A Randomized Phase II Study of Bevacizumab (NSC 704865) Combined With Vincristine, Topotecan and Cyclophosphamide in Patients With First Recurrent Ewing Sarcoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 7
- 试验地点
- 1
- 主要终点
- The Occurrence of Limiting Toxicity in an Eligible and Evaluable Patient.
研究概览
简要总结
This phase II trial study has a 6-patient feasibility portion studying the tolerability of chemotherapy with vincristine sulfate together with topotecan hydrochloride, cyclophosphamide, and bevacizumab in treating young patients with refractory or first recurrent extracranial Ewing's sarcoma. If the therapy is considered tolerable, this feasibility run-in will be followed by a randomized phase II portion studying giving vincristine sulfate together with topotecan hydrochloride, and cyclophosphamide to see how well it works compared with giving vincristine sulfate together with topotecan hydrochloride, cyclophosphamide, and bevacizumab in treating young patients with refractory or first recurrent extracranial Ewing's sarcoma. Drugs used in chemotherapy, such as vincristine sulfate, topotecan hydrochloride, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop tumor growth by blocking blood flow to the tumor. Giving combination chemotherapy together with bevacizumab may kill more tumor cells.
详细描述
PRIMARY OBJECTIVES:
I. To determine the feasibility of administering bevacizumab in combination with vincristine (vincristine sulfate), topotecan hydrochloride, and cyclophosphamide (VTC) to younger patients with refractory or first recurrent Ewing sarcoma.
II. To compare the progression-free survival of patients treated with VTC with bevacizumab vs VTC without bevacizumab.
SECONDARY OBJECTIVES:
I. To estimate the response rate to 2 cycles of VTC compared to 2 cycles of VTC/bevacizumab.
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
- 1 Year 至 29 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •ALT =< 5 times ULN for age
- •Urine protein: creatinine ratio =< 0.5 OR 24-hour urine protein < 1,000 mg
- •At least 6 weeks since other prior substantial bone marrow radiation
- •At least 28 days since prior major surgical procedures (e.g., resection of tumor, laparotomy, thoracotomy, or open biopsy)
- •At least 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas)
- •At least 2 weeks since prior local palliative radiotherapy (e.g., small port)
- •Diagnosis of extracranial Ewing sarcoma or primitive neuroectodermal tumor of bone or soft tissue meeting 1 of the following criteria: I) a first recurrence of localized disease; II) a first recurrence of initially metastatic disease; III) disease refractory to initial conventional therapy
- •Patients must have RECIST-measurable disease documented by clinical, radiographic, or histological criteria
- •Patients who do not have measurable disease (e.g., bone scan-determined metastatic disease only) remain eligible for the study and will be evaluable for disease-free progression
- •Karnofsky performance status (PS) 50-100% (> 16 years of age) OR Lansky PS 50-100% (=< 16 years of age )
- •Life expectancy >= 8 weeks
- •Absolute neutrophil count >= 1,000/μL
- •NOTE: Patients with tumor metastatic to bone marrow are permitted to receive transfusions to maintain hemoglobin and platelet counts. These patients will not be evaluable for hematologic toxicity. Patients who are refractory to platelet infusions (i.e., unable to maintain platelet counts > 75,000/μL) and have marrow involvement and platelet counts < 75,000/μL are not eligible
- •Fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy
- •At least 1 week since prior therapy with a biologic agent or growth factor
- •Patients must have histological verification of the malignancy at original diagnosis
- •Histological confirmation of relapse is highly recommended but not mandatory
- •Prior initial therapy with topotecan hydrochloride is allowed as long as > 2 years have elapsed since the initial diagnosis of Ewing sarcoma
- •Prior therapy with cyclophosphamide or vincristine is allowed
- •Minor surgical procedures (e.g., biopsies) for limited purposes of tissue retrieval allowed
- •Minor procedures include indwelling IV catheter placement and needle biopsy for diagnostic purposes
- •For minor surgeries, patients should not receive the first planned dose of bevacizumab until the wound is healed and 7 days have elapsed
- •At least 6 months since prior craniospinal radiotherapy or radiotherapy to >= 50% of the pelvis
- •At least 3 months since prior autologous stem cell transplantation (SCT)
- •Platelet count >= 75,000/μL (transfusion independent)
- •Hemoglobin >= 8.0 g/dL (may receive RBC transfusions)
- •Direct bilirubin =< 1.5 times upper limit of normal (ULN) for age
- •Creatinine clearance or radioisotope GFR >= 70 mL/min OR serum creatinine normal for age
- •Hypertension must be well controlled on stable doses of medication for >= 2 weeks prior to enrollment
- •Negative pregnancy test
- •Female patients who are lactating must agree to stop breast-feeding
- •II) The patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
- •Shortening fraction > 28% OR ejection fraction > 50%
- •Recovered from any prior surgical procedure
