Induction Chemotherapy Using Cyclophosphamide and Topotecan in Treating Patients Who Are Undergoing Autologous Peripheral Stem Cell Transplantation for Newly Diagnosed or Progressive Neuroblastoma

Children's Oncology Group

Status and phase

Completed

Phase 1

Conditions

Neuroblastoma

Treatments

Procedure: conventional surgery

Drug: vincristine sulfate

Drug: isotretinoin

Drug: cyclophosphamide

Drug: melphalan

Drug: doxorubicin hydrochloride

Procedure: peripheral blood stem cell transplantation

Drug: etoposide

Drug: topotecan hydrochloride

Radiation: radiation therapy

Biological: filgrastim

Drug: cisplatin

Study type

Interventional

Funder types

NETWORK

NIH

Identifiers

NCT00070200

COG-ANBL02P1 (Other Identifier)

CDR0000330140 (Other Identifier)

ANBL02P1

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy, such as topotecan and cyclophosphamide, use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with autologous stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects of induction chemotherapy using cyclophosphamide and topotecan in treating patients who are undergoing surgery and autologous stem cell transplantation followed by radiation therapy for newly diagnosed or progressive neuroblastoma.

Full description

OBJECTIVES:

Primary

Determine the toxicity and feasibility of adding cyclophosphamide and topotecan to induction therapy in patients with newly diagnosed or progressive high-risk neuroblastoma undergoing autologous peripheral blood stem cell (PBSC) transplantation.
Determine the feasibility of PBSC mobilization and in vivo PBSC tumor purging in these patients after treatment with this regimen.

Secondary

Determine tumor response rate in patients treated with this regimen.
Determine the pharmacokinetics of this regimen in these patients.
Determine whether topotecan affects cyclophosphamide pharmacokinetics in these patients.
Correlate host DNA with toxicity and cyclophosphamide and topotecan pharmacokinetics in patients treated with this regimen.
Determine toxicity in patients treated with this regimen.

OUTLINE: This is a pilot, multicenter study. Patients are stratified according to diagnosis (newly diagnosed vs initially stage 1, 2, or 4S that progressed to stage 4 without interval chemotherapy).

Induction therapy: Patients receive 6 courses of induction therapy.
- Courses 1 and 2: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5 and filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 6 and continuing until blood counts recover.
- Course 3: Patients receive etoposide IV over 2 hours on days 1-3, cisplatin IV over 1 hour on days 1-4, and G-CSF SC or IV beginning on day 5 and continuing until blood counts recover.
- Course 4: Patients receive cyclophosphamide IV over 6 hours on day 1 and doxorubicin IV and vincristine IV continuously over 24 hours on days 1-3. Patients also receive G-CSF SC or IV beginning on day 4 and continuing until blood counts recover.
- Course 5: Patients receive etoposide, cisplatin, and G-CSF as in course 3.
- Course 6: Patients receive cyclophosphamide, doxorubicin, vincristine, and G-CSF as in course 4.

Treatment repeats every 21 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity.

Consolidation therapy: Within 4-6 weeks after completing induction therapy, patients receive melphalan IV on days -7 to -5 and etoposide IV and carboplatin IV continuously over 24 hours on days -7 to -4.
Stem cell transplantation: Peripheral blood stem cells are collected after course 2 of induction therapy and infused on day 0. Patients receive G-CSF IV beginning on day 0 and continuing until blood counts recover.
Surgery: After course 5 of induction therapy, patients undergo surgery.
Radiotherapy: Beginning 28-42 days after transplantation, patients receive 12 fractions of local radiotherapy to all areas of residual soft tissue disease and the primary tumor site, even if completely resected.
Maintenance therapy: Beginning 66 days after transplantation, patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for a total of 6 courses.

Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 10-29 patients will be accrued for this study within 2 years.

Enrollment

31 patients

Sex

All

Ages

Under 30 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed neuroblastoma or ganglioneuroblastoma meeting 1 of the following staging criteria:
- Newly diagnosed disease, at least 1 year of age, and meets criteria for 1 of the following:
  - International Neuroblastoma Staging System (INSS) stage 2a/2b with MYCN amplification (greater than 10) AND unfavorable pathology
  - INSS stage 3 with MYCN amplification OR unfavorable pathology
- Newly diagnosed INSS stage 4 disease meeting criteria for 1 of the following:
  - Over 18 months of age
  - Age 12 to 18 months with any unfavorable biologic feature (MYCN amplification, unfavorable pathology, and/or DNA index=1) or any biologic feature that is indeterminant, unsatisfactory, or unknown
    - No INSS stage 4 disease and age 12 to 18 months with all 3 favorable biologic features (i.e., nonamplified MYCN, favorable pathology, and DNA index greater than 1)
- Newly diagnosed INSS stage 3, 4, or 4S disease AND under 1 year of age with MYCN amplification
- At least 1 year of age and initially diagnosed with INSS stage 1, 2, or 4S disease that progressed to stage 4 without interval chemotherapy
  - Must have been enrolled on COG-ANBL00B1 at initial diagnosis

PATIENT CHARACTERISTICS:

Age

30 and under at initial diagnosis

Performance status

Not specified

Life expectancy

Not specified

Hematopoietic

Absolute neutrophil count at least 1,000/mm^3*
Platelet count at least 100,000/mm^3* (transfusion independent)
Hemoglobin at least 10.0 g/dL* (red blood cell transfusions allowed) NOTE: *Granulocytopenia, anemia, and/or thrombocytopenia allowed for patients with tumor metastatic to the bone marrow

Hepatic

Bilirubin no greater than 1.5 mg/dL
ALT less than 300 IU/L

Renal

Creatinine no greater than 1.5 mg/dL
Creatinine clearance or radioisotope glomerular filtration rate at least 60 mL/min

Cardiovascular

ECG normal
Shortening fraction at least 27% by echocardiogram OR
Ejection fraction at least 50% by MUGA

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy

Not specified

Chemotherapy

See Disease Characteristics
No more than 1 prior chemotherapy course on the low- or intermediate-risk neuroblastoma studies (COG-P9641, COG-A3961) prior to determination of MYCN amplification and Shimada histology

Endocrine therapy

Not specified

Radiotherapy

Prior localized emergency radiotherapy to sites of life-threatening or function-threatening disease allowed

Surgery

Not specified

Other

No other prior systemic therapy

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

31 participants in 1 patient group

All patients

Experimental group

Description:

Induction Cycles 1 and 2 (CT) (21 days each), Cyclophosphamide (Days 1 thru 5) weight based dosage (\> 12 kg 400 mg/m2/day, \< 12 kg 13.3 mg/kg/day, \< 2 years old N/A. Topotecan (Days 1 thru 5) weight based dosage (\> 12 kg 1.2 mg/m2/day, \< 12 kg 0.04 mg/kg/day, \< 2 years old 0.04 mg/kg/day). Filgrastim (Days 6 →) weight based dosage (\> 12 kg 5 micrograms/kg, \< 12 kg 5 micrograms /kg, \< 2 years old 5 micrograms /kg.

Treatment: