PEPI: Protracted Etoposide in a Phase II Upfront Window for Induction Therapy for High Risk Neuroblastoma
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Neuroblastoma
Trial Information
PEPI: Protracted Etoposide in a Phase II Upfront Window for Induction Therapy for High Risk Neuroblastoma
Neuroblastoma is the most common extracranial solid tumor of childhood. Approximately half
of the children newly diagnosed with this tumor will have metastatic disease or
histologically aggressive large tumors that are at "high risk" for treatment failure.
Therapy for high risk neuroblastoma consists of intensive chemotherapy, surgery, radiation
therapy, high dose therapy with autologous hematopoietic stem cell rescue (HDT/SCR), and
biologic agents such as retinoids. Dose intensification has long been the focus of clinical
research with development of maximum intensity induction regimens and multiple cycles of
HDT/SCR. The majority of tumors will respond initially to this combination therapy, but
relapse is common with a three-year event free survival of 30 to 40%. Additionally, the risk
of acute and chronic toxicities from therapy is high and increases with intensification.
Review of risk factors for relapse or progressive disease suggests that response of tumors
to induction chemotherapy is a predictor of poor outcomes with current treatment strategies.
Novel approaches to induction therapy may be beneficial to the overall survival of children
with HRNB; because the response rate to induction has historically been good, care must be
taken when modifying the standard regimens. The trial that follows aims to address the
initial tumor response by changing the dosing of etoposide, a known effective agent in both
newly- diagnosed and salvage therapy, from bolus to protracted dosing. This dosing schedule
may provide an anti- angiogenic effect as well as a cytotoxic anti-tumor effect. If this
regimen proves equally effective as prior regimens it could serve as a backbone for the
incorporation of other novel targeted agents. Additional research to improve understanding
of neuroblastoma, the patients, and the impacts of therapy are also included for design of
future clinical trials.
This study will evaluate the efficacy of protracted etoposide in combination with standard
Cisplatin dosing. Although the most common schedule for children has historically been 50
mg/m2/day for 21 days, in this study the dose will be reduced to 14 days. A 14 day schedule
will allow other chemotherapy to be given on a 21 day schedule while keeping the total
cumulative dose of etoposide within the range of other prior effective regimens.
Inclusion Criteria:
Pts can be enrolled but receive standard etoposide bolus dosing based on clinical
conditions at diagnosis (need for emergency intervention because of renal, neurologic, or
airway compromise). Pts who meet all other eligibility criteria may also choose to
participate in the clinical trial w/o receiving the upfront window protracted dosing of
etoposide; these children will receive standard etoposide bolus dosing.
Less than 18 yo at diagnosis
DIAGNOSIS Neuroblastoma or ganglioneuroblastoma verified by histology and/or demonstration
of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites.
Pts with newly diagnosed neuroblastoma and age 365 or more days with the following: * INSS
Stage 2a/2b with MYCN amplification , AND unfavorable pathology * INSS Stage 3 with MYCN
amplification AND/OR unfavorable pathology
Pts with newly diagnosed neuroblastoma with INSS Stage 4 are eligible with the following:
* Age more than 18 months (greater than 547 days) regardless of biologic features * Age 12
to 18 months (365-547 days) with any unfavorable biologic feature (MYCN amplification,
unfavorable pathology and/or DNA index equal to 1) or any biologic feature that is
indeterminant/unsatisfactory/unknown.
Pts with newly diagnosed neuroblastoma and age less than 365 days with INSS Stage 3, 4, 4S
neuroblastoma with MYCN amplification (more than 10).
Pts 365 days or more initially diagnosed with INSS stage 1, 2, 4S who develop distant
metastatic disease (meet criteria for INSS stage 4).
Pts may have had no prior systemic therapy except:
- Localized emergency radiation to sites of life threatening or function-threatening
disease
- No more than one cycle of chemotherapy according to the intergroup low or
intermediate risk neuroblastoma studies prior to determination of MYCN amplification
and histology.
TIME FROM DIAGNOSIS Pts must be entered on this study - Within 3 weeks of diagnosis -
After recovery from only 1 cycle of chemo on low/intermediate risk NB therapy, - Within 3
weeks of progression with widely metastatic tumor for INSS stage 1, 2, 4S if they received
no prior chemotherapy.
HEMATOPOIETIC FUNCTION
- ANC 750/µL or more
- Plt 75,000/µL or more
- or bone marrow involvement with tumor.
LIVER FUNCTION Pts must have adequate liver function defined as
- Direct Bilirubin 1.5 mg/dL or less
- AST and ALT 5 x ULN or less
Pts of childbearing potential must practice an effective method of birth control while on
study.
Exclusion Criteria:
Patients who do not meet inclusion criteria.
Patients who are pregnant or lactating are not eligible.
EXCLUSION CRITERIA UPFRONT WINDOW Patients can be enrolled onto Stratum 1 but receive
standard etoposide bolus dosing based on clinical conditions at diagnosis. Patients who
meet all other eligibility criteria may also choose to participate in the clinical trial
without receiving the upfront window protracted dosing of etoposide; these children will
receive standard etoposide bolus dosing.
Patients whose tumor requires emergency intervention because of spinal cord compression,
CNS compromise, or airway compromise.
Patients requiring dialysis.
If the patient and/or the patient's legally authorized guardian chose to participate in
the clinical trial but chose to not participate in the phase II upfront window.
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Response Rate Associated With Two Cycles of Cisplatin With Protracted Oral Etoposide When Administered as Up-front Window Therapy to Previously Untreated Children With High Risk Neuroblastoma Tumors.
Outcome Time Frame:
2 months
Safety Issue:
No
Principal Investigator
Peter Zage, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Baylor College of Medicine
Authority:
United States: Institutional Review Board
Study ID:
H20255
NCT ID:
NCT00578864
Start Date:
March 2007
Completion Date:
March 2014
Related Keywords:
- Neuroblastoma
- Neuroblastoma
- Etoposide
- Cisplatin
- Adriamycin
- Cyclophosphamide
- Cytoxan
- Neuroblastoma
Name | Location |
|---|---|
| Texas Children's Hospital | Houston, Texas |
