Cargando…
Clinical trial protocol for PanDox: a phase I study of targeted chemotherapy delivery to non-resectable primary pancreatic tumours using thermosensitive liposomal doxorubicin (ThermoDox®) and focused ultrasound
BACKGROUND: The dense stroma of pancreatic ductal adenocarcinomas is a major barrier to drug delivery. To increase the local drug diffusion gradient, high doses of chemotherapeutic agent doxorubicin can be released from thermally-sensitive liposomes (ThermoDox®) using ultrasound-mediated hyperthermi...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10517508/ https://www.ncbi.nlm.nih.gov/pubmed/37741968 http://dx.doi.org/10.1186/s12885-023-11228-z |
_version_ | 1785109337715245056 |
---|---|
author | Spiers, Laura Gray, Michael Lyon, Paul Sivakumar, Shivan Bekkali, Noor Scott, Shaun Collins, Linda Carlisle, Robert Wu, Feng Middleton, Mark Coussios, Constantin |
author_facet | Spiers, Laura Gray, Michael Lyon, Paul Sivakumar, Shivan Bekkali, Noor Scott, Shaun Collins, Linda Carlisle, Robert Wu, Feng Middleton, Mark Coussios, Constantin |
author_sort | Spiers, Laura |
collection | PubMed |
description | BACKGROUND: The dense stroma of pancreatic ductal adenocarcinomas is a major barrier to drug delivery. To increase the local drug diffusion gradient, high doses of chemotherapeutic agent doxorubicin can be released from thermally-sensitive liposomes (ThermoDox®) using ultrasound-mediated hyperthermia at the tumour target. PanDox is designed as a Phase 1 single centre study to investigate enhancing drug delivery to adult patients with non-operable pancreatic ductal adenocarcinomas. The study compares a single cycle of either conventional doxorubicin alone or ThermoDox® with focused ultrasound-induced hyperthermia for targeted drug release. METHODS: Adults with non-resectable pancreatic ductal adenocarcinoma are allocated to receive a single cycle of either doxorubicin alone (Arm A) or ThermoDox® with focused ultrasound-induced hyperthermia (Arm B), based on patient- and tumour-specific safety conditions. Participants in Arm B will undergo a general anaesthetic and pre-heating of the tumour by extra-corporal focused ultrasound (FUS). Rather than employing invasive thermometry, ultrasound parameters are derived from a patient-specific treatment planning model to reach the 41 °C target temperature for drug release. ThermoDox® is then concurrently infused with further ultrasound exposure. Tumour biopsies at the targeted site from all patients are analysed post-treatment using high performance liquid chromatography to quantify doxorubicin delivered to the tumour. The primary endpoint is defined as a statistically significant enhancement in concentration of total intra-tumoural doxorubicin, comparing samples from patients receiving liposomal drug with FUS to free drug alone. Participants are followed for 21 days post-treatment to assess secondary endpoints, including radiological assessment to measure changes in tumour activity by Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST) criteria, adverse events and patient-reported symptoms. DISCUSSION: This early phase study builds on previous work targeting tumours in the liver to investigate whether enhancement of chemotherapy delivery using ultrasound-mediated hyperthermia can be translated to the stroma-dense environment of pancreatic ductal adenocarcinoma. If successful, it could herald a new approach towards managing these difficult-to-treat tumours. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04852367. Registered 21(st) April 2022. EudraCT number: 2019–003950-10 (Registered 2019) Iras Project ID: 272253 (Registered 2019) Ethics Number: 20/EE/0284. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-023-11228-z. |
format | Online Article Text |
id | pubmed-10517508 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-105175082023-09-24 Clinical trial protocol for PanDox: a phase I study of targeted chemotherapy delivery to non-resectable primary pancreatic tumours using thermosensitive liposomal doxorubicin (ThermoDox®) and focused ultrasound Spiers, Laura Gray, Michael Lyon, Paul Sivakumar, Shivan Bekkali, Noor Scott, Shaun Collins, Linda Carlisle, Robert Wu, Feng Middleton, Mark Coussios, Constantin BMC Cancer Study Protocol BACKGROUND: The dense stroma of pancreatic ductal adenocarcinomas is a major barrier to drug delivery. To increase the local drug diffusion gradient, high doses of chemotherapeutic agent doxorubicin can be released from thermally-sensitive liposomes (ThermoDox®) using ultrasound-mediated hyperthermia at the tumour target. PanDox is designed as a Phase 1 single centre study to investigate enhancing drug delivery to adult patients with non-operable pancreatic ductal adenocarcinomas. The study compares a single cycle of either conventional doxorubicin alone or ThermoDox® with focused ultrasound-induced hyperthermia for targeted drug release. METHODS: Adults with non-resectable pancreatic ductal adenocarcinoma are allocated to receive a single cycle of either doxorubicin alone (Arm A) or ThermoDox® with focused ultrasound-induced hyperthermia (Arm B), based on patient- and tumour-specific safety conditions. Participants in Arm B will undergo a general anaesthetic and pre-heating of the tumour by extra-corporal focused ultrasound (FUS). Rather than employing invasive thermometry, ultrasound parameters are derived from a patient-specific treatment planning model to reach the 41 °C target temperature for drug release. ThermoDox® is then concurrently infused with further ultrasound exposure. Tumour