Sirolimus in Treating Young Patients With Relapsed or Refractory Acute Leukemia or Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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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 lymphoma.

Detailed Description
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OBJECTIVES: 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.

Official Title
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A Phase I Trial Of Sirolimus In Relapsed/Refractory Leukemia And Non-Hodgkin's Lymphoma

Conditions
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Leukemia, Lymphoma

Intervention / Treatment
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* Drug: sirolimus


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: 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 evidence Disease for which there is no known curative therapy PATIENT CHARACTERISTICS: Age 21 and under Performance status Karnofsky 50-100% (patients over 10 years of age) Lansky 50-100% (patients 10 years of age and under) Life expectancy At least 4 weeks Hematopoietic 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 Hepatic Bilirubin no greater than 1.5 times normal alanine aminotransferase (ALT) no greater than 5 times normal Albumin at least 2 g/dL Renal 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 Cardiovascular Shortening fraction at least 28% by echocardiogram OR Ejection fraction at least 50% by gated radionuclide Other 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 (mTOR) inhibitors 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 bacteremia No active graft-versus-host disease PRIOR CONCURRENT THERAPY: Biologic 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 Chemotherapy Recovered from all prior chemotherapy More than 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) Prior hydroxyurea within the past 2 weeks is allowed provided peripheral blast count has been stable or rising for at least 3 days Endocrine therapy Prior corticosteroids within the past 2 weeks are allowed provided peripheral blast count has been stable or rising for at least 3 days Radiotherapy 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 Surgery Not specified Other No other concurrent investigational antineoplastic drugs No concurrent administration of any of the following: Ketoconazole Tacrolimus Cyclosporine Rifampin Diltiazem

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus<br>This is a dose escalation study including 4-dose levels. Subjects will receive a one-time loading dose of sirolimus on day 0, time 0. Subsequent dosing at the assigned dose level will start 24 hours following the initial loading dose | Drug: sirolimus<br>* 3-6 subjects will be enrolled into each dose level<br>* Other names: Rapamune;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity as assessed by Common Toxicity Criteria (CTC) toxicity criteria after the first course of treatment | Subjects will be assessed for toxicity on days 3, 7 and 21 | within 21 days following administration of sirolimus | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response as assessed by radiologic scans after each course of treatment | Response will be assessed on day 21 of cycle 1 | day 21 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent childhood lymphoblastic lymphoma, recurrent childhood small noncleaved cell lymphoma, recurrent childhood large cell lymphoma, recurrent childhood acute myeloid leukemia, recurrent childhood acute lymphoblastic leukemia