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A Randomized Study of Purged Versus Unpurged Peripheral Blood Stem Cell Transplant Following Dose Intensive Induction Therapy for High Risk Neuroblastoma


Phase 3
N/A
30 Years
Not Enrolling
Both
Neuroblastoma

Thank you

Trial Information

A Randomized Study of Purged Versus Unpurged Peripheral Blood Stem Cell Transplant Following Dose Intensive Induction Therapy for High Risk Neuroblastoma


OBJECTIVES:

Primary

- 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
patients.

- 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.

Secondary

- 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
regimens.

- 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
reached.

- 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
characteristics.

All patients undergo delayed surgical resection of the residual tumor after course 5 of
induction chemotherapy.

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
courses.

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.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed newly diagnosed neuroblastoma OR ganglioneuroblastoma,
and/or evidence of clumps of tumor cells in bone marrow with elevated urinary
catecholamine metabolites, meeting 1 of the following criteria:

- Age greater than 18 months with stage IV disease, regardless of biologic factors

- Age 12-18 months with stage IV disease meeting one of the following criteria:

- Any unfavorable biologic feature (e.g., MYCN amplification, unfavorable
pathology, and/or DNA index = 1)

- Any biologic feature that is indeterminate, unsatisfactory, or unknown

- At least 1 year old with the following:

- Stage IIa/IIb with MYCN amplification (> 10) AND unfavorable pathology

- Stage III with MYCN amplification (> 10) OR unfavorable pathology

- Stage I, II, or IVS with disease progression to stage IV without interval
chemotherapy

- No more than 3 weeks since progression

- Must have been enrolled on protocol CCG-B973, COG-ANBL00B1, or POG-9047

- Less than 1 year old with the following:

- Stage III, IV, or IVS disease with MYCN amplification (> 10)

- Registration on protocol COG-ANBL00B1 required within 14 days of diagnosis

PATIENT CHARACTERISTICS:

Age:

- See Disease Characteristics

- 30 and under at time of diagnosis

Performance status:

- Not specified

Life expectancy:

- Not specified

Hematopoietic:

- Absolute neutrophil count ≥ 1,000/mm^3

- Platelet count ≥ 100,000/mm^3

- Inadequate hematopoiesis secondary to bone marrow involvement with > 10% tumor
infiltration allowed

Hepatic:

- Bilirubin ≤ 1.5 mg/dL

- ALT ≤ 300 units/L

Renal:

- Creatinine ≤ 1.5 mg/dL

- Creatinine clearance or glomerular filtration rate ≥ 60 mL/min

Cardiovascular:

- ECG normal

- Ejection fraction ≥ 55% by echocardiogram or MUGA OR

- Fractional shortening ≥ 28% by echocardiogram

Other:

- Able to tolerate peripheral blood stem cell collection

- HIV negative

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception for at least 1 month prior to,
during, and for 1 month after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy:

- Not specified

Chemotherapy:

- See Disease Characteristics

- No more than 1 prior course of chemotherapy on the Intergroup low/intermediate risk
neuroblastoma study (P9641, A3961)

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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event-free survival rate

Outcome Time Frame:

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

Safety Issue:

No

Principal Investigator

Susan G. Kreissman, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Duke Cancer Institute

Authority:

United States: Federal Government

Study ID:

A3973

NCT ID:

NCT00004188

Start Date:

February 2001

Completion Date:

Related Keywords:

  • Neuroblastoma
  • localized resectable neuroblastoma
  • regional neuroblastoma
  • disseminated neuroblastoma
  • stage 4S neuroblastoma
  • localized unresectable neuroblastoma
  • Neuroblastoma

