PEPI: Protracted Etoposide in a Phase II Upfront Window for Induction Therapy for High Risk Neuroblastoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 13
- 试验地点
- 1
- 主要终点
- Response Rate Associated With Two Cycles of Cisplatin With Protracted Oral Etoposide When Administered as Up-front Window Therapy to Previously Untreated Children With High Risk Neuroblastoma Tumors.
研究概览
简要总结
High-risk neuroblastoma is an aggressive childhood cancer that shows up as a lump or mass in the belly or around the spinal cord in the chest, neck, or pelvis. Often the tumor has spread around the body to the bones or to the soft center of the bone, called the bone marrow. High-risk neuroblastoma often responds to treatment at first, but it frequently comes back and may be even more difficult to treat.
Chemotherapy (drug treatments for cancer) is usually given at high doses in short bursts (3 to 5 days) followed by a few weeks of rest and recovery. This burst and recovery is called a "cycle" and usually takes about 21 days. Some scientists and physicians have tried to give chemotherapy at lower doses for more days, called "metronomic" chemotherapy. This method of giving chemotherapy has been used to treat neuroblastoma that has failed more standard types of treatment (relapsed neuroblastoma) and has shown some promise for those patients. One of the reasons it may work is by killing the blood vessels that feed the tumor as well as killing tumor cells themselves (the way that burst chemotherapy works). We think that giving a burst of chemotherapy together with metronomic therapy may kill the tumor while decreasing the side effects that we have seen in the past.
Treatment for high risk neuroblastoma usually occurs in 3 stages: induction, consolidation, and maintenance. During the induction phase, patients will receive chemotherapy and possibly more surgery to get rid of most of the tumor cells. Most of the chemotherapy drugs during induction will be given in the standard burst method. One of the chemotherapy drugs, etoposide, will be given in lower, metronomic doses. The doctors will study how the tumors respond and the side effects patients have. After induction most childrens' tumors will have disappeared, also called remission. These children will receive the second stage of treatment called consolidation. During this stage, subjects will receive radiation treatments to the tumor and then higher doses of chemotherapy. Because of the side effects of the high doses of chemotherapy, we will collect and store some special blood cells (called hematopoietic stem cells) early in treatment and keep them frozen. After the high doses of chemotherapy, these cells will be thawed and given to the subject. . This is called hematopoietic stem cell transplant (HSCT). The final stage of treatment, called maintenance, consists of a drug taken by mouth for 6 months.
Surgery to remove large, or bulky, tumors is a standard part of treatment for high risk neuroblastoma. A few children can have their main tumor removed before chemotherapy, but most require the tumor to shrink first. Surgery has usually been scheduled for after 3 to 5 cycles of therapy, but no one really knows how quickly the tumors are ready to come out. Because chemotherapy has significant side effects that can change the risks of surgery, we will study how early surgeries to remove tumors can happen.
This study is being done to evaluate the outcomes of disease response and survival in children with high risk neuroblastoma treated on this regimen.
详细描述
Induction Phase Overview The induction phase is approximately 15 weeks long. Chemotherapy is generally given every 3 weeks, each 3 week block is called a "cycle". During these 15 weeks we will treat subjects with chemotherapy 5 times using combinations of 4 different chemotherapy drugs. All IV chemotherapy drugs will be given in the hospital. During this 15 weeks doctors will try to collect special blood cells called hematopoietic stem cells. If the subject's tumor has not been removed completely you will have a surgery to take the rest of the tumor out as soon as possible once it has shrunk with the first two cycles of chemotherapy.
Induction Phase Chemotherapy During the first 2 cycles of chemotherapy all children will receive two drugs: cisplatin and etoposide. Cisplatin is given through an IV for everyone. If participating in the research treatment plan, etoposide by mouth mouth for 14 days. After the first two cycles we will repeat studies to see if the tumor has shrunk. Then all children will receive two other chemotherapy drugs called cyclophosphamide and adriamycin during the 3rd cycle. If the subject responded to the first two cycles, the 4th cycle will be IV cisplatin and oral etoposide again; if the subject did not respond to the first two cycles, the 4th cycle will be IV cisplatin with standard IV etoposide. The 5th cycle will again be adriamycin and cyclophosphamide.
If subjects choose not to participate in the research treatment plan, or are not eligible for the research treatment plan, cycle 1, 2, and 4 will be IV Cisplatin and IV Etoposide.