- •Sexually active patients of childbearing potential must agree to use effective contraception
- •Patients on full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 are eligible if both of these criteria are met:
- •I) The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
排除标准
- •Radiological or clinical evidence for parenchymal brain metastases or neuro axis involvement
- •Documented, chronic nonhealing wound, ulcer, or significant traumatic injury (those with bone fractures, including pathological fractures, or requiring surgical intervention) within the past 28 days
- •Other bone complications
- •Deep venous thrombosis (including pulmonary embolism) within the past 3 months
- •Recent (i.e., within 6 months) arterial thromboembolic events, including transient ischemic attack or cerebrovascular accident
- •History of myocardial infarction, severe or unstable angina, or peripheral vascular disease Prior bevacizumab
- •Radiotherapy or surgery for local control of recurrent disease concurrently with bevacizumab (bevacizumab must be held if radiotherapy or surgery is required)
- •Radiotherapy to localized painful lesions is allowed, provided >= 1 measurable lesion is not irradiated
- •Radiotherapy for local metastatic tumor control allowed after the first 2 courses of therapy
- •Other cancer chemotherapy or immunomodulating agents
- •Steroid use is allowed
- •Prior allogeneic SCT
研究组 & 干预措施
Arm I (Feasibility assessment of VTCB)
Patients receive bevacizumab IV over 30-90 minutes on day 1, vincristine sulfate IV on days 1, 8, and 15, and topotecan hydrochloride IV over 30 minutes and cyclophosphamide IV over 60 minutes on days 1-5. Treatment repeats every 21 days (except during weeks 14, 15 [course 5], 17, 18 [course 6], 26, 27 [course 9], 29, and 30 [course 10] when no chemotherapy is given) for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: topotecan hydrochloride (Drug)
Arm II (VTCB)
Patients receive bevacizumab, vincristine sulfate, topotecan hydrochloride, and cyclophosphamide as in Arm I.
干预措施: topotecan hydrochloride (Drug)
Arm I (Feasibility assessment of VTCB)
Patients receive bevacizumab IV over 30-90 minutes on day 1, vincristine sulfate IV on days 1, 8, and 15, and topotecan hydrochloride IV over 30 minutes and cyclophosphamide IV over 60 minutes on days 1-5. Treatment repeats every 21 days (except during weeks 14, 15 [course 5], 17, 18 [course 6], 26, 27 [course 9], 29, and 30 [course 10] when no chemotherapy is given) for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: vincristine sulfate (Drug)
Arm I (Feasibility assessment of VTCB)
Patients receive bevacizumab IV over 30-90 minutes on day 1, vincristine sulfate IV on days 1, 8, and 15, and topotecan hydrochloride IV over 30 minutes and cyclophosphamide IV over 60 minutes on days 1-5. Treatment repeats every 21 days (except during weeks 14, 15 [course 5], 17, 18 [course 6], 26, 27 [course 9], 29, and 30 [course 10] when no chemotherapy is given) for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: cyclophosphamide (Drug)
Arm I (Feasibility assessment of VTCB)
Patients receive bevacizumab IV over 30-90 minutes on day 1, vincristine sulfate IV on days 1, 8, and 15, and topotecan hydrochloride IV over 30 minutes and cyclophosphamide IV over 60 minutes on days 1-5. Treatment repeats every 21 days (except during weeks 14, 15 [course 5], 17, 18 [course 6], 26, 27 [course 9], 29, and 30 [course 10] when no chemotherapy is given) for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: bevacizumab (Biological)
Arm II (VTCB)
Patients receive bevacizumab, vincristine sulfate, topotecan hydrochloride, and cyclophosphamide as in Arm I.
干预措施: vincristine sulfate (Drug)
Arm II (VTCB)
Patients receive bevacizumab, vincristine sulfate, topotecan hydrochloride, and cyclophosphamide as in Arm I.
干预措施: cyclophosphamide (Drug)
Arm II (VTCB)
Patients receive bevacizumab, vincristine sulfate, topotecan hydrochloride, and cyclophosphamide as in Arm I.
干预措施: bevacizumab (Biological)
Arm III (CTC)
Patients receive vincristine, topotecan hydrochloride, and cyclophosphamide as in arm I.
干预措施: topotecan hydrochloride (Drug)
Arm III (CTC)
Patients receive vincristine, topotecan hydrochloride, and cyclophosphamide as in arm I.
干预措施: vincristine sulfate (Drug)
Arm III (CTC)
Patients receive vincristine, topotecan hydrochloride, and cyclophosphamide as in arm I.
干预措施: cyclophosphamide (Drug)
结局指标
主要结局
The Occurrence of Limiting Toxicity in an Eligible and Evaluable Patient.
时间窗: First 2 courses (42 days) of therapy
Limiting toxicity defined as Any Grade IV hematological toxicities lasting longer than 7 days, myelosuppression causing delays \> 14 days in delivery of therapy, \> Grade 3 thromboembolic events, \> Grade 3 bleeding events, \> Grade 2 hypertension, \> Grade 2 proteinuria.
Time to Disease Progression in Patients Receiving VTC With or Without Bevacizumab
时间窗: Maximum of 5 years after enrollment
Time from enrollment to disease progression, death, second malignant neoplasm, or last patient follow-up whichever occurs first. Patients who experience disease progression, death or second malignant neoplasm will be considered to have experienced an event; otherwise the patient will be considered censored at last follow-up.
次要结局
未报告次要终点