Study of Fixed vs. Flexible Filgrastim to Accelerate Bone Marrow Recovery After Chemotherapy in Children With Cancer

PRIMARY OBJECTIVES:

I. To compare the effect of flexible vs. fixed administration of G-CSF (filgrastim) on the
parameters of hematological recovery including duration of absolute neutrophil count (ANC) <
500/uL; time to ANC recovery >= 1,000/uL and time to platelet recovery >= 75,000/uL in
children receiving myelotoxic chemotherapy.

SECONDARY OBJECTIVES:

I. To compare the effect of flexible vs. fixed administration of G-CSF on the incidence of
febrile neutropenia and number of hospital days on antibiotics following myelotoxic
chemotherapy.

II. To evaluate the number of days of platelet transfusion events after chemotherapy cycles
with flexible vs. fixed administration of G-CSF.

III. To evaluate on the incidence and duration of G-CSF-related side effects including
extremities/back pain and headaches after chemotherapy courses followed by flexible vs.
fixed administration of G-CSF.

IV. To evaluate the peripheral blood progenitor responses and subsets of progenitor cells
(cluster of differentiation [CD]34/41/61/117/10/19/11b/33) to chemotherapy followed by
flexible vs. fixed administration of G-CSF.

OUTLINE:

CHEMOTHERAPY: Depending on their diagnosis patients are assigned to 1 of 3 chemotherapy
regimens.

ICE: Patients receive etoposide intravenously (IV) over 1 hour on days 1-3, ifosfamide IV
over 3 hours on days 1-3, and carboplatin IV over 1 hour on day 4. Patients with recurrent
Hodgkin lymphoma receive etoposide and ifosfamide on days 1-3 and carboplatin on day 3.

ICT: Patients receive topotecan hydrochloride IV over 30 minutes on days 1-3, and ifosfamide
and carboplatin as in ICE.

OPEC: Patients receive vincristine sulfate on days 1, 8, and 15; etoposide IV over 1 hour on
days 1-3; cyclophosphamide IV over 1 hour on days 1-2; and cisplatin IV over 6 hours on day
4.

For all chemotherapy regimens, treatment repeats every 21 days for 2 courses. Patients are
then randomized to 1 of 2 treatment arms.

ARM I (fixed filgrastim): Patients receive filgrastim subcutaneously (SC) once daily (QD)
started at 24 hours after completion of chemotherapy and stopped when ANC reaches at least
1,000/uL post nadir.

ARM II (flexible filgrastim): Patients receive filgrastim SC QD started on the first day
after chemotherapy when ANC falls below 1,000/uL and stopped when ANC reaches at least
1,000/uL post nadir.

After completion of the first filgrastim treatment, patients cross-over to the other
filgrastim arm and repeat the same course of chemotherapy as before. After completion of the
second filgrastim treatment, chemotherapy treatment may continue for up to 5 (OPEC) or 6
(ICE, ICT) courses in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

- Subjects must have or have had at initial diagnosis, histologic proof of their
malignancy; young children with primary embryonal brain tumor treated according to
Head Start protocol are eligible; subjects with bone marrow involvement are NOT
eligible for study

- Patients will receive repeated cycles of identical chemotherapy that will likely
result in grades III-IV hematological toxicity; patients will be treated outside of
Children's Oncology Group (COG) protocols with specific requirements for schedule of
G-CSF administration; the following categories of patients treated at Children's
Hospital of Michigan are eligible for this study:

- Patients with brain tumors treated according to Head Start II protocol with
vincristine, etoposide, cyclophosphamide, and cisplatin (OPEC) chemotherapy;

- Patients with recurrent Hodgkin lymphoma treated with ICE (ifosfamide,
carboplatin, etoposide) chemotherapy;

- Patients with recurrent solid tumors including sarcomas, Wilms' tumor,
neuroblastomas, or brain tumors treated with high dose ICE or ICT (ifosfamide,
carboplatin, topotecan) chemotherapy

- Patients with UH Wilms' tumor treated with CE (cyclophosphamide, etoposide);
patients with neuroblastoma treated with CE (carboplatin, etoposide);

- Patients with soft tissue sarcomas treated with IA (ifosfamide, doxorubicin);

- Patients with osteosarcoma treated with high dose ifosfamide

- Subjects must have fully recovered from the toxic effects of any prior therapy; at
least 3 weeks should have elapsed since the last dose of chemotherapy (6 weeks in the
case of nitrosourea containing therapy); subjects must have recovered from previous
colony-stimulating factor therapy and have been off colony-stimulating factors
(G-CSF, granulocyte macrophage colony-stimulating factor [GM-CSF], interleukin
[IL]-11) for more than 10 days and off erythropoietin for 30 days

- ANC > 1000/uL

- Platelet count > 100,000/uL

- Creatinine clearance or glomerular filtration rate (GFR) which is greater than or
equal to 70 ml/min/1.73 m^2

- Bilirubin less than 1.5 x normal limit (NL)

- Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate
transaminase (SGPT) less than 2.5 x NL for age

- Subjects should have a normal ejection fraction (per institutional limits), no
evidence of cardiac arrhythmias requiring therapy, and a fractional shortening of >
28%

- All subjects must have a life expectancy of 12 weeks or more

- Diagnostic categories

- Sarcoma (soft tissue and bone)

- Kidney tumors

- Brain tumors

- Other solid tumors (gonadal and germ cell tumors, retinoblastoma, neuroblastoma,
and miscellaneous tumors)

- Hodgkin lymphoma

- Performance status must be > 60 from Lansky (age 1 to 16) or Karnofsky (age > 16)

Exclusion Criteria:

- Subjects with any of the following will NOT be eligible for study:

- Bone marrow involvement

- Active myelogenous leukemia, or history of myelogenous leukemia

- Pregnancy