Here is the induction treatment:
Treatment #1, 2, and 4:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Pts can be enrolled but receive standard etoposide bolus dosing based on clinical conditions at diagnosis (need for emergency intervention because of renal, neurologic, or airway compromise). Pts who meet all other eligibility criteria may also choose to participate in the clinical trial w/o receiving the upfront window protracted dosing of etoposide; these children will receive standard etoposide bolus dosing.
- •Less than 18 yo at diagnosis
- •DIAGNOSIS Neuroblastoma or ganglioneuroblastoma verified by histology and/or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites.
- •Pts with newly diagnosed neuroblastoma and age 365 or more days with the following: * INSS Stage 2a/2b with MYCN amplification , AND unfavorable pathology * INSS Stage 3 with MYCN amplification AND/OR unfavorable pathology
- •Pts with newly diagnosed neuroblastoma with INSS Stage 4 are eligible with the following: * Age more than 18 months (greater than 547 days) regardless of biologic features * Age 12 to 18 months (365-547 days) with any unfavorable biologic feature (MYCN amplification, unfavorable pathology and/or DNA index equal to 1) or any biologic feature that is indeterminant/unsatisfactory/unknown.
- •Pts with newly diagnosed neuroblastoma and age less than 365 days with INSS Stage 3, 4, 4S neuroblastoma with MYCN amplification (more than 10).
- •Pts 365 days or more initially diagnosed with INSS stage 1, 2, 4S who develop distant metastatic disease (meet criteria for INSS stage 4).
- •Pts may have had no prior systemic therapy except:
- •Localized emergency radiation to sites of life threatening or function-threatening disease
- •No more than one cycle of chemotherapy according to the intergroup low or intermediate risk neuroblastoma studies prior to determination of MYCN amplification and histology.
- •TIME FROM DIAGNOSIS Pts must be entered on this study - Within 3 weeks of diagnosis - After recovery from only 1 cycle of chemo on low/intermediate risk NB therapy, - Within 3 weeks of progression with widely metastatic tumor for INSS stage 1, 2, 4S if they received no prior chemotherapy.
- •HEMATOPOIETIC FUNCTION
- •ANC 750/µL or more
- •Plt 75,000/µL or more
- •or bone marrow involvement with tumor.
- •LIVER FUNCTION Pts must have adequate liver function defined as
- •Direct Bilirubin 1.5 mg/dL or less
- •AST and ALT 5 x ULN or less
- •Pts of childbearing potential must practice an effective method of birth control while on study.
排除标准
- •Patients who do not meet inclusion criteria.
- •Patients who are pregnant or lactating are not eligible.
- •EXCLUSION CRITERIA UPFRONT WINDOW Patients can be enrolled onto Stratum 1 but receive standard etoposide bolus dosing based on clinical conditions at diagnosis. Patients who meet all other eligibility criteria may also choose to participate in the clinical trial without receiving the upfront window protracted dosing of etoposide; these children will receive standard etoposide bolus dosing.
- •Patients whose tumor requires emergency intervention because of spinal cord compression, CNS compromise, or airway compromise.
- •Patients requiring dialysis.
- •If the patient and/or the patient's legally authorized guardian chose to participate in the clinical trial but chose to not participate in the phase II upfront window.
研究组 & 干预措施
Protracted Oral Etoposide
Protracted oral etoposide for cycles 1, 2 and 4 of induction. Etoposide will be given in combination with IV cisplatin (a standard of care agent). If a subject does not respond after cycle 2, cycle 4 will be bolus etoposide in combination with IV cisplatin.
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: Protracted Oral Etoposide (Drug)
Protracted Oral Etoposide
Protracted oral etoposide for cycles 1, 2 and 4 of induction. Etoposide will be given in combination with IV cisplatin (a standard of care agent). If a subject does not respond after cycle 2, cycle 4 will be bolus etoposide in combination with IV cisplatin.
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: Doxorubicin (Drug)
Protracted Oral Etoposide
Protracted oral etoposide for cycles 1, 2 and 4 of induction. Etoposide will be given in combination with IV cisplatin (a standard of care agent). If a subject does not respond after cycle 2, cycle 4 will be bolus etoposide in combination with IV cisplatin.
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: Cisplatin (Drug)
Protracted Oral Etoposide
Protracted oral etoposide for cycles 1, 2 and 4 of induction. Etoposide will be given in combination with IV cisplatin (a standard of care agent). If a subject does not respond after cycle 2, cycle 4 will be bolus etoposide in combination with IV cisplatin.
