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Oblimersen Plus Combination Chemotherapy and Dexrazoxane in Treating Children and Adolescents With Relapsed or Refractory Solid Tumors

Primary Purpose

Cardiac Toxicity, Unspecified Childhood Solid Tumor, Protocol Specific

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
oblimersen sodium
dexrazoxane hydrochloride
doxorubicin hydrochloride
cyclophosphamide
filgrastim
laboratory biomarker analysis
pharmacological study
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cardiac Toxicity

Eligibility Criteria

1 Year - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Histologically confirmed solid tumor at original diagnosis that has failed standard therapy or for which no standard therapy exists Patients must have a disease for which there is no known curative potential Patients must meet the following criteria for bone marrow function: Status post stem cell transplantation (SCT) Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 (transfusion independent) Hemoglobin at least 8.0 g/dL (RBC transfusions allowed) No lymphomas No CNS tumors or known metastatic disease to the brain or spinal cord Performance status - Karnofsky 50-100% (age 11 to 21) Performance status - Lansky 50-100% (age 1 to 10) At least 8 weeks See Disease Characteristics Bilirubin no greater than 1.5 times upper limit of normal (ULN) ALT no greater than 3 times ULN No significant hepatic dysfunction Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min Creatinine, based on age, as follows: Age 1 to 5: no greater than 0.8 mg/dL Age 6 to 10: no greater than 1.0 mg/dL Age 11 to 15: no greater than 1.2 mg/dL Age 16 to 21: no greater than 1.5 mg/dL No significant renal dysfunction Shortening fraction at least 28% by echocardiogram Ejection fraction at least 45% by MUGA No significant pulmonary dysfunction Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No serious uncontrolled infections No other end-organ dysfunction that would preclude study entry No other clinically significant systemic illness See Disease Characteristics Recovered from prior immunotherapy At least 1 week since prior growth factors or other biologic agents At least 6 months since prior autologous SCT At least 6 months since prior allogeneic bone marrow transplantation and recovered with no evidence of graft-versus-host disease No concurrent immunomodulating agents No concurrent prophylactic growth factors during the first course of the study No concurrent immunotherapy or other biologic therapy Recovered from prior chemotherapy At least 2 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) No prior life-time cumulative doxorubicin dose of more than 450 mg/m^2 or equivalent No other concurrent chemotherapy Concurrent chronic steroids allowed Recovered from prior radiotherapy More than 2 weeks since prior localized palliative radiotherapy (small port) More than 6 months since prior substantial radiotherapy to bone marrow (craniospinal radiotherapy, total body irradiation, or hemi-pelvic radiotherapy) No concurrent radiotherapy Concurrent chronic medications (e.g., narcotics or antiepileptics) allowed No other concurrent investigational agents No other concurrent cancer therapy

Sites / Locations

  • Children's Oncology Group

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (Oblimersen sodium, cytotoxic chemotherapy)

Arm Description

See detailed description.

Outcomes

Primary Outcome Measures

Dose-limiting toxic effects and recommended phase II dose, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0
Change in pharmacokinetic behavior of this regimen
Antitumor activity
Biologic activity of oblimersen in mononuclear cells and tumor tissues, in terms of B-cell lymphoma 2 (bcl-2) and related protein expression

Secondary Outcome Measures

Full Information

First Posted
June 6, 2002
Last Updated
January 16, 2013
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00039481
Brief Title
Oblimersen Plus Combination Chemotherapy and Dexrazoxane in Treating Children and Adolescents With Relapsed or Refractory Solid Tumors
Official Title
A Phase I Trial Of G3139 (BCL-2 Antisense, NSC# 683428, IND# 58842) Combined With Cytotoxic Chemotherapy In Relapsed Childhood Solid Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
January 2013
Overall Recruitment Status
Completed
Study Start Date
November 2002 (undefined)
Primary Completion Date
October 2005 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
Phase I trial to study the effectiveness of oblimersen plus combination chemotherapy and dexrazoxane in treating children and adolescents who have relapsed or refractory solid tumors. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Oblimersen may increase the effectiveness of doxorubicin and cyclophosphamide by making the tumor cells more sensitive to the drug. Chemoprotective drugs such as dexrazoxane may protect normal cells from the side effects of chemotherapy
Detailed Description
OBJECTIVES: I. Determine the dose-limiting toxic effects and recommended phase II dose of oblimersen when combined with cyclophosphamide, doxorubicin, and dexrazoxane in pediatric patients with relapsed or refractory solid tumors. II. Determine the pharmacokinetic behavior of this regimen in these patients. III. Determine, preliminarily, the antitumor activity of oblimersen in these patients. IV. Assess the biologic activity of oblimersen in mononuclear cells and tumor tissues, in terms of bcl-2 and related protein expression, in these patients. OUTLINE: This is a 2-part, multicenter, dose-escalation study. Part A: Patients receive oblimersen IV continuously on days 1-7. Patients also receive dexrazoxane IV followed by doxorubicin IV over 15 minutes followed by cyclophosphamide IV over 1 hour on days 5 and 6. Filgrastim (G-CSF) is administered subcutaneously once daily beginning on day 8 and continuing until blood counts recover. Treatment repeats every 21 days for up to 18 courses (1 year) in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease whose shortening fraction falls below 28% by echocardiogram or whose total life-time cumulative anthracycline dose exceeds 750 mg/m^2 may receive additional courses of oblimersen and cyclophosphamide without doxorubicin and dexrazoxane. Cohorts of 3-6 patients receive escalating doses of oblimersen until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Part B: Patients receive oblimersen at the MTD determined in part A and escalating doses of dexrazoxane, doxorubicin, and cyclophosphamide on the same treatment schedule as in part A. Cohorts of 3-6 patients receive escalating doses of dexrazoxane, doxorubicin, and cyclophosphamide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients are followed for survival. PROJECTED ACCRUAL: A total of 12-15 patients will be accrued for this study within 1-2 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cardiac Toxicity, Unspecified Childhood Solid Tumor, Protocol Specific

