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

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.

Inclusion Criteria:

- Patients 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.