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

Study Overview
=================
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.

Official Title
-----------------
A Phase I Trial Of G3139 (BCL-2 Antisense, NSC# 683428, IND# 58842) Combined With Cytotoxic Chemotherapy In Relapsed Childhood Solid Tumors

Conditions
-----------------
Cardiac Toxicity, Unspecified Childhood Solid Tumor, Protocol Specific

Intervention / Treatment
-----------------
* Biological: oblimersen sodium
* Drug: dexrazoxane hydrochloride
* Drug: doxorubicin hydrochloride
* Drug: cyclophosphamide
* Biological: filgrastim
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (Oblimersen sodium, cytotoxic chemotherapy)<br>See detailed description. | Biological: oblimersen sodium<br>* Given IV<br>* Other names: Genasense;Drug: dexrazoxane hydrochloride<br>* Given IV<br>* Other names: Zinecard;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: Adriamycin RDF;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Biological: filgrastim<br>* Given SC<br>* Other names: Neupogen;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxic effects and recommended phase II dose, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0 |  | Up to day 21 | 
| Change in pharmacokinetic behavior of this regimen |  | Days 1 (pre-infusion), 5, 6, and 8 (end of infusion) | 
| Antitumor activity |  | Up to day 21 | 
| Biologic activity of oblimersen in mononuclear cells and tumor tissues, in terms of B-cell lymphoma 2 (bcl-2) and related protein expression |  | Up to day 21 |