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

This study has suspended participant recruitment.
(Determining future of trial)
Sponsor:
Collaborator:
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):
Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier:
NCT01162551
First received: June 25, 2010
Last updated: June 7, 2013
Last verified: June 2013
  Purpose

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.


Condition Intervention Phase
Cancer
Leukemia
Lymphoma
Drug: Sirolimus and Methotrexate
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Children's Hospital of Philadelphia:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Estimated Enrollment: 17
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)
Intervention Details:
    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.

    Other Names:
    • SIROLIMUS
    • AY-22989
    • rapamycin
    • Rapamune®
    • METHOTREXATE
    • MTX
    • amethopterin
    • Trexall®
Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   up to 25 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01162551

Locations
United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Children's Hospital of Philadelphia
The Leukemia and Lymphoma Society
Investigators
Principal Investigator: Susan R. Rheingold, MD Children's Hospital of Philadelphia
  More Information

Publications:
Luger S, Perl A, Kemner A. A phase I dose escalation study of the mTOR inhibitor sirolimus and MEC chemotherapy targeting signal transduction in leukemic stem cells for acute myeloid leukemia. . Blood. 2006;106:161.
Sheen C, Vincent T, Barrett D, Horwitz EM, Hulitt J, Strong E, Grupp SA, and Teachey DT: Statins are active in acute lymphoblastic leukemia: A therapy that may treat ALL and prevent avascular necrosis. Br. J. Haematol. 2011 In press.
Barrett D, Brown VI, Grupp SA, Teachey DT. Targeting the PI3K/Akt/mTOR signaling axis in children with hematologic malignancies. Pediatric Drugs. 2011. In press

Responsible Party: Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT01162551     History of Changes
Other Study ID Numbers: 10-007444, 6137-09
Study First Received: June 25, 2010
Last Updated: June 7, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Children's Hospital of Philadelphia:
Leukemia
Non-Hodgkin's Lymphoma

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Methotrexate
Sirolimus
Everolimus
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on August 20, 2014