Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Neuroblastoma

Condition(s) targeted: Neuroblastoma

Intervention: carboplatin (Drug); cisplatin (Drug); cyclophosphamide (Drug); doxorubicin hydrochloride (Drug); etoposide (Drug); filgrastim (Drug); isotretinoin (Drug); melphalan (Drug); topotecan hydrochloride (Drug); vincristine (Drug); autologous bone marrow transplantation (Procedure); bone marrow ablation with stem cell support (Procedure); chemotherapy (Procedure); colony-stimulating factor therapy (Procedure); conventional surgery (Procedure); differentiation therapy (Procedure); high-dose chemotherapy (Procedure); peripheral blood stem cell transplantation (Procedure); radiation therapy (Procedure)

Phase: Phase 3

Status: Completed

Sponsored by: Children's Oncology Group

Official(s) and/or principal investigator(s):
Susan G. Kreissman, MD, Study Chair, Affiliation: Duke University

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

PURPOSE: This randomized phase III trial is studying peripheral stem cell transplantation with treated peripheral stem cells following combination chemotherapy to see how well it works compared to peripheral stem cell transplantation with untreated peripheral stem cells following combination chemotherapy in treating patients with neuroblastoma.

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

Study design: Treatment, Randomized, Active Control

Primary outcome: Event-free survival rate

Secondary outcome:

Time to engrafment

CD34 content

Tumor content as measured by reverse transcriptase polymerase chain reaction

Detailed description: 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.

Minimum age: N/A. Maximum age: 30 Years. Gender(s): Both.

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

Comprehensive Cancer Center at University of Alabama at Birmingham, Birmingham, Alabama 35294, United States

Alberta Children's Hospital, Calgary, Alberta T2T 5C7, Canada

Phoenix Children's Hospital, Phoenix, Arizona 85016-7710, United States

Children's & Women's Hospital of British Columbia, Vancouver, British Columbia V6H 3V4, Canada

Children's Hospital and Health Center - San Diego, San Diego, California 92123-4282, United States

Children's Hospital Central California, Madera, California 93638-8762, United States

Children's Hospital Los Angeles, Los Angeles, California 90027, United States

Jonathan Jaques Children's Cancer Center at Miller Children's Hospital, Long Beach, California 90801, United States

Kaiser Permanente Medical Center - Oakland, Sacramento, California 95825, United States

Loma Linda University Cancer Institute at Loma Linda University Medical Center, Loma Linda, California 92354, United States

Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, Los Angeles, California 90048-1865, United States

Southern California Permanente Medical Group, Downey, California 90242-2814, United States

Stanford Cancer Center at Stanford University Medical Center, Stanford, California 94305, United States

UCSF Comprehensive Cancer Center, San Francisco, California 94115, United States

Children's Hospital Cancer Center, Denver, Colorado 80218-1088, United States

Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center, Farmington, Connecticut 06360-2875, United States

Children's National Medical Center, Washington, District of Columbia 20010-2970, United States

All Children's Hospital, St. Petersburg, Florida 33701, United States

Broward General Medical Center Cancer Center, Ft. Lauderdale, Florida 33316, United States

Kaplan Cancer Center at St. Mary's Medical Center, West Palm Beach, Florida 33407, United States

Lee Cancer Care of Lee Memorial Health System, Fort Myers, Florida 33901, United States

Memorial Cancer Institute at Memorial Regional Hospital, Hollywood, Florida 33021, United States

St. Joseph's Cancer Institute at St. Joseph's Hospital, Tampa, Florida 33607, United States

University of Florida Shands Cancer Center, Gainesville, Florida 32610-0232, United States

Children's Memorial Hospital - Chicago, Chicago, Illinois 60614, United States

Southern Illinois University School of Medicine, Springfield, Illinois 62794-9620, United States

University of Illinois at Chicago Cancer Center, Chicago, Illinois 60612-7243, United States

Indiana University Cancer Center, Indianapolis, Indiana 46202-5289, United States

St. Vincent Indianapolis Hospital, Indianapolis, Indiana 46260, United States

Blank Children's Hospital, Des Moines, Iowa 50309, United States

Holden Comprehensive Cancer Center at University of Iowa, Iowa City, Iowa 52242-1083, United States

Kosair Children's Hospital, Louisville, Kentucky 40232, United States

Markey Cancer Center at University of Kentucky Chandler Medical Center, Lexington, Kentucky 40536-0084, United States

CancerCare of Maine at Eastern Maine Medial Center, Bangor, Maine 04401, United States

Alvin and Lois Lapidus Cancer Institute at Sinai Hospital, Baltimore, Maryland 21215, United States

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston, Massachusetts 02115, United States

Breslin Cancer Center at Ingham Regional Medical Center, Lansing, Michigan 48910, United States

C.S. Mott Children's Hospital at University of Michigan, Ann Arbor, Michigan 48109-0238, United States

CCOP - Kalamazoo, Kalamazoo, Michigan 49007-5341, United States

Spectrum Health Cancer Care - Butterworth Campus, Grand Rapids, Michigan 49503-2560, United States

