RATIONALE: Drugs used in chemotherapy such as sirolimus use different ways to stop cancer
cells from dividing so they stop growing or die.
PURPOSE: This phase I trial is studying the side effects and best dose of sirolimus in
treating young patients with relapsed or refractory acute leukemia or non-Hodgkin's
- Determine the maximum tolerated dose of sirolimus in pediatric patients with refractory
or relapsed acute leukemia or non-Hodgkin's lymphoma.
- Determine the dose-limiting toxic effects of this drug in these patients.
- Determine the trough levels produced by this drug in these patients.
- Determine the anti-leukemia/lymphoma activity of this drug in these patients.
OUTLINE: This is an open-label, dose-escalation study.
Patients receive oral sirolimus once daily on days 1-21. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of sirolimus until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
of 6 patients experience dose-limiting toxicity.
Patients are followed for survival.
PROJECTED ACCRUAL: A total of 3-30 patients will be accrued for this study within 2 years.
- Histologically confirmed diagnosis of 1 of the following:
- Acute lymphoblastic leukemia (ALL) OR acute myeloid leukemia (AML)
- At least 25% blasts in the bone marrow
- Recurrent or refractory disease
- Non-Hodgkin's lymphoma (NHL)
- Second or greater relapse as determined by physical or radiological
- Disease for which there is no known curative therapy
- 21 and under
- Karnofsky 50-100% (patients over 10 years of age)
- Lansky 50-100% (patients 10 years of age and under)
- At least 4 weeks
- Absolute neutrophil count at least 1,000/mm^3*
- Platelet count at least 75,000/mm^3 (transfusion independent)*
- Hemoglobin at least 8.0 g/dL (may receive red blood cells (RBC) transfusions)* NOTE:
*Patients with ALL, AML, and NHL with tumor metastatic to bone marrow, with
granulocytopenia, anemia, and/or thrombocytopenia are eligible, but will not be
evaluable for hematological toxicity
- Bilirubin no greater than 1.5 times normal
- alanine aminotransferase (ALT) no greater than 5 times normal
- Albumin at least 2 g/dL
- Creatinine based on age, as follows:
- No greater than 0.8 mg/dL (5 years of age and under)
- No greater than 1.0 mg/dL (6 to 10 years of age)
- No greater than 1.2 mg/dL (11 to 15 years of age)
- No greater than 1.5 mg/dL (over 15 years of age) OR
- Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min
- Shortening fraction at least 28% by echocardiogram OR
- Ejection fraction at least 50% by gated radionuclide
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- Able to ingest oral medication
- No known allergy to sirolimus, tacrolimus, or other mammalian target of rapamycin
- No uncontrolled active infection
- Fungal disease must be stable for at least 2 weeks prior to study entry
- Documented negative blood cultures prior to study entry for patients with
- No active graft-versus-host disease
PRIOR CONCURRENT THERAPY:
- Recovered from prior immunotherapy
- More than 1 week since prior hematopoietic growth factors except for epoetin alfa
- At least 7 days since prior biologic antineoplastic agents
- At least 3 months since prior bone marrow or stem cell transplantation
- Recovered from all prior chemotherapy
- More than 2 weeks since prior myelosuppressive chemotherapy (4 weeks for
- Prior hydroxyurea within the past 2 weeks is allowed provided peripheral blast count
has been stable or rising for at least 3 days
- Prior corticosteroids within the past 2 weeks are allowed provided peripheral blast
count has been stable or rising for at least 3 days
- Recovered from prior radiotherapy
- At least 2 weeks since prior local palliative radiotherapy
- At least 4 weeks since prior craniospinal radiotherapy or radiation to the pelvis of
50% or more
- At least 4 weeks since prior substantial bone marrow radiotherapy
- No concurrent radiotherapy, except for emergent situations or persistent
extramedullary disease with resolution of bone marrow disease
- Not specified
- No other concurrent investigational antineoplastic drugs
- No concurrent administration of any of the following: