A Phase I Trial Testing TH-302, a Tumor-selective Hypoxia-Activated Cytotoxic Prodrug, in Combination With Preoperative Chemoradiotherapy in Patients With Distal Esophageal and Esophago-gastric Junction Adenocarcinoma
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- 主要终点
- Dose Limiting Toxicity (DLT )
研究概览
简要总结
Open-label, single-center phase 1 study of an investigational agent TH-302 and standard chemoradiotherapy with a 3+3 dose escalation design through 3 dose levels.
详细描述
Rationale:
Neoadjuvant chemoradiotherapy followed by surgery remains the standard of care for esophageal cancer patients. Both limited local response as well as distant metastases are a common cause of treatment failure. Combining TH-302 with chemo-radiotherapy may improve outcome by:
- Direct cytotoxic effect of TH-302 on hypoxic cells of the primary tumor without enhancing normal tissue toxicity.
- Increase the sensitivity of the primary tumor to chemo-radiotherapy by decreasing the hypoxic fraction.
- A bystander cytotoxic effect of TH-302 on normoxic cells adjacent to hypoxic cells of the primary tumor.
- A potential cytotoxic effect on micro-metastasis.
Objective:
Primary objective
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Histologically proven adenocarcinoma of the esophagus
- •Age >18 years
- •UICC T2-4 N0-2 M0, potentially resectable disease
- •Patient discussed at tumour board (multidisciplinary team meeting)
- •No evident tumor invasion in nearby regions like aorta or trachea
- •WHO performance status 0-2
- •Less than 10 % weight loss in the past 6 months
- •Laboratory requirements within 7 days prior to enrollment (start chemoradiotherapy):
- •Haematology:
- •haemoglobin >10g/dl
- •absolute neutrophils ≥ 1.5 x 109/L
- •platelets ≥ 100x109/L
- •Biochemistry:
- •bilirubin within institutional normal limits
- •AST(SGOT)/ALT (SGPT) ≤ 2.5 institutional upper limit
- •Creatinine clearance ≥ 60 ml/min
- •Willing and able to comply with the study prescriptions
- •No history of prior thoracic radiotherapy
- •No severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia
- •Women should not be pregnant or lactating
- •No known infection with HIV, hepatitis B or C or any other active infection
- •Normal ECG with careful evaluation of QT/QTc
- •Have given written informed consent before patient registration
排除标准
- •Recent (< 3 months) severe cardiac disease (arrhythmia, congestive heart failure, infarction)
- •Patients with difficult peripheral intravenous access
- •History of prior thoracic radiotherapy
- •severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia
- •Women who are pregnant or lactating
- •Known infection with HIV, hepatitis B or C or any other active infection
研究组 & 干预措施
treatment
treatment arm: TH-302 pre-treatment day 4 and weekly during treatment. 5 x carboplatin and paclitaxel, radiotherapy: 23 x 1.8Gy HX4 scans day 1 and day 8,surgery 6-10 weeks after chemo-radiotherapy
干预措施: TH-302 (Drug)
treatment
treatment arm: TH-302 pre-treatment day 4 and weekly during treatment. 5 x carboplatin and paclitaxel, radiotherapy: 23 x 1.8Gy HX4 scans day 1 and day 8,surgery 6-10 weeks after chemo-radiotherapy
干预措施: HX4 scan (Other)
treatment
treatment arm: TH-302 pre-treatment day 4 and weekly during treatment. 5 x carboplatin and paclitaxel, radiotherapy: 23 x 1.8Gy HX4 scans day 1 and day 8,surgery 6-10 weeks after chemo-radiotherapy
干预措施: Carboplatin (Drug)
treatment
treatment arm: TH-302 pre-treatment day 4 and weekly during treatment. 5 x carboplatin and paclitaxel, radiotherapy: 23 x 1.8Gy HX4 scans day 1 and day 8,surgery 6-10 weeks after chemo-radiotherapy
干预措施: Paclitaxel (Drug)
treatment
treatment arm: TH-302 pre-treatment day 4 and weekly during treatment. 5 x carboplatin and paclitaxel, radiotherapy: 23 x 1.8Gy HX4 scans day 1 and day 8,surgery 6-10 weeks after chemo-radiotherapy
干预措施: Radiotherapy (Radiation)
treatment
treatment arm: TH-302 pre-treatment day 4 and weekly during treatment. 5 x carboplatin and paclitaxel, radiotherapy: 23 x 1.8Gy HX4 scans day 1 and day 8,surgery 6-10 weeks after chemo-radiotherapy
干预措施: surgery (Procedure)
结局指标
主要结局
Dose Limiting Toxicity (DLT )
时间窗: within 30days postoperative
To determine the DLT and define the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D)
次要结局
- hypoxia response in tumor(day 4 and day 8)
- rate of pathological Complete Remission (pCR)(within 30 days after surgery)
- histopathologic negative circumferential resection margin (CRM) rate(within 30 days after surgery)
- Local recurrence rate(within 30 days after surgery)
- distance recurrence rate(within 30 days after surgery)
- Progression free survival(within 30 days after surgery)
- overall survival(within 30 days after surgery)
- metabolic response(within 30 days after surgery)