Comparing Two Different Myeloablation Therapies in Treating Young Patients Who Are Undergoing a Stem Cell Transplant for High-Risk Neuroblastoma
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| ClinicalTrials.gov Identifier: NCT00567567 |
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Recruitment Status :
Completed
First Posted : December 5, 2007
Results First Posted : June 27, 2017
Last Update Posted : April 28, 2022
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Sponsor:
Children's Oncology Group
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group
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Brief Summary:
This randomized phase III trial compares two different high-dose chemotherapy regimens followed by a stem cell transplant in treating younger patients with high-risk neuroblastoma. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments before a peripheral blood stem cell transplant helps kill any tumor cells that are in the body and helps make room in the patient?s bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. High-dose chemotherapy and radiation therapy is then 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 high- chemotherapy. It is not yet known which regimen of high-dose chemotherapy is more effective for patients with high-risk neuroblastoma undergoing a peripheral blood stem cell transplant.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Localized Resectable Neuroblastoma Localized Unresectable Neuroblastoma Recurrent Neuroblastoma Regional Neuroblastoma Stage 4 Neuroblastoma Stage 4S Neuroblastoma | Procedure: Autologous Hematopoietic Stem Cell Transplantation Drug: Carboplatin Drug: Cisplatin Drug: Cyclophosphamide Drug: Doxorubicin Hydrochloride Drug: Etoposide Radiation: External Beam Radiation Therapy Biological: Filgrastim Drug: Isotretinoin Other: Laboratory Biomarker Analysis Drug: Melphalan Procedure: Peripheral Blood Stem Cell Transplantation Other: Pharmacological Study Drug: Thiotepa Drug: Topotecan Hydrochloride Drug: Vincristine Sulfate Liposome | Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 665 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase III Randomized Trial of Single vs. Tandem Myeloablative Consolidation Therapy for High-Risk Neuroblastoma |
| Actual Study Start Date : | November 5, 2007 |
| Actual Primary Completion Date : | February 27, 2015 |
| Actual Study Completion Date : | March 31, 2022 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Neuroblastoma
MedlinePlus related topics:
Neuroblastoma
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Consolidation Arm A: single myeloablative consolidation
Patients receive melphalan IV over 15-30 minutes on days -7 to -5, etoposide IV over 24 hours and carboplatin IV over 24 hours on days -7 to -4, and G-CSF SC or IV beginning on day 0 and continuing until blood counts recover. Patients undergo autologous PBSCT on day 0.
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Procedure: Autologous Hematopoietic Stem Cell Transplantation
Undergo autologous peripheral blood stem cell transplant
Other Names:
Drug: Carboplatin Given IV
Other Names:
Drug: Cisplatin Given IV
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Radiation: External Beam Radiation Therapy Undergo EBRT
Other Names:
Biological: Filgrastim Given IV or SC
Other Names:
Drug: Isotretinoin Given orally
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Melphalan Given IV
Other Names:
Procedure: Peripheral Blood Stem Cell Transplantation Undergo autologous peripheral blood stem cell transplant
Other Names:
Other: Pharmacological Study Correlative studies Drug: Topotecan Hydrochloride Given IV
Other Names:
Drug: Vincristine Sulfate Liposome Given IV
Other Name: Marqibo |
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Experimental: Consolidation Arm B: tandem myeloablative consolidation
Patients receive thiotepa IV over 2 hours on days -7 to -5, cyclophosphamide IV over 1 hour on days -5 to -2, and G-CSF SC or IV beginning on day 0 and continuing until blood counts recover. Following clinical recovery from initial myeloablative therapy, patients also receive melphalan, etoposide, and carboplatin as in Arm A. Patients undergo autologous PBSCT on day 0.
