Thermodox + MR-HIFU for Cancer

No longer recruiting at 1 trial location

Overseen By General HIFU trials

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's National Research Institute

Must not be taking: Anticancer agents, Investigational agents

Disqualifiers: Pregnancy, Serious infections, Organ dysfunction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Up to 18 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for individuals with solid tumors unresponsive to other therapies. It combines a chemotherapy drug, Lyso-thermosensitive Liposomal Doxorubicin (ThermoDox), with MR-HIFU, a technique using focused ultrasound waves to heat and destroy cancer cells. The aim is to determine if this combination can effectively target and treat difficult-to-manage tumors. Individuals with recurrent or treatment-resistant solid tumors, located in areas accessible by ultrasound, may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in cancer care.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop all current medications. However, you cannot receive any other anti-cancer therapy (chemotherapy, biological therapy, radiation therapy) while participating in this trial.

Will I have to stop taking my current medications?

The trial requires that you stop taking any other anti-cancer therapies, including chemotherapy, biological therapy, and radiation therapy, before participating. However, the protocol does not specify about other non-cancer medications, so it's best to discuss your current medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Lyso-thermosensitive Liposomal Doxorubicin (LTLD) holds promise for safety. One study used LTLD to deliver doxorubicin, a cancer drug, directly to tumors when heated. This method targets the tumor, reducing harm to healthy tissues. The study found that side effects were generally mild and similar to those of traditional doxorubicin, already used in cancer treatment.

For the MR-guided high-intensity focused ultrasound (MR-HIFU) component, research indicates it is a safe and noninvasive way to treat tumors. It targets the tumor directly, avoiding harm to nearby healthy tissues. Studies have reported that MR-HIFU is well-tolerated by patients, with few side effects.

Together, these treatments aim to improve safety by focusing on the tumor and sparing healthy tissue. However, since this trial is in an early phase, ongoing monitoring for any new safety information remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Thermodox and MR-HIFU for cancer treatment because it offers a unique approach compared to traditional chemotherapy. Unlike standard treatments, which typically involve systemic chemotherapy that affects the whole body, this method uses lyso-thermosensitive liposomal doxorubicin (LTLD), a targeted drug delivery system. This system releases the chemotherapy drug doxorubicin directly at the tumor site when heated, minimizing damage to healthy tissues. Additionally, MR-HIFU provides precise hyperthermia and ablation, enhancing drug delivery and effectiveness. This approach aims to increase treatment precision and potentially reduce side effects, which is why it's generating excitement among researchers.

What evidence suggests that ThermoDox + MR-HIFU might be an effective treatment for cancer?

This trial will evaluate the combination of Lyso-thermosensitive Liposomal Doxorubicin (LTLD) and Magnetic Resonance-Guided High Intensity Focused Ultrasound (MR-HIFU) for cancer treatment. Research has shown that LTLD is promising when combined with heat, as studies have found that this combination can kill more cancer cells and help patients with certain tumors live longer. Heat aids the drug in reaching tumors more effectively.

MR-HIFU is a noninvasive treatment that targets tumors without harming nearby healthy tissue. It has treated various cancers by precisely heating and destroying tumor cells. Using LTLD and MR-HIFU together might be effective because both utilize heat to enhance cancer treatment. Early research suggests this combination could powerfully treat difficult tumors. ^{1 2 5 6 7}

Who Is on the Research Team?

AeRang Kim, MD, PhD

Principal Investigator

Children's National Research Institute

Are You a Good Fit for This Trial?

This trial is for individuals aged 12 or older with certain types of solid tumors that have not responded to standard treatments. Participants must be in a stable health condition, with specific requirements for blood cell counts and organ function. They should have at least one tumor accessible to HIFU treatment and no other curative options available.

Inclusion Criteria

I have recovered from side effects of all my previous cancer treatments.

My kidney function is normal or near normal.

I can do most activities but need help with some.

Exclusion Criteria

I have a tumor in my skull.

I cannot stay still for long periods during treatments.

You are currently taking other medications for cancer treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive LTLD infusion followed by MR-HIFU hyperthermia and ablation therapy in 21-day cycles

Up to 18 weeks

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Lyso-thermosensitive Liposomal Doxorubicin
• Magnetic Resonance-Guided High Intensity Focused Ultrasound

Trial Overview The study tests the combination of LTLD (a type of chemotherapy) with MR-HIFU, which uses magnetic resonance imaging to guide focused ultrasound for heating and destroying cancer cells. The goal is to see if this approach is effective in treating relapsed or refractory solid tumors.

How Is the Trial Designed?

Group I: All Patients Experimental Treatment 2 Interventions

LTLD 50 mg/m2 will be administered intravenously over 30 minutes on day 1 of every 21-day cycle. MR-HIFU hyperthermia will follow infusion (+/- 30 minutes) for one hour to a target area with a target temperature of 40-45°C followed by ablation therapy (\>55°C). The HIFU hyperthermia regimen will have a duration of at least 60 minutes and will then be followed by ablation therapy. Patients may receive up to a total of 6 cycles. Subsequent treatment cycles may treat alternative target lesions. Disease status will be evaluated using standard imaging techniques (CT/MR) post each cycle.

Lyso-thermosensitive Liposomal Doxorubicin is already approved in United States, European Union for the following indications:

Approved in United States as ThermoDox for:

• Liver cancer

Approved in European Union as ThermoDox for:

• Liver cancer

Who Is Running the Clinical Trial?

Children's National Research Institute

Lead Sponsor

Trials

227

Recruited

258,000+

Published Research Related to This Trial

In a study using a rabbit tumor model, extending mild hyperthermia duration to 40 minutes significantly increased the concentration of doxorubicin in heated tumors by nearly six times compared to unheated tumors.

The therapeutic ratio improved from 1.9-fold to 4.4-fold when comparing drug delivery to the heated tumor versus the heart, indicating that longer heating enhances localized drug delivery without increasing systemic exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longer heating duration increases localized doxorubicin deposition and therapeutic index in Vx2 tumors using MR-HIFU mild hyperthermia and thermosensitive liposomal doxorubicin. Bing, C., Patel, P., Staruch, RM., et al.[2020]

In a study involving 12 rabbits with Vx2 tumours, the combination of thermosensitive liposomal doxorubicin (TLD) and mild hyperthermia from MR-HIFU significantly reduced tumour growth compared to TLD alone, with four out of six rabbits surviving to the study's end point of 60 days.

The treatment was well-tolerated, showing no significant drug or hyperthermia-related toxicity, as indicated by stable body weight and blood parameters, suggesting a safe approach for localized drug delivery in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperthermia-mediated doxorubicin release from thermosensitive liposomes using MR-HIFU: therapeutic effect in rabbit Vx2 tumours. Staruch, RM., Hynynen, K., Chopra, R.[2022]

In a study involving 12 rats with tumors, high-intensity focused ultrasound (HIFU) significantly improved the distribution and accumulation of temperature-sensitive liposomes containing doxorubicin within the tumor, leading to more homogeneous drug delivery compared to control tumors.

HIFU treatment not only enhanced the immediate release of the encapsulated contrast agent but also allowed doxorubicin to spread further from blood vessels into the tumor, potentially increasing its therapeutic effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Magnetic resonance guided high-intensity focused ultrasound mediated hyperthermia improves the intratumoral distribution of temperature-sensitive liposomal doxorubicin. de Smet, M., Hijnen, NM., Langereis, S., et al.[2018]

This study investigates the use of Lyso-Thermosensitive Liposomal Doxorubicin (LTLD) combined with mild local hyperthermia to enhance drug delivery specifically to breast tumors while minimizing systemic toxicity, involving 12 chemotherapy-naïve patients with stage IV HER2-negative breast cancer.

The primary focus is on assessing the safety, tolerability, and feasibility of this approach, with the potential to improve local tumor control and reduce the need for extensive surgery in advanced breast cancer cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I feasibility study of Magnetic Resonance guided High Intensity Focused Ultrasound-induced hyperthermia, Lyso-Thermosensitive Liposomal Doxorubicin and cyclophosphamide in de novo stage IV breast cancer patients: study protocol of the i-GO study. de Maar, JS., Suelmann, BBM., Braat, MNGJA., et al.[2021]

Lyso-thermosensitive liposomal doxorubicin (LTLD) is the first heat-activated liposomal drug carrier tested in human clinical trials, designed to deliver chemotherapy directly to heated tumors.

LTLD works by accumulating in tumors and releasing its cytotoxic agent when activated by heat, which enhances the concentration of the drug at the target site, potentially improving treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug development of lyso-thermosensitive liposomal doxorubicin: Combining hyperthermia and thermosensitive drug delivery. Borys, N., Dewhirst, MW.[2022]

The combination of radiofrequency ablation (RFA) and lyso-thermosensitive liposomal doxorubicin (LTLD) resulted in a significantly larger coagulation volume compared to RFA alone, indicating enhanced tumor destruction in patients with unresectable hepatocellular carcinoma (HCC).

