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

This study has suspended participant recruitment.
(Temporarily stopped for assessment.)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT01798004
First received: January 6, 2013
Last updated: September 18, 2014
Last verified: September 2014

January 6, 2013
September 18, 2014
April 2013
October 2014   (final data collection date for primary outcome measure)
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] version [v] 4.0) during the consolidation phase of therapy [ Time Frame: Up to 28 days post-consolidation therapy ] [ Designated as safety issue: Yes ]
A one-sided O'Brien-Fleming group-sequential boundary (truncated at 2.38 standard deviations, so that the study is more conservative within the first 38 patients than in the later part of accrual) with a sample size of 96 will be used to monitor the number of patients who experience at least one unacceptable toxicity within 28 days of completing post-transplant radiotherapy.
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 ] [ Designated as safety issue: Yes ]
The primary study endpoint is the tolerability of the BuMel regimen, which will be quantified as the number of patients who experience one or more unacceptable toxicities (severe SOS (Sinusoidal obstruction syndrome) or Grade 4-5 pulmonary toxicity per CTCv.4.0) during the Consolidation phase of therapy.
Complete list of historical versions of study NCT01798004 on ClinicalTrials.gov Archive Site
  • Incidence of non-hematologic organ toxicity (grade 3 and higher) and all cause mortality graded according to CTC v4.0 [ Time Frame: Up to 180 days ] [ Designated as safety issue: Yes ]
    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.
  • Response rate determined using the International Response Criteria [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • EFS [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • First dose area under the curve (AUC) and average daily AUC for busulfan [ Time Frame: Within 28 days following consolidation ] [ Designated as safety issue: No ]
    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.
  • Percentage of centrally reviewed post-course 4 MIBG scans reporting a Curie score considered to have been determined in "real time" [ Time Frame: Up to week 12 (course 4 of induction therapy) ] [ Designated as safety issue: No ]
  • Percentage of MIBG scans receiving institutionally and centrally reviewed and automated Advanced Assisted Scoring Platform Curie scores within 1 unit of each other [ Time Frame: Up to week 12 (course 4 of induction therapy) ] [ Designated as safety issue: No ]
    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.
  • Proportion of high-risk neuroblastoma patients for whom ALK status can be obtained [ Time Frame: Within 6 weeks of diagnosis ] [ Designated as safety issue: No ]
  • Proportion of high-risk neuroblastoma patients with MYCN non-amplified tumors for whom molecular profiling results can be obtained [ Time Frame: Within 8 weeks of diagnosis ] [ Designated as safety issue: No ]
  • Melphalan pharmacokinetics and the combination of busulfan and melphalan AUC (Optional) [ Time Frame: Within 28 days post-consolidation ] [ Designated as safety issue: No ]
    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.
  • Response Rates [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Will be assessed by determining the response rates for high-risk neuroblastoma patients undergoing Induction therapy followed by Consolidation with BuMel and local radiotherapy. Response will be determined using the International Response Criteria.
  • Event Free Survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Will be assessed by determining the event-free survival rates for high-risk neuroblastoma patients undergoing Induction therapy followed by Consolidation with BuMel and local radiotherapy.
  • Overall Survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Will be assessed by determining the overall survival rates for high-risk neuroblastoma patients undergoing Induction therapy followed by Consolidation with BuMel and local radiotherapy.
  • Incidence of non-hematologic organ toxicity (grade 3 and higher) and all cause mortality graded according to the National Cancer Institute (NCI) CTC v3.0 [ Time Frame: Up to 180 days ] [ Designated as safety issue: Yes ]
    Will be assessed by a descriptive analysis of the relationship between busulfan pharmacokinetics with the occurrence of non-hematologic toxicities. In addition, the 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. Both the first dose AUC and the average daily AUC for busulfan will be required to perform the comparative analyses with non-hematologic toxicity, event-free and overall survival.
  • First dose area under the curve (AUC) and average daily AUC for busulfan [ Time Frame: Within 28 days following Consolidation ] [ Designated as safety issue: No ]
    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.
  • Concordance between central reviewers and institutional reviewers with Curie scoring for consistency. [ Time Frame: Up to week 12 (cycle 4 of induction therapy) ] [ Designated as safety issue: No ]
    Will be assessed by calculating the percentage of MIBG scans receiving institutionally and centrally reviewed Curie scores within 1 unit of each other, at diagnosis and after Cycle 4 of Induction therapy. Up to 138 MIBG scans are expected at diagnosis and up to 124 MIBG scans from the 90% of patients estimated to be MIBG avid are projected post-Cycle 4 of Induction therapy, for a total of up to 262 MIBG scans.
  • Correlate melphalan pharmacokinetics with non-hematologic toxicity measured by average daily area under the curve (AUC) [ Time Frame: Within 28 days following completion of Consolidation therapy ] [ Designated as safety issue: No ]
    Will be assessed by a descriptive analysis of the relationship between melphalan pharmacokinetics and the combination of busulfan and melphalan AUC with the occurrence of non-hematologic toxicities. 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.
  • Feasibility of performing Curie scores in "real time" [ Time Frame: Within 21 days of Cycle 4 ] [ Designated as safety issue: No ]
    Will be assessed by calculating the percentage of centrally reviewed post-Cycle 4 MIBG scans reporting a Curie score which will be considered to have been determined in "real time." The date of scan acquisition is defined as the date of completion of the MIBG scan. The central review process will be deemed acceptable if ≥ 90% of submitted post-Cycle 4 MIBG scans complete the central review process within 21 days of scan acquisition
  • Proportion of high-risk neuroblastoma patients for whom ALK status can be obtained [ Time Frame: Within 6 weeks of diagnosis ] [ Designated as safety issue: No ]
    Will be assessed by calculating the proportion of high-risk neuroblastoma patients for whom ALK status can be obtained within 4-6 weeks of diagnosis.
  • Proportion of high-risk neuroblastoma patients with MYCN non-amplified tumors for whom molecular profiling results can be obtained [ Time Frame: Within 8 weeks of diagnosis ] [ Designated as safety issue: No ]
    Will be assessed by determining the proportion of high-risk neuroblastoma patients with MYCN non-amplified tumors for whom molecular profiling results can be obtained within 6-8 weeks of diagnosis.
Not Provided
Not Provided
 
Busulfan, Melphalan, and Stem Cell Transplant After Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma
Pilot Study Using Myeloablative Busulfan/Melphalan (BuMel) Consolidation Following Induction Chemotherapy for Patients With Newly Diagnosed High-Risk Neuroblastoma

This pilot clinical trial studies busulfan, melphalan, and stem cell transplant after chemotherapy in treating patients with newly diagnosed neuroblastoma. 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.

PRIMARY OBJECTIVES:

I. 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.

SECONDARY OBJECTIVES:

I. 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.

II. 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.

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

IV. 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.

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

VI. 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.

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

VIII. 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. 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, doxorubicin hydrochloride IV over 24 hours on days 1-3 and mesna IV over 15-30 minutes on days 1-2. 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.

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.

Interventional
Not Provided
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Disseminated Neuroblastoma
  • Localized Resectable Neuroblastoma
  • Localized Unresectable Neuroblastoma
  • Regional Neuroblastoma
  • Stage 4S Neuroblastoma
  • 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 Name: 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 Name: 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
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.

Interventions:
  • Drug: cyclophosphamide
  • Drug: topotecan hydrochloride
  • Drug: cisplatin
  • Drug: etoposide
  • Drug: vincristine sulfate
  • Drug: doxorubicin hydrochloride
  • Radiation: external beam radiation therapy
  • Drug: busulfan
  • Drug: melphalan
  • Procedure: autologous hematopoietic stem cell transplantation
  • Procedure: peripheral blood stem cell transplantation
  • Other: pharmacological study
  • Other: laboratory biomarker analysis
  • Biological: filgrastim
  • Drug: mesna
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Suspended
160
Not Provided
October 2014   (final data collection date for primary outcome measure)

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
Both
up to 30 Years
No
Contact information is only displayed when the study is recruiting subjects
United States,   Canada,   Australia,   New Zealand
 
NCT01798004
ANBL12P1, NCI-2012-02211, COG-ANBL12P1, ANBL12P1, ANBL12P1, U10CA098543, U10CA180886
Yes
Children's Oncology Group
Children's Oncology Group
National Cancer Institute (NCI)
Principal Investigator: Mary Meaghan Granger, MD Children's Oncology Group
Children's Oncology Group
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP