Potentiation of Cisplatin-based Chemotherapy by Digoxin in Advanced Unresectable Head and Neck Cancer Patients
试验速览
- 阶段
- 1 期
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Appearance of the grade 3 or 4 (Adverse Events graded by NCI CTC version 4.0) clinical or biological toxicity of the combination of digoxin to cisplatin-based chemotherapy during the study
研究概览
简要总结
Introduction: Patients with primary unresectable advanced head and neck squamous cell carcinomas (HNSCC) have a poor prognosis with a median survival of 22 months (Hauswald H Radiat Oncol 2011). They are usually treated with induction chemotherapy followed by radiochemotherapy or platinum-based concomitant radiochemotherapy. Most patients achieve an objective clinical response contrasting with a high rate of local recurrence and distant metastases in the year following radiochemotherapy (Argiris A Ann Oncol 2011). Improvement of the efficacy of chemotherapy remains therefore a major clinical goal for this group of patients. During the past years, the investigators demonstrated that some conventional chemotherapeutics (anthracycline, oxaliplatin...) induce a type of "immunogenic" cell death (ICD) characterized by the exposure of calreticulin on the tumor cell surface, the secretion of ATP and the release of high-mobility group box 1 (HMGB1) resulting in activation of tumor immunity (Galluzzi L Nat Rev Drug Discov 2012). The investigators recently showed that the Na/K-ATPase inhibitor, digoxin, favors ICD, when combined with cisplatin, a drug known not to induce ICD. In preclinical models, a synergy between cisplatin and digoxin which led to a significant therapeutic improvement (Menger L Sci Transl Med 2012) has been observed. This effect seems to be mediated by the immune system as the combined therapy induced intratumor T cell infiltration producing cytokines (Menger L Sci Transl Med 2012).
Hypothesis: Based on our preclinical data, the hypothesis is that adding digoxin to the conventional cisplatin based induction chemotherapy regimen in unresectable advanced HNSCC will increase the efficacy of this therapy via the induction of anti-tumor immunity.
Objectives:
Main: the primary objective is to assess the clinical and biological safety of the combination of digoxin to cisplatin-based chemotherapy.
Secondary: The secondary objectives are to investigate biological markers of efficacy by analyzing the recruitment of functional T cells in tumour biopsies after treatment with the combination of digoxin and chemotherapy.
详细描述
Introduction:
Patients with primary unresectable advanced head and neck squamous cell carcinomas (HNSCC) have a poor prognosis with a median survival of 22 months (Hauswald H Radiat Oncol 2011). They are usually treated with induction chemotherapy followed by radiochemotherapy or platinum-based concomitant radiochemotherapy. Most patients achieve an objective clinical response contrasting with a high rate of local recurrence and distant metastases in the year following radiochemotherapy (Argiris A Ann Oncol 2011). Improvement of the efficacy of chemotherapy remains therefore a major clinical goal for this group of patients. During the past years, it was demonstrate that some conventional chemotherapeutics (anthracycline, oxaliplatin...) induce a type of "immunogenic" cell death (ICD) characterized by the exposure of calreticulin on the tumor cell surface, the secretion of ATP and the release of HMGB1 resulting in activation of tumor immunity (Galluzzi L Nat Rev Drug Discov 2012). The Na/K-ATPase inhibitor, digoxin, favors ICD, when combined with cisplatin, a drug known not to induce ICD. In preclinical models, a synergy was observed between cisplatin and digoxin which led to a significant therapeutic improvement (Menger L Sci Transl Med 2012). This effect seems to be mediated by the immune system as the combined therapy induced intratumor T cell infiltration producing cytokines (Menger L Sci Transl Med 2012).
Hypothesis:
Based on our preclinical data, the hypothesis is that adding digoxin to the conventional cisplatin based induction chemotherapy regimen in unresectable advanced HNSCC will increase the efficacy of this therapy via the induction of anti-tumor immunity.
Objectives:
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
- 19 Years 至 69 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients of both sexes, with primary unresectable, advanced (stage III-IV) HNSCC to be treated by cisplatin-based chemotherapy.
- •Life expectancy > 12 months.
- •Age > 18 and < 70
- •WHO PS : 0-2
- •Signed informed consent
- •creatinine clearance : MDRD > 60ml/min/1,73m2
- •Affiliation to the French Social Security Health Care plan
排除标准
- •Difficulties planned for the 6 month follow up during the study period
- •Swallowing disorder preventing digoxin treatment
- •Severe aortic stenosis or idiopathic hypertrophic subaortic stenosis at the pretreatment echocardiography.
- •Hypertrophic or dilated or restrictive cardiomyopathy at the pretreatment echocardiography
- •Severe cardiac condition contraindicating the use of digoxin (Constrictive pericarditis, acute cor pulmonale, myocarditis...)
- •Acute Myocardial infarction within the past 3 months
- •Severe ventricular arrhythmias on ECG at rest including frequent ventricular extrasystoles, ventricular tachycardia/fibrillation
- •Second and third degree atrio-ventricular block or sick sinus syndrome on resting ECG without pacemaker
- •Wolf Parkinson White syndrome on ECG at rest
- •Renal insufficiency (estimated glomerular filtration rate by the MDRD formula < 60 ml/min/1.73m2)
- •Liver insufficiency (Child-Pugh grades B and C)
- •Severe uncorrected electrolyte disturbances (hypercalcemia, hypokaliemia, hypomagnesemia...)
- •Known hypersensitivity reaction to digoxin
- •Compelling indication for continuous use of digoxin
- •Use of drugs contraindicated with oral digoxin (Midodrine, calcium salt, millepertuis, sultopride, phenytoin, yellow fever vaccine, live attenuated vaccine)
- •Absence of effective contraception methods for men and women during the study and 6 months after the end of the study
- •Pregnancy and breastfeeding at inclusion, during the study and 6 months after the end of the study
- •HPV positive tumors (These tumors are associated with very good response to chemotherapy alone)
- •History of another cancer which treatment is ongoing
研究组 & 干预措施
DIGHANC
Patients meeting all inclusion /exclusion criteria, will be given 3 cycles of the following regimen: 1) digoxin (0.25 mg/day) for a 7-day period (digitalization time) from Day 1 to Day 7; 2) chemotherapy regimen TPF protocol from Day 8 to D12 (continuous perfusion of fluorouracil for 120h, Cisplatin at Day 10 and Docetaxel at Day 11) administered in combination with digoxin 0.25 mg/day from Day 8 to Day 9; 3) a 15-day period off treatment.
干预措施: Digoxin (Drug)
结局指标
主要结局
Appearance of the grade 3 or 4 (Adverse Events graded by NCI CTC version 4.0) clinical or biological toxicity of the combination of digoxin to cisplatin-based chemotherapy during the study
时间窗: 18 weeks
次要结局
- Radiological response after chemotherapy(At 18 weeks)
- Biological efficacy: monitored by analysis of T cells recruitment(At 18 weeks)
- Clinical response after chemotherapy by fibroscopy (tumor seize)(At 18 weeks)
- Biological efficacy: monitored by analysis of subpopulations of T cells(At 18 weeks)
- Biological efficacy: expression of IFN gamma assessed by quantitative RT-PCR assay(At 18 weeks)
- Biological efficacy: expression of IL-17 assessed by quantitative RT-PCR assay(At 18 weeks)
- Progression Free Survival (PFS): Death or recurrence (clinical and/or radiological analysis)(10 days after each cycle of chemotherapy and two weeks after the end of the third cycle of chemotherapy)