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

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

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

Study Overview

• Status: Completed
• Conditions: Unspecified Childhood Solid Tumor, Protocol Specific; Cardiac Toxicity
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: cyclophosphamide; Biological: oblimersen sodium; Other: pharmacological study; Drug: doxorubicin hydrochloride; Drug: dexrazoxane hydrochloride; Biological: filgrastim

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Arcadia, California, United States, 91006-3776
      • Children's Oncology Group

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 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

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: Treatment (Oblimersen sodium, cytotoxic chemotherapy); See detailed description.

Other: laboratory biomarker analysis; Correlative studies; Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Biological: oblimersen sodium; Given IV; Other Names: augmerosen; G3139; G3139 bcl-2 antisense oligodeoxynucleotide; Genasense; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM; Adriamycin PFS; Adriamycin RDF; ADR; Adria; Drug: dexrazoxane hydrochloride; Given IV; Other Names: Cardioxane; Savene; Totect; Zinecard; Biological: filgrastim; Given SC; Other Names: G-CSF; Neupogen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Susan Rheingold, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start: November 1, 2002
• Primary Completion (Actual): October 1, 2005

Study Registration Dates

• First Submitted: June 6, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): January 17, 2013
• Last Update Submitted That Met QC Criteria: January 16, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Wounds and Injuries; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Cardiotoxicity; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cardiotonic Agents; Antibiotics, Antineoplastic; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Oblimersen; Dexrazoxane; Razoxane
• Other Study ID Numbers: NCI-2012-01872; U01CA097452 (U.S. NIH Grant/Contract); ADVL0211; CDR0000069387 (Registry Identifier: PDQ (Physician Data Query))