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

Sponsor

Children's Hospital of Philadelphia (Other)

Overall Status

Terminated

CT.gov ID

NCT00068302

Collaborator

National Childhood Cancer Foundation (Other), The Leukemia and Lymphoma Society (Other)

Enrollment

Location

Arm

126

Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Lymphoma	Drug: sirolimus	Phase 1

Detailed 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

10 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jan 1, 2003

Actual Primary Completion Date :

Apr 1, 2009

Actual Study Completion Date :

Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sirolimus 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 3-6 subjects will be enrolled into each dose level Other Names: rapamycin Rapamune

Arm

Intervention/Treatment

Experimental: Sirolimus

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

3-6 subjects will be enrolled into each dose level

Other Names:

rapamycin

Rapamune

Outcome Measures

Primary Outcome Measures

Toxicity as assessed by Common Toxicity Criteria (CTC) toxicity criteria after the first course of treatment [within 21 days following administration of sirolimus]
Subjects will be assessed for toxicity on days 3, 7 and 21

Secondary Outcome Measures

Response as assessed by radiologic scans after each course of treatment [day 21]
Response will be assessed on day 21 of cycle 1

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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