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

Neuroblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00004188
• Other study ID #: A3973
• Secondary ID: COG-A3973CCG-A39
• Status: Completed
• Phase: Phase 3
• First received: January 21, 2000
• Last updated: May 16, 2013
• Start date: February 2001

Study information

• Verified date: May 2013
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 495
• Est. primary completion date: October 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 30 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Neuroblastoma

Intervention

Biological:
• filgrastim
Given IV

Drug:
• carboplatin
Given IV
• cisplatin
Given IV
• cyclophosphamide
Given IV
• doxorubicin hydrochloride
Given IV
• etoposide
Given IV
• isotretinoin
Given IV
• melphalan
Given IV
• topotecan hydrochloride
Given IV
• vincristine sulfate
Given IV

Procedure:
• autologous bone marrow transplantation

• bone marrow ablation with stem cell support

• conventional surgery
All patients undergo delayed surgical resection of the residual tumor after course 5 of induction chemotherapy
• peripheral blood stem cell transplantation

Radiation:
• radiation therapy
After completion of consolidation (at least 28 days from stem cell infusion), all patients receive local radiotherapy daily over 7 days

Locations

Country	Name	City	State
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Children's Hospital of Western Ontario	London	Ontario
Canada	McGill Cancer Centre at McGill University	Montreal	Quebec
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Allan Blair Cancer Centre at Pasqua Hospital	Regina	Saskatchewan
Canada	Janeway Children's Health and Rehabilitation Centre	St. John's	Newfoundland and Labrador
Canada	Centre Hospitalier Universitaire de Quebec	Ste-Foy	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	Children's & Women's Hospital of British Columbia	Vancouver	British Columbia
United States	University of New Mexico Cancer Research and Treatment Center	Albuquerque	New Mexico
United States	Texas Tech University Health Sciences Center School of Medicine	Amarillo	Texas
United States	C.S. Mott Children's Hospital at University of Michigan	Ann Arbor	Michigan
United States	Mission Hospitals - Memorial Campus	Asheville	North Carolina
United States	Children's Hospital of Austin	Austin	Texas
United States	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital	Baltimore	Maryland
United States	CancerCare of Maine at Eastern Maine Medial Center	Bangor	Maine
United States	Comprehensive Cancer Center at University of Alabama at Birmingham	Birmingham	Alabama
United States	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts
United States	Fletcher Allen Health Care - University Health Center Campus	Burlington	Vermont
United States	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina
United States	Presbyterian Cancer Center at Presbyterian Hospital	Charlotte	North Carolina
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	University of Illinois at Chicago Cancer Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Palmetto Health South Carolina Cancer Center	Columbia	South Carolina
United States	Columbus Children's Hospital	Columbus	Ohio
United States	Children's Medical Center - Dayton	Dayton	Ohio
United States	Children's Hospital Cancer Center	Denver	Colorado
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Southern California Permanente Medical Group	Downey	California
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center	Farmington	Connecticut
United States	Lee Cancer Care of Lee Memorial Health System	Fort Myers	Florida
United States	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas
United States	Broward General Medical Center Cancer Center	Ft. Lauderdale	Florida
United States	University of Florida Shands Cancer Center	Gainesville	Florida
United States	Spectrum Health Cancer Care - Butterworth Campus	Grand Rapids	Michigan
United States	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin
United States	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan
United States	Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	Memorial Cancer Institute at Memorial Regional Hospital	Hollywood	Florida
United States	Edwards Comprehensive Cancer Center at Cabell Huntington Hospital	Huntington	West Virginia
United States	Indiana University Cancer Center	Indianapolis	Indiana
United States	St. Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa
United States	CCOP - Kalamazoo	Kalamazoo	Michigan
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	East Tennessee Children's Hospital	Knoxville	Tennessee
United States	Breslin Cancer Center at Ingham Regional Medical Center	Lansing	Michigan
United States	Sunrise Hospital and Medical Center	Las Vegas	Nevada
United States	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Markey Cancer Center at University of Kentucky Chandler Medical Center	Lexington	Kentucky
United States	St. Barnabas Medical Center	Livingston	New Jersey
United States	Loma Linda University Cancer Institute at Loma Linda University Medical Center	Loma Linda	California
United States	Jonathan Jaques Children's Cancer Center at Miller Children's Hospital	Long Beach	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center	Los Angeles	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Covenant Children's Hospital	Lubbock	Texas
United States	Children's Hospital Central California	Madera	California
United States	University of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin
United States	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin
United States	Midwest Children's Cancer Center	Milwaukee	Wisconsin
United States	Children's Hospital of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	Fairview University Medical Center - University Campus	Minneapolis	Minnesota
United States	Mary Babb Randolph Cancer Center at West Virginia University Hospitals	Morgantown	West Virginia
United States	Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	NYU Cancer Institute at New York University Medical Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Children's Hospital of Omaha	Omaha	Nebraska
United States	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska
United States	St. Joseph's Hospital and Medical Center	Paterson	New Jersey
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Cancer Institute at Oregon Health and Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Massey Cancer Center at Virginia Commonwealth University	Richmond	Virginia
United States	Carilion Cancer Center of Western Virginia	Roanoke	Virginia
United States	Kaiser Permanente Medical Center - Oakland	Sacramento	California
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Children's Hospital and Health Center - San Diego	San Diego	California
United States	UCSF Comprehensive Cancer Center	San Francisco	California
United States	Sioux Valley Hospital and University of South Dakota Medical Center	Sioux Falls	South Dakota
United States	Providence Cancer Center at Sacred Heart Medical Center	Spokane	Washington
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Siteman Cancer Center at Barnes-Jewish Hospital	St. Louis	Missouri
United States	All Children's Hospital	St. Petersburg	Florida
United States	Stanford Cancer Center at Stanford University Medical Center	Stanford	California
United States	St. Joseph's Cancer Institute at St. Joseph's Hospital	Tampa	Florida
United States	Medical College of Ohio Cancer Institute	Toledo	Ohio
United States	Toledo Hospital	Toledo	Ohio
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Kaplan Cancer Center at St. Mary's Medical Center	West Palm Beach	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (7)

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. — View 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. — View 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):

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. — View 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 Ch — View Citation

Naranjo A, Parisi MT, Shulkin BL, London WB, Matthay KK, Kreissman SG, Yanik GA. Comparison of ¹²³I-metaiodobenzylguanidine (MIBG) and ¹³¹I-MIBG semi-quantitative scores in predicting survival in patients with stage 4 neuroblastoma: a report from the Chil — View 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.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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		Up to day 42	Yes
Secondary	Time to engraftment	Engraftment is defined as three consecutive measurements of ANC > 500.	Up to 6 years	No
Secondary	CD34 content		Up to 6 years	No
Secondary	Tumor content as measured by reverse transcriptase polymerase chain reaction		Up to 6 years	No