NCT01162551

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
5

participants targeted

Target at below P25 for phase_2 cancer

Timeline
Completed

Started May 2010

Longer than P75 for phase_2 cancer

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

May 1, 2010

Completed
2 months until next milestone

First Submitted

Initial submission to the registry

June 25, 2010

Completed
19 days until next milestone

First Posted

Study publicly available on registry

July 14, 2010

Completed
6.6 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

February 1, 2017

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

February 1, 2017

Completed
2.5 years until next milestone

Results Posted

Study results publicly available

August 6, 2019

Completed
Last Updated

August 6, 2019

Status Verified

July 1, 2019

Enrollment Period

6.8 years

First QC Date

June 25, 2010

Results QC Date

March 22, 2019

Last Update Submit

July 12, 2019

Conditions

CancerLeukemiaLymphoma

Keywords

LeukemiaNon-Hodgkin's Lymphoma

Outcome Measures

Primary Outcomes (1)

  • 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 Outcomes (1)

  • Number of Dose Adjustments To Maintain Trough Levels

    Day 28

Study Arms (1)

Sirolimus and Methotrexate

EXPERIMENTAL

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

Interventions

Sirolimus and MethotrexateDRUG

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.

Also known as: SIROLIMUS, AY-22989, rapamycin, Rapamune®, METHOTREXATE, MTX, amethopterin, Trexall®
Sirolimus and Methotrexate

Eligibility Criteria

AgeUp to 25 Years
Sexall
Healthy VolunteersNo
Age GroupsChild (0-17), Adult (18-64)

You may qualify if:

  • 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

You may not qualify if:

  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (8)

  • 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.

    PMID: 18544682BACKGROUND

  • 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.

    PMID: 17635004BACKGROUND

  • 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.

    PMID: 16195324BACKGROUND

  • 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.

    PMID: 14657335BACKGROUND

  • 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.

    BACKGROUND

  • 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.

    PMID: 21844871BACKGROUND

  • 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.

    PMID: 21554258BACKGROUND

  • 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.

    PMID: 22845486BACKGROUND

MeSH Terms

Conditions

NeoplasmsLeukemiaLymphomaLymphoma, Non-Hodgkin

Interventions

SirolimusMethotrexate

Condition Hierarchy (Ancestors)

Neoplasms by Histologic TypeHematologic DiseasesHemic and Lymphatic DiseasesLymphoproliferative DisordersLymphatic DiseasesImmunoproliferative DisordersImmune System Diseases

Intervention Hierarchy (Ancestors)

MacrolidesLactonesOrganic ChemicalsAminopterinPterinsPteridinesHeterocyclic Compounds, 2-RingHeterocyclic Compounds, Fused-RingHeterocyclic Compounds

Results Point of Contact

Title
Susan Rheingold, MD
Organization
CHOP
cancertrials@email.chop.edu
215-590-2801

Study Officials

  • Susan R. Rheingold, MD

    Children's Hospital of Philadelphia

    PRINCIPAL INVESTIGATOR

Publication Agreements

PI is Sponsor Employee
Yes

Study Design

Study Type
interventional
Phase
phase 2
Allocation
NA
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

June 25, 2010

First Posted

July 14, 2010

Study Start

May 1, 2010

Primary Completion

February 1, 2017

Study Completion

February 1, 2017

Last Updated

August 6, 2019

Results First Posted

August 6, 2019

Record last verified: 2019-07

Locations

US(1)