Dose Intensive Chemotherapy for Children Less Than Ten Years of Age Newly-Diagnosed With Malignant Brain Tumors: A Pilot Study of Two Alternative Intensive Induction Chemotherapy Regimens, Followed by Consolidation With Myeloablative Chemotherapy (Thiotepa and Carboplatin, With or Without Etoposide) and Autologous Stem Cell Rescue [HEAD START III]
试验速览
- 阶段
- 3 期
- 入组人数
- 120
- 试验地点
- 37
- 主要终点
- Time to tumor progression, disease recurrence, or death of any cause
研究概览
简要总结
RATIONALE: 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. A bone marrow or peripheral stem cell transplant using stem cells from the patient may be able to replace blood-forming cells that were destroyed by chemotherapy. This may allow more chemotherapy to be given so that more tumor cells are killed.
PURPOSE: This phase III trial is studying how well giving combination chemotherapy with or without etoposide followed by an autologous stem cell transplant works in treating young patients with previously untreated malignant brain tumors.
详细描述
OBJECTIVES:
Primary
- Determine the 2-year event-free survival (EFS) and overall survival (OS) of pediatric patients with previously untreated nondisseminated medulloblastoma (< 4 years of age), disseminated medulloblastoma (< 10 years of age), or noncerebellar primitive neuroectodermal tumors (PNET) (disseminated or non-disseminated) treated with induction chemotherapy followed by consolidation with myeloablative chemotherapy and autologous hematopoietic stem cell rescue.
- Determine the toxicity of this regimen in these patients.
- Determine the mortality of patients treated with this regimen.
Secondary
- Determine the complete and partial response rates after completion of induction chemotherapy in these patients stratified according to pathology (medulloblastoma vs noncerebellar PNET vs high-grade gliomas vs atypical teratoid/rhabdoid tumors vs choroid plexus carcinomas and atypical papillomas vs ependymomas).
- Describe the EFS and OS of these patients stratified according to additional diagnoses (atypical teratoid/rhabdoid tumors vs choroid plexus carcinomas and atypical choroid plexus papillomas vs ependymomas vs high-grade gliomas).
- Describe the time to progression and patterns of relapse in these patients stratified by diagnosis and radiotherapy received (< 6 years of age with evidence of no residual tumor pre-transplant and no post-transplant consolidation radiotherapy vs < 6 years of age with residual tumor present pre-transplant treated with post-transplant consolidation radiotherapy vs > 6 years of age treated with post-transplant consolidation radiotherapy).
- Determine the neuropsychometric function, endocrinologic function, and physical growth in these patients stratified according to radiotherapy received (none vs reduced-volume craniospinal radiotherapy vs focused local-field radiotherapy).
研究设计
- 研究类型
- Interventional
- 主要目的
- Treatment
入排标准
- 年龄范围
- — 至 10 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Regimen C
Patients receive induction therapy of vincristine IV on days 1, 8, and 15 of courses 1-3, oral temozolomide once daily on days 1-5, and carboplatin IV over 4 hours on days 1 and 2. Patients also receive G-CSF SC beginning on day 6 and continuing until blood counts recover. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients receive consolidation therapy of carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours on days -5 to -3, undergo reinfusion of bone marrow or peripheral blood stem cells on day 0, and receive G-CSF SC beginning on day 1 and continuing until blood counts recover. Beginning within 6 weeks after transplantation, some patients undergo radiotherapy once daily 5 days a week for 4-6 weeks in the absence of disease progression or unacceptable toxicity and some patients undergo radiotherapy if there is evidence of tumor remaining after completion of induction chemotherapy.
干预措施: carboplatin (Drug)
Regimen C
Patients receive induction therapy of vincristine IV on days 1, 8, and 15 of courses 1-3, oral temozolomide once daily on days 1-5, and carboplatin IV over 4 hours on days 1 and 2. Patients also receive G-CSF SC beginning on day 6 and continuing until blood counts recover. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients receive consolidation therapy of carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours on days -5 to -3, undergo reinfusion of bone marrow or peripheral blood stem cells on day 0, and receive G-CSF SC beginning on day 1 and continuing until blood counts recover. Beginning within 6 weeks after transplantation, some patients undergo radiotherapy once daily 5 days a week for 4-6 weeks in the absence of disease progression or unacceptable toxicity and some patients undergo radiotherapy if there is evidence of tumor remaining after completion of induction chemotherapy.
干预措施: temozolomide (Drug)
Regimen C
Patients receive induction therapy of vincristine IV on days 1, 8, and 15 of courses 1-3, oral temozolomide once daily on days 1-5, and carboplatin IV over 4 hours on days 1 and 2. Patients also receive G-CSF SC beginning on day 6 and continuing until blood counts recover. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients receive consolidation therapy of carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours on days -5 to -3, undergo reinfusion of bone marrow or peripheral blood stem cells on day 0, and receive G-CSF SC beginning on day 1 and continuing until blood counts recover. Beginning within 6 weeks after transplantation, some patients undergo radiotherapy once daily 5 days a week for 4-6 weeks in the absence of disease progression or unacceptable toxicity and some patients undergo radiotherapy if there is evidence of tumor remaining after completion of induction chemotherapy.
干预措施: thiotepa (Drug)
Regimen C
Patients receive induction therapy of vincristine IV on days 1, 8, and 15 of courses 1-3, oral temozolomide once daily on days 1-5, and carboplatin IV over 4 hours on days 1 and 2. Patients also receive G-CSF SC beginning on day 6 and continuing until blood counts recover. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients receive consolidation therapy of carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours on days -5 to -3, undergo reinfusion of bone marrow or peripheral blood stem cells on day 0, and receive G-CSF SC beginning on day 1 and continuing until blood counts recover. Beginning within 6 weeks after transplantation, some patients undergo radiotherapy once daily 5 days a week for 4-6 weeks in the absence of disease progression or unacceptable toxicity and some patients undergo radiotherapy if there is evidence of tumor remaining after completion of induction chemotherapy.
干预措施: vincristine sulfate (Drug)
Regimen C
Patients receive induction therapy of vincristine IV on days 1, 8, and 15 of courses 1-3, oral temozolomide once daily on days 1-5, and carboplatin IV over 4 hours on days 1 and 2. Patients also receive G-CSF SC beginning on day 6 and continuing until blood counts recover. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients receive consolidation therapy of carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours on days -5 to -3, undergo reinfusion of bone marrow or peripheral blood stem cells on day 0, and receive G-CSF SC beginning on day 1 and continuing until blood counts recover. Beginning within 6 weeks after transplantation, some patients undergo radiotherapy once daily 5 days a week for 4-6 weeks in the absence of disease progression or unacceptable toxicity and some patients undergo radiotherapy if there is evidence of tumor remaining after completion of induction chemotherapy.
干预措施: autologous bone marrow transplantation (Procedure)
Regimen C
Patients receive induction therapy of vincristine IV on days 1, 8, and 15 of courses 1-3, oral temozolomide once daily on days 1-5, and carboplatin IV over 4 hours on days 1 and 2. Patients also receive G-CSF SC beginning on day 6 and continuing until blood counts recover. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients receive consolidation therapy of carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours on days -5 to -3, undergo reinfusion of bone marrow or peripheral blood stem cells on day 0, and receive G-CSF SC beginning on day 1 and continuing until blood counts recover. Beginning within 6 weeks after transplantation, some patients undergo radiotherapy once daily 5 days a week for 4-6 weeks in the absence of disease progression or unacceptable toxicity and some patients undergo radiotherapy if there is evidence of tumor remaining after completion of induction chemotherapy.
干预措施: autologous hematopoietic stem cell transplantation (Procedure)
Regimen C
Patients receive induction therapy of vincristine IV on days 1, 8, and 15 of courses 1-3, oral temozolomide once daily on days 1-5, and carboplatin IV over 4 hours on days 1 and 2. Patients also receive G-CSF SC beginning on day 6 and continuing until blood counts recover. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients receive consolidation therapy of carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours on days -5 to -3, undergo reinfusion of bone marrow or peripheral blood stem cells on day 0, and receive G-CSF SC beginning on day 1 and continuing until blood counts recover. Beginning within 6 weeks after transplantation, some patients undergo radiotherapy once daily 5 days a week for 4-6 weeks in the absence of disease progression or unacceptable toxicity and some patients undergo radiotherapy if there is evidence of tumor remaining after completion of induction chemotherapy.
