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

Children's Hospital of Philadelphia (CHOP)

Status and phase: Terminated; Phase 1

Conditions: Lymphoma; Leukemia

Treatments: Drug: sirolimus

Study type: Interventional

Funder types: Other

Identifiers

NCT00068302

CHP-IRB-2002-12-3086

CHP-755

CDR0000321392

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 10 patients

Sex: All

Ages: Under 21 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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10 participants in 1 patient group

Sirolimus

Experimental group

Description:

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

Treatment:

Drug: sirolimus