Targeting Ischemia-Induced Autophagy Dependence in Hepatocellular Carcinoma (TAQE)

April 15, 2026 updated by: VA Office of Research and Development

Targeting Ischemia-Induced Autophagy Dependence in Hepatocellular Carcinoma Through Image-guided Locoregional Therapy

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 (TA(C)E) is an endovascular locoregional embolotherapy that involves hepatic artery embolization with intra-arterial infusion of a chemotherapeutic agent. TA(C)E is considered the standard of care for treating unresectable HCC in the remaining 80% of patients. While TA(C)E 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 TA(C)E, indicating tumor cells develop an adaptive metabolic stress response (MSR) enabling their survival under TA(C)E-induced nutrient and oxygen deprivation.

In preliminary studies, the investigators have demonstrated that HCC cells are pre-programmed to survive TA(C)E-induced ischemia through enhanced function of autophagy. Moreover, TA(C)E-induced ischemia results in quiescence in surviving HCC cells and a dependence on autophagy. As such, these data demonstrate that TA(C)E 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 TA(C)E 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 Type

Interventional

Enrollment (Estimated)

93

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104-4551
        • Recruiting
        • Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
        • Contact:
        • Principal Investigator:
          • Terence P Gade, MD PhD
        • Sub-Investigator:
          • David E. Kaplan, MD MSc

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Male or female, aged 18 years, meeting criteria for diagnosis of BCLC B HCC and referred to undergo TACE
  • HCC measuring 3 cm in minimum transverse diameter and meets LI-RADS 5 criteria based on cross-sectional imaging as determined by a board-certified, sub-specialty trained radiologist
  • Childs Pugh Turcotte A/B7, Performance Status 0
  • Informed of investigational nature of this study with provision of signed and dated informed consent form
  • Stated willingness to comply with all study procedures and availability for the duration of the study

Exclusion Criteria:

  • QT prolongation on ECG
  • Retinopathy on ophthalmologic examination

  • Females who are pregnant or breast feeding at the time of screening will not be eligible for this study

    • a serum or urine pregnancy test will be performed in women of child-bearing potential at screening
  • Prior LRT or systemic therapy to the target lesion
  • Contraindication to contrast enhanced MRI or metallic implant within the liver.
  • HCQ allergy, porphyria, uncontrolled psoriasis, and existing retinopathy
  • Lesion not amenable to biopsy based on pre-TACE imaging as determined by treating interventional radiologist
  • Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subject's safety or successful participation in the study)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Transarterial Embolization with Hydroxychloroquine
Intra-arterial hydroxychloroquine in Lipiodol + transarterial embolization followed by oral hydroxychloroquine
Drug: Hydroxychloroquine
Hydroxychloroquine to be administered intra-arterially at time of transarterial embolization as well as orally for 6 weeks following the procedure
Drug: Lipiodol
Lipiodol is an FDA-approved drug delivered agent and embolic which is administered as standard of care for transarterial embolization for hepatocellular carcinoma. Lipiodol will be administered intra-arterially in both arms at the time of procedure.
Placebo Comparator: Transarterial Embolization without Hydroxychloquine
Intra-arterial Lipiodol + transarterial embolization followed by oral placebo
Drug: Lipiodol
Lipiodol is an FDA-approved drug delivered agent and embolic which is administered as standard of care for transarterial embolization for hepatocellular carcinoma. Lipiodol will be administered intra-arterially in both arms at the time of procedure.
Drug: Placebo
Placebo will be administered orally for 6 weeks following the procedure to patients in arm 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Local Progression Free Survival
Time Frame: 6 months following treatment
Local progression free survival will be determined on a per lesion basis based on follow-up cross-sectional imaging and modified response evaluation criteria in solid tumors
6 months following treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Office of Research and Development

Investigators

  • Principal Investigator: Terence P Gade, MD PhD, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2026

Primary Completion (Estimated)

September 30, 2029

Study Completion (Estimated)

October 15, 2030

Study Registration Dates

First Submitted

April 5, 2023

First Submitted That Met QC Criteria

April 21, 2023

First Posted (Actual)

May 3, 2023

Study Record Updates

Last Update Posted (Actual)

April 16, 2026

Last Update Submitted That Met QC Criteria

April 15, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ONCC-008-22S
  • IO1CX002542 (Other Grant/Funding Number: VA CSR&D)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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