干预措施: peripheral blood stem cell transplantation (Procedure)
Regimen C
Patients receive induction therapy of vincristine IV on days 1, 8, and 15 of courses 1-3, oral temozolomide once daily on days 1-5, and carboplatin IV over 4 hours on days 1 and 2. Patients also receive G-CSF SC beginning on day 6 and continuing until blood counts recover. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients receive consolidation therapy of carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours on days -5 to -3, undergo reinfusion of bone marrow or peripheral blood stem cells on day 0, and receive G-CSF SC beginning on day 1 and continuing until blood counts recover. Beginning within 6 weeks after transplantation, some patients undergo radiotherapy once daily 5 days a week for 4-6 weeks in the absence of disease progression or unacceptable toxicity and some patients undergo radiotherapy if there is evidence of tumor remaining after completion of induction chemotherapy.
干预措施: radiation therapy (Radiation)
Regimen D2
In courses 1, 3, and 5, patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, vincristine IV on days 1, 8, and 15 (in courses1 and 3), and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In courses 2 and 4, patients receive oral temozolomide once daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV over 1 hour on days 11 and 12, vincristine IV on days 1, 8, and 15 (in course 2), and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients receive consolidation therapy as in regimen C in combination with etoposide IV over 3 hours on days -5 to -3 and undergo autologous bone marrow or peripheral blood stem cell transplantation, receive G-CSF, and undergo radiotherapy as in regimen C.
干预措施: carboplatin (Drug)
Regimen D2
In courses 1, 3, and 5, patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, vincristine IV on days 1, 8, and 15 (in courses1 and 3), and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In courses 2 and 4, patients receive oral temozolomide once daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV over 1 hour on days 11 and 12, vincristine IV on days 1, 8, and 15 (in course 2), and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients receive consolidation therapy as in regimen C in combination with etoposide IV over 3 hours on days -5 to -3 and undergo autologous bone marrow or peripheral blood stem cell transplantation, receive G-CSF, and undergo radiotherapy as in regimen C.
干预措施: cisplatin (Drug)
Regimen D2
In courses 1, 3, and 5, patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, vincristine IV on days 1, 8, and 15 (in courses1 and 3), and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In courses 2 and 4, patients receive oral temozolomide once daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV over 1 hour on days 11 and 12, vincristine IV on days 1, 8, and 15 (in course 2), and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients receive consolidation therapy as in regimen C in combination with etoposide IV over 3 hours on days -5 to -3 and undergo autologous bone marrow or peripheral blood stem cell transplantation, receive G-CSF, and undergo radiotherapy as in regimen C.
干预措施: cyclophosphamide (Drug)
Regimen D2
In courses 1, 3, and 5, patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, vincristine IV on days 1, 8, and 15 (in courses1 and 3), and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In courses 2 and 4, patients receive oral temozolomide once daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV over 1 hour on days 11 and 12, vincristine IV on days 1, 8, and 15 (in course 2), and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients receive consolidation therapy as in regimen C in combination with etoposide IV over 3 hours on days -5 to -3 and undergo autologous bone marrow or peripheral blood stem cell transplantation, receive G-CSF, and undergo radiotherapy as in regimen C.
干预措施: etoposide (Drug)
Regimen D2
In courses 1, 3, and 5, patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, vincristine IV on days 1, 8, and 15 (in courses1 and 3), and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In courses 2 and 4, patients receive oral temozolomide once daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV over 1 hour on days 11 and 12, vincristine IV on days 1, 8, and 15 (in course 2), and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients receive consolidation therapy as in regimen C in combination with etoposide IV over 3 hours on days -5 to -3 and undergo autologous bone marrow or peripheral blood stem cell transplantation, receive G-CSF, and undergo radiotherapy as in regimen C.
