    1. Negative pregnancy test in women of childbearing potential
    2. Use of an effective contraceptive method during the whole treatment and
    3. up to 3 months after the completion of treatment in males and females
  12. prior informed consent signed

Exclusion Criteria:

  1. Patients requiring daily systemic corticosteroids are not eligible; patients must not have received systemic corticosteroids within 7 days of enrollment on study
  2. Patients who are currently receiving another investigational drug are not eligible
  3. Patients who are currently receiving other anti-cancer agents are not eligible
  4. Patients with a history of any grade autoimmune disorder are not eligible; asymptomatic laboratory abnormalities (e.g. antinuclear antibody [ANA], rheumatoid factor, altered thyroid function studies) will not render a patient ineligible in the absence of a diagnosis of an autoimmune disorder
  5. Patients with >= grade 2 hypothyroidism due to history of autoimmunity are not eligible; note: hypothyroidism due to previous irradiation on thyroidectomy will not impact eligibility
  6. Patients who have an uncontrolled infection are not eligible.
  7. Patients with active autoimmune disease. (any autoimmune state requiring medical treatment-including chronic medications)all immune modifying drugs should be stopped at least 7 days prior to enrollment.

学习计划

本节提供研究计划的详细信息,包括研究的设计方式和研究的衡量标准。

研究是如何设计的?

设计细节

  • 主要用途:治疗
  • 分配:不适用
  • 介入模型:单组作业
  • 屏蔽:无(打开标签)

武器和干预

参与者组/臂
干预/治疗
实验性的:progressive/relapsed solid tumors
patient with progressive/relapsed solid tumors who failed first line therapy
treatment with IV Nivolumab 3mg/kg every 2 weeks . after a month-addition of low dose cyclophosphamide at a starting dose of 50 mg/kg/day x7 days every 14 days with dose adaptation based on level of Tregulatory cells on follow up immunophenotype.

研究衡量的是什么?

主要结果指标

结果测量
措施说明
大体时间
Event free survival
大体时间:6 months
Rate of patients with stable disease/tumor response at 6 months
6 months
Overall survival
大体时间:6 and 12 months
Rate of patients alive at 6 months and 12 months
6 and 12 months

次要结果测量

结果测量
措施说明
大体时间
evaluation of predictors for response
大体时间:12 months
correlation between levels of PD1 receptor expression in the tumor and genomic signature with response
12 months

合作者和调查者

在这里您可以找到参与这项研究的人员和组织。

研究记录日期

这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查,以确保它们在发布到公共网站之前符合特定的质量控制标准。

研究主要日期

学习开始

2016年11月1日

初级完成 (预期的)

2019年11月1日

研究完成 (预期的)

2020年3月1日

研究注册日期

首次提交

2016年9月11日

首先提交符合 QC 标准的

2016年9月14日

首次发布 (估计)

2016年9月15日

研究记录更新

最后更新发布 (估计)

2016年9月15日

上次提交的符合 QC 标准的更新

2016年9月14日

最后验证

2016年9月1日

更多信息

与本研究相关的术语

计划个人参与者数据 (IPD)

计划共享个人参与者数据 (IPD)?

此信息直接从 clinicaltrials.gov 网站检索,没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求,请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改,我们的网站上也会自动更新.

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