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: Cyclophosphamide (Drug)
Protracted Oral Etoposide
Protracted oral etoposide for cycles 1, 2 and 4 of induction. Etoposide will be given in combination with IV cisplatin (a standard of care agent). If a subject does not respond after cycle 2, cycle 4 will be bolus etoposide in combination with IV cisplatin.
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: Mesna (Drug)
Protracted Oral Etoposide
Protracted oral etoposide for cycles 1, 2 and 4 of induction. Etoposide will be given in combination with IV cisplatin (a standard of care agent). If a subject does not respond after cycle 2, cycle 4 will be bolus etoposide in combination with IV cisplatin.
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: Hematopoietic Factor (Drug)
Protracted Oral Etoposide
Protracted oral etoposide for cycles 1, 2 and 4 of induction. Etoposide will be given in combination with IV cisplatin (a standard of care agent). If a subject does not respond after cycle 2, cycle 4 will be bolus etoposide in combination with IV cisplatin.
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: Primary tumor resection (Procedure)
IV Bolus Etoposide
IV bolus etoposide in combination with IV cisplatin will be given for cycles 1,2, and 4 of induction chemotherapy for patients who are not eligible for the experimental arm (e.g.require emergent treatment)
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: Doxorubicin (Drug)
IV Bolus Etoposide
IV bolus etoposide in combination with IV cisplatin will be given for cycles 1,2, and 4 of induction chemotherapy for patients who are not eligible for the experimental arm (e.g.require emergent treatment)
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: IV Bolus Etoposide (Drug)
IV Bolus Etoposide
IV bolus etoposide in combination with IV cisplatin will be given for cycles 1,2, and 4 of induction chemotherapy for patients who are not eligible for the experimental arm (e.g.require emergent treatment)
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: Cisplatin (Drug)
IV Bolus Etoposide
IV bolus etoposide in combination with IV cisplatin will be given for cycles 1,2, and 4 of induction chemotherapy for patients who are not eligible for the experimental arm (e.g.require emergent treatment)
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: Cyclophosphamide (Drug)
IV Bolus Etoposide
IV bolus etoposide in combination with IV cisplatin will be given for cycles 1,2, and 4 of induction chemotherapy for patients who are not eligible for the experimental arm (e.g.require emergent treatment)
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: Mesna (Drug)
IV Bolus Etoposide
IV bolus etoposide in combination with IV cisplatin will be given for cycles 1,2, and 4 of induction chemotherapy for patients who are not eligible for the experimental arm (e.g.require emergent treatment)
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: Hematopoietic Factor (Drug)
IV Bolus Etoposide
IV bolus etoposide in combination with IV cisplatin will be given for cycles 1,2, and 4 of induction chemotherapy for patients who are not eligible for the experimental arm (e.g.require emergent treatment)
All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.
干预措施: Primary tumor resection (Procedure)
结局指标
主要结局
Response Rate Associated With Two Cycles of Cisplatin With Protracted Oral Etoposide When Administered as Up-front Window Therapy to Previously Untreated Children With High Risk Neuroblastoma Tumors.
时间窗: 2 months
Partial response or better
Rate of Toxicities Associated With Cisplatin With Protracted Oral Etoposide When Administered as Up-front Window Therapy to Previously Untreated Children With High Risk Neuroblastoma.
时间窗: 2 months
If a patient experiences any one of the following toxicities, attributed to induction chemotherapy cycles 1, or 2, that patient will be counted as having a dose limiting toxicity. 13.2.1.1 Inability to achieve ANC \> 750 by Day 35 from start of chemotherapy cycle 1 or 2 (unless documented tumor involvement of marrow) 13.2.1.2 Inability to achieve platelet count at least 75,000 by Day 35 from start of chemotherapy cycle 1 or 2 (unless documented tumor involvement of marrow) 13.2.1.3 Any Grade 2 or greater toxicity non-hematopoietic/non-mucosal (mucositis/stomatitis) that is not reversible to Grade 1 or baseline by day 21 from start of chemotherapy cycle excluding Hematopoietic toxicity Mucositis/stomatitis Anorexia, nausea, vomiting Febrile neutropenia
次要结局
- Number of Patients Who Have Surgery After the Second Cycle of Induction Therapy(2 months)
- Event Free Survival in Children With High Risk Neuroblastoma Treated on This Regimen.(3 years)
- Overall Survival in Children With High Risk Neuroblastoma Treated on This Regimen.(3 years)
研究者
Heidi Russell
Principal investigator
Baylor College of Medicine