Name

Location

Indiana University Cancer CenterIndianapolis, Indiana  46202-5265
Duke Comprehensive Cancer CenterDurham, North Carolina  27710
Rhode Island HospitalProvidence, Rhode Island  02903
University of Texas Health Science Center at San AntonioSan Antonio, Texas  78284-7811
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
CCOP - KalamazooKalamazoo, Michigan  49007-3731
Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health CenterFarmington, Connecticut  06360-2875
Van Elslander Cancer Center at St. John Hospital and Medical CenterGrosse Pointe Woods, Michigan  48236
Marshfield Clinic - Marshfield CenterMarshfield, Wisconsin  54449
Newark Beth Israel Medical CenterNewark, New Jersey  07112
New York Medical CollegeValhalla, New York  10595
University of Wisconsin Comprehensive Cancer CenterMadison, Wisconsin  53792
Holden Comprehensive Cancer Center at University of IowaIowa City, Iowa  52242-1002
Siteman Cancer Center at Barnes-Jewish HospitalSaint Louis, Missouri  63110
Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical CenterLebanon, New Hampshire  03756-0002
St. Barnabas Medical CenterLivingston, New Jersey  07039
Cleveland Clinic Taussig Cancer CenterCleveland, Ohio  44195
Children's Hospital Los AngelesLos Angeles, California  90027-0700
Children's National Medical CenterWashington, District of Columbia  20010-2970
Children's Mercy HospitalKansas City, Missouri  64108
St. Joseph's Hospital and Medical CenterPaterson, New Jersey  07503
Children's Hospital of PittsburghPittsburgh, Pennsylvania  15213
All Children's HospitalSt. Petersburg, Florida  33701
Children's Memorial Hospital - ChicagoChicago, Illinois  60614
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer InstituteBoston, Massachusetts  02115
University of New Mexico Cancer Research and Treatment CenterAlbuquerque, New Mexico  87131
Cook Children's Medical Center - Fort WorthFort Worth, Texas  76104
UCSF Comprehensive Cancer CenterSan Francisco, California  94115
Fletcher Allen Health Care - University Health Center CampusBurlington, Vermont  05401
Phoenix Children's HospitalPhoenix, Arizona  85016-7710
Southern California Permanente Medical GroupDowney, California  90242
Children's Hospital Central CaliforniaMadera, California  93638-8762
Southern Illinois University School of MedicineSpringfield, Illinois  62794-9658
Kosair Children's HospitalLouisville, Kentucky  40202-3830
Children's Hospital of OmahaOmaha, Nebraska  68114
Sunrise Hospital and Medical CenterLas Vegas, Nevada  89109-2306
Children's Medical Center - DaytonDayton, Ohio  45404
Palmetto Health South Carolina Cancer CenterColumbia, South Carolina  29203
East Tennessee Children's HospitalKnoxville, Tennessee  37901
Texas Tech University Health Sciences Center School of MedicineAmarillo, Texas  79106
Children's Hospital of AustinAustin, Texas  78701
Covenant Children's HospitalLubbock, Texas  79410
Markey Cancer Center at University of Kentucky Chandler Medical CenterLexington, Kentucky  40536-0084
Cancer Institute at Oregon Health and Science UniversityPortland, Oregon  97201-3098
Blumenthal Cancer Center at Carolinas Medical CenterCharlotte, North Carolina  28232-2861
Fairview University Medical Center - University CampusMinneapolis, Minnesota  55455
Sioux Valley Hospital and University of South Dakota Medical CenterSioux Falls, South Dakota  57117-5134
Stanford Cancer Center at Stanford University Medical CenterStanford, California  94305
Comprehensive Cancer Center at University of Alabama at BirminghamBirmingham, Alabama  35294
Loma Linda University Cancer Institute at Loma Linda University Medical CenterLoma Linda, California  92354
Jonathan Jaques Children's Cancer Center at Miller Children's HospitalLong Beach, California  90801
Kaiser Permanente Medical Center - OaklandSacramento, California  95825
Children's Hospital and Health Center - San DiegoSan Diego, California  92123-4282
Lee Cancer Care of Lee Memorial Health SystemFort Myers, Florida  33901
Broward General Medical Center Cancer CenterFt. Lauderdale, Florida  33316
University of Florida Shands Cancer CenterGainesville, Florida  32610-0232
St. Joseph's Cancer Institute at St. Joseph's HospitalTampa, Florida  33607
Kaplan Cancer Center at St. Mary's Medical CenterWest Palm Beach, Florida  33407
St. Vincent Indianapolis HospitalIndianapolis, Indiana  46260
Blank Children's HospitalDes Moines, Iowa  50309
CancerCare of Maine at Eastern Maine Medial CenterBangor, Maine  04401
Alvin and Lois Lapidus Cancer Institute at Sinai HospitalBaltimore, Maryland  21215
C.S. Mott Children's Hospital at University of MichiganAnn Arbor, Michigan  48109-0238
Spectrum Health Cancer Care - Butterworth CampusGrand Rapids, Michigan  49503-2560
Breslin Cancer Center at Ingham Regional Medical CenterLansing, Michigan  48910
NYU Cancer Institute at New York University Medical CenterNew York, New York  10016
Mission Hospitals - Memorial CampusAsheville, North Carolina  28801
Presbyterian Cancer Center at Presbyterian HospitalCharlotte, North Carolina  28233-3549
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Toledo HospitalToledo, Ohio  43606
Massey Cancer Center at Virginia Commonwealth UniversityRichmond, Virginia  23298-0037
Carilion Cancer Center of Western VirginiaRoanoke, Virginia  24029
Providence Cancer Center at Sacred Heart Medical CenterSpokane, Washington  99220-2555
Edwards Comprehensive Cancer Center at Cabell Huntington HospitalHuntington, West Virginia  25701
Mary Babb Randolph Cancer Center at West Virginia University HospitalsMorgantown, West Virginia  26506
St. Vincent Hospital Regional Cancer CenterGreen Bay, Wisconsin  54307-3508
UNMC Eppley Cancer Center at the University of Nebraska Medical CenterOmaha, Nebraska  68198-7680
Memorial Cancer Institute at Memorial Regional HospitalHollywood, Florida  33021
Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical CenterLos Angeles, California  90048-1865
Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical SchoolNew Brunswick, New Jersey  08903
Cancer Center at Hackensack University Medical CenterHackensack, New Jersey  07601
Children's Hospital Cancer CenterDenver, Colorado  80218
University of Illinois at Chicago Cancer CenterChicago, Illinois  60612
Columbus Children's HospitalColumbus, Ohio  43205-2696
Medical College of Ohio Cancer InstituteToledo, Ohio  43614
Children's Hospital of Minnesota - MinneapolisMinneapolis, Minnesota  55404