A Phase 2, Investigator Initiated Study to Determine the Safety, Efficacy and CNS Penetration of TH-302 in Recurrent High Grade Astrocytoma Following Bevacizumab
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- Time to Progression
研究概览
简要总结
The Primary Objectives are:
- To determine the extent by which TH-302 is able to penetrate the blood brain barrier and affect tumor tissue
- To assess the safety of single dose TH-302 in patients with high grade glioma undergoing surgery
- To assess the safety of TH-302 in combination with bevacizumab for patients with high grade glioma
- To determine the MTD and DLT(s) of TH-302 in combination with bevacizumab
The Secondary Objectives are:
To determine the progression-free survival with or without debulking craniotomy for patients treated with combination bevacizumab and TH-302 following recurrence on single agent bevacizumab
详细描述
Single center, dose-escalation, prospective study with TH-302 single dose at 575 mg/m2 or placebo administered preoperatively, followed by postoperative combination therapy bevacizumab at 10mg/kg every 2 weeks and TH-302 at 240 - 670 mg/m2 every 2 weeks (4 week cycle) until disease progression. Subjects will be randomized (2:1) to receive pre-operative dose of TH-302 (surgical subjects only). Subjects not receiving surgery will receive combination therapy of bevacizumab at 10 mg/kg every 2 weeks and TH-302 at 240-670 mg/m2 every 2 weeks (4 week cycle) starting from Cycle 1, Day 1 until disease progression.
This study will use a classic dose escalation design to determine the MTD of TH-302 when used in combination with bevacizumab. The dose of TH-302 will be escalated in cohorts of 3-6 subjects. The initial dose of TH-302 will be 240 mg/m2. A dose level minus 1 will be built into the study in the event that subjects experience excessive toxicity at Dose Level 1. Dose escalation will continue to 340 mg/m2 and 670 mg/m2.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Single (Participant)
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
- •At least 18 years of age
- •Ability to understand the purposes and risks of the study and has signed a written informed consent form approved by the investigator's IRB/Ethics Committee
- •Histologically confirmed high grade astrocytoma
- •Progression following both standard combined modality treatment with radiation and temozolomide chemotherapy, as well as anti-angiogenic therapy (ie, bevacizumab)
- •Recovered from toxicities of prior therapy to grade 0 or 1
- •ECOG performance status of 0 or 1
- •Life expectancy of at least 3 months
- •Acceptable liver function
- •Acceptable renal function
- •Acceptable hematologic status
- •All women of childbearing potential must have a negative serum pregnancy test and male and female subjects must agree to use effective means of contraception (surgical sterilization or the use or barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 6 months after the last dose
排除标准
- •The subject is receiving warfarin (or other coumarin derivatives) and is unable to switch to low molecular weight heparin (LMWH) before the first dose of study drug.
- •The subject has evidence of acute intracranial or intratumoral hemorrhage either by MRI or computerized tomography (CT) scan. Subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin are eligible.
- •The subject is unable to undergo MRI scan (eg, has pacemaker).
- •The subject has received enzyme-inducing anti-epileptic agents within 14 days of study drug (eg, carbamazepine, phenytoin, phenobarbital, primidone).
- •The subject has not recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Grade ≤ 1 from AEs (except alopecia, anemia and lymphopenia) due to surgery, antineoplastic agents, investigational drugs, or other medications that were administered prior to study drug.
- •The subject has evidence of wound dehiscence
- •Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, symptoms due to hypoxemia or oxygen saturation <90% by pulse oximetry after a 2 minute walk) or in the opinion of the investigator any physiological state likely to cause normal tissue hypoxia
- •The subject is pregnant or breast-feeding.
- •The subject has serious intercurrent illness
- •The subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding.
- •The subject has received any of the following prior anticancer therapy:
- •Non-standard radiation therapy such as brachytherapy, systemic radioisotope therapy (RIT), or intra-operative radiotherapy (IORT). Note: stereotactic radiosurgery (SRS) is allowed
- •Antiangiogenic agents whose primary mode of action is through the VEGF signaling within 21 days prior to first dose of study drug (surgical subjects only)
- •Non-bevacizumab systemic therapy (including investigational agents and small-molecule kinase inhibitors) or non-cytotoxic hormonal therapy (eg, tamoxifen) within 7 days or 5 half-lives, whichever is shorter, prior first dose of study drug
- •Biologic agents (antibodies, immune modulators, vaccines, cytokines) within 21 days prior to first dose of study drug
- •Nitrosoureas or mitomycin C within 42 days, or metronomic/protracted low-dose chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days, prior to first dose of study drug
- •Prior treatment with carmustine wafers
- •Prior treatment with TH-302
研究组 & 干预措施
Cohort 1
Subjects received TH-302 single dose at 575 mg/m2 or placebo administered preoperative in a 2:1 randomization and were then administered 240 mg/m2 of TH-302 post-operative.
干预措施: TH-302 preoperative (Drug)
Cohort 1
Subjects received TH-302 single dose at 575 mg/m2 or placebo administered preoperative in a 2:1 randomization and were then administered 240 mg/m2 of TH-302 post-operative.
干预措施: Placebo (Drug)
Cohort 1
Subjects received TH-302 single dose at 575 mg/m2 or placebo administered preoperative in a 2:1 randomization and were then administered 240 mg/m2 of TH-302 post-operative.
干预措施: TH-302 (escalating) with bevacizumab 10mg/kg (Drug)
Cohort 2
Surgical subjects will receive TH-302 at 340 mg/m2 every 2 weeks (4 week cycles) starting after surgery from Cycle 1, Day 1 until disease progression.
干预措施: TH-302 preoperative (Drug)
Cohort 2
Surgical subjects will receive TH-302 at 340 mg/m2 every 2 weeks (4 week cycles) starting after surgery from Cycle 1, Day 1 until disease progression.
干预措施: TH-302 (escalating) with bevacizumab 10mg/kg (Drug)
Cohort 3
Surgical or Non-Surgical subjects will receive TH-302 at 480 mg/m2 every 2 weeks (4 week cycles) starting after surgery from Cycle 1, Day 1 until disease progression.
干预措施: TH-302 (escalating) with bevacizumab 10mg/kg (Drug)
Cohort 4
Non-surgical subjects will receive a dose up to 670 mg/m2 of TH-302
干预措施: TH-302 (escalating) with bevacizumab 10mg/kg (Drug)
结局指标
主要结局
Time to Progression
时间窗: 2 years
Time from initiation study until radiographic progression by RANO criteria
次要结局
未报告次要终点