Trial of Sirolimus and Methotrexate in Relapsed/Refractory Lymphoblastic Leukemia and Lymphoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase 2 Trial of Sirolimus and Methotrexate in Relapsed/Refractory Lymphoblastic Leukemia and Lymphoma

Conditions
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Cancer, Leukemia, Lymphoma

Intervention / Treatment
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* Drug: Sirolimus and Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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.

Ages Eligible for Study
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Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus and Methotrexate<br>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 | Drug: Sirolimus and Methotrexate<br>* Single Arm Efficacy Trial: 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.<br>* Other names: Trexall®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | 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). | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Dose Adjustments To Maintain Trough Levels | One goal of this study is to maintain trough levels of sirolimus within a certain range. The outcome measure counts the number of dose adjustments up or down that were needed to meet goal level based on weekly tough level measurements. | Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Non-Hodgkin's Lymphoma