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

• 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.

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.

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.

• Cancer
• Leukemia
• Lymphoma

• 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. Epub 2008 Jun 10.
• 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.
• 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. Epub 2005 Sep 29.
• 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. Epub 2003 Dec 1.
• 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.

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.