A Randomized Study of Purged Versus Unpurged Peripheral Blood Stem Cell Transplant Following Dose Intensive Induction Therapy for High Risk Neuroblastoma
- Compare the event-free survival in patients with newly diagnosed high risk
neuroblastoma or ganglioneuroblastoma treated with myeloablative consolidation
chemotherapy and autologous purged versus unpurged peripheral blood stem cells (PBSC).
- Compare the time to engraftment and CD34 content and tumor content by reverse
transcriptase polymerase chain reaction (RT-PCR) of purged versus unpurged PBSC in
patients treated with these regimens.
- Determine event-free survival of patients treated with dose intensive induction
chemotherapy comprising cyclophosphamide, doxorubicin, and vincristine alternating with
cisplatin and etoposide.
- Determine the toxicity of this dose-intensive induction chemotherapy regimen in these
- Evaluate tumor resectability at second look or delayed surgery, response (complete
response and very good partial response) at completion of induction therapy, tumor
content of peripheral blood and bone marrow, and the comparison of historical data from
CCG-3891 induction therapy in these patients.
- Compare the toxicity of this myeloablative consolidation regimen using purged vs
unpurged PBSC in these patients.
- Determine if event-free survival is predictable by RT-PCR positivity of the stem cell,
minimal residual disease in bone marrow and peripheral blood after transplantation by
immunocytology, and extent of disease as measured by MIBG after transplantation in
patients treated with these regimens.
- Evaluate the prognostic impact of tumor biology on event free survival in patients
treated with these regimens.
- Determine the incidence of relapse in the primary site after radiotherapy and in
irradiated versus unirradiated metastatic sites in these patients.
- Assess the toxicity and tolerability of maintenance therapy with topotecan and
cyclophosphamide after intensive induction therapy in patients who decline or are
unable to receive myeloablative therapy.
- Determine the health-related quality of life of patients treated with these regimens.
- Compare late effects of these regimens on the growth, endocrine, pulmonary, and cardiac
function of these patients vs general population standards.
- Determine the incidence of second malignant neoplasms in patients treated with these
- Determine the variability of isotretinoin pharmacokinetics and relationship to
pharmacogenomic parameters in these patients.
- Correlate the isotretinoin pharmacokinetics and pharmacogenomic parameters and/or
genetic variations in isotretinoin metabolic enzymes with event-free survival or
systemic toxicity in these patients.
OUTLINE: This is a randomized study. Patients are randomized to one of two treatment arms
for peripheral blood stem cell (PBSC) collection.
All patients receive induction chemotherapy comprising cyclophosphamide IV over 6 hours on
days 0 and 1, doxorubicin IV and vincristine IV continuously over 72 hours on days 0-2, and
filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 3 and continuing until blood
counts recover for courses 1, 2, 4, and 6. Treatment alternates with courses 3 and 5
comprising etoposide IV over 2 hours on days 0-2, cisplatin IV over 1 hour on days 0-3, and
G-CSF SC or IV beginning on day 4 and continuing until blood counts recover. Induction
chemotherapy repeats every 3 weeks or when blood counts recover in the absence of disease
progression or unacceptable toxicity.
After course 2 or 3 of induction chemotherapy, patients undergo PBSC collection, either
purged or unpurged, depending on randomization. Patients continue on daily G-CSF until cell
collection is complete.
- Arm I: Patients undergo unpurged PBSC collection until the target cell count is
- Arm II: Patients undergo purged PBSC collection until the target cell count is reached.
Patients with immunocytology positive PBSC undergo purged autologous bone marrow collection
or repeat purged or unpurged PBSC collection depending on individual patient
All patients undergo delayed surgical resection of the residual tumor after course 5 of
After induction therapy, patients achieving complete response, very good partial response,
or partial response receive consolidation therapy comprising melphalan IV on days -7 to -5
followed by carboplatin IV and etoposide IV continuously over days -7 to -4. Patients
receive purged or unpurged PBSC infusion or purged autologous bone marrow transplantation on
day 0 followed by G-CSF SC or IV beginning 4 hours after completion of transplantation and
continuing until blood counts recover. Beginning on day 66, patients receive oral
isotretinoin twice daily for 14 days. Isotretinoin therapy repeats every 4 weeks for 6
After completion of consolidation (at least 28 days from stem cell infusion), all patients
receive local radiotherapy daily over 7 days.
