Autophagy Inhibition + TACE for Liver Cancer

(TAQE Trial)

Overseen By David E Kaplan, MD MSc

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: VA Office of Research and Development

Disqualifiers: QT prolongation, Retinopathy, Pregnancy, others

Compensation: Varies

Number of Visits: 4

Duration: 6 weeks

93 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the drug Hydroxychloroquine in combination with TACE for liver cancer?

Research shows that combining chloroquine, an autophagy inhibitor, with TACE (a liver cancer treatment) enhances its anticancer effects in a rabbit liver tumor model. Additionally, inhibiting autophagy with hydroxychloroquine has been shown to increase the effectiveness of other cancer treatments, suggesting potential benefits in liver cancer therapy. ^{1 2 3 4 5}

Is the combination of Autophagy Inhibition and TACE for Liver Cancer safe for humans?

Hydroxychloroquine, an autophagy inhibitor, is generally considered safe for humans but can cause eye-related side effects, such as toxic maculopathy (damage to the central part of the retina). It has been used in various clinical trials for different conditions, including cancer, to evaluate its safety and effects. ^{2 3 5 6 7}

How does the drug Hydroxychloroquine combined with TACE differ from other liver cancer treatments?

This treatment is unique because it combines Hydroxychloroquine, an autophagy inhibitor, with TACE (a procedure that blocks blood supply to the tumor), potentially enhancing the anticancer effects by preventing cancer cells from using their self-defense mechanism to survive under stress. ^{1 3 7 8 9}

What is the purpose of this trial?

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.

Research Team

Terence P Gade, MD PhD

Principal Investigator

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Eligibility Criteria

This trial is for adults diagnosed with a specific stage of liver cancer (BCLC B HCC) who are about to undergo TACE therapy. They must have a tumor at least 3 cm wide, be in relatively good health (Childs Pugh Turcotte A/B7, Performance Status 0), and agree to follow the study rules. People can't join if they're pregnant or breastfeeding, have had previous treatments on the target lesion, suffer from certain eye conditions or heart issues, or have other serious medical problems.

Inclusion Criteria

My liver cancer is at least 3 cm wide and meets specific imaging criteria.

I am 18 or older with a diagnosis of intermediate-stage liver cancer and referred for a specific liver cancer treatment.

Informed of investigational nature of this study with provision of signed and dated informed consent form

Exclusion Criteria

I am not pregnant or breastfeeding.

QT prolongation on ECG

Contraindication to contrast enhanced MRI or metallic implant within the liver

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intra-arterial hydroxychloroquine with transarterial embolization followed by oral hydroxychloroquine for 6 weeks

6 weeks

1 visit (in-person) for embolization, daily oral medication

Follow-up

Participants are monitored for safety and effectiveness after treatment, including tumor biopsies and serum sampling

6 months

Follow-up visits at 3-4 weeks and 5-6 weeks post-treatment

Treatment Details

Interventions

• Hydroxychloroquine
• Lipiodol
• Placebo
• TACE

Trial Overview The study tests whether adding Hydroxychloroquine—an autophagy inhibitor—to standard TACE treatment improves outcomes by killing more cancer cells and boosting anti-tumor immunity compared to TACE alone. Some patients will receive Lipiodol with Hydroxychloroquine while others get Lipiodol with a placebo.

Participant Groups

Group I: Transarterial Embolization with Hydroxychloroquine Experimental Treatment 2 Interventions

Intra-arterial hydroxychloroquine in Lipiodol + transarterial embolization followed by oral hydroxychloroquine

Group II: Transarterial Embolization without Hydroxychloquine Placebo Group 2 Interventions

Intra-arterial Lipiodol + transarterial embolization followed by oral placebo

Hydroxychloroquine is already approved in United States, European Union for the following indications:

Approved in United States as Plaquenil for:

• Malaria
• Rheumatoid Arthritis
• Systemic Lupus Erythematosus

Approved in European Union as Plaquenil for:

• Malaria
• Rheumatoid Arthritis
• Systemic Lupus Erythematosus

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Findings from Research

A 71-year-old woman experienced retinal toxicity after taking hydroxychloroquine for 5 years, highlighting the risk of ocular side effects, particularly toxic maculopathy, associated with this medication.

The only effective treatment for hydroxychloroquine toxicity is to discontinue the drug, but the toxic effects may continue to progress due to the slow clearance of the medication, emphasizing the importance of regular eye examinations before and during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retinal toxicity secondary to Plaquenil therapy. Hanna, B., Holdeman, NR., Tang, RA., et al.[2016]

References

1. Australia pubmed.ncbi.nlm.nih.gov

Chloroquine promotes the anticancer effect of TACE in a rabbit VX2 liver tumor model. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Autophagy Agents in Clinical Trials for Cancer Therapy: A Brief Review. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma. [2023]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Effects of chronic exposure of hydroxychloroquine/chloroquine on the risk of cancer, metastasis, and death: a population-based cohort study on patients with connective tissue diseases. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Retinal toxicity secondary to Plaquenil therapy. [2016]

7. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and Pharmacodynamic Assessment of Hydroxychloroquine in Breast Cancer. [2023]

8. Germany pubmed.ncbi.nlm.nih.gov

Blocking autophagy with chloroquine aggravates lipid accumulation and reduces intracellular energy synthesis in hepatocellular carcinoma cells, both contributing to its anti-proliferative effect. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Principles and current strategies for targeting autophagy for cancer treatment. [2022]