Phase III Randomized Trial of Single vs. Tandem Myeloablative Consolidation Therapy for High-Risk Neuroblastoma
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 665
- 试验地点
- 190
- 主要终点
- Incidence Rate of Local Recurrence
研究概览
简要总结
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.
详细描述
PRIMARY OBJECTIVES:
I. To improve the 3-year event-free survival (EFS) rate of high-risk neuroblastoma patients through treatment with a tandem consolidation of thiotepa/cyclophosphamide followed by carboplatin/etoposide/melphalan (CEM) as compared to single CEM consolidation.
II. To improve the rate of end-induction complete response and very good partial response, compared to historical controls, by use of a topotecan-containing induction regimen.
III. To improve the 3-year local control rate, compared to historical controls, by increasing the local dose of radiation to the residual primary tumor for patients with less than a gross total resection.
SECONDARY OBJECTIVES:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 30 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •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)
- •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
- •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
- •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
排除标准
- 未提供
研究组 & 干预措施
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.
干预措施: Autologous Hematopoietic Stem Cell Transplantation (Procedure)
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.
干预措施: Carboplatin (Drug)
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.
干预措施: Cisplatin (Drug)
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.
干预措施: Peripheral Blood Stem Cell Transplantation (Procedure)
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.
干预措施: Cyclophosphamide (Drug)
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.
干预措施: Doxorubicin Hydrochloride (Drug)
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.
干预措施: Etoposide (Drug)
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.
干预措施: External Beam Radiation Therapy (Radiation)
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.
干预措施: Filgrastim (Biological)
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.
干预措施: Isotretinoin (Drug)
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.
干预措施: Laboratory Biomarker Analysis (Other)
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.
干预措施: Melphalan (Drug)
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.
干预措施: Pharmacological Study (Other)
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.
干预措施: Topotecan Hydrochloride (Drug)
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.
干预措施: Vincristine Sulfate Liposome (Drug)
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.
干预措施: Autologous Hematopoietic Stem Cell Transplantation (Procedure)
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.
干预措施: Carboplatin (Drug)
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.
干预措施: Cisplatin (Drug)
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.
干预措施: Cyclophosphamide (Drug)
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.
干预措施: Doxorubicin Hydrochloride (Drug)
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.
干预措施: Etoposide (Drug)
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.
干预措施: External Beam Radiation Therapy (Radiation)
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.
干预措施: Filgrastim (Biological)
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.
干预措施: Isotretinoin (Drug)
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.
干预措施: Laboratory Biomarker Analysis (Other)
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.
干预措施: Melphalan (Drug)
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.
干预措施: Peripheral Blood Stem Cell Transplantation (Procedure)
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.
干预措施: Pharmacological Study (Other)
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.
干预措施: Thiotepa (Drug)
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.
干预措施: Topotecan Hydrochloride (Drug)
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.
干预措施: Vincristine Sulfate Liposome (Drug)
结局指标
主要结局
Incidence Rate of Local Recurrence
时间窗: 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.
Event-free Survival Rate
时间窗: 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
时间窗: 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.
次要结局
- Surgical Response(Up to 3 years)
- Type of Surgical or Radiotherapy Complication(Up to 3 years)
- Duration of Greater Than or Equal to Grade 3 Neutropenia(Through completion of a participant's first cycle during induction, including treatment delays, assessed up to 39 days)
- Duration of Greater Than or Equal to Grade 3 Thrombocytopenia(Through completion of a participant's first cycle during induction, including treatment delays, assessed up to 46 days)
- Pharmacogenetic Variants in Patients Enrolled on Either A3973, ANBL0032, ANBL0931, ANBL0532 and Future High Risk Studies(At baseline)
- Proportion of Patients With a Polymorphism(Through completion of a participant's first two cycles during induction, including treatment delays, assessed up to 69 days)
- Intraspinal Extension(Up to 5 years)
- Peak Serum Concentration of Isotretinoin in Patients Enrolled on Either A3973, ANBL0032, ANBL0931, ANBL0532 and Future High Risk Studies(Day 1 of each course)
- Topotecan Systemic Clearance(Day 1 of courses 1-2)
- Presence and Function of T Cells Capable of Recognizing Neuroblastoma(Up to 6 months (end of therapy))
- Enumeration of Peripheral Blood Cluster of Differentiation (CD)3, CD4, and CD8 Cells(Up to 6 months after completion of assigned myeloablation therapy)
- Proportion of Patients With Neuroblastoma Detected in Bone Marrow and Peripheral Blood Using RT-PCR Technique(Baseline)
- 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).(Up to 3 years)
- 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(Up to 3 years)