Patients not undergoing transplantation or who are ineligible for consolidation therapy
receive maintenance therapy comprising cyclophosphamide IV over 30 minutes followed by
topotecan IV over 30 minutes on days 0-4. Patients receive G-CSF SC or IV beginning on day 5
and continuing until blood counts recover. Maintenance therapy repeats every 3 weeks for 3
courses. After completion of maintenance therapy, patients receive radiotherapy as outlined
above. Patients then receive oral isotretinoin twice daily for 14 days. Isotretinoin therapy
repeats every 4 weeks for 6 courses.
Quality of life is assessed at 1* and 5 years.
Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then
annually thereafter or until disease progression.
NOTE: * Patients under 5 years of age at 1 year are not assessed until 5 years.
PROJECTED ACCRUAL: A total of 486 patients will be accrued for this study within 4 years.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Event-free survival rate
Time from study registration until the time of the first occurrence of either relapse, progression, secondary malignancy, or death, or until the time of last contact with the patient if none of these events occurs, assessed up to 6 years
Susan G. Kreissman, MD
Duke Cancer Institute
United States: Federal Government
|Indiana University Cancer Center||Indianapolis, Indiana 46202-5265|
|Duke Comprehensive Cancer Center||Durham, North Carolina 27710|
|Rhode Island Hospital||Providence, Rhode Island 02903|
|University of Texas Health Science Center at San Antonio||San Antonio, Texas 78284-7811|
|Midwest Children's Cancer Center||Milwaukee, Wisconsin 53226|
|CCOP - Kalamazoo||Kalamazoo, Michigan 49007-3731|
|Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center||Farmington, Connecticut 06360-2875|
|Van Elslander Cancer Center at St. John Hospital and Medical Center||Grosse Pointe Woods, Michigan 48236|
|Marshfield Clinic - Marshfield Center||Marshfield, Wisconsin 54449|
|Newark Beth Israel Medical Center||Newark, New Jersey 07112|
|New York Medical College||Valhalla, New York 10595|
|University of Wisconsin Comprehensive Cancer Center||Madison, Wisconsin 53792|
|Holden Comprehensive Cancer Center at University of Iowa||Iowa City, Iowa 52242-1002|
|Siteman Cancer Center at Barnes-Jewish Hospital||Saint Louis, Missouri 63110|
|Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center||Lebanon, New Hampshire 03756-0002|
|St. Barnabas Medical Center||Livingston, New Jersey 07039|
|Cleveland Clinic Taussig Cancer Center||Cleveland, Ohio 44195|
|Children's Hospital Los Angeles||Los Angeles, California 90027-0700|
|Children's National Medical Center||Washington, District of Columbia 20010-2970|
|Children's Mercy Hospital||Kansas City, Missouri 64108|
|St. Joseph's Hospital and Medical Center||Paterson, New Jersey 07503|
|Children's Hospital of Pittsburgh||Pittsburgh, Pennsylvania 15213|
|All Children's Hospital||St. Petersburg, Florida 33701|
|Children's Memorial Hospital - Chicago||Chicago, Illinois 60614|
|Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute||Boston, Massachusetts 02115|
|University of New Mexico Cancer Research and Treatment Center||Albuquerque, New Mexico 87131|
|Cook Children's Medical Center - Fort Worth||Fort Worth, Texas 76104|
|UCSF Comprehensive Cancer Center||San Francisco, California 94115|
|Fletcher Allen Health Care - University Health Center Campus||Burlington, Vermont 05401|
|Phoenix Children's Hospital||Phoenix, Arizona 85016-7710|
|Southern California Permanente Medical Group||Downey, California 90242|
|Children's Hospital Central California||Madera, California 93638-8762|
|Southern Illinois University School of Medicine||Springfield, Illinois 62794-9658|
|Kosair Children's Hospital||Louisville, Kentucky 40202-3830|
|Children's Hospital of Omaha||Omaha, Nebraska 68114|
|Sunrise Hospital and Medical Center||Las Vegas, Nevada 89109-2306|
|Children's Medical Center - Dayton||Dayton, Ohio 45404|
