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

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

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.

Study Overview

• Status: Completed
• Conditions: Neuroblastoma
• Intervention / Treatment: Drug: cyclophosphamide; Radiation: radiation therapy; Drug: etoposide; Drug: vincristine sulfate; Drug: cisplatin; Drug: doxorubicin hydrochloride; Procedure: conventional surgery; Procedure: peripheral blood stem cell transplantation; Biological: filgrastim; Drug: melphalan; Drug: topotecan hydrochloride; Drug: isotretinoin

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
• United States
  • California
    • San Francisco, California, United States, 94143-0106
      • UCSF Comprehensive Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital - Chicago
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle
    • Tacoma, Washington, United States, 98405
      • Mary Bridge Children's Hospital and Health Center - Tacoma

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 30 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: All patients; 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.

Drug: cyclophosphamide; Radiation: radiation therapy; Drug: etoposide; Drug: vincristine sulfate; Drug: cisplatin; Drug: doxorubicin hydrochloride; Procedure: conventional surgery; Procedure: peripheral blood stem cell transplantation; Biological: filgrastim; Drug: melphalan; Drug: topotecan hydrochloride; Drug: isotretinoin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of toxic deaths		Length of study
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
Tumor contamination of PBSCs	Tumor contamination of PBSCs as measured by immunohistochemical analysis following cycle 2 induction;	Length of study
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
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

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Julie R. Park, MD, Seattle Children's Hospital

Publications and helpful links

General Publications

• 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 study. J Clin Oncol. 2011 Nov 20;29(33):4351-7. doi: 10.1200/JCO.2010.34.3293. Epub 2011 Oct 17.

Study record dates

Study Major Dates

• Study Start: March 1, 2004
• Primary Completion (Actual): September 1, 2006
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: October 3, 2003
• First Submitted That Met QC Criteria: October 6, 2003
• First Posted (Estimate): October 7, 2003

Study Record Updates

• Last Update Posted (Estimate): February 13, 2014
• Last Update Submitted That Met QC Criteria: February 12, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: disseminated neuroblastoma; localized unresectable neuroblastoma; recurrent neuroblastoma; stage 4S neuroblastoma; regional neuroblastoma; localized resectable neuroblastoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Antibiotics, Antineoplastic; Topoisomerase I Inhibitors; Cyclophosphamide; Etoposide; Melphalan; Doxorubicin; Liposomal doxorubicin; Vincristine; Topotecan; Isotretinoin
• Other Study ID Numbers: ANBL02P1; CDR0000330140 (Other Identifier: Clinical Trials.gov); COG-ANBL02P1 (Other Identifier: Children's Oncology Group)