Ignite Creation Date:
2024-05-06 @ 6:57 PM
Last Modification Date:
2024-10-26 @ 2:57 PM
Study NCT ID:
NCT05842174
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-02-13
First Post:
2023-04-05
Brief Title:
Targeting Ischemia-Induced Autophagy Dependence in Hepatocellular Carcinoma
Sponsor:
VA Office of Research and Development
Organization:
VA Office of Research and Development
Study Overview
Official Title:
Targeting Ischemia-Induced Autophagy Dependence in Hepatocellular Carcinoma Through Image-guided Locoregional Therapy
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
TAQE
Brief Summary:
Trans-arterial chemoembolization TACE is the most commonly used therapy for patients with unresectable hepatocellular carcinoma HCC TACE is a minimally invasive procedure that involves placing a catheter into the artery in the liver that feeds the tumor administering chemotherapeutics and then blocking the artery with embolics in order to kill tumor cells by depriving them of essential oxygen and nutrients While TACE has a proven survival benefit local recurrence is common and long-term survival rates are poor Prior studies demonstrate that HCC cells survive the oxygen and nutrient deprivation through autophagy a process of cellular self-eating to provide nutrients required for survival The proposed project will leverage this dependency to develop a novel approach to TACE that integrates autophagy inhibition to improve therapeutic response by increasing tumor cell killing and enhancing anti-tumor immunity
Detailed Description:
Surgical resection or liver transplantation remain the only curative options for patients with hepatocellular carcinoma HCC However fewer than 20 of patients with HCC are candidates for resection Transarterial embolization with or without chemotherapy TACE is an endovascular locoregional embolotherapy that involves hepatic artery embolization with intra-arterial infusion of a chemotherapeutic agent TACE is considered the standard of care for treating unresectable HCC in the remaining 80 of patients While TACE has a proven survival benefit local recurrence is common and long-term survival rates are poor Moreover only 44 of treated HCCs demonstrate extensive necrosis on pathology following TACE indicating tumor cells develop an adaptive metabolic stress response MSR enabling their survival under TACE-induced nutrient and oxygen deprivation
In preliminary studies the investigators have demonstrated that HCC cells are pre-programmed to survive TACE-induced ischemia through enhanced function of autophagy Moreover TACE-induced ischemia results in quiescence in surviving HCC cells and a dependence on autophagy As such these data demonstrate that TACE offers a unique opportunity to constrain metabolic phenotypes in order to generate this targetable dependency in HCC The proposed project will build on this prior work to 1 study a novel TACE paradigm which targets this ischemia-induced dependency on autophagy using hydroxychloroquine HCQ and 2 characterizes the efficacy and evolution of autophagy inhibition using HCQ as well as associated alterations in anti-tumor immunity To achieve these goals this submission proposes a first in human early phase prospective clinical trial to assess the safety and efficacy of autophagy inhibition using intra-arterial IA HCQ with TAE followed by maintenance of autophagy inhibition with daily oral HCQ for 6 weeks following embolization Follow-up tumor biopsies and serum sampling 3-4 and 5-6 weeks after embolization will inform on the on-target efficacy of autophagy inhibition and its effect on the tumor microenvironment and immune response
This trial will pursue three aims 1 to establish the clinical safety of the combination of the autophagy inhibitor HCQ with TAE to treat patients with intermediate stage HCC phase 1 2 to compare the short-term efficacy of HCQ with TAE versus TAE alone in patients with intermediate stage HCC phase 2 and 3 to characterize differences in local and systemic immune modulation following TAE as compared to IA HCQ TAE
In preliminary studies the investigators have demonstrated that HCC cells are pre-programmed to survive TACE-induced ischemia through enhanced function of autophagy Moreover TACE-induced ischemia results in quiescence in surviving HCC cells and a dependence on autophagy As such these data demonstrate that TACE offers a unique opportunity to constrain metabolic phenotypes in order to generate this targetable dependency in HCC The proposed project will build on this prior work to 1 study a novel TACE paradigm which targets this ischemia-induced dependency on autophagy using hydroxychloroquine HCQ and 2 characterizes the efficacy and evolution of autophagy inhibition using HCQ as well as associated alterations in anti-tumor immunity To achieve these goals this submission proposes a first in human early phase prospective clinical trial to assess the safety and efficacy of autophagy inhibition using intra-arterial IA HCQ with TAE followed by maintenance of autophagy inhibition with daily oral HCQ for 6 weeks following embolization Follow-up tumor biopsies and serum sampling 3-4 and 5-6 weeks after embolization will inform on the on-target efficacy of autophagy inhibition and its effect on the tumor microenvironment and immune response
This trial will pursue three aims 1 to establish the clinical safety of the combination of the autophagy inhibitor HCQ with TAE to treat patients with intermediate stage HCC phase 1 2 to compare the short-term efficacy of HCQ with TAE versus TAE alone in patients with intermediate stage HCC phase 2 and 3 to characterize differences in local and systemic immune modulation following TAE as compared to IA HCQ TAE
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| IO1CX002542 | OTHER_GRANT | VA CSRD | None |