Trial of Sirolimus and Methotrexate in Relapsed/Refractory Lymphoblastic Leukemia and Lymphoma
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.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase 2 Trial of Sirolimus and Methotrexate in Relapsed/Refractory Lymphoblastic Leukemia and Lymphoma|
- Efficacy and toxicity of oral sirolimus when given with oral methotrexate [ Time Frame: Disease status will be assessed every 28 days, toxicity will be assessed continually. ] [ Designated as safety issue: Yes ]Determine the efficacy of oral sirolimus when given in combination with methotrexate in children with refractory/relapsed ALL or NHL.
- Quantitate trough levels of sirolimus [ Time Frame: Trough levels will be checked weekly during study participation. ] [ Designated as safety issue: No ]To measure and quantitate the trough levels produced by administration of oral sirolimus in children with refractory/relapsed lymphoblastic leukemia or lymphoma. One goal of this study is to maintain trough levels of sirolimus within a certain range, therefore adjustments will be made in sirolimus doses based on trough levels.
- Evaluate effect of sirolimus on intracellular targets [ Time Frame: The biology studies will be evaluated during study participation when peripheral blood and/or bone marrow is collected. ] [ Designated as safety issue: No ]To evaluate the effect of sirolimus on intracellular targets, including ribosomal protein s6 (a marker of mTOR inhibition), AKT, P27kip1, DHFR, cyclin D1, Rb, and STAT5 in peripheral blood mononuclear cells, peripheral blood lymphoblasts, and bone marrow lymphoblasts.
|Study Start Date:||May 2010|
|Estimated Study Completion Date:||December 2015|
|Estimated Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
Drug: Sirolimus and Methotrexate
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01162551
|United States, Pennsylvania|
|The Children's Hospital of Philadelphia|
|Philadelphia, Pennsylvania, United States, 19104|
|Principal Investigator:||Susan R. Rheingold, MD||Children's Hospital of Philadelphia|