Clinical trial NCT00004188: Combination Chemotherapy and Peripheral Stem Cell Transplantation 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neuroblastoma
Keywords: localized resectable neuroblastoma
regional neuroblastoma
disseminated neuroblastoma
stage 4S neuroblastoma
localized unresectable neuroblastoma
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Enrollment: 495
Sex: ALL
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility 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

Primary outcomes:
measure: Event-free survival rate
timeFrame: 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
measure: Rate of occurrence of toxic (non disease-related) deaths where a toxic death will be "counted" if it occurs prior to the initiation of the immunotherapy
timeFrame: Up to day 42
Secondary outcomes:
measure: Time to engraftment
timeFrame: Up to 6 years
measure: CD34 content
timeFrame: Up to 6 years
measure: Tumor content as measured by reverse transcriptase polymerase chain reaction
timeFrame: Up to 6 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Comprehensive Cancer Center at University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Downey
country: United States
facility: Southern California Permanente Medical Group
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Cancer Institute at Loma Linda University Medical Center
state: California
city: Long Beach
country: United States
facility: Jonathan Jaques Children's Cancer Center at Miller Children's Hospital
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
state: California
city: Madera
country: United States
facility: Children's Hospital Central California
state: California
city: Sacramento
country: United States
facility: Kaiser Permanente Medical Center - Oakland
state: California
city: San Diego
country: United States
facility: Children's Hospital and Health Center - San Diego
state: California
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center at Stanford University Medical Center
state: California
city: Denver
country: United States
facility: Children's Hospital Cancer Center
state: Colorado
city: Farmington
country: United States
facility: Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center
state: Connecticut
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Fort Myers
country: United States
facility: Lee Cancer Care of Lee Memorial Health System
state: Florida
city: Ft. Lauderdale
country: United States
facility: Broward General Medical Center Cancer Center
state: Florida
city: Gainesville
country: United States
facility: University of Florida Shands Cancer Center
state: Florida
city: Hollywood
country: United States
facility: Memorial Cancer Institute at Memorial Regional Hospital
state: Florida
city: St. Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Tampa
country: United States
facility: St. Joseph's Cancer Institute at St. Joseph's Hospital
state: Florida
city: West Palm Beach
country: United States
facility: Kaplan Cancer Center at St. Mary's Medical Center
state: Florida
city: Chicago
country: United States
facility: University of Illinois at Chicago Cancer Center
state: Illinois
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University School of Medicine
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: St. Vincent Indianapolis Hospital
state: Indiana
city: Des Moines
country: United States
facility: Blank Children's Hospital
state: Iowa
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center at University of Iowa
state: Iowa
city: Lexington
country: United States
facility: Markey Cancer Center at University of Kentucky Chandler Medical Center
state: Kentucky
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: Bangor
country: United States
facility: CancerCare of Maine at Eastern Maine Medial Center
state: Maine
city: Baltimore
country: United States
facility: Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
state: Maryland
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: C.S. Mott Children's Hospital at University of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health Cancer Care - Butterworth Campus
state: Michigan
city: Grosse Pointe Woods
country: United States
facility: Van Elslander Cancer Center at St. John Hospital and Medical Center
state: Michigan
city: Kalamazoo
country: United States
facility: CCOP - Kalamazoo
state: Michigan
city: Lansing
country: United States
facility: Breslin Cancer Center at Ingham Regional Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospital of Minnesota - Minneapolis
state: Minnesota
city: Minneapolis
country: United States
facility: Fairview University Medical Center - University Campus
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: St. Louis
country: United States
facility: Siteman Cancer Center at Barnes-Jewish Hospital
state: Missouri
city: Omaha
country: United States
facility: Children's Hospital of Omaha
state: Nebraska
city: Omaha
country: United States
facility: UNMC Eppley Cancer Center at the University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: Sunrise Hospital and Medical Center
state: Nevada
city: Lebanon
country: United States
facility: Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Hackensack
country: United States
facility: Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Livingston
country: United States
facility: St. Barnabas Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
state: New Jersey
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: Paterson
country: United States
facility: St. Joseph's Hospital and Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Research and Treatment Center
state: New Mexico
city: New York
country: United States
facility: NYU Cancer Institute at New York University Medical Center