biopsies at the targeted site from all patients are analysed post-treatment using high performance liquid chromatography to quantify doxorubicin delivered to the tumour. The primary endpoint is defined as a statistically significant enhancement in concentration of total intra-tumoural doxorubicin, comparing samples from patients receiving liposomal drug with FUS to free drug alone. Participants are followed for 21 days post-treatment to assess secondary endpoints, including radiological assessment to measure changes in tumour activity by Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST) criteria, adverse events and patient-reported symptoms. DISCUSSION: This early phase study builds on previous work targeting tumours in the liver to investigate whether enhancement of chemotherapy delivery using ultrasound-mediated hyperthermia can be translated to the stroma-dense environment of pancreatic ductal adenocarcinoma. If successful, it could herald a new approach towards managing these difficult-to-treat tumours. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04852367. Registered 21(st) April 2022. EudraCT number: 2019–003950-10 (Registered 2019) Iras Project ID: 272253 (Registered 2019) Ethics Number: 20/EE/0284. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-023-11228-z. BioMed Central 2023-09-23 /pmc/articles/PMC10517508/ /pubmed/37741968 http://dx.doi.org/10.1186/s12885-023-11228-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Study Protocol Spiers, Laura Gray, Michael Lyon, Paul Sivakumar, Shivan Bekkali, Noor Scott, Shaun Collins, Linda Carlisle, Robert Wu, Feng Middleton, Mark Coussios, Constantin Clinical trial protocol for PanDox: a phase I study of targeted chemotherapy delivery to non-resectable primary pancreatic tumours using thermosensitive liposomal doxorubicin (ThermoDox®) and focused ultrasound |
title | Clinical trial protocol for PanDox: a phase I study of targeted chemotherapy delivery to non-resectable primary pancreatic tumours using thermosensitive liposomal doxorubicin (ThermoDox®) and focused ultrasound |
title_full | Clinical trial protocol for PanDox: a phase I study of targeted chemotherapy delivery to non-resectable primary pancreatic tumours using thermosensitive liposomal doxorubicin (ThermoDox®) and focused ultrasound |
title_fullStr | Clinical trial protocol for PanDox: a phase I study of targeted chemotherapy delivery to non-resectable primary pancreatic tumours using thermosensitive liposomal doxorubicin (ThermoDox®) and focused ultrasound |
title_full_unstemmed | Clinical trial protocol for PanDox: a phase I study of targeted chemotherapy delivery to non-resectable primary pancreatic tumours using thermosensitive liposomal doxorubicin (ThermoDox®) and focused ultrasound |
title_short | Clinical trial protocol for PanDox: a phase I study of targeted chemotherapy delivery to non-resectable primary pancreatic tumours using thermosensitive liposomal doxorubicin (ThermoDox®) and focused ultrasound |
title_sort | clinical trial protocol for pandox: a phase i study of targeted chemotherapy delivery to non-resectable primary pancreatic tumours using thermosensitive liposomal doxorubicin (thermodox®) and focused ultrasound |
topic | Study Protocol |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10517508/ https://www.ncbi.nlm.nih.gov/pubmed/37741968 http://dx.doi.org/10.1186/s12885-023-11228-z |
work_keys_str_mv | AT spierslaura clinicaltrialprotocolforpandoxaphaseistudyoftargetedchemotherapydeliverytononresectableprimarypancreatictumoursusingthermosensitiveliposomaldoxorubicinthermodoxandfocusedultrasound AT graymichael clinicaltrialprotocolforpandoxaphaseistudyoftargetedchemotherapydeliverytononresectableprimarypancreatictumoursusingthermosensitiveliposomaldoxorubicinthermodoxandfocusedultrasound AT lyonpaul clinicaltrialprotocolforpandoxaphaseistudyoftargetedchemotherapydeliverytononresectableprimarypancreatictumoursusingthermosensitiveliposomaldoxorubicinthermodoxandfocusedultrasound AT sivakumarshivan clinicaltrialprotocolforpandoxaphaseistudyoftargetedchemotherapydeliverytononresectableprimarypancreatictumoursusingthermosensitiveliposomaldoxorubicinthermodoxandfocusedultrasound AT bekkalinoor clinicaltrialprotocolforpandoxaphaseistudyoftargetedchemotherapydeliverytononresectableprimarypancreatictumoursusingthermosensitiveliposomaldoxorubicinthermodoxandfocusedultrasound AT scottshaun clinicaltrialprotocolforpandoxaphaseistudyoftargetedchemotherapydeliverytononresectableprimarypancreatictumoursusingthermosensitiveliposomaldoxorubicinthermodoxandfocusedultrasound AT collinslinda clinicaltrialprotocolforpandoxaphaseistudyoftargetedchemotherapydeliverytononresectableprimarypancreatictumoursusingthermosensitiveliposomaldoxorubicinthermodoxandfocusedultrasound AT carlislerobert clinicaltrialprotocolforpandoxaphaseistudyoftargetedchemotherapydeliverytononresectableprimarypancreatictumoursusingthermosensitiveliposomaldoxorubicinthermodoxandfocusedultrasound AT wufeng clinicaltrialprotocolforpandoxaphaseistudyoftargetedchemotherapydeliverytononresectableprimarypancreatictumoursusingthermosensitiveliposomaldoxorubicinthermodoxandfocusedultrasound AT middletonmark clinicaltrialprotocolforpandoxaphaseistudyoftargetedchemotherapydeliverytononresectableprimarypancreatictumoursusingthermosensitiveliposomaldoxorubicinthermodoxandfocusedultrasound AT coussiosconstantin clinicaltrialprotocolforpandoxaphaseistudyoftargetedchemotherapydeliverytononresectableprimarypancreatictumoursusingthermosensitiveliposomaldoxorubicinthermodoxandfocusedultrasound |