|Palmetto Health South Carolina Cancer Center||Columbia, South Carolina 29203|
|East Tennessee Children's Hospital||Knoxville, Tennessee 37901|
|Texas Tech University Health Sciences Center School of Medicine||Amarillo, Texas 79106|
|Children's Hospital of Austin||Austin, Texas 78701|
|Covenant Children's Hospital||Lubbock, Texas 79410|
|Markey Cancer Center at University of Kentucky Chandler Medical Center||Lexington, Kentucky 40536-0084|
|Cancer Institute at Oregon Health and Science University||Portland, Oregon 97201-3098|
|Blumenthal Cancer Center at Carolinas Medical Center||Charlotte, North Carolina 28232-2861|
|Fairview University Medical Center - University Campus||Minneapolis, Minnesota 55455|
|Sioux Valley Hospital and University of South Dakota Medical Center||Sioux Falls, South Dakota 57117-5134|
|Stanford Cancer Center at Stanford University Medical Center||Stanford, California 94305|
|Comprehensive Cancer Center at University of Alabama at Birmingham||Birmingham, Alabama 35294|
|Loma Linda University Cancer Institute at Loma Linda University Medical Center||Loma Linda, California 92354|
|Jonathan Jaques Children's Cancer Center at Miller Children's Hospital||Long Beach, California 90801|
|Kaiser Permanente Medical Center - Oakland||Sacramento, California 95825|
|Children's Hospital and Health Center - San Diego||San Diego, California 92123-4282|
|Lee Cancer Care of Lee Memorial Health System||Fort Myers, Florida 33901|
|Broward General Medical Center Cancer Center||Ft. Lauderdale, Florida 33316|
|University of Florida Shands Cancer Center||Gainesville, Florida 32610-0232|
|St. Joseph's Cancer Institute at St. Joseph's Hospital||Tampa, Florida 33607|
|Kaplan Cancer Center at St. Mary's Medical Center||West Palm Beach, Florida 33407|
|St. Vincent Indianapolis Hospital||Indianapolis, Indiana 46260|
|Blank Children's Hospital||Des Moines, Iowa 50309|
|CancerCare of Maine at Eastern Maine Medial Center||Bangor, Maine 04401|
|Alvin and Lois Lapidus Cancer Institute at Sinai Hospital||Baltimore, Maryland 21215|
|C.S. Mott Children's Hospital at University of Michigan||Ann Arbor, Michigan 48109-0238|
|Spectrum Health Cancer Care - Butterworth Campus||Grand Rapids, Michigan 49503-2560|
|Breslin Cancer Center at Ingham Regional Medical Center||Lansing, Michigan 48910|
|NYU Cancer Institute at New York University Medical Center||New York, New York 10016|
|Mission Hospitals - Memorial Campus||Asheville, North Carolina 28801|
|Presbyterian Cancer Center at Presbyterian Hospital||Charlotte, North Carolina 28233-3549|
|Cincinnati Children's Hospital Medical Center||Cincinnati, Ohio 45229-3039|
|Toledo Hospital||Toledo, Ohio 43606|
|Massey Cancer Center at Virginia Commonwealth University||Richmond, Virginia 23298-0037|
|Carilion Cancer Center of Western Virginia||Roanoke, Virginia 24029|
|Providence Cancer Center at Sacred Heart Medical Center||Spokane, Washington 99220-2555|
|Edwards Comprehensive Cancer Center at Cabell Huntington Hospital||Huntington, West Virginia 25701|
|Mary Babb Randolph Cancer Center at West Virginia University Hospitals||Morgantown, West Virginia 26506|
|St. Vincent Hospital Regional Cancer Center||Green Bay, Wisconsin 54307-3508|
|UNMC Eppley Cancer Center at the University of Nebraska Medical Center||Omaha, Nebraska 68198-7680|
|Memorial Cancer Institute at Memorial Regional Hospital||Hollywood, Florida 33021|
|Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center||Los Angeles, California 90048-1865|
|Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School||New Brunswick, New Jersey 08903|
|Cancer Center at Hackensack University Medical Center||Hackensack, New Jersey 07601|
|Children's Hospital Cancer Center||Denver, Colorado 80218|
|University of Illinois at Chicago Cancer Center||Chicago, Illinois 60612|
|Columbus Children's Hospital||Columbus, Ohio 43205-2696|
|Medical College of Ohio Cancer Institute||Toledo, Ohio 43614|
|Children's Hospital of Minnesota - Minneapolis||Minneapolis, Minnesota 55404|