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

Neuroblastoma Clinical Trial

Official title:

A Pilot Induction Regimen Incorporating Topotecan for Treatment of Newly Diagnosed High Risk Neuroblastoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00070200
• Other study ID #: ANBL02P1
• Secondary ID: CDR0000330140COG
• Status: Completed
• Phase: Phase 1
• First received: October 3, 2003
• Last updated: February 12, 2014
• Start date: March 2004
• Est. completion date: December 2013

Study information

• Verified date: February 2014
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: December 2013
• Est. primary completion date: September 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 30 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Neuroblastoma

Intervention

Biological:
• filgrastim

Drug:
• cisplatin

• cyclophosphamide

• doxorubicin hydrochloride

• etoposide

• isotretinoin

• melphalan

• topotecan hydrochloride

• vincristine sulfate

Procedure:
• conventional surgery

• peripheral blood stem cell transplantation

Radiation:
• radiation therapy

Locations

Country	Name	City	State
Australia	Westmead Hospital	Westmead	New South Wales
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	UCSF Comprehensive Cancer Center	San Francisco	California
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington
United States	Mary Bridge Children's Hospital and Health Center - Tacoma	Tacoma	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia, 

References & Publications (1)

Park JR, Scott JR, Stewart CF, London WB, Naranjo A, Santana VM, Shaw PJ, Cohn SL, Matthay KK. Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children's Oncology Group — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients who are classified as a "success"	Given that the documented delivered dose intensity of chemotherapy in current induction regimens is 75-85% of the intended dose intensity,5,78 we shall consider an individual patient as a "success" in terms of feasibility if the patient is able to receive 75% or more of the intended chemotherapy doses of known active agents.	Length of study	Yes
Secondary	Number of toxic deaths		Length of study	Yes
Secondary	Proportion of patients with dose limiting toxicities during induction cycle 1 and 2	Dose limiting toxicities during induction cycle 1 and 2 will be used to modify the topotecan dosage if necessary and to address Primary Aim 1 in a descriptive fashion.	Length of study	Yes
Secondary	Tumor contamination of PBSCs	Tumor contamination of PBSCs as measured by immunohistochemical analysis following cycle 2 induction;	Length of study	Yes
Secondary	Inability to adequately mobilize PBSCs	Inability to adequately mobilize PBSCs, defined as a harvest of < 1.5 x 10 6 CD 34 cells/kg. A patient will be designated a PBSCs "failure" if either a) or b) is the case.	Length of study	No
Secondary	Assessment of response	After completion of induction therapy. Response will be determined using the International Response Criteria defined elsewhere in the protocol. The tumor response rate will be defined as the proportion of patients who achieve a CR, VGPR, or PR after completion of induction therapy.	Length of study	No