Van Elslander Cancer Center at St. John Hospital and Medical Center, Grosse Pointe Woods, Michigan 48236, United States

Children's Hospital of Minnesota - Minneapolis, Minneapolis, Minnesota 55404, United States

Fairview University Medical Center - University Campus, Minneapolis, Minnesota 55455, United States

Children's Mercy Hospital, Kansas City, Missouri 64108, United States

Siteman Cancer Center at Barnes-Jewish Hospital, St. Louis, Missouri 63110, United States

Children's Hospital of Omaha, Omaha, Nebraska 68114-4113, United States

UNMC Eppley Cancer Center at the University of Nebraska Medical Center, Omaha, Nebraska 68198-3330, United States

Sunrise Hospital and Medical Center, Las Vegas, Nevada 89109-2306, United States

Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756-0002, United States

Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey 07601, United States

Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, United States

Newark Beth Israel Medical Center, Newark, New Jersey 07112, United States

St. Barnabas Medical Center, Livingston, New Jersey 07039, United States

St. Joseph's Hospital and Medical Center, Paterson, New Jersey 07503, United States

University of New Mexico Cancer Research and Treatment Center, Albuquerque, New Mexico 87131-5636, United States

New York Medical College, Valhalla, New York 10595, United States

NYU Cancer Institute at New York University Medical Center, New York, New York 10016, United States

Janeway Children's Health and Rehabilitation Centre, St. John's, Newfoundland and Labrador A1B 3V6, Canada

Blumenthal Cancer Center at Carolinas Medical Center, Charlotte, North Carolina 28232-2861, United States

Duke Comprehensive Cancer Center, Durham, North Carolina 27710, United States

Mission Hospitals - Memorial Campus, Asheville, North Carolina 28801, United States

Presbyterian Cancer Center at Presbyterian Hospital, Charlotte, North Carolina 28233-3549, United States

Children's Medical Center - Dayton, Dayton, Ohio 45404-1815, United States

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, United States

Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio 44195-5217, United States

Columbus Children's Hospital, Columbus, Ohio 43205-2696, United States

Medical College of Ohio Cancer Institute, Toledo, Ohio 43614, United States

Toledo Hospital, Toledo, Ohio 43606, United States

Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada

Children's Hospital of Western Ontario, London, Ontario N6A 4G5, Canada

Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

McMaster Children's Hospital at Hamilton Health Sciences, Hamilton, Ontario L8N 3Z5, Canada

Cancer Institute at Oregon Health and Science University, Portland, Oregon 97239-3098, United States

Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States

Centre Hospitalier Universitaire de Quebec, Ste-Foy, Quebec G1V 4G2, Canada

McGill Cancer Centre at McGill University, Montreal, Quebec H3H 1P3, Canada

Rhode Island Hospital, Providence, Rhode Island 02903, United States

Allan Blair Cancer Centre at Pasqua Hospital, Regina, Saskatchewan S4T 7T1, Canada

Palmetto Health South Carolina Cancer Center, Columbia, South Carolina 29203, United States

Sioux Valley Hospital and University of South Dakota Medical Center, Sioux Falls, South Dakota 57117-5039, United States

East Tennessee Children's Hospital, Knoxville, Tennessee 37916, United States

Children's Hospital of Austin, Austin, Texas 78701, United States

Cook Children's Medical Center - Fort Worth, Fort Worth, Texas 76104-9958, United States

Covenant Children's Hospital, Lubbock, Texas 79410, United States

Texas Tech University Health Sciences Center School of Medicine, Amarillo, Texas 79106, United States

University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7811, United States

Fletcher Allen Health Care - University Health Center Campus, Burlington, Vermont 05405, United States

Carilion Cancer Center of Western Virginia, Roanoke, Virginia 24029, United States

Massey Cancer Center at Virginia Commonwealth University, Richmond, Virginia 23298-0037, United States

Providence Cancer Center at Sacred Heart Medical Center, Spokane, Washington 99220-2555, United States

Edwards Comprehensive Cancer Center at Cabell Huntington Hospital, Huntington, West Virginia 25701, United States

Mary Babb Randolph Cancer Center at West Virginia University Hospitals, Morgantown, West Virginia 26506, United States

Marshfield Clinic - Marshfield Center, Marshfield, Wisconsin 54449, United States

Midwest Children's Cancer Center, Milwaukee, Wisconsin 53226, United States

St. Vincent Hospital Regional Cancer Center, Green Bay, Wisconsin 54307-3508, United States

University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792-6164, United States

Clinical trial summary from the National Cancer Institute's PDQ® database

Related publications:

Cantos MF, Gerstle JT, Irwin MS, Pappo A, Farley S, Cheang T, Kim PC. Surgical challenges associated with intensive treatment protocols for high-risk neuroblastoma. J Pediatr Surg. 2006 May;41(5):960-5.

Kushner BH, Budnick A, Kramer K, Modak S, Cheung NK. Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer. 2006 Jul 15;107(2):417-22.

Starting date: February 2001
Last updated: December 25, 2007