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

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ClinicalTrials.gov Identifier: NCT01798004
Recruitment Status : Suspended (CRM: 31684 - CTEP PIO requested)
First Posted : February 25, 2013
Results First Posted : February 9, 2017
Last Update Posted : March 17, 2017
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

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
Disseminated Neuroblastoma Localized Resectable Neuroblastoma Localized Unresectable Neuroblastoma Regional Neuroblastoma Stage 4S Neuroblastoma 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 Applicable

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 150 participants
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
Study Start Date : April 2013
Actual Primary Completion Date : July 2015
Estimated Study Completion Date : October 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma

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 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




Primary Outcome Measures :
  1. The Tolerability of BuMel Regimen [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to 5 years ]
  3. EFS [ Time Frame: Up to 5 years ]
  4. Overall Survival [ Time Frame: Up to 5 years ]
  5. First Dose Area Under the Curve (AUC) and Average Daily AUC for Busulfan [ Time Frame: 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" [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Within 8 weeks of diagnosis ]
  10. Melphalan Pharmacokinetics and the Combination of Busulfan and Melphalan AUC (Optional) [ Time Frame: 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.



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Ages Eligible for Study:   up to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01798004


  Show 121 Study Locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
Principal Investigator: Mary Meaghan Granger, MD Children's Oncology Group

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT01798004     History of Changes
Other Study ID Numbers: ANBL12P1
NCI-2012-02211 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
COG-ANBL12P1
ANBL12P1 ( Other Identifier: Children's Oncology Group )
ANBL12P1 ( Other Identifier: CTEP )
U10CA098543 ( U.S. NIH Grant/Contract )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: February 25, 2013    Key Record Dates
Results First Posted: February 9, 2017
Last Update Posted: March 17, 2017
Last Verified: November 2016

Additional relevant MeSH terms:
Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Liposomal doxorubicin
Etoposide phosphate
Cisplatin
Cyclophosphamide
Doxorubicin
Etoposide
Vincristine
Melphalan
Busulfan
Topotecan
Mesna
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists