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Busulfan, Melphalan, and Stem Cell Transplant After Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma

Sponsor
Children's Oncology Group (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT01798004
Collaborator
National Cancer Institute (NCI) (NIH)
150
Enrollment
121
Locations
1
Arm
1.2
Patients Per Site

Study Details

Study Description

Brief Summary

This pilot clinical trial studies busulfan, melphalan, and stem cell transplant after chemotherapy in treating patients with newly diagnosed neuroblastoma that is likely to come back or spread. Giving chemotherapy to the entire body before a stem cell transplant stops the growth of tumor cells by stopping them from dividing or killing them. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy or radiation therapy is given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

Condition or Disease Intervention/Treatment Phase
N/A

Detailed Description

PRIMARY OBJECTIVES:
  1. To determine if the acute toxicity of an autologous stem cell transplant with a busulfan-melphalan (BuMel) based regimen is tolerable when given as consolidation therapy for high-risk neuroblastoma.
EXPLORATORY OBJECTIVES:

  1. To determine the incidence of non-hematologic organ toxicity (grade 3 and higher) and all cause mortality in patients undergoing autologous stem cell transplant with a BuMel based regimen followed by local radiotherapy for the treatment of high-risk neuroblastoma.

  2. To describe response rates, event-free survival (EFS), and overall survival (OS) for patients undergoing induction therapy followed by consolidation with myeloablative BuMel preparative regimen and local radiotherapy for the treatment of high-risk neuroblastoma.

  3. To correlate busulfan pharmacokinetics with non-hematologic toxicity following a BuMel based autologous transplant regimen and event-free survival and overall survival.

  4. To determine the feasibility of performing Curie scores in "real time," as assessed by central scan committee review of a 123 I-meta-iodobenzylguanidine (MIBG) scan obtained after cycle 4 of induction therapy.

  5. To examine the concordance between central reviewers and institutional reviewers in performing Curie scoring at diagnosis and after cycle 4 of induction therapy.

  6. To determine the feasibility of detecting aberrations in the anaplastic lymphoma kinase (ALK) gene in tumors obtained at the time of diagnosis in patients with high-risk neuroblastoma.

  7. To determine the feasibility of performing molecular profiling of neuroblastoma tumors obtained at the time of diagnosis in patients with high-risk neuroblastoma.

  8. To correlate melphalan pharmacokinetics with non-hematologic toxicity following a BuMel based autologous transplant regimen and event-free survival and overall survival.

OUTLINE:
INDUCTION THERAPY:

COURSES 1-2: Patients receive cyclophosphamide intravenously (IV) over 15-30 minutes, topotecan hydrochloride IV over 30 minutes on days 1-5 and filgrastim subcutaneously (SC) or IV once daily (QD) beginning on day 6 or pegfilgrastim SQ once on day 6. Treatment repeats every 3 weeks for 2 courses.

COURSES 3 AND 5: Patients receive cisplatin IV over 1 hour on days 1-4 and etoposide IV over 1-2 hours on days 1-3 and filgrastim subcutaneously (SC) or IV once daily (QD) beginning on day 6 or pegfilgrastim SQ once on day 6. Treatment repeats every 3 weeks for 2 courses.

COURSE 4: Patients receive cyclophosphamide IV over 1-6 hours on days 1-2, vincristine sulfate IV over 1 minute on days 1-3, doxorubicin hydrochloride IV over 24 hours on days 1-3 and mesna IV over 15-30 minutes on days 1-2 and filgrastim subcutaneously (SC) or IV once daily (QD) beginning on day 6 or pegfilgrastim SQ once on day 6. Treatment repeats every 3 weeks for 1 course.

Treatment continues in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY: Beginning 4-8 weeks following the 5th course of induction therapy, patients receive busulfan IV over 3 hours on days -6 to -3 and melphalan IV on day -1. Patients undergo autologous stem cell transplant (ASCT) on day 0 and filgrastim SC or IV beginning on day 0 until recovery.

Some patients also undergo external beam radiation therapy (EBRT) after induction and consolidation.

After completion of study treatment, patients are followed up every 3 months for 1 year, and then every 6 months for 4 years.

Study Design

Study Type:
Interventional
Actual Enrollment :
150 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Pilot Study Using Myeloablative Busulfan/Melphalan (BuMel) Consolidation Following Induction Chemotherapy for Patients With Newly Diagnosed High-Risk Neuroblastoma
Actual Study Start Date :
Apr 8, 2013
Actual Primary Completion Date :
Jul 28, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (induction therapy, consolidation therapy, ASCT)

INDUCTION THERAPY: COURSES 1-2: Patients receive cyclophosphamide IV over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5. Treatment repeats every 3 weeks for 2 courses. COURSES 3 AND 5: Patients receive cisplatin IV over 1 hour on days 1-4 and etoposide IV over 1-2 hours on days 1-3. Treatment repeats every 3 weeks for 2 courses. COURSE 4: Patients receive cyclophosphamide IV over 1-6 hours on days 1-2, vincristine sulfate IV over 1 minute on days 1-3, and doxorubicin hydrochloride IV over 24 hours on days 1-3. Treatment repeats every 3 weeks for 1 course. Treatment continues in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: Beginning 4-8 weeks following the 5th course of induction therapy, patients receive busulfan IV over 3 hours on days -6 to -3 and melphalan IV on day -1. Patients undergo ASCT on day 0. Some patients also undergo EBRT after induction and consolidation.

Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana

    • Drug: topotecan hydrochloride
    Given IV
    Other Names:
  • hycamptamine
  • Hycamtin
  • SKF S-104864-A
  • TOPO

    • Drug: cisplatin
    Given IV
    Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP

    • Drug: etoposide
    Given IV
    Other Names:
  • EPEG
  • VP-16
  • VP-16-213

    • Drug: vincristine sulfate
    Given IV
    Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS

    • Drug: doxorubicin hydrochloride
    Given IV
    Other Names:
  • ADM
  • ADR
  • Adria

    • Radiation: external beam radiation therapy
    Undergo EBRT
    Other Names:
  • EBRT

    • Drug: busulfan
    Given IV
    Other Names:
  • BSF
  • BU
  • Misulfan
  • Mitosan
  • Myeloleukon

    • Drug: melphalan
    Given IV
    Other Names:
  • Alkeran
  • CB-3025
  • L-PAM
  • L-phenylalanine mustard
  • L-Sarcolysin

    • Procedure: autologous hematopoietic stem cell transplantation
    Undergo autologous peripheral blood stem cell transplant

    Procedure: peripheral blood stem cell transplantation
    Undergo autologous peripheral blood stem cell transplant
    Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell

    • Other: pharmacological study
    Correlative studies
    Other Names:
  • pharmacological studies

    • Other: laboratory biomarker analysis
    Optional correlative studies

    Biological: filgrastim
    Given SC or IV
    Other Names:
  • G-CSF
  • Neupogen

    • Drug: mesna
    Given IV
    Other Names:
  • mercaptoethane sulfonate
  • Mesnex
  • MSA

    		•

    Outcome Measures

    Primary Outcome Measures

    1. The Tolerability of BuMel Regimen [Up to 28 days post-consolidation therapy, up to 1 year]

      Number of patients who experience one or more unacceptable toxicities (severe sinusoidal obstruction syndrome [SOS] or Grade 4-5 pulmonary toxicity per Common Toxicity Criteria [CTC] v.4.0) during the Consolidation phase of therapy.

    Other Outcome Measures

    1. Incidence of Non-hematologic Organ Toxicity (Grade 3 and Higher) and All Cause Mortality Graded According to CTC v4.0 [Up to 180 days]

      Assessed by a descriptive analysis of the incidence of grade 3-5 non-hematologic toxicities (CTC v4.0) and all-cause mortality during consolidation therapy. In addition, a descriptive analysis of "late" onset grade 4-5 pulmonary and hepatic complications that occur within 180 days of the start of consolidation therapy will be examined, regardless if the patient has proceeded to other therapy (including chimeric antibody) during that 180 day period.

    2. Response Rate Determined Using the International Response Criteria [Up to 5 years]

    3. EFS [Up to 5 years]

    4. Overall Survival [Up to 5 years]

    5. First Dose Area Under the Curve (AUC) and Average Daily AUC for Busulfan [Within 28 days following consolidation]

      Relationship with occurrence of non-hematologic toxicities assessed by a descriptive analysis. Association between busulfan exposure levels as measured by the area under the curve (AUC) and event-free survival and overall survival will be examined using Cox proportional hazards models.

    6. Percentage of Centrally Reviewed Post-course 4 MIBG Scans Reporting a Curie Score Considered to Have Been Determined in "Real Time" [Up to week 12 (course 4 of induction therapy)]

    7. Percentage of MIBG Scans Receiving Institutionally and Centrally Reviewed and Automated Advanced Assisted Scoring Platform Curie Scores Within 1 Unit of Each Other [Up to week 12 (course 4 of induction therapy)]

      Cohen's kappa will be calculated to evaluate the concordance in Curie scores between each of the scoring methods at each time point. Up to 160 MIBG scans are expected at diagnosis and up to 144 MIBG scans from the 90% of patients estimated to be MIBG avid are projected post-course 4 of induction therapy, for a total of up to 304 MIBG scans.

    8. Proportion of High-risk Neuroblastoma Patients for Whom ALK Status Can be Obtained [Within 6 weeks of diagnosis]

    9. Proportion of High-risk Neuroblastoma Patients With MYCN Non-amplified Tumors for Whom Molecular Profiling Results Can be Obtained [Within 8 weeks of diagnosis]

    10. Melphalan Pharmacokinetics and the Combination of Busulfan and Melphalan AUC (Optional) [Within 28 days post-consolidation]

      A descriptive analysis of the relationship between melphalan pharmacokinetics and the combination of busulfan and melphalan AUC with the occurrence of non-hematologic toxicities within 28 days following completion of consolidation will be assessed. In addition, the association between melphalan exposure levels as measured by the AUC and event-free survival and overall survival will be examined using Cox proportional hazards models.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 30 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Patients must have a diagnosis of neuroblastoma (International Classification of Diseases for Oncology [ICD-O] morphology 9500/3) or ganglioneuroblastoma (nodular or intermixed) verified by histology or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites; patients with the following disease stages at diagnosis are eligible, if they meet the other specified criteria

    • Patients with newly diagnosed neuroblastoma with International Neuroblastoma Staging

    System (INSS) stage 4 are eligible with the following:

    • V-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or

    • Age > 18 months (> 547 days) regardless of biologic features or

    • Age 12-18 months (365-547 days) with any of the following 3 unfavorable biologic features (MYCN amplification, unfavorable pathology and/or deoxyribonucleic acid [DNA] index = 1) or any biologic feature that is indeterminate/unsatisfactory/unknown

    • Patients with newly diagnosed neuroblastoma with INSS stage 3 are eligible with the following:

    • MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or

    • Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status

    • Patients with newly diagnosed neuroblastoma with INSS stage 2A/2B with MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features

    • Patients with newly diagnosed neuroblastoma with INSS stage 4S with MYCN amplification (> 4-fold increase in MYCN expression signals as compared to reference signals), regardless of additional biologic features

    • Patients >= 365 days initially diagnosed with neuroblastoma INSS stage 1, 2, 4S who progressed to a stage 4 without interval chemotherapy; these patients must have been enrolled on ANBL00B1; study enrollment on ANBL12P1 must occur within 4 weeks of progression to stage 4 for INSS stage 1, 2, 4S

    • Patients must not have had prior systemic therapy except for localized emergency radiation to sites of life-threatening or function-threatening disease and/or no more than 1 cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (as per P9641, A3961, ANBL0531, or similar) prior to determination of MYCN amplification status and histology

    • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

    • Age 1 month to < 6 months: 0.4 mg/dL

    • Age 6 months to < 1 year: 0.5 mg/dL

    • Age 1 to < 2 years: 0.6 mg/dL

    • Age 2 to < 6 years: 0.8 mg/dL

    • Age 6 to < 10 years: 1 mg/dL

    • Age 10 to < 13 years: 1.2 mg/dL

    • Age 13 to < 16 years: 1.5 mg/dL (males), 1.4 mg/dL (females)

    • Age >= 16 years: 1.7 mg/dL (males), 1.4 mg/dL (females)

    • Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and

    • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x ULN for age

    • Shortening fraction of >= 27% by echocardiogram, or

    • Ejection fraction of >= 50% by radionuclide evaluation

    • No known contraindication to peripheral blood stem cell (PBSC) collection; examples of contraindications might be a weight or size less than that determined to be feasible at the collecting institution, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure

    • All patients and/or their parents or legal guardians must sign a written informed consent

    • All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

    Exclusion Criteria:

    • Patients that are 12-18 months of age with INSS stage 4 and all 3 favorable biologic features (ie, nonamplified MYCN, favorable pathology, and DNA index > 1) are not eligible

    • Female patients who are pregnant are ineligible

    • Lactating females are not eligible unless they have agreed not to breastfeed their infants

    • Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained

    • Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital of Alabama Birmingham Alabama United States 35233
    2 Southern California Permanente Medical Group Downey California United States 90242
    3 City of Hope Duarte California United States 91010
    4 Loma Linda University Medical Center Loma Linda California United States 92354
    5 Children's Hospital Los Angeles Los Angeles California United States 90027
    6 Children's Hospital and Research Center at Oakland Oakland California United States 94609-1809
    7 Kaiser Permanente-Oakland Oakland California United States 94611
    8 Childrens Hospital of Orange County Orange California United States 92868-3874
    9 Lucile Packard Children's Hospital Stanford University Palo Alto California United States 94304
    10 University of California at Davis Cancer Center Sacramento California United States 95817
    11 Rady Children's Hospital - San Diego San Diego California United States 92123
    12 University of California San Francisco Medical Center-Parnassus San Francisco California United States 94143
    13 Children's Hospital Colorado Aurora Colorado United States 80045
    14 Connecticut Children's Medical Center Hartford Connecticut United States 06106
    15 Alfred I duPont Hospital for Children Wilmington Delaware United States 19803
    16 Children's National Medical Center Washington District of Columbia United States 20010
    17 Lombardi Comprehensive Cancer Center at Georgetown University Washington District of Columbia United States 20057
    18 Golisano Children's Hospital of Southwest Florida Fort Myers Florida United States 33908
    19 University of Florida Gainesville Florida United States 32610
    20 Memorial Healthcare System - Joe DiMaggio Children's Hospital Hollywood Florida United States 33021
    21 Nemours Children's Clinic-Jacksonville South Jacksonville Florida United States 32207
    22 University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida United States 33136
    23 Baptist Hospital of Miami Miami Florida United States 33176
    24 Florida Hospital Orlando Orlando Florida United States 32803
    25 Nemours Children's Hospital Orlando Florida United States 32827
    26 Nemours Children's Clinic - Pensacola Pensacola Florida United States 32504
    27 All Children's Hospital Saint Petersburg Florida United States 33701
    28 Saint Joseph Children's Hospital of Tampa Tampa Florida United States 33607
    29 Children's Healthcare of Atlanta - Egleston Atlanta Georgia United States 30322
    30 Georgia Regents University Medical Center Augusta Georgia United States 30912
    31 Memorial University Medical Center Savannah Georgia United States 31404
    32 Lurie Children's Hospital-Chicago Chicago Illinois United States 60611
    33 University of Illinois Chicago Illinois United States 60612
    34 University of Chicago Chicago Illinois United States 60637
    35 Loyola University Medical Center Maywood Illinois United States 60153
    36 Saint Jude Midwest Affiliate Peoria Illinois United States 61602
    37 Southern Illinois University Springfield Illinois United States 62702
    38 Riley Hospital for Children Indianapolis Indiana United States 46202
    39 Saint Vincent Hospital and Health Services Indianapolis Indiana United States 46260
    40 Blank Children's Hospital Des Moines Iowa United States 50309
    41 University of Kentucky Lexington Kentucky United States 40536
    42 Kosair Children's Hospital Louisville Kentucky United States 40202
    43 Children's Hospital New Orleans New Orleans Louisiana United States 70118
    44 Maine Children's Cancer Program Scarborough Maine United States 04074
    45 Sinai Hospital of Baltimore Baltimore Maryland United States 21215
    46 Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center Baltimore Maryland United States 21287
    47 Walter Reed National Military Medical Center Bethesda Maryland United States 20889-5600
    48 Floating Hospital for Children at Tufts Medical Center Boston Massachusetts United States 02111
    49 Massachusetts General Hospital Cancer Center Boston Massachusetts United States 02114
    50 Dana-Farber Cancer Institute Boston Massachusetts United States 02115
    51 C S Mott Children's Hospital Ann Arbor Michigan United States 48109
    52 Wayne State University/Karmanos Cancer Institute Detroit Michigan United States 48201
    53 Bronson Methodist Hospital Kalamazoo Michigan United States 49007
    54 Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis Minnesota United States 55404
    55 University of Minnesota Medical Center-Fairview Minneapolis Minnesota United States 55455
    56 Mayo Clinic Rochester Minnesota United States 55905
    57 University of Mississippi Medical Center Jackson Mississippi United States 39216
    58 Columbia Regional Columbia Missouri United States 65201
    59 The Childrens Mercy Hospital Kansas City Missouri United States 64108
    60 Washington University School of Medicine Saint Louis Missouri United States 63110
    61 Saint John's Mercy Medical Center Saint Louis Missouri United States 63141
    62 Children's Hospital and Medical Center of Omaha Omaha Nebraska United States 68114
    63 University of Nebraska Medical Center Omaha Nebraska United States 68198
    64 Nevada Cancer Research Foundation CCOP Las Vegas Nevada United States 89106
    65 Children's Specialty Center of Nevada II Las Vegas Nevada United States 89109
    66 Summerlin Hospital Medical Center Las Vegas Nevada United States 89144
    67 Dartmouth Hitchcock Medical Center Lebanon New Hampshire United States 03756
    68 Hackensack University Medical Center Hackensack New Jersey United States 07601
    69 Saint Barnabas Medical Center Livingston New Jersey United States 07039
    70 Morristown Memorial Hospital Morristown New Jersey United States 07962
    71 UMDNJ - Robert Wood Johnson University Hospital New Brunswick New Jersey United States 08903
    72 Newark Beth Israel Medical Center Newark New Jersey United States 07112
    73 Saint Joseph's Regional Medical Center Paterson New Jersey United States 07503
    74 University of New Mexico Albuquerque New Mexico United States 87106
    75 Montefiore Medical Center - Moses Campus Bronx New York United States 10467-2490
    76 Winthrop University Hospital Mineola New York United States 11501
    77 The Steven and Alexandra Cohen Children's Medical Center of New York New Hyde Park New York United States 11040
    78 Columbia University Medical Center New York New York United States 10032
    79 University of Rochester Rochester New York United States 14642
    80 State University of New York Upstate Medical University Syracuse New York United States 13210
    81 Mission Hospital-Memorial Campus Asheville North Carolina United States 28801
    82 University of North Carolina Chapel Hill North Carolina United States 27599
    83 Duke University Medical Center Durham North Carolina United States 27710
    84 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229
    85 Rainbow Babies and Childrens Hospital Cleveland Ohio United States 44106
    86 Cleveland Clinic Foundation Cleveland Ohio United States 44195
    87 Nationwide Children's Hospital Columbus Ohio United States 43205
    88 Dayton Children's Hospital Dayton Ohio United States 45404
    89 The Toledo Hospital/Toledo Children's Hospital Toledo Ohio United States 43606
    90 Mercy Children's Hospital Toledo Ohio United States 43608
    91 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    92 Lehigh Valley Hospital - Muhlenberg Bethlehem Pennsylvania United States 18017
    93 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    94 Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania United States 15224
    95 Medical University of South Carolina Charleston South Carolina United States 29425
    96 Palmetto Health Richland Columbia South Carolina United States 29203
    97 BI-LO Charities Children's Cancer Center Greenville South Carolina United States 29605
    98 T C Thompson Children's Hospital Chattanooga Tennessee United States 37403
    99 East Tennessee Childrens Hospital Knoxville Tennessee United States 37916
    100 Vanderbilt-Ingram Cancer Center Nashville Tennessee United States 37232
    101 University of Texas Southwestern Medical Center Dallas Texas United States 75390
    102 Cook Children's Medical Center Fort Worth Texas United States 76104
    103 Baylor College of Medicine Houston Texas United States 77030
    104 Methodist Children's Hospital of South Texas San Antonio Texas United States 78229
    105 University of Texas Health Science Center at San Antonio San Antonio Texas United States 78229
    106 Naval Medical Center - Portsmouth Portsmouth Virginia United States 23708-2197
    107 Virginia Commonwealth University Richmond Virginia United States 23298
    108 Seattle Children's Hospital Seattle Washington United States 98105
    109 Providence Sacred Heart Medical Center and Children's Hospital Spokane Washington United States 99204
    110 University of Wisconsin Hospital and Clinics Madison Wisconsin United States 53792
    111 Marshfield Clinic Marshfield Wisconsin United States 54449
    112 Princess Margaret Hospital for Children Perth Western Australia Australia 6008
    113 British Columbia Children's Hospital Vancouver British Columbia Canada V6H 3V4
    114 CancerCare Manitoba Winnipeg Manitoba Canada R3E 0V9
    115 IWK Health Centre Halifax Nova Scotia Canada B3J 3G9
    116 McMaster Children's Hospital at Hamilton Health Sciences Hamilton Ontario Canada L8N 3Z5
    117 Hospital for Sick Children Toronto Ontario Canada M5G 1X8
    118 The Montreal Children's Hospital of the MUHC Montreal Quebec Canada H3H 1P3
    119 Centre Hospitalier Universitaire Sainte-Justine Montreal Quebec Canada H3T 1C5
    120 Centre Hospitalier Universitaire de Quebec Ste-Foy Quebec Canada G1V 4G2
    121 Starship Children's Hospital Grafton Auckland New Zealand 1145

    Sponsors and Collaborators

    • Children's Oncology Group
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Mary Meaghan Granger, MD, Children's Oncology Group

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Children's Oncology Group
    ClinicalTrials.gov Identifier:
    NCT01798004
    Other Study ID Numbers:
    • ANBL12P1
    • NCI-2012-02211
    • COG-ANBL12P1
    • ANBL12P1
    • ANBL12P1
    • U10CA098543
    • U10CA180886
    First Posted:
    Feb 25, 2013
    Last Update Posted:
    Mar 7, 2022
    Last Verified:
    Mar 1, 2022
    Additional relevant MeSH terms:
    Neuroblastoma
    Cyclophosphamide
    Melphalan
    Busulfan
    Doxorubicin
    Liposomal doxorubicin
    Etoposide
    Vincristine
    Etoposide phosphate
    Topotecan
    Mesna

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title All Patients
    Arm/Group Description Induction with multi-agent chemotherapy followed by Consolidation with BuMel chemotherapy + ASCT + XRT
    Period Title: Overall Study
    STARTED 150
    COMPLETED 63
    NOT COMPLETED 87

    Baseline Characteristics

    Arm/Group Title All Patients
    Arm/Group Description Induction with multi-agent chemotherapy followed by Consolidation with BuMel chemotherapy + ASCT + XRT
    Overall Participants 150
    Age (Count of Participants)
    <=18 years
    149
    99.3%
    Between 18 and 65 years
    1
    0.7%
    >=65 years
    0
    0%
    Age (Years) [Median (Full Range) ]
    Median (Full Range) [Years]
    3.1
    Sex: Female, Male (Count of Participants)
    Female
    60
    40%
    Male
    90
    60%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    19
    12.7%
    Not Hispanic or Latino
    129
    86%
    Unknown or Not Reported
    2
    1.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    11
    7.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    21
    14%
    White
    107
    71.3%
    More than one race
    0
    0%
    Unknown or Not Reported
    11
    7.3%
    Region of Enrollment (participants) [Number]
    New Zealand
    1
    0.7%
    Canada
    14
    9.3%
    United States
    132
    88%
    Australia
    3
    2%

    Outcome Measures

    1. Primary Outcome
    Title The Tolerability of BuMel Regimen
    Description Number of patients who experience one or more unacceptable toxicities (severe sinusoidal obstruction syndrome [SOS] or Grade 4-5 pulmonary toxicity per Common Toxicity Criteria [CTC] v.4.0) during the Consolidation phase of therapy.
    Time Frame Up to 28 days post-consolidation therapy, up to 1 year

    Outcome Measure Data

    Analysis Population Description
    All eligible and evaluable patients who received at least one dose of either busulfan or melphalan.
    Arm/Group Title All Patients
    Arm/Group Description Induction with multi-agent chemotherapy followed by Consolidation with BuMel Chemotherapy+ASCT+XRT
    Measure Participants 101
    Number [participants]
    9
    6%
    2. Other Pre-specified Outcome
    Title Incidence of Non-hematologic Organ Toxicity (Grade 3 and Higher) and All Cause Mortality Graded According to CTC v4.0
    Description Assessed by a descriptive analysis of the incidence of grade 3-5 non-hematologic toxicities (CTC v4.0) and all-cause mortality during consolidation therapy. In addition, a descriptive analysis of "late" onset grade 4-5 pulmonary and hepatic complications that occur within 180 days of the start of consolidation therapy will be examined, regardless if the patient has proceeded to other therapy (including chimeric antibody) during that 180 day period.
    Time Frame Up to 180 days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    3. Other Pre-specified Outcome
    Title Response Rate Determined Using the International Response Criteria
    Description
    Time Frame Up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    4. Other Pre-specified Outcome
    Title EFS
    Description
    Time Frame Up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    5. Other Pre-specified Outcome
    Title Overall Survival
    Description
    Time Frame Up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    6. Other Pre-specified Outcome
    Title First Dose Area Under the Curve (AUC) and Average Daily AUC for Busulfan
    Description Relationship with occurrence of non-hematologic toxicities assessed by a descriptive analysis. Association between busulfan exposure levels as measured by the area under the curve (AUC) and event-free survival and overall survival will be examined using Cox proportional hazards models.
    Time Frame Within 28 days following consolidation

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    7. Other Pre-specified Outcome
    Title Percentage of Centrally Reviewed Post-course 4 MIBG Scans Reporting a Curie Score Considered to Have Been Determined in "Real Time"
    Description
    Time Frame Up to week 12 (course 4 of induction therapy)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Other Pre-specified Outcome
    Title Percentage of MIBG Scans Receiving Institutionally and Centrally Reviewed and Automated Advanced Assisted Scoring Platform Curie Scores Within 1 Unit of Each Other
    Description Cohen's kappa will be calculated to evaluate the concordance in Curie scores between each of the scoring methods at each time point. Up to 160 MIBG scans are expected at diagnosis and up to 144 MIBG scans from the 90% of patients estimated to be MIBG avid are projected post-course 4 of induction therapy, for a total of up to 304 MIBG scans.
    Time Frame Up to week 12 (course 4 of induction therapy)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    9. Other Pre-specified Outcome
    Title Proportion of High-risk Neuroblastoma Patients for Whom ALK Status Can be Obtained
    Description
    Time Frame Within 6 weeks of diagnosis

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Other Pre-specified Outcome
    Title Proportion of High-risk Neuroblastoma Patients With MYCN Non-amplified Tumors for Whom Molecular Profiling Results Can be Obtained
    Description
    Time Frame Within 8 weeks of diagnosis

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    11. Other Pre-specified Outcome
    Title Melphalan Pharmacokinetics and the Combination of Busulfan and Melphalan AUC (Optional)
    Description A descriptive analysis of the relationship between melphalan pharmacokinetics and the combination of busulfan and melphalan AUC with the occurrence of non-hematologic toxicities within 28 days following completion of consolidation will be assessed. In addition, the association between melphalan exposure levels as measured by the AUC and event-free survival and overall survival will be examined using Cox proportional hazards models.
    Time Frame Within 28 days post-consolidation

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame Four ineligible patients were excluded from the Adverse Event tables, so even though 150 patients enrolled on the study and are summarized in the Participant Flow template, only 146 were at risk for adverse events.
    Adverse Event Reporting Description
    Arm/Group Title All Patients
    Arm/Group Description Induction with multi-agent chemotherapy followed by Consolidation with BuMel chemotherapy + ASCT + XRT
    All Cause Mortality
    All Patients
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    All Patients
    Affected / at Risk (%) # Events
    Total 10/146 (6.8%)
    Gastrointestinal disorders
    Ascites 1/146 (0.7%) 1
    General disorders
    Death NOS 2/146 (1.4%) 2
    Multi-organ failure 1/146 (0.7%) 1
    Hepatobiliary disorders
    Hepatobiliary disorders - Other, specify 1/146 (0.7%) 1
    Infections and infestations
    Lung infection 2/146 (1.4%) 2
    Sepsis 1/146 (0.7%) 1
    Upper respiratory infection 1/146 (0.7%) 1
    Investigations
    Aspartate aminotransferase increased 1/146 (0.7%) 1
    Blood bilirubin increased 1/146 (0.7%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify 2/146 (1.4%) 2
    Respiratory, thoracic and mediastinal disorders
    Atelectasis 1/146 (0.7%) 1
    Bronchopulmonary hemorrhage 1/146 (0.7%) 1
    Dyspnea 2/146 (1.4%) 2
    Hypoxia 2/146 (1.4%) 2
    Pleural effusion 1/146 (0.7%) 1
    Pulmonary edema 1/146 (0.7%) 1
    Respiratory failure 2/146 (1.4%) 2
    Other (Not Including Serious) Adverse Events
    All Patients
    Affected / at Risk (%) # Events
    Total 82/146 (56.2%)
    Blood and lymphatic system disorders
    Anemia 1/146 (0.7%) 1
    Febrile neutropenia 30/146 (20.5%) 33
    Cardiac disorders
    Asystole 1/146 (0.7%) 1
    Cardiac arrest 1/146 (0.7%) 1
    Sinus bradycardia 1/146 (0.7%) 1
    Sinus tachycardia 2/146 (1.4%) 2
    Ear and labyrinth disorders
    Hearing impaired 5/146 (3.4%) 6
    Gastrointestinal disorders
    Abdominal distension 2/146 (1.4%) 2
    Abdominal pain 3/146 (2.1%) 3
    Anal pain 1/146 (0.7%) 1
    Ascites 4/146 (2.7%) 5
    Colitis 1/146 (0.7%) 1
    Diarrhea 5/146 (3.4%) 5
    Enterocolitis 2/146 (1.4%) 2
    Gastrointestinal disorders - Other, specify 2/146 (1.4%) 2
    Lower gastrointestinal hemorrhage 1/146 (0.7%) 2
    Mucositis oral 46/146 (31.5%) 46
    Nausea 8/146 (5.5%) 9
    Vomiting 7/146 (4.8%) 7
    General disorders
    Fever 2/146 (1.4%) 2
    Multi-organ failure 1/146 (0.7%) 1
    Pain 4/146 (2.7%) 4
    Hepatobiliary disorders
    Hepatic pain 1/146 (0.7%) 2
    Hepatobiliary disorders - Other, specify 1/146 (0.7%) 1
    Portal hypertension 2/146 (1.4%) 2
    Immune system disorders
    Anaphylaxis 1/146 (0.7%) 1
    Autoimmune disorder 1/146 (0.7%) 1
    Infections and infestations
    Catheter related infection 4/146 (2.7%) 6
    Infections and infestations - Other, specify 11/146 (7.5%) 13
    Lung infection 1/146 (0.7%) 1
    Peritoneal infection 1/146 (0.7%) 1
    Sepsis 4/146 (2.7%) 5
    Tracheitis 1/146 (0.7%) 1
    Injury, poisoning and procedural complications
    Intraoperative arterial injury 1/146 (0.7%) 1
    Intraoperative hemorrhage 4/146 (2.7%) 4
    Intraoperative venous injury 1/146 (0.7%) 1
    Investigations
    Alanine aminotransferase increased 7/146 (4.8%) 8
    Aspartate aminotransferase increased 9/146 (6.2%) 10
    Blood bilirubin increased 13/146 (8.9%) 15
    Electrocardiogram QT corrected interval prolonged 1/146 (0.7%) 1
    GGT increased 1/146 (0.7%) 1
    Investigations - Other, specify 1/146 (0.7%) 1
    Neutrophil count decreased 4/146 (2.7%) 5
    Platelet count decreased 2/146 (1.4%) 2
    Weight gain 6/146 (4.1%) 7
    White blood cell decreased 2/146 (1.4%) 2
    Metabolism and nutrition disorders
    Acidosis 1/146 (0.7%) 1
    Anorexia 28/146 (19.2%) 34
    Dehydration 1/146 (0.7%) 1
    Hyperglycemia 8/146 (5.5%) 8
    Hyperkalemia 2/146 (1.4%) 2
    Hypertriglyceridemia 1/146 (0.7%) 1
    Hypoalbuminemia 1/146 (0.7%) 1
    Hypocalcemia 5/146 (3.4%) 5
    Hypoglycemia 1/146 (0.7%) 1
    Hypokalemia 27/146 (18.5%) 35
    Hyponatremia 5/146 (3.4%) 5
    Hypophosphatemia 5/146 (3.4%) 5
    Nervous system disorders
    Seizure 1/146 (0.7%) 1
    Vasovagal reaction 1/146 (0.7%) 1
    Psychiatric disorders
    Anxiety 1/146 (0.7%) 1
    Renal and urinary disorders
    Acute kidney injury 1/146 (0.7%) 1
    Respiratory, thoracic and mediastinal disorders
    Adult respiratory distress syndrome 1/146 (0.7%) 1
    Apnea 1/146 (0.7%) 1
    Dyspnea 1/146 (0.7%) 1
    Epistaxis 3/146 (2.1%) 3
    Hypoxia 7/146 (4.8%) 8
    Pleural effusion 2/146 (1.4%) 3
    Pneumothorax 2/146 (1.4%) 2
    Pulmonary edema 1/146 (0.7%) 1
    Respiratory failure 3/146 (2.1%) 3
    Respiratory, thoracic and mediastinal disorders - Other, specify 1/146 (0.7%) 1
    Sore throat 1/146 (0.7%) 1
    Vascular disorders
    Capillary leak syndrome 1/146 (0.7%) 1
    Hypertension 2/146 (1.4%) 2
    Hypotension 3/146 (2.1%) 4
    Thromboembolic event 1/146 (0.7%) 1
    Vascular disorders - Other, specify 1/146 (0.7%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Must obtain prior Sponsor approval.

    Results Point of Contact

    Name/Title Results Reporting Coordinator
    Organization Children's Oncology Group
    Phone 626-447-0064
    Email resultsreportingcoordinator@childrensoncologygroup.org
    Responsible Party:
    Children's Oncology Group
    ClinicalTrials.gov Identifier:
    NCT01798004
    Other Study ID Numbers:
    • ANBL12P1
    • NCI-2012-02211
    • COG-ANBL12P1
    • ANBL12P1
    • ANBL12P1
    • U10CA098543
    • U10CA180886
    First Posted:
    Feb 25, 2013
    Last Update Posted:
    Mar 7, 2022
    Last Verified:
    Mar 1, 2022