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Asheville
country: United States
facility: Mission Hospitals - Memorial Campus
state: North Carolina
city: Charlotte
country: United States
facility: Blumenthal Cancer Center at Carolinas Medical Center
state: North Carolina
city: Charlotte
country: United States
facility: Presbyterian Cancer Center at Presbyterian Hospital
state: North Carolina
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Columbus
country: United States
facility: Columbus Children's Hospital
state: Ohio
city: Dayton
country: United States
facility: Children's Medical Center - Dayton
state: Ohio
city: Toledo
country: United States
facility: Toledo Hospital
state: Ohio
city: Toledo
country: United States
facility: Medical College of Ohio Cancer Institute
state: Ohio
city: Portland
country: United States
facility: Cancer Institute at Oregon Health and Science University
state: Oregon
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Columbia
country: United States
facility: Palmetto Health South Carolina Cancer Center
state: South Carolina
city: Sioux Falls
country: United States
facility: Sioux Valley Hospital and University of South Dakota Medical Center
state: South Dakota
city: Knoxville
country: United States
facility: East Tennessee Children's Hospital
state: Tennessee
city: Amarillo
country: United States
facility: Texas Tech University Health Sciences Center School of Medicine
state: Texas
city: Austin
country: United States
facility: Children's Hospital of Austin
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center - Fort Worth
state: Texas
city: Lubbock
country: United States
facility: Covenant Children's Hospital
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Burlington
country: United States
facility: Fletcher Allen Health Care - University Health Center Campus
state: Vermont
city: Richmond
country: United States
facility: Massey Cancer Center at Virginia Commonwealth University
state: Virginia
city: Roanoke
country: United States
facility: Carilion Cancer Center of Western Virginia
state: Virginia
city: Spokane
country: United States
facility: Providence Cancer Center at Sacred Heart Medical Center
state: Washington
city: Huntington
country: United States
facility: Edwards Comprehensive Cancer Center at Cabell Huntington Hospital
state: West Virginia
city: Morgantown
country: United States
facility: Mary Babb Randolph Cancer Center at West Virginia University Hospitals
state: West Virginia
city: Green Bay
country: United States
facility: St. Vincent Hospital Regional Cancer Center
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Comprehensive Cancer Center
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Clinic - Marshfield Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Midwest Children's Cancer Center
state: Wisconsin
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Children's & Women's Hospital of British Columbia
state: British Columbia
city: St. John's
country: Canada
facility: Janeway Children's Health and Rehabilitation Centre
state: Newfoundland and Labrador
city: Hamilton
country: Canada
facility: McMaster Children's Hospital at Hamilton Health Sciences
state: Ontario
city: London
country: Canada
facility: Children's Hospital of Western Ontario
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: McGill Cancer Centre at McGill University
state: Quebec
city: Ste-Foy
country: Canada
facility: Centre Hospitalier Universitaire de Quebec
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre at Pasqua Hospital
state: Saskatchewan
Study officials:
affiliation: Duke Cancer Institute
name: Susan G. Kreissman, MD
role: STUDY_CHAIR
References:
citation: Dubois SG, Geier E, Batra V, Yee SW, Neuhaus J, Segal M, Martinez D, Pawel B, Yanik G, Naranjo A, London WB, Kreissman S, Baker D, Attiyeh E, Hogarty MD, Maris JM, Giacomini K, Matthay KK. Evaluation of Norepinephrine Transporter Expression and Metaiodobenzylguanidine Avidity in Neuroblastoma: A Report from the Children's Oncology Group. Int J Mol Imaging. 2012;2012:250834. doi: 10.1155/2012/250834. Epub 2012 Sep 25.
citation: 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. doi: 10.1016/j.jpedsurg.2006.01.059.
citation: 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. doi: 10.1002/cncr.22004.
citation: Landier W, Knight K, Wong FL, Lee J, Thomas O, Kim H, Kreissman SG, Schmidt ML, Chen L, London WB, Gurney JG, Bhatia S. Ototoxicity in children with high-risk neuroblastoma: prevalence, risk factors, and concordance of grading scales--a report from the Children's Oncology Group. J Clin Oncol. 2014 Feb 20;32(6):527-34. doi: 10.1200/JCO.2013.51.2038. Epub 2014 Jan 13.
citation: Naranjo A, Parisi MT, Shulkin BL, London WB, Matthay KK, Kreissman SG, Yanik GA. Comparison of (1)(2)(3)I-metaiodobenzylguanidine (MIBG) and (1)(3)(1)I-MIBG semi-quantitative scores in predicting survival in patients with stage 4 neuroblastoma: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2011 Jul 1;56(7):1041-5. doi: 10.1002/pbc.22991. Epub 2011 Feb 15.
citation: Yanik GA, Parisi MT, Naranjo A, et al.: MIBG scoring as a prognostic indicator in patients with stage IV neuroblastoma: A COG study. [Abstract] J Clin Oncol 28 (Suppl 15): A-9516, 2010.
citation: Kreissman SG, Villablanca JG, Diller L, et al.: Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): a Children's Oncology Group (COG A3973) study. [Abstract] J Clin Oncol 25 (Suppl 18): A-9505, 527s, 2007.
citation: Kreissman SG, Seeger RC, Matthay KK, London WB, Sposto R, Grupp SA, Haas-Kogan DA, Laquaglia MP, Yu AL, Diller L, Buxton A, Park JR, Cohn SL, Maris JM, Reynolds CP, Villablanca JG. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol. 2013 Sep;14(10):999-1008. doi: 10.1016/S1470-2045(13)70309-7. Epub 2013 Jul 25.