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (Oblimersen sodium, cytotoxic chemotherapy)
Arm Type
Experimental
Arm Description
See detailed description.
Intervention Type
Biological
Intervention Name(s)
oblimersen sodium
Other Intervention Name(s)
augmerosen, G3139, G3139 bcl-2 antisense oligodeoxynucleotide, Genasense
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
dexrazoxane hydrochloride
Other Intervention Name(s)
Cardioxane, Savene, Totect, Zinecard
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
doxorubicin hydrochloride
Other Intervention Name(s)
ADM, ADR, Adria, Adriamycin PFS, Adriamycin RDF
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
CPM, CTX, Cytoxan, Endoxan, Endoxana
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
filgrastim
Other Intervention Name(s)
G-CSF, Neupogen
Intervention Description
Given SC
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Dose-limiting toxic effects and recommended phase II dose, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0
Time Frame
Up to day 21
Title
Change in pharmacokinetic behavior of this regimen
Time Frame
Days 1 (pre-infusion), 5, 6, and 8 (end of infusion)
Title
Antitumor activity
Time Frame
Up to day 21
Title
Biologic activity of oblimersen in mononuclear cells and tumor tissues, in terms of B-cell lymphoma 2 (bcl-2) and related protein expression
Time Frame
Up to day 21

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically confirmed solid tumor at original diagnosis that has failed standard therapy or for which no standard therapy exists Patients must have a disease for which there is no known curative potential Patients must meet the following criteria for bone marrow function: Status post stem cell transplantation (SCT) Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 (transfusion independent) Hemoglobin at least 8.0 g/dL (RBC transfusions allowed) No lymphomas No CNS tumors or known metastatic disease to the brain or spinal cord Performance status - Karnofsky 50-100% (age 11 to 21) Performance status - Lansky 50-100% (age 1 to 10) At least 8 weeks See Disease Characteristics Bilirubin no greater than 1.5 times upper limit of normal (ULN) ALT no greater than 3 times ULN No significant hepatic dysfunction Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min Creatinine, based on age, as follows: Age 1 to 5: no greater than 0.8 mg/dL Age 6 to 10: no greater than 1.0 mg/dL Age 11 to 15: no greater than 1.2 mg/dL Age 16 to 21: no greater than 1.5 mg/dL No significant renal dysfunction Shortening fraction at least 28% by echocardiogram Ejection fraction at least 45% by MUGA No significant pulmonary dysfunction Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No serious uncontrolled infections No other end-organ dysfunction that would preclude study entry No other clinically significant systemic illness See Disease Characteristics Recovered from prior immunotherapy At least 1 week since prior growth factors or other biologic agents At least 6 months since prior autologous SCT At least 6 months since prior allogeneic bone marrow transplantation and recovered with no evidence of graft-versus-host disease No concurrent immunomodulating agents No concurrent prophylactic growth factors during the first course of the study No concurrent immunotherapy or other biologic therapy Recovered from prior chemotherapy At least 2 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) No prior life-time cumulative doxorubicin dose of more than 450 mg/m^2 or equivalent No other concurrent chemotherapy Concurrent chronic steroids allowed Recovered from prior radiotherapy More than 2 weeks since prior localized palliative radiotherapy (small port) More than 6 months since prior substantial radiotherapy to bone marrow (craniospinal radiotherapy, total body irradiation, or hemi-pelvic radiotherapy) No concurrent radiotherapy Concurrent chronic medications (e.g., narcotics or antiepileptics) allowed No other concurrent investigational agents No other concurrent cancer therapy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Susan Rheingold
Organizational Affiliation
Children's Oncology Group
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Oncology Group
City
Arcadia
State/Province
California
ZIP/Postal Code
91006-3776
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Oblimersen Plus Combination Chemotherapy and Dexrazoxane in Treating Children and Adolescents With Relapsed or Refractory Solid Tumors

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