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Procedure: Autologous Hematopoietic Stem Cell Transplantation
Undergo autologous peripheral blood stem cell transplant
Other Names:
Drug: Carboplatin Given IV
Other Names:
Drug: Cisplatin Given IV
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Radiation: External Beam Radiation Therapy Undergo EBRT
Other Names:
Biological: Filgrastim Given IV or SC
Other Names:
Drug: Isotretinoin Given orally
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Melphalan Given IV
Other Names:
Procedure: Peripheral Blood Stem Cell Transplantation Undergo autologous peripheral blood stem cell transplant
Other Names:
Other: Pharmacological Study Correlative studies Drug: Thiotepa Given IV
Other Names:
Drug: Topotecan Hydrochloride Given IV
Other Names:
Drug: Vincristine Sulfate Liposome Given IV
Other Name: Marqibo |
Primary Outcome Measures :
- Event-free Survival Rate [ Time Frame: Three years, from time of randomization ]Comparison of EFS curves, starting from the time of randomization, by treatment group (single CEM vs. tandem CEM)
- Response After Induction Therapy [ Time Frame: Study enrollment to the end of induction therapy ]Per the International Response Criteria: measurable tumor defined as product of longest x widest perpendicular diameter. Elevated catecholamine levels, tumor cell invasion of bone marrow also considered measurable tumor. Complete Response (CR)-no evidence of primary tumor or metastases. Very Good Partial Response (VGPR)->90% reduction of primary tumor; no metastases; no new bone lesions, all pre-existing lesions improved. Partial Response (PR)-50-90% reduction of primary tumor; >50% reduction in measurable sites of metastases; 0-1 bone marrow samples with tumor; number of positive bone sites decreased by >50%. Mixed Response (MR)->50% reduction of any measurable lesion (primary or metastases) with <50% reduction in other sites; no new lesions; <25% increase in any existing lesion. No Response (NR)-no new lesions; <50% reduction but <25% increase in any existing legions. Progressive Disease (PD)-any new/increased measurable lesion by >25%; previous negative marrow positive.
- Incidence Rate of Local Recurrence [ Time Frame: Up to 3 years ]Cumulative incidence rate of local recurrence comparison between ANBL0532 patients randomized or assigned to receive single CEM transplant and boost radiation versus the historical A3973 patients who were transplanted and received boost radiation.
Secondary Outcome Measures :
- Duration of Greater Than or Equal to Grade 3 Neutropenia [ Time Frame: Through completion of a participant's first cycle during induction, including treatment delays, assessed up to 39 days ]A logistic regression model will be used to test the ability of the number of days of neutropenia to predict the presence of a polymorphism.
- Duration of Greater Than or Equal to Grade 3 Thrombocytopenia [ Time Frame: Through completion of a participant's first cycle during induction, including treatment delays, assessed up to 46 days ]A logistic regression model will be used to test the ability of the number of days of thrombocytopenia to predict the presence of a polymorphism.
- Proportion of Patients With a Polymorphism [ Time Frame: Through completion of a participant's first two cycles during induction, including treatment delays, assessed up to 69 days ]A chi-square test will be used to test whether the response rate after two cycles of induction therapy and the presence of a polymorphism are independent in the study population.
- Surgical Response [ Time Frame: Up to 3 years ]Percentage of patients who achieved a surgical complete resection
- Type of Surgical or Radiotherapy Complication [ Time Frame: Up to 3 years ]The Percentage of patients who experienced surgical or radiotherapy complications will be calculated. The complications are: bowel obstruction, chylous leaf, renal injury/atrophy/loss and diarrhea.
- Intraspinal Extension [ Time Frame: Up to 5 years ]Percentage of patients with primary tumors with intraspinal extension.
- Peak Serum Concentration of Isotretinoin in Patients Enrolled on Either A3973, ANBL0032, ANBL0931, ANBL0532 and Future High Risk Studies [ Time Frame: Day 1 of each course ]Median peak serum concentration level of isotretinoin for patients enrolled on ANBL0532
- Pharmacogenetic Variants in Patients Enrolled on Either A3973, ANBL0032, ANBL0931, ANBL0532 and Future High Risk Studies [ Time Frame: At baseline ]To determine if pharmacogenomic variations are predictive of EFS, a logrank test comparison of patients with vs without a given polymorphism will be made. A Fisher's exact test will test for association of the presence of a polymorphism with the occurrence of systemic toxicity (CTC grade 3 or 4 skin, hypercalcemia, or hepatic toxicity). These tests will be performed for UGT1A1, UGT2B7, CYP2C8 and CYP3A7 alleles.
- Topotecan Systemic Clearance [ Time Frame: Day 1 of courses 1-2 ]Median topotecan systemic clearance for courses 1 and 2.
- Presence and Function of T Cells Capable of Recognizing Neuroblastoma [ Time Frame: Up to 6 months (end of therapy) ]
- Enumeration of Peripheral Blood Cluster of Differentiation (CD)3, CD4, and CD8 Cells [ Time Frame: Up to 6 months after completion of assigned myeloablation therapy ]A descriptive comparison of the median number of T-cells (CD3, CD4, CD8) between treatment arms (single vs. tandem myeloablative regimens) will be performed.
- Proportion of Patients With Neuroblastoma Detected in Bone Marrow and Peripheral Blood Using RT-PCR Technique [ Time Frame: Baseline ]Will be calculated overall and by treatment arm.
