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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00075634
First received: January 9, 2004
Last updated: September 27, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
Recurrent Neuroblastoma
Unspecified Childhood Solid Tumor, Protocol Specific
Drug: decitabine
Drug: doxorubicin hydrochloride
Drug: cyclophosphamide
Biological: filgrastim
Biological: pegfilgrastim
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • MTD of decitabine, based on incidence of DLT graded according to NCI CTCAE version 3.0 (Part A) [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]
  • Caspase-8 expression in bone marrow or tumor biopsy samples (Part B) [ Time Frame: Up to 28 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Objective response rate [ Time Frame: Up to 56 days ] [ Designated as safety issue: No ]
    Confidence intervals will be reported in addition to the estimated response rates.

  • Percent of apoptotic cells as assessed by a TUNEL assay [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    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.


Enrollment: 21
Study Start Date: December 2003
Primary Completion Date: September 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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

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.

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00075634

Locations
United States, California
Children's Oncology Group
Arcadia, California, United States, 91006-3776
Sponsors and Collaborators
Investigators
Principal Investigator: Rani George COG Phase I Consortium
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00075634     History of Changes
Other Study ID Numbers: NCI-2012-01807, NCI-2012-01807, CDR0000347393, COG-ADVL0215, ADVL0215, ADVL0215, U01CA097452
Study First Received: January 9, 2004
Last Updated: September 27, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neoplasms
Neuroblastoma
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Neuroectodermal Tumors, Primitive, Peripheral
Cyclophosphamide
Decitabine
Doxorubicin
Lenograstim
Liposomal doxorubicin
Adjuvants, Immunologic
Alkylating Agents
Antibiotics, Antineoplastic
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 22, 2014