PanDox: Feasibility of Enhanced Chemotherapy Delivery to Non-resectable Primary Pancreatic Tumours Using Thermosensitive Liposomal Doxorubicin (ThermoDox®) and Focused Ultrasound
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- To quantify the enhancement in intratumoural doxorubicin concentration when delivered with ThermoDox® and mild hyperthermia generated non-invasively by focused ultrasound (FUS) compared to free drug alone
研究概览
简要总结
This study will combine focused ultrasound to generate heat, and a heat-sensitive chemotherapy drug (ThermoDox®), delivered into the blood of participants with non-resectable pancreatic cancer. We will compare this to standard delivery of chemotherapy - the drug Doxorubicin given into the blood without the addition of ultrasound. We aim to determine whether the novel approach to delivering chemotherapy with heating the tumour by focused ultrasound can enhance the amount of drug delivered to pancreatic tumours. This will be measured by analysing a biopsy sample of treated tumour.
详细描述
PanDox is a phase I prospective, non-randomised, safety cohort study with the primary aim to quantify the enhancement in delivery of intratumoural doxorubicin concentration in pancreatic tumours, for a given systemic dose. Drug release is triggered from systemically circulating ThermoDox® by highly localized hyperthermia induced by extracorporeal ultrasound-guided FUS device at sub-ablative powers.
The study will have all patients recruited from a single UK site (Oxford) and will comprise adult patients with non-resectable pancreatic adenocarcinomas.
Patients referred to Oncology will have cross-sectional imaging reviewed for suitability of tumour targeting, and MDT (Multi-Disciplinary Team) agreement before being approached. Screening comprises clinical history and examination, routine blood tests, cardiac assessment by ECG (Electrocardiogram) and ECHO (Echocardiogram), abdominal ultrasound examination and a pre-operative assessment to ensure suitability for general anaesthetic. Suitability of potential target lesions will be based on ultrasound examination.
The study has an open label design with all participants receiving a single dose of either standard doxorubicin OR systemic ThermoDox® with ultrasound guided FUS targeted at a pancreas tumour using the Model JC200 Focused Ultrasound Tumour Therapeutic System (Haifu Medical, JC200), which is clinically approved (CE-marked) for tumour therapy in Europe and China.
Participants who successfully complete screening will be allocated to either Arm A (doxorubicin) or Arm B (ThermoDox® with FUS) based on pre-determined checklist. This is to ensure feasibility and safety of patients to undergo FUS. It also permits patients who have successfully completed screening, but who are not suitable for FUS, to participate in a clinical trial.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 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
- •Able to give informed consent prior to any screening procedures being performed and is able and willing to comply with the protocol and its requirements.
- •Male or Female, aged 18 years or above.
- •Prior histological confirmation of pancreatic adenocarcinoma
- •Non-resectable or metastatic (stage IV)
- •The primary pancreatic lesion measuring at least 1.5cm minimum diameter and amenable to EUS biopsy sampling
- •ECOG performance status 0-1 (Appendix 1)
- •Left ventricular ejection fraction (LVEF) ≥ 50% as determined by echocardiogram
- •Willing to allow his or her General Practitioner and Consultant, if appropriate, to be notified of participation in the trial.
- •Life expectancy of at least 3 months
- •Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use highly effective contraception during the trial and for 6 months thereafter.
- •Participant has clinically acceptable laboratory results during screening window:
- •Lab Test Value required Haemoglobin (Hb) (transfusion to achieve this allowed) ≥ 9g/dL Neutrophils ≥ 1.5 109/L Platelet count ≥ 100 109/L ALT ≤ 2.5 x ULN Alkaline phosphatase ≤ 5 x ULN Serum Bilirubin (stenting to achieve this allowed) ≤ 1.5 x ULN Creatinine Clearance (Calculated by Cockcroft-Gault criteria) ≥ 50ml/min INR <1.5 unless taking oral anticoagulant (this to be stopped at least 1 week prior to biopsy, at which point this INR limit will then apply)
排除标准
- •A patient will be ineligible for inclusion in this study if any of the following criteria apply:
- •Significant renal or hepatic impairment.
- •Unstable ischemic heart disease, cardiac dysrhythmias, coronary/peripheral artery bypass graft or cerebrovascular accident within 6 months prior to starting treatment
- •Uncontrolled arterial hypertension despite medical treatment.
- •Ongoing congestive heart failure or cardiac dysrhythmias of NCI CTCAE Grade ≥2 or uncontrolled atrial fibrillation.
- •On-going significant infection (chest, urine, blood, intra-abdominal).