干预措施: methotrexate (Drug)
Regimen D2
In courses 1, 3, and 5, patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, vincristine IV on days 1, 8, and 15 (in courses1 and 3), and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In courses 2 and 4, patients receive oral temozolomide once daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV over 1 hour on days 11 and 12, vincristine IV on days 1, 8, and 15 (in course 2), and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients receive consolidation therapy as in regimen C in combination with etoposide IV over 3 hours on days -5 to -3 and undergo autologous bone marrow or peripheral blood stem cell transplantation, receive G-CSF, and undergo radiotherapy as in regimen C.
干预措施: temozolomide (Drug)
Regimen D2
In courses 1, 3, and 5, patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, vincristine IV on days 1, 8, and 15 (in courses1 and 3), and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In courses 2 and 4, patients receive oral temozolomide once daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV over 1 hour on days 11 and 12, vincristine IV on days 1, 8, and 15 (in course 2), and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients receive consolidation therapy as in regimen C in combination with etoposide IV over 3 hours on days -5 to -3 and undergo autologous bone marrow or peripheral blood stem cell transplantation, receive G-CSF, and undergo radiotherapy as in regimen C.
干预措施: thiotepa (Drug)
Regimen D2
In courses 1, 3, and 5, patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, vincristine IV on days 1, 8, and 15 (in courses1 and 3), and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In courses 2 and 4, patients receive oral temozolomide once daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV over 1 hour on days 11 and 12, vincristine IV on days 1, 8, and 15 (in course 2), and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients receive consolidation therapy as in regimen C in combination with etoposide IV over 3 hours on days -5 to -3 and undergo autologous bone marrow or peripheral blood stem cell transplantation, receive G-CSF, and undergo radiotherapy as in regimen C.
干预措施: vincristine sulfate (Drug)
Regimen D2
In courses 1, 3, and 5, patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, vincristine IV on days 1, 8, and 15 (in courses1 and 3), and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In courses 2 and 4, patients receive oral temozolomide once daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV over 1 hour on days 11 and 12, vincristine IV on days 1, 8, and 15 (in course 2), and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients receive consolidation therapy as in regimen C in combination with etoposide IV over 3 hours on days -5 to -3 and undergo autologous bone marrow or peripheral blood stem cell transplantation, receive G-CSF, and undergo radiotherapy as in regimen C.
干预措施: autologous bone marrow transplantation (Procedure)
Regimen D2
In courses 1, 3, and 5, patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, vincristine IV on days 1, 8, and 15 (in courses1 and 3), and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In courses 2 and 4, patients receive oral temozolomide once daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV over 1 hour on days 11 and 12, vincristine IV on days 1, 8, and 15 (in course 2), and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients receive consolidation therapy as in regimen C in combination with etoposide IV over 3 hours on days -5 to -3 and undergo autologous bone marrow or peripheral blood stem cell transplantation, receive G-CSF, and undergo radiotherapy as in regimen C.
干预措施: autologous hematopoietic stem cell transplantation (Procedure)
Regimen D2
In courses 1, 3, and 5, patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, vincristine IV on days 1, 8, and 15 (in courses1 and 3), and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In courses 2 and 4, patients receive oral temozolomide once daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV over 1 hour on days 11 and 12, vincristine IV on days 1, 8, and 15 (in course 2), and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients receive consolidation therapy as in regimen C in combination with etoposide IV over 3 hours on days -5 to -3 and undergo autologous bone marrow or peripheral blood stem cell transplantation, receive G-CSF, and undergo radiotherapy as in regimen C.
干预措施: peripheral blood stem cell transplantation (Procedure)
Regimen D2
In courses 1, 3, and 5, patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, vincristine IV on days 1, 8, and 15 (in courses1 and 3), and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In courses 2 and 4, patients receive oral temozolomide once daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV over 1 hour on days 11 and 12, vincristine IV on days 1, 8, and 15 (in course 2), and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients receive consolidation therapy as in regimen C in combination with etoposide IV over 3 hours on days -5 to -3 and undergo autologous bone marrow or peripheral blood stem cell transplantation, receive G-CSF, and undergo radiotherapy as in regimen C.
干预措施: radiation therapy (Radiation)
结局指标
主要结局
Time to tumor progression, disease recurrence, or death of any cause
Event-free survival at 2 years
Toxicity
次要结局
- Response to induction as assessed by one-time tumor measurements at baseline and after completion of induction chemotherapy
- Time to death
- Overall survival