- EFS Pts Non-randomly Assigned to Single CEM (12-18 Mths, Stg. 4, MYCN Nonamplified Tumor/Unfavorable or Indeterminant Histopathology/Diploid DNA Content & Pts>547 Days, Stg.3, MYCN Nonamplified Tumor AND Unfavorable or Indeterminant Histopathology). [ Time Frame: Up to 3 years ]Kaplan-Meier curves of EFS will be plotted, and the proportion of responders to induction therapy will be tabulated.
- OS in Patients 12-18 Months, Stage 4, MYCN Nonamplified Tumor/Unfavorable Histopathology/Diploid DNA Content/Indeterminant Histology/Ploidy and Patients > 547 Days, Stage 3, MYCN Nonamplified Tumor AND Unfavorable Histopathology/Indeterminant Histology [ Time Frame: Up to 3 years ]Kaplan-Meier curves of OS will be plotted, and the proportion of responders to induction therapy will be tabulated.
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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:
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Diagnosis of neuroblastoma or ganglioneuroblastoma by histology or as evidenced by the presence of clumps of tumor cells in bone marrow and elevated catecholamine metabolites in urine meeting any of the following criteria:
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Patients with newly diagnosed neuroblastoma with International Neuroblastoma Staging System (INSS) stage 4 disease are eligible with the following:
- MYCN amplification (i.e., greater than four-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features
- Age > 18 months (i.e., > 547 days) regardless of biologic features
- Age 12-18 months (i.e., 365-547 days) with none of the following three favorable biologic features (i.e., non-amplified MYCN, favorable pathology, and deoxyribonucleic acid [DNA] index > 1)
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Patients with newly diagnosed neuroblastoma with INSS stage 3 are eligible with the following:
- MYCN amplification (i.e., greater than four-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features
- Age > 18 months (i.e., > 547 days) with unfavorable pathology, regardless of MYCN status
- Patients with newly diagnosed INSS stage 2a or 2b with MYCN amplification (i.e., greater than four-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features
- Patients with newly diagnosed INSS stage 4s with MYCN amplification (i.e., greater than four-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features
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Patients >= 365 days initially diagnosed with INSS stage 1, 2, or 4S and who progressed to a stage 4 without interval chemotherapy
- Must have been enrolled on COG-ANBL00B1
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Creatinine clearance or radioisotope glomerular filtration rate ? 70mL/min OR serum creatinine based on age/gender as follows:
- 1 month to < 6 months: 0.4 mg/dL
- 6 months to < 1 year: 0.5 mg/dL
- 1 to < 2 years: 0.6 mg/dL
- 2 to < 6 years: 0.8 mg/dL
- 6 to < 10 years: 1 mg/dL
- 10 to < 13 years: 1.2 mg/dL
- 10 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female)
- >= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)
- Total bilirubin ? 1.5 times upper limit of normal (ULN) for age
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 10 times ULN for age
- Not pregnant or nursing
- Negative pregnancy test
- Shortening fraction >= 27% by echocardiogram (ECHO) OR left ventricular ejection fraction (LVEF) >= 50% by radionuclide angiogram
- No known contraindication (e.g., size, weight or physical condition) to peripheral blood stem cell collection
- No prior systemic therapy except for localized emergency radiation to sites of life-threatening or function-threatening disease
- No more than one course of chemotherapy per low- or intermediate-risk neuroblastoma therapy prior to determination of MYCN amplification and histology
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): NCT00567567
Locations
Show 190 study locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Julie R Park | Children's Oncology Group |
Study Documents (Full-Text)
Documents provided by Children's Oncology Group:
Documents provided by Children's Oncology Group:
Study Protocol and Statistical Analysis Plan [PDF] August 16, 2011
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Children's Oncology Group |
| ClinicalTrials.gov Identifier: | NCT00567567 |
| Other Study ID Numbers: |
ANBL0532 NCI-2009-01065 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) CDR0000576571 08-524 COG-ANBL0532 ANBL0532 ( Other Identifier: Childrens Oncology Group ) ANBL0532 ( Other Identifier: CTEP ) U10CA180886 ( U.S. NIH Grant/Contract ) U10CA098543 ( U.S. NIH Grant/Contract ) |
| First Posted: | December 5, 2007 Key Record Dates |
| Results First Posted: | June 27, 2017 |
| Last Update Posted: | April 28, 2022 |
| Last Verified: | December 2021 |
Additional relevant MeSH terms:
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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 Vitamin A Cyclophosphamide Melphalan Mechlorethamine Thiotepa |
Nitrogen Mustard Compounds Cisplatin Carboplatin Doxorubicin Liposomal doxorubicin Etoposide Vincristine Etoposide phosphate Topotecan Tretinoin Podophyllotoxin Isotretinoin Lenograstim Immunosuppressive Agents Immunologic Factors |