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


Phase 1
1 Year
21 Years
Not Enrolling
Both
Recurrent Neuroblastoma, Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

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


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.


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of decitabine, based on incidence of DLT graded according to NCI CTCAE version 3.0 (Part A)

Outcome Time Frame:

Up to 28 days

Safety Issue:

Yes

Principal Investigator

Rani George

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-01807

NCT ID:

NCT00075634

Start Date:

August 2003

Completion Date:

Related Keywords:

  • Recurrent Neuroblastoma
  • Unspecified Childhood Solid Tumor, Protocol Specific
  • Neuroblastoma
  • Neoplasms

Name

Location

Children's Oncology GroupArcadia, California  91006-3776