A Phase II Trial of Oral Pazopanib Plus Oral Topotecan Metronomic Antiangiogenic Therapy for Recurrent Glioblastoma Multiforme (A)Without Prior Bevacizumab Exposure and (B) After Failing Prior Bevacizumab
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 35
- 试验地点
- 1
- 主要终点
- Proportion of Patients That Have Progressive Survival (PFS) at Six Months From Patient Registration for Bevacizumab Naive Patients and PFS at 3 Months for Patients With Prior Bevacizumab Treatment
研究概览
简要总结
Background:
Glioblastoma is the most common and most aggressive type of malignant brain tumor. The drug pazopanib is used to treat people with a type of kidney cancer. Topotecan is used to treat lung cancer. Both topotecan and pazopanib have individually been used to treat patients with glioblastoma and some anti-tumor activity has been found. Researchers want to see if these two drugs together may be able to help people with glioblastoma.
Objectives:
To learn if pazopanib with topotecan can help control glioblastoma. Also, to study the safety of this drug combination.
Eligibility:
Adults at least 18 years old whose glioblastoma has returned after treatment.
Design:
Participants will be screened with:
Medical history
Physical exam
Blood and urine tests
Brain computed tomography (CT) or magnetic resonance imaging (MRI) For these, participants lay in a machine that takes pictures.
Chest CT scan or x-ray
Heart electrocardiogram (EKG)
A questionnaire about quality of life
Participants will be assigned to a study group.
Participants will take the study drugs for 28-day cycles for up to 1 year. They will take capsules of topotecan by mouth once every day. They will take tablets of pazopanib by mouth once every day.
Participants will write in a diary the times they take the study drugs.
Participants will have several study visits during each cycle. These may include
Blood pressure measurement
Blood and urine tests
EKG
Physical exam and/or neurological exam
Brain MRI or CT scan to check the status of the disease
A symptom questionnaire
At the end of treatment, participants will have a physical exam. They may have blood drawn.
Participants will have follow-up calls once every 3 months to check.
详细描述
Background
- Glioblastoma (GBM) is the most common primary brain tumor. With optimal treatment,consisting of focal radiotherapy with concurrent chemotherapy, followed by adjuvant chemotherapy, median survival is 14.6 months. Most patients have evidence of tumor progression within one year of diagnosis despite treatment. At progression, treatment options are limited and mostly ineffective.
- Recently, bevacizumab was approved for recurrent GBM patients who fail bevacizumab indicate a short survival, on the order of 10 weeks, an approximate PFS 3 and 6 months of 0%.
- Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGFR), Platelet-derived growth factor receptors (PDGFR), and c-Kit, and was recently Food and Drug Administration (FDA) approved for advanced renal cell carcinoma.
- Topotecan is an orally bioavailable topoisomerase I and Hypoxia-inducible factor 1 (HIF-1) alpha inhibitor with reasonably high central nervous system (CNS)/cerebrospinal fluid (CSF) penetration
- Recent pre-clinical reports have begun to argue for the clinical testing of metronomic chemotherapy administration in various cancers. The theory of improved activity of Pazopanib + Topotecan administered metronomically is based on targeting tumor vasculature (both existing capillary endothelial cells and circulating bone marrow derived endothelial cell precursors), immune modulation, as well as tumor cell HIF-1 alpha inhibition, and the induction of Deoxyribonucleic acid (DNA) damage. Further support for the combination comes from recent data tying drug-induced VEGF inhibition to the induction of HIF-1 alpha activity in GBM suggesting possible synergy between Pazopanib and Topotecan
- The combination of Topotecan and Pazopanib has been directly demonstrated as active in
animal models
Objectives
- 6 month progression free survival rate for recurrent glioblastoma (rGBM) patients with no prior bevacizumab exposure treated with pazopanib and topotecan (Group A).
- 3 month progression free survival rate for rGBM patients with prior bevacizumab exposure treated with pazopanib and topotecan (Group B).
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
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 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
Glioblastoma or Gliosarcoma With No Prior Bevacizumab Exposure
Topotecan .25 mg and pazopanib 600 mg are administered orally daily until progression, up to one year.
干预措施: topotecan (Drug)
Glioblastoma or Gliosarcoma With No Prior Bevacizumab Exposure
Topotecan .25 mg and pazopanib 600 mg are administered orally daily until progression, up to one year.
干预措施: pazopanib (Drug)
Glioblastoma or Gliosarcoma With Prior Bevacizumab Exposure
Topotecan .25 mg and pazopanib 600 mg are administered orally daily until progression, up to one year.
干预措施: topotecan (Drug)
Glioblastoma or Gliosarcoma With Prior Bevacizumab Exposure
Topotecan .25 mg and pazopanib 600 mg are administered orally daily until progression, up to one year.
干预措施: pazopanib (Drug)
结局指标
主要结局
Proportion of Patients That Have Progressive Survival (PFS) at Six Months From Patient Registration for Bevacizumab Naive Patients and PFS at 3 Months for Patients With Prior Bevacizumab Treatment
时间窗: six months from patient registration for bevacizumab naive patients, and 3 months from patient registration for patients with prior bevacizumab treatment
PFS was evaluated using the Kaplan-Meier product-limit survival curve methodology. For participants with no prior bevacizumab exposure, PFS is defined as 2 or more participants who are progression free at 6 months. For participants with prior bevacizumab exposure, PFS is defined as 1 or more participants who are progression free at 3 months. Progression is a 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) or clear worsening of evaluable disease or the appearance of any new lesions.
次要结局
- Mean Symptom Interference Score Between Responders and Non-responders at Baseline and by Cycle(Baseline, and Cycles 1-6)
- Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)(Date treatment consent signed to date off study, approximately 20 months and 18 days for the first Arm/Group, and 28 months and 23 days for the second Arm/Group.)
- Overall Survival(From date of registration to date of death due to any cause, up to 5 years.)
- Mean Symptom Severity Score Between Responders and Non-responders at Baseline and by Cycle(Baseline, and Cycles 1-6)
研究者
Kevin Camphausen, M.D.
Principal Investigator
National Cancer Institute (NCI)