Back to results

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

Primary Purpose

Cancer, Leukemia, Lymphoma

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Sirolimus and Methotrexate

About this trial

This is an interventional treatment trial for Cancer focused on measuring Leukemia, Non-Hodgkin's Lymphoma

Eligibility Criteria

undefined - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

The Children's Hospital of Philadelphia

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sirolimus and Methotrexate

Arm Description

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

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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.

Full Information

NCT ID

NCT01162551

First Posted

June 25, 2010

Last Updated

July 12, 2019

Sponsor

Children's Hospital of Philadelphia

Collaborators

The Leukemia and Lymphoma Society

1. Study Identification

Unique Protocol Identification Number

NCT01162551

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2019

Overall Recruitment Status

Completed

Study Start Date

May 2010 (undefined)

Primary Completion Date

February 2017 (Actual)

Study Completion Date

February 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Children's Hospital of Philadelphia

Collaborators

The Leukemia and Lymphoma Society

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cancer, Leukemia, Lymphoma

Keywords

Leukemia, Non-Hodgkin's Lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sirolimus and Methotrexate

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Sirolimus and Methotrexate

Other Intervention Name(s)

SIROLIMUS, AY-22989, rapamycin, Rapamune®, METHOTREXATE, MTX, amethopterin, Trexall®

Intervention Description

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.

Primary Outcome Measure Information:

Title

Response Rate

Description

Time Frame

Day 28

Secondary Outcome Measure Information:

Title

Number of Dose Adjustments To Maintain Trough Levels

Description

Time Frame

Day 28

10. Eligibility

Sex

All

Maximum Age & Unit of Time

25 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Susan R. Rheingold, MD

Organizational Affiliation

Children's Hospital of Philadelphia

Official's Role

Principal Investigator

Facility Information:

Facility Name

The Children's Hospital of Philadelphia

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

18544682

Citation

Teachey DT, Sheen C, Hall J, Ryan T, Brown VI, Fish J, Reid GS, Seif AE, Norris R, Chang YJ, Carroll M, Grupp SA. mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia. Blood. 2008 Sep 1;112(5):2020-3. doi: 10.1182/blood-2008-02-137141. Epub 2008 Jun 10.

Results Reference

background

PubMed Identifier

17635004

Citation

Houghton PJ, Morton CL, Kolb EA, Gorlick R, Lock R, Carol H, Reynolds CP, Maris JM, Keir ST, Billups CA, Smith MA. Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008 Apr;50(4):799-805. doi: 10.1002/pbc.21296.

Results Reference

background

PubMed Identifier

16195324

Citation

Teachey DT, Obzut DA, Cooperman J, Fang J, Carroll M, Choi JK, Houghton PJ, Brown VI, Grupp SA. The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood. 2006 Feb 1;107(3):1149-55. doi: 10.1182/blood-2005-05-1935. Epub 2005 Sep 29.

Results Reference

background

PubMed Identifier

14657335

Citation

Brown VI, Fang J, Alcorn K, Barr R, Kim JM, Wasserman R, Grupp SA. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15113-8. doi: 10.1073/pnas.2436348100. Epub 2003 Dec 1.

Results Reference

background

Citation

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.

Results Reference

background

PubMed Identifier

21844871

Citation

Morrison DJ, Hogan LE, Condos G, Bhatla T, Germino N, Moskowitz NP, Lee L, Bhojwani D, Horton TM, Belitskaya-Levy I, Greenberger LM, Horak ID, Grupp SA, Teachey DT, Raetz EA, Carroll WL. Endogenous knockdown of survivin improves chemotherapeutic response in ALL models. Leukemia. 2012 Feb;26(2):271-9. doi: 10.1038/leu.2011.199. Epub 2011 Aug 16.

Results Reference

background

PubMed Identifier

21554258

Citation

Sheen C, Vincent T, Barrett D, Horwitz EM, Hulitt J, Strong E, Grupp SA, Teachey DT. Statins are active in acute lymphoblastic leukaemia (ALL): a therapy that may treat ALL and prevent avascular necrosis. Br J Haematol. 2011 Nov;155(3):403-7. doi: 10.1111/j.1365-2141.2011.08696.x. Epub 2011 May 9. No abstract available.

Results Reference

background

PubMed Identifier

22845486

Citation

Barrett D, Brown VI, Grupp SA, Teachey DT. Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies. Paediatr Drugs. 2012 Oct 1;14(5):299-316. doi: 10.2165/11594740-000000000-00000.

Results Reference

background

Learn more about this trial

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

We'll reach out to this number within 24 hrs