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PanDox: Targeted Doxorubicin in Pancreatic Tumours (PanDox)

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ClinicalTrials.gov Identifier: NCT04852367
Recruitment Status : Recruiting
First Posted : April 21, 2021
Last Update Posted : August 27, 2021
Sponsor:
Collaborators:
National Institute for Health Research, United Kingdom
Celsion
Information provided by (Responsible Party):
University of Oxford

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Pancreatic Ductal Adenocarcinoma Pancreatic Cancer Stage IV Pancreatic Cancer Non-resectable Pancreatic Cancer Metastatic Device: Focused Ultrasound Drug: Doxorubicin Drug: ThermoDox Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: prospective non-randomised safety cohort study
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: PanDox: Feasibility of Enhanced Chemotherapy Delivery to Non-resectable Primary Pancreatic Tumours Using Thermosensitive Liposomal Doxorubicin (ThermoDox®) and Focused Ultrasound
Actual Study Start Date : June 16, 2021
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Active Comparator: 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.
Drug: Doxorubicin
Doxorubicin infusion

Experimental: 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.
Device: Focused Ultrasound
Focused ultrasound targetting the tumour at subablative powers, to facilitate drug release

Drug: ThermoDox
ThermoDox infusion




Primary Outcome Measures :
  1. 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 [ Time Frame: 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


Secondary Outcome Measures :
  1. Number of adverse events related to ThermoDox® and FUS compared to free drug alone [ Time Frame: for 21 days post intervention ]

    No statistically significant increase in low grade (I-II) adverse events related to drug+FUS cf drug alone, according to toxicities graded by NCI CTCAE v5.0

    No statistically significant increase in high grade (III and above) adverse events related to drug+FUS cf drug alone, according to toxicities graded by NCI CTCAE v5.0


  2. Change in radiologically-assessed tumour activity in patients treated with ThermoDox® and FUS, compared to free drug alone [ Time Frame: Pre-treatment, and 14 days post treatment ]
    A statistically significant reduction in tumour activity between targeted tumour sites receiving drug with FUS, compared to drug alone, as determined either by SUVmax or by PERCIST response criteria (SULpeak) on FDG-PET-CT scans performed pre- and post intervention.

  3. Change in patient symptom scores in patients with pancreatic cancer treated with of ThermoDox® and FUS compared to those treated with doxorubicin [ Time Frame: Pre-treatment, within 30 hours post treatment, 14 days and 21 days post treatment ]
    No significant difference in patient symptom scores following treatment with FUS with ThermoDox® vs Doxorubicin alone, according to a pancreatic cancer-specific Quality of Life questionnaire (EORTC QLQ - PAN26)


Other Outcome Measures:
  1. To assess effects of ThermoDox® and FUS treatment compared to free drug alone on pancreatic tumour biomarkers [ Time Frame: Taken pre-treatment and 21 days post-treatment ]
    A statistically significant reduction in tumour markers CA19-9 and CEA as measured pre and post treatment, in plasma samples



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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)

Exclusion Criteria:

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04852367


Contacts
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Contact: PanDox Trial Team +44 (0)1865 227198 octo-pandox@oncology.ox.ac.uk

Locations
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United Kingdom
Oxford University Hospitals NHS Trust Recruiting
Oxford, United Kingdom, OX3 7LE
Principal Investigator: Mark R Middleton, PhD, FRCP         
Sponsors and Collaborators
University of Oxford
National Institute for Health Research, United Kingdom
Celsion
Investigators
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Principal Investigator: Mark Middleton Consultant Medical Oncologist and Professor of Experimental Cancer Medicine
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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT04852367    
Other Study ID Numbers: OCTO_095
First Posted: April 21, 2021    Key Record Dates
Last Update Posted: August 27, 2021
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Plan to anonymise patient data (assigned trial number) and results to be published in peer reviewed journal as anonymous data points/averaged data

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Oxford:
Focused ultrasound
Doxorubicin
Thermodox
Thermosensitive Liposome
Drug delivery
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action