Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Help guide our efforts to modernize ClinicalTrials.gov.
Send us your comments by March 14, 2020.

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01162551
Recruitment Status : Completed
First Posted : July 14, 2010
Results First Posted : August 6, 2019
Last Update Posted : August 6, 2019
Sponsor:
Collaborator:
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):
Children's Hospital of Philadelphia

Brief Summary:

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 or disease Intervention/treatment Phase
Cancer Leukemia Lymphoma Drug: Sirolimus and Methotrexate Phase 2

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Trial of Sirolimus and Methotrexate in Relapsed/Refractory Lymphoblastic Leukemia and Lymphoma
Study Start Date : May 2010
Actual Primary Completion Date : February 2017
Actual Study Completion Date : February 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Leukemia Lymphoma

Arm Intervention/treatment
Experimental: 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

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®




Primary Outcome Measures :
  1. Response Rate [ Time Frame: 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).


Secondary Outcome Measures :
  1. Number of Dose Adjustments To Maintain Trough Levels [ Time Frame: Day 28 ]
    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.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01162551


Locations
Layout table for location information
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
Layout table for investigator information
Principal Investigator: Susan R. Rheingold, MD Children's Hospital of Philadelphia
  Study Documents (Full-Text)

Documents provided by Children's Hospital of Philadelphia:

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.

Layout table for additonal information
Responsible Party: Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT01162551    
Other Study ID Numbers: 10-007444
6137-09 ( Other Grant/Funding Number: Leukemia and Lymphoma Society )
First Posted: July 14, 2010    Key Record Dates
Results First Posted: August 6, 2019
Last Update Posted: August 6, 2019
Last Verified: July 2019
Keywords provided by Children's Hospital of Philadelphia:
Leukemia
Non-Hodgkin's Lymphoma
Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Sirolimus
Methotrexate
Everolimus
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
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
Anti-Bacterial Agents
Anti-Infective Agents