Phase 2 Trial of Sirolimus and Methotrexate in Relapsed/Refractory Lymphoblastic Leukemia and Lymphoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Response Rate
研究概览
简要总结
This is a phase 2 study looking at efficacy and toxicity of oral sirolimus in combination with oral methotrexate in children with refractory/relapsed ALL or NHL.
Secondary objectives include characterizing the trough levels produced by administration of oral sirolimus in children with refractory/relapsed ALL/NHL and to evaluate the effect of sirolimus on intracellular targets related to mTOR inhibition.
详细描述
At present children who have bone marrow or combined bone marrow and extramedullary relapses of acute leukemia while on therapy have 5-20% of long-term survival. Newer, targeted agents need to be identified and integrated into the present cytotoxic chemotherapy regimens. Biologically targeted cancer agents, including signal transduction inhibitors like mammalian target of rapamycin inhibitors (MTIs), have shown great promise in treating hematologic malignancies. A Phase 1 trial of sirolimus (an MTI) alone performed at CHOP has been well tolerated with no DLTs and has evidence of hitting the biologic target. While signal transduction inhibitors may be efficacious as single agents, it is more likely that these targeted agents will demonstrate greater efficacy in combination with other cytotoxic agents.Based upon pre-clinical humanized ALL mouse models we propose to study the toxicity and efficacy of adding sirolimus to oral methotrexate in relapsed and refractory patients.
Patients < 25 years of age, at time of enrollment, with second or greater relapse of ALL or NHL (lymphoblastic lymphoma or peripheral T-cell lymphoma) are eligible. ALL patients must have at least 10% blasts in their marrow and NHL patients must have radiologic or physical evidence of recurrence.
Patients will be started on daily oral sirolimus that is dosed based upon goal trough levels and weekly oral methotrexate. All therapy can be done as an outpatient.
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
- — 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients </= 25 years of age, at time of enrollment, with second or greater relapse of ALL or NHL. For ALL must have histologic diagnosis with >10% blasts in the marrow and for lymphoblastic lymphoma or peripheral T-cell lymphoma must have radiologic or physical evidence of recurrence.
- •Lansky > 50% or Karnofsky > 50%
- •Negative Pregnancy Test
- •Creatinine clearance or radioisotope GFR > 70ml/min/m2 OR serum creatinine based on age /gender
- •Pulse ox >94%
- •Total Bilirubin <1.5 x normal for age
- •ALT < 5 x normal for age
- •Albumin > 2g/dL
- •Shortening fraction by echo > 28% OR ejection fraction > 50% by gated radionuclide study
排除标准
- •Patient has known allergies to sirolimus,FK-506 or mTOR inhibitors
- •Patient is taking other investigational anti-neoplastic drugs
- •Patient received no myelosuppressive chemo within 14 days
- •< 14 days have elapsed since local palliative XRT (small port) < 28 days since prior craniospinal XRT or 50% radiation of pelvis <28 days if other substantial BM radiation
- •Hematopoietic growth factors within 7 days of entry (except erythropoietin.)
- •Patient has taken any biologic agents within 14 days
- •Post BMT/SCT - evidence of active GVHD, at least > 3 months must have elapsed
- •Patient has uncontrolled infection (if patients with fungal disease, stable for < 14 days and patients with bacteremia without negative blood culture
- •Existing non-hematologic toxicities > grade 2
- •Use of steroids or hydroxyurea is permitted upto 14 days prior to entry.
研究组 & 干预措施
Sirolimus and Methotrexate
Sirolimus: Oral bolus on day 1, then daily oral dose days 2-28. Dose will be altered to maintain a sirolimus trough level between ≥ 8 and ≤ 13. Trough levels will be checked weekly.
Methotrexate: Oral 20 mg/m2/week on Days 2, 9, 16, 23.
One cycle is 28 days
干预措施: Sirolimus and Methotrexate (Drug)
结局指标
主要结局
Response Rate
时间窗: Day 28
Number of participants who achieve a Complete Response (CR), Complete Response with in the absence of total platelet recovery (CRp), or Partial Response (PR). Per response criteria in this protocol: Complete Response (CR) - M1 bone marrow (\<5% blasts) with no evidence of circulating blasts or extramedullary disease and recovery of peripheral blood counts (absolute neutrophil count (ANC)\> 500/μL and platelets \> 50,000/ μL); Complete Response in the absence of total platelet recovery (CRp) - M1 bone marrow (\<5% blasts) with no evidence of circulating blasts or extramedullary disease with recovery of peripheral blood counts except for platelets (ANC\> 500/μL, platelets \< 50,000uL); and Partial Response (PR) - M2 bone marrow (5% but \<25% blasts), with no evidence of circulating blasts or extramedullary disease and normalization of peripheral blood counts (ANC \> 500/μL and platelets \>50,000/μL).
次要结局
- Number of Dose Adjustments To Maintain Trough Levels(Day 28)