Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Active	21 and under	Other	CHP-755 CHP-IRB-2002-12-3086, NCT00068302

Objectives

1. Determine the maximum tolerated dose of sirolimus in pediatric patients with refractory or relapsed acute leukemia or non-Hodgkin's lymphoma.
2. Determine the dose-limiting toxic effects of this drug in these patients.
3. Determine the trough levels produced by this drug in these patients.
4. Determine the anti-leukemia/lymphoma activity of this drug in these patients.

Entry 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

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

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/mm³*
• Platelet count at least 75,000/mm³ (transfusion independent)*
• Hemoglobin at least 8.0 g/dL (may receive 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
• 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

Expected Enrollment

A total of 3-30 patients will be accrued for this study within 2 years.

Outcomes

Toxicity as assessed by CTC toxicity criteria after the first course of treatment

Response as assessed by radiologic scans after each course of treatment

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.

Trial Contact Information

Trial Lead Organizations

Children's Hospital of Philadelphia

Susan Rheingold, MD, Protocol chair		Ph: 215-590-2801 Email: rheingold@email.chop.edu

U.S.A.
Pennsylvania
	Philadelphia
	Children's Hospital of Philadelphia
		Susan Rheingold, MD	Ph:  215-590-2801
			Email: rheingold@email.chop.edu

Registry Information
Official Title		A Phase I Trial Of Sirolimus In Relapsed/Refractory Leukemia And Non-Hodgkin's Lymphoma
Trial Start Date		2003-01-30
Registered in ClinicalTrials.gov		NCT00068302
Date Submitted to PDQ		2003-07-14
Information Last Verified		2009-07-05

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