Neoplasms

All Conditions

Rare Diseases

Neuroblastoma

Ganglioneuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Dermatologic Agents

Anti-Infective Agents

Amino Acids

Etoposide

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Topotecan

Vincristine

Melphalan

Cisplatin

Lenograstim

Etoposide phosphate

Podophyllotoxin

Busulfan

Mechlorethamine

Nitrogen Mustard Compounds

Mesna

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Adjuvants, Immunologic

Tubulin Modulators

Antimitotic Agents

Topoisomerase I Inhibitors

Protective Agents

Keratolytic Agents

Phenylalanine

Alanine

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.

Undergo autologous peripheral blood stem cell transplant

Autologous Hematopoietic Stem Cell Transplantation

Doxorubicin Hydrochloride

External Beam Radiation Therapy

Filgrastim

Laboratory Biomarker Analysis

Peripheral Blood Stem Cell Transplantation

Pharmacological Study

Topotecan Hydrochloride

Vincristine Sulfate

Mary Meaghan P Granger

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.

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.

EXPLORATORY 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.

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

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.

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.

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.

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.

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.

National Cancer Institute (NCI)

Children's Oncology Group

Induction with multi-agent chemotherapy followed by Consolidation with BuMel chemotherapy + ASCT + XRT

All Patients

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

New Zealand

Canada

United States

Australia

Region of Enrollment

Results Reporting Coordinator

Induction with multi-agent chemotherapy followed by Consolidation with BuMel Chemotherapy+ASCT+XRT

All eligible and evaluable patients who received at least one dose of either busulfan or melphalan.

The Tolerability of BuMel Regimen

Incidence of Non-hematologic Organ Toxicity (Grade 3 and Higher) and All Cause Mortality Graded According to CTC v4.0

Response Rate Determined Using the International Response Criteria

Overall Survival

First Dose Area Under the Curve (AUC) and Average Daily AUC for Busulfan

Percentage of Centrally Reviewed Post-course 4 MIBG Scans Reporting a Curie Score Considered to Have Been Determined in "Real Time"

Percentage of MIBG Scans Receiving Institutionally and Centrally Reviewed and Automated Advanced Assisted Scoring Platform Curie Scores Within 1 Unit of Each Other

Proportion of High-risk Neuroblastoma Patients for Whom ALK Status Can be Obtained

Proportion of High-risk Neuroblastoma Patients With MYCN Non-amplified Tumors for Whom Molecular Profiling Results Can be Obtained

Melphalan Pharmacokinetics and the Combination of Busulfan and Melphalan AUC (Optional)

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Busulfan, Melphalan, and Stem Cell Transplant After Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma	NCT01798004	Ganglioneurobla... Stage 1 Neurobl... Stage 2 Neurobl... Stage 2A Neurob... Stage 2B Neurob... Stage 3 Neurobl... Stage 4 Neurobl... Stage 4S Neurob...	Autologous Hema... Busulfan Cisplatin Cyclophosphamid... Doxorubicin Hyd... Etoposide External Beam R... Filgrastim Laboratory Biom... Melphalan Mesna Peripheral Bloo... Pharmacological... Topotecan Hydro... Vincristine Sul...	- 30 Years	Children's Oncology Group
Busulfan, Melphalan, and Stem Cell Transplant After Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma	NCT01798004	Ganglioneurobla... Stage 1 Neurobl... Stage 2 Neurobl... Stage 2A Neurob... Stage 2B Neurob... Stage 3 Neurobl... Stage 4 Neurobl... Stage 4S Neurob...	Autologous Hema... Busulfan Cisplatin Cyclophosphamid... Doxorubicin Hyd... Etoposide External Beam R... Filgrastim Laboratory Biom... Melphalan Mesna Peripheral Bloo... Pharmacological... Topotecan Hydro... Vincristine Sul...	- 30 Years	Children's Oncology Group

Spots Global Cancer Trial Database for stage 1 neuroblastoma