Patients receiving the combination treatment had a longer overall survival (mean 68.5 months) compared to those treated with RFA alone (mean 46.0 months), suggesting that this combined approach may improve clinical outcomes without increasing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thermosensitive liposomal doxorubicin plus radiofrequency ablation increased tumor destruction and improved survival in patients with medium and large hepatocellular carcinoma: A randomized, double-blinded, dummy-controlled clinical trial in a single center. Yang, W., Lee, JC., Chen, MH., et al.[2022]

The maximum tolerated dose (MTD) of lyso-thermosensitive liposomal doxorubicin (LTLD) was determined to be 50 mg/m², with dose-limiting toxicity observed at 60 mg/m², indicating a safe dosage for use in combination with radiofrequency ablation.

LTLD was associated with manageable side effects, specifically reversible neutropenia and leukopenia, suggesting it can be safely administered alongside RF ablation for treating liver tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of heat-deployed liposomal doxorubicin during radiofrequency ablation for hepatic malignancies. Wood, BJ., Poon, RT., Locklin, JK., et al.[2023]

Temperature-sensitive liposomes (TSLs) can effectively release doxorubicin and an MRI contrast agent when heated to 42°C, while remaining stable at normal body temperature (37°C), indicating a controlled drug delivery mechanism.

In a proof-of-concept study with rat tumors, the release of doxorubicin was successfully monitored using MRI, showing that the concentration of the contrast agent correlated with the drug uptake, suggesting a promising method for tracking drug delivery in real-time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Magnetic resonance imaging of high intensity focused ultrasound mediated drug delivery from temperature-sensitive liposomes: an in vivo proof-of-concept study. de Smet, M., Heijman, E., Langereis, S., et al.[2022]

Lyso-thermosensitive liposomes (LTSLs) can effectively release chemotherapy drugs when exposed to mild hyperthermia, and this study demonstrates a successful method for inducing and maintaining this hyperthermia in large tissue volumes using ultrasound-guided focused ultrasound (FUS).

In a first-in-human clinical trial (TARDOX), this targeted hyperthermia approach led to localized chemo-ablation in liver tumors, showcasing the potential for LTSLs in enhancing drug delivery and treatment efficacy in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Large-Volume Hyperthermia for Safe and Cost-Effective Targeted Drug Delivery Using a Clinical Ultrasound-Guided Focused Ultrasound Device. Lyon, PC., Mannaris, C., Gray, M., et al.[2021]

Combining low temperature sensitive liposomes (LTSLs) with magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) significantly increases doxorubicin concentrations in tumors, achieving 7.6 times more drug in the tumor compared to free doxorubicin.

The LTSL + MR-HIFU treatment not only enhances the overall drug concentration but also improves the distribution of doxorubicin throughout the tumor, reaching both the core and periphery, which could lead to more effective cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Image-guided drug delivery with magnetic resonance guided high intensity focused ultrasound and temperature sensitive liposomes in a rabbit Vx2 tumor model. Ranjan, A., Jacobs, GC., Woods, DL., et al.[2022]

Citations

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Lyso-Thermosensitive Liposomal Doxorubicin for ... One promising strategy to improve the efficacy of intravesical chemotherapy is the use of hyperthermia as an adjunct to therapy. Synergistic cytotoxic effects ...

2. aacrjournals.org aacrjournals.org/clincancerres/article/24/1/73/15127/Phase-III-HEAT-Study-Adding-Lyso-Thermosensitive

Phase III HEAT Study Adding Lyso-Thermosensitive ... This study evaluates the safety and efficacy of RFA alone and RFA combined with a heat-sensitive liposomal doxorubicin, LTLD, in patients with intermediate-size ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0928098725000235

Ultrasound-assisted efficient targeting of doxorubicin to the ... Premature drug release is the primary hindrance to the effective function of the lyso-thermosensitive liposomes (LTSLs) of doxorubicin (Dox) ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10054554/

Recent Preclinical and Clinical Progress in Liposomal ... Despite the improvement in safety properties of liposomal encapsulated DOX (in Doxil and Myocet), the efficacy is not superior to conventional DOX.

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Thermosensitive liposomal doxorubicin plus radiofrequency... Thermosensitive liposomal doxorubicin plus radiofrequency ablation increased tumor destruction and improved survival in patients with medium and large ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