- •Uncontrolled diabetes.
- •Scheduled elective surgery or other procedures requiring general anaesthesia during the trial.
- •Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such procedure
- •Previous targeted therapies to the pancreatic adenocarcinoma (including radiofrequency ablation or radiotherapy)
- •History of other malignancy less than 3 years before the diagnosis of current cancer, EXCLUDING the following: Non-melanoma skin cancer, in situ carcinoma of the cervix treated surgically with curative intent, other malignant tumours that have been treated curatively and patient is deemed disease-free
- •Endocrine therapy - patients with prostate cancer may continue to receive endocrine therapy to maintain castrate levels of androgens
- •Known allergic reactions to any of the drugs or liposomal components or intravenous imaging agents used in this study
- •Resting ECG with QTc >480msec at 2 or more time points within a 24h period (using Fredericia correction).
- •Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that the investigator considers would make the patient a poor trial candidate, would impart excess risk associated with study participation or drug administration or could interfere with protocol compliance or the interpretation of trial results.
- •Female participant who is pregnant, lactating or planning pregnancy during the course of the trial. However, those female patients who have a negative serum pregnancy test before enrolment and agree to use one highly effective form of contraception (oral, injected or implanted hormonal contraception or intrauterine device) in addition to condom plus spermicide, for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.
- •Male patients with partners of child-bearing potential unless they agree to take measures not to father children by using one form of highly effective contraception including: oral, injected or implanted hormonal contraception or intra-uterine device in addition to condom plus spermicide, during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel) during the trial and for six months afterwards to prevent exposure to the foetus or neonate.
- •Participants who have participated in another research trial involving an investigational product in the past 12 weeks.
- •Severe immunologic defect or compromised bone marrow function.
- •Patients who are serologically positive for Hepatitis B, Hepatitis C or HIV.
- •Previous doxorubicin and epirubicin must not have exceeded 450 mg/m2 and 900 mg/m2, respectively.
- •Patients who have a contraindication to MRI scans, for example patients who have a cardiac pacemaker, will be excluded from Arm B (as per Arm Assignment criteria, Appendix 3 of protocol).
研究组 & 干预措施
Arm A (Doxorubicin)
a single intravenous dose of Doxorubicin, 50 mg/ m2 in 250 mL of normal saline or 5% dextrose over a 30-min infusion is delivered as per local practice.
干预措施: Doxorubicin (Drug)
Arm B (ThermoDox + Focused Ultrasound)
under general anaesthetic, patients receive FUS, which is moved through the target tumour volume to raise the bulk tumour temperature above the thermal release threshold. At presumed target temperature, a single intravenous dose of ThermoDox®, 50 mg/ m2 in 250 mL of normal saline or 5% dextrose over a 30-min infusion is delivered concurrently to FUS, in line with the pharmacy manual provided by the manufacturer. FUS will continue following infusion, for no longer than two hours from infusion commencing.
干预措施: Focused Ultrasound (Device)
Arm B (ThermoDox + Focused Ultrasound)
under general anaesthetic, patients receive FUS, which is moved through the target tumour volume to raise the bulk tumour temperature above the thermal release threshold. At presumed target temperature, a single intravenous dose of ThermoDox®, 50 mg/ m2 in 250 mL of normal saline or 5% dextrose over a 30-min infusion is delivered concurrently to FUS, in line with the pharmacy manual provided by the manufacturer. FUS will continue following infusion, for no longer than two hours from infusion commencing.
干预措施: ThermoDox (Drug)
结局指标
主要结局
To quantify the enhancement in intratumoural doxorubicin concentration when delivered with ThermoDox® and mild hyperthermia generated non-invasively by focused ultrasound (FUS) compared to free drug alone
时间窗: within 30 hours of intervention
A statistically significant enhancement in concentration of total intra-tumoural doxorubicin from tumour biopsies at the targeted tumour site receiving drug with FUS compared to drug alone. Quantification of inter-tumoural drug release will be achieved using a GLP HPLC (High Pressure Liquid Chromatography) assay
次要结局
- Number of adverse events related to ThermoDox® and FUS compared to free drug alone(for 21 days post intervention)
- Change in radiologically-assessed tumour activity in patients treated with ThermoDox® and FUS, compared to free drug alone(Pre-treatment, and 14 days post treatment)
- Change in patient symptom scores in patients with pancreatic cancer treated with of ThermoDox® and FUS compared to those treated with doxorubicin(Pre-treatment, within 30 hours post treatment, 14 days and 21 days post treatment)