A Phase I Trial Of G3139 (BCL-2 Antisense, NSC# 683428, IND# 58842) Combined With Cytotoxic Chemotherapy In Relapsed Childhood Solid Tumors
1 Year
21 Years
Both
Cardiac Toxicity, Unspecified Childhood Solid Tumor, Protocol Specific
Trial Information
A Phase I Trial Of G3139 (BCL-2 Antisense, NSC# 683428, IND# 58842) Combined With Cytotoxic Chemotherapy In Relapsed Childhood Solid Tumors
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.
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
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Dose-limiting toxic effects and recommended phase II dose, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0
Outcome Time Frame:
Up to day 21
Safety Issue:
No
Principal Investigator
Susan Rheingold
Investigator Role:
Principal Investigator
Investigator Affiliation:
Children's Oncology Group
Authority:
United States: Food and Drug Administration
Study ID:
NCI-2012-01872
NCT ID:
NCT00039481
Start Date:
November 2002
Completion Date:
Related Keywords:
- Cardiac Toxicity
- Unspecified Childhood Solid Tumor, Protocol Specific
- Neoplasms
Name | Location |
|---|---|
| Children's Oncology Group | Arcadia, California 91006-3776 |
