Bortezomib in Treating Young Patients With Refractory or Recurrent Leukemia

A Phase I Study of PS-341 (Velcade, Bortezomib) in Pediatric Patients With Refractory/Recurrent Leukemias

This phase I trial is studying the side effects and best dose of bortezomib in treating young patients with refractory or recurrent leukemia. Bortezomib may stop the growth of cancer cells by blocking the enzymes necessary for their growth.

Study Overview

• Status: Completed
• Conditions: Childhood Acute Promyelocytic Leukemia (M3); Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Blastic Phase Chronic Myelogenous Leukemia
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Drug: bortezomib

Detailed Description

OBJECTIVES: Primary I. Determine the maximum tolerated dose and recommended phase II dose of bortezomib in children with refractory or recurrent leukemia.

II. Determine the toxic effects of this drug in these patients. III. Determine the pharmacokinetics of this drug in these patients.

Secondary I. Determine, preliminarily, the antitumor activity of this drug in these patients.

II. Determine, preliminarily, the biologic activity of this drug in these patients.

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.

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

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Arcadia, California, United States, 91006-3776
      • COG Phase I Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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
• Performance status - Karnofsky 50-100% (for patients age 11 to 21)
• Performance status - Lansky 50-100% (for patients age 10 and under)
• Platelet count ≥ 20,000/mm^3*
• Hemoglobin ≥ 8.0 g/dL*
• WBC < 20,000/mm^3** (hydroxyurea for cytoreduction allowed)
• No hyperleukocytosis (i.e., WBC > 100,000/mm^3)
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT ≤ 5 times ULN
• Albumin ≥ 2 g/dL
• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min

• 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
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No uncontrolled infection
• 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
• Recovered from prior chemotherapy
• At least 24 hours since prior hydroxyurea for cytoreduction
• At least 6 weeks since prior nitrosoureas
• No concurrent chemotherapy
• At least 7 days since prior steroids (except as premedication prior to blood product transfusion)
• 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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; 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.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: bortezomib; Given IV; Other Names: MLN341; LDP 341; VELCADE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose and recommended phase II dose	Up to 21 days
Toxicity as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 3.0	Up to 2 years
Pharmacokinetics as assessed by confidence intervals (CI), area under the curve (AUC), and half-life (T ½)	Pretreatment, days 1, 8, 18-22 of course 1

Secondary Outcome Measures

Outcome Measure	Time Frame
Antitumor activity	Up to 2 years
Correlate apoptosis and NF-kB activation	Prestudy, days 8 and 18

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Terzah Horton, COG Phase I Consortium

Study record dates

Study Major Dates

• Study Start: January 1, 2004
• Primary Completion (Actual): March 1, 2006

Study Registration Dates

• First Submitted: February 10, 2004
• First Submitted That Met QC Criteria: February 11, 2004
• First Posted (Estimate): February 12, 2004

Study Record Updates

• Last Update Posted (Estimate): June 5, 2013
• Last Update Submitted That Met QC Criteria: June 4, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Neoplastic Processes; Leukemia, Lymphoid; Cell Transformation, Neoplastic; Carcinogenesis; Leukemia, Myeloid, Acute; Leukemia; Leukemia, Myeloid; Recurrence; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Blast Crisis; Leukemia, Promyelocytic, Acute; Antineoplastic Agents; Bortezomib
• Other Study ID Numbers: NCI-2012-01809; U01CA097452 (U.S. NIH Grant/Contract); ADVL0317; CDR0000350340; COG-ADVL0317