TAQE: Targeting Ischemia-Induced Autophagy Dependence in Hepatocellular Carcinoma

Sponsor

VA Office of Research and Development (U.S. Fed)

Overall Status

Not yet recruiting

CT.gov ID

NCT05842174

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Drug: Hydroxychloroquine Drug: Lipiodol Drug: Placebo	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

93 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Sep 1, 2023

Anticipated Primary Completion Date :

Aug 31, 2027

Anticipated Study Completion Date :

Aug 31, 2028

Arms and Interventions

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

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

Drug: Placebo

Placebo will be administered orally for 6 weeks following the procedure to patients in arm 2

Outcome Measures

Primary Outcome Measures

Local Progression Free Survival [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)