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

National Cancer Institute (NCI)

Status and phase

Completed

Phase 1

Conditions

Cardiac Toxicity

Unspecified Childhood Solid Tumor, Protocol Specific

Treatments

Drug: doxorubicin hydrochloride

Biological: filgrastim

Other: laboratory biomarker analysis

Drug: dexrazoxane hydrochloride

Biological: oblimersen sodium

Other: pharmacological study

Drug: cyclophosphamide

Study type

Interventional

Funder types

NIH

Identifiers

NCT00039481

ADVL0211

NCI-2012-01872

CDR0000069387 (Registry Identifier)

U01CA097452 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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

Full 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.

Enrollment

15 patients

Sex

All

Ages

1 to 21 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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