Decitabine, Doxorubicin, and Cyclophosphamide in Treating Children With Relapsed or Refractory Solid Tumors or Neuroblastoma

A Phase I Study of Decitabine (NSC# 127716, IND# 50733) in Combination With Doxorubicin and Cyclophosphamide in the Treatment of Relapsed or Refractory Solid Tumors

This phase I trial is studying the side effects and best dose of decitabine when given together with doxorubicin and cyclophosphamide in treating children with relapsed or refractory solid tumors or neuroblastoma. Drugs used in chemotherapy, such as decitabine, doxorubicin, and cyclophosphamide, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

Study Overview

• Status: Completed
• Conditions: Unspecified Childhood Solid Tumor, Protocol Specific; Recurrent Neuroblastoma
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: cyclophosphamide; Other: pharmacological study; Drug: doxorubicin hydrochloride; Biological: filgrastim; Drug: decitabine; Biological: pegfilgrastim

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of decitabine in combination with doxorubicin and cyclophosphamide in children with relapsed or refractory solid tumors or neuroblastoma.

II. Determine the toxic effects of this regimen in these patients. III. Determine whether decitabine induces tumor caspase-8 demethylation and expression in these patients.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics of low-dose decitabine in these patients. II. Determine the biological and clinical response in patients treated with this regimen.

III. Compare patterns of peripheral blood gene expression, using gene expression profiling, in patients before and after treatment with decitabine.

OUTLINE: This is a multicenter, dose-escalation study of decitabine.

PART A (solid tumor patients): Patients receive decitabine IV over 1 hour on days 0-6 and doxorubicin IV over 15 minutes and cyclophosphamide IV over 1 hour on day 7. Patients then receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 8 and continuing until blood counts recover OR pegfilgrastim SC once on day 8 or 9*. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of decitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

NOTE: *For patients > 45 kg

PART B (neuroblastoma patients): Once the MTD is determined for part A, patients are treated as in part A at the MTD.

Patients are followed at 30 days.

• Study Type: Interventional
• Enrollment (Actual): 21
• 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 diagnosis of either of the following:

  • Solid tumor (part A)

    • No lymphoma

  • Neuroblastoma (part B)

    • Original diagnosis may be based on elevated urine vanillylmandelic acid (VMA) and homovanillic acid (HVA) and bone marrow examination

    • Accessible disease by bone marrow aspirate or tumor biopsy

      • No laparotomy, thoracotomy, endoscopy, or craniotomy for biopsy
• No known curative therapy OR therapy proven to prolong survival with an acceptable quality of life available
• No known brain or spinal cord metastases
• No CNS tumors
• Performance status - Karnofsky 50-100% (patients 11 to 21 years of age)
• Performance status - Lansky 50-100% (patients ≤ 10 years of age)

• Parts A and B without bone marrow infiltration:

  • Absolute neutrophil count ≥ 1,000/mm^3
  • Platelet count ≥ 100,000/mm^3 (transfusion independent)

• Part B with bone marrow infiltration (i.e., tumor metastatic to bone marrow with granulocytopenia, anemia, and/or thrombocytopenia):

  • Absolute neutrophil count ≥ 750/mm^3
  • Platelet count ≥ 50,000/mm^3 (transfusion independent)
• Hemoglobin ≥ 8.0 g/dL (transfusion allowed)
• No sickle cell anemia
• Bilirubin ≤ 1.5 mg/dL
• ALT ≤ 5 times upper limit of normal
• No significant hepatic dysfunction that would compromise the tolerability of decitabine or interfere with study procedures or results

• Creatinine based on age as follows:

  • ≤ 0.8 mg/dL (5 years of age and under)
  • ≤ 1.0 mg/dL (6 to 10 years of age)
  • ≤ 1.2 mg/dL (11 to 15 years of age)
  • ≤ 1.5 mg/dL (16 to 21 years of age)
• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min
• No significant renal dysfunction that would compromise the tolerability of decitabine or interfere with study procedures or results
• Shortening fraction ≥ 28% by echocardiogram
• Ejection fraction of ≥ 45% by MUGA
• No significant pulmonary dysfunction that would compromise the tolerability of decitabine or interfere with study procedures or results
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No prior allergic reaction attributed to compounds of similar chemical or biological composition to agents used in this study
• No uncontrolled serious infection
• No significant end-organ dysfunction that would compromise the tolerability of decitabine or interfere with study procedures or results
• Recovered from prior immunotherapy
• At least 7 days since prior biologic therapy
• More than 1 week since prior growth factor therapy (2 weeks for pegfilgrastim)
• More than 2 weeks since prior epoetin alfa
• At least 6 months since prior autologous stem cell transplantation

• At least 6 months since prior allogeneic bone marrow transplantation

  • Patients must have full organ recovery and no evidence of graft-versus-host disease
• No concurrent immunomodulating agents
• No concurrent immunotherapy
• No concurrent biologic therapy
• No concurrent epoetin alfa
• Recovered from prior chemotherapy
• More than 2 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas)
• Prior total lifetime cumulative anthracycline dose ≤ 450 mg/m^2 of doxorubicin or equivalent
• No other concurrent chemotherapy
• No concurrent hydroxyurea
• Recovered from prior radiotherapy
• More than 2 weeks since prior local palliative small port radiotherapy
• More than 6 months since prior substantial bone marrow irradiation (e.g., cranio-spinal irradiation, total body irradiation, or hemi-pelvic irradiation)
• No concurrent radiotherapy
• No other concurrent anticancer therapy
• No other concurrent investigational agents
• Concurrent oral iron supplementation for patients with a known iron deficiency or a microcytic hypochromic anemia allowed

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: Arm I; PART A (solid tumor patients): Patients receive decitabine IV over 1 hour on days 0-6 and doxorubicin IV over 15 minutes and cyclophosphamide IV over 1 hour on day 7. Patients then receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 8 and continuing until blood counts recover OR pegfilgrastim SC once on day 8 or 9*. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. PART B (neuroblastoma patients): Once the MTD is determined for part A, patients are treated as in part A at the MTD.

Other: laboratory biomarker analysis; Correlative studies; Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM; Adriamycin PFS; Adriamycin RDF; ADR; Adria; Biological: filgrastim; Given SC; Other Names: G-CSF; Neupogen; Drug: decitabine; Given IV; Other Names: DAC; 5-aza-dCyd; 5AZA; Biological: pegfilgrastim; Given SC; Other Names: Filgrastim SD-01; Neulasta; SD-01 sustained duration G-CSF; GCSF-SD01

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
MTD of decitabine, based on incidence of DLT graded according to NCI CTCAE version 3.0 (Part A)	Up to 28 days
Caspase-8 expression in bone marrow or tumor biopsy samples (Part B)	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	Confidence intervals will be reported in addition to the estimated response rates.	Up to 56 days
Percent of apoptotic cells as assessed by a TUNEL assay	A sign test or other appropriate nonparametric test may be used to assess whether there was an increase in the percent of apoptotic cells after treatment.	Up to 1 year

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Rani George, COG Phase I Consortium

Study record dates

Study Major Dates

• Study Start: December 1, 2003
• Primary Completion (Actual): September 1, 2007

Study Registration Dates

• First Submitted: January 9, 2004
• First Submitted That Met QC Criteria: January 11, 2004
• First Posted (Estimate): January 12, 2004

Study Record Updates

• Last Update Posted (Estimate): September 30, 2013
• Last Update Submitted That Met QC Criteria: September 27, 2013
• Last Verified: September 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Cyclophosphamide; Decitabine; Lenograstim; Azacitidine; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: NCI-2012-01807 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U01CA097452 (U.S. NIH Grant/Contract); CDR0000347393; COG-ADVL0215; ADVL0215 (Other Identifier: CTEP)