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

Alternate Title

Bortezomib in Treating Young Patients With Refractory or Recurrent Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	1 to 21	NCI	COG-ADVL0317 NCT00077467, ADVL0317

Objectives

Primary

1. Determine the maximum tolerated dose and recommended phase II dose of bortezomib in children with refractory or recurrent leukemia.
2. Determine the toxic effects of this drug in these patients.
3. Determine the pharmacokinetics of this drug in these patients.

Secondary

1. Determine, preliminarily, the antitumor activity of this drug in these patients.
2. Determine, preliminarily, the biologic activity of this drug in these patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed leukemia of 1 of the following types:
  • Acute lymphoblastic leukemia
  • Acute myeloid leukemia
  • Chronic myelogenous leukemia in blast crisis



• Relapsed or refractory disease



• Immunophenotypically confirmed disease, either at initial diagnosis or relapse



• More than 25% blasts in the bone marrow (M3 bone marrow)



• Active extramedullary disease (except leptomeningeal disease) allowed



• No known curative therapy or therapy proven to prolong survival with an acceptable quality of life available

Prior/Concurrent Therapy:

Biologic therapy

• Recovered from prior immunotherapy
• At least 7 days since prior filgrastim (G-CSF) or sargramostim (GM-CSF)
• At least 7 days since prior biologic agents
• At least 3 months since prior stem cell transplantation or rescue and no evidence of active graft-versus-host disease
• No concurrent prophylactic G-CSF during course 1 of study
• No concurrent immunotherapy
• No concurrent biologic therapy

Chemotherapy

• Recovered from prior chemotherapy
• At least 24 hours since prior hydroxyurea for cytoreduction
• At least 6 weeks since prior nitrosoureas
• No concurrent chemotherapy

Endocrine therapy

• At least 7 days since prior steroids (except as premedication prior to blood product transfusion)

Radiotherapy

• Recovered from prior radiotherapy
• At least 2 weeks since prior small port local palliative radiotherapy
• At least 3 months since prior total body irradiation, craniospinal irradiation, or irradiation to more than 50% of the pelvis
• At least 6 weeks since other prior substantial bone marrow radiotherapy
• No concurrent radiotherapy

Surgery

• Not specified

Other

• At least 7 days since prior retinoids
• No other concurrent investigational agents
• No other concurrent anticancer agents
• No concurrent anticonvulsant medications known to activate the cytochrome p450 system (e.g., phenytoin, carbamazepine, or phenobarbital)
  • Concurrent benzodiazepines and gabapentin are allowed

Patient Characteristics:

Age

• 1 to 21

Performance status

• Karnofsky 50-100% (for patients age 11 to 21)

  OR

• Lansky 50-100% (for patients age 10 and under)

Life expectancy

• Not specified

Hematopoietic

• Platelet count ≥ 20,000/mm³*
• Hemoglobin ≥ 8.0 g/dL*
• WBC < 20,000/mm³** (hydroxyurea for cytoreduction allowed)
• No hyperleukocytosis (i.e., WBC > 100,000/mm³)

 [Note: *Transfusion allowed]

 [Note: **An exception may be made at the discretion of the investigator]

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT ≤ 5 times ULN
• Albumin ≥ 2 g/dL

Renal

• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min

  OR

• Creatinine based on age as follows:
  • ≤ 0.8 mg/dL for patients age 5 and under
  • ≤ 1.0 mg/dL for patients age 6 to 10
  • ≤ 1.2 mg/dL for patients age 11 to 15
  • ≤ 1.5 mg/dL for patients age 16 to 21

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No uncontrolled infection

Expected Enrollment

A total of 3-36 patients will be accrued for this study within 1.5-36 months.

Outcomes

Maximum tolerated dose and recommended phase II dose
Toxicity as assessed by CTCAE 3.0
Pharmacokinetics as assessed by CI, area under the curve (AUC), and half-life (T ½)

Antitumor activity
Correlate apoptosis and NF-kB activation

Outline

This is a dose-escalation, open-label, multicenter study.

Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of bortezomib 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.

Horton TM, Pati D, Plon SE, et al.: A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: a Children's Oncology Group study. Clin Cancer Res 13 (5): 1516-22, 2007.[PUBMED Abstract]

Horton TM, Thompson PA, Bomgaars LR, et al.: A phase I study of bortezomib (PS-341) in pediatric patients with relapsed or refractory leukemia: a Children's Oncology Group study. [Abstract] J Clin Oncol 24 (Suppl 18): A-9021, 507s, 2006.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Terzah Horton, MD, PhD, Protocol chair		Ph: 832-824-4269 Email: tmhorton@txccc.org
Lisa Bomgaars, MD, Protocol co-chair		Ph: 832-824-4588 Email: lbomgaars@txccc.org

Registry Information
Official Title		A Phase I Study of PS-341 (Velcade, Bortezomib) in Pediatric Patients with Refractory/Recurrent Leukemias
Trial Start Date		2004-01-05
Registered in ClinicalTrials.gov		NCT00077467
Date Submitted to PDQ		2003-12-29
Information Last Verified		2005-12-12
NCI Grant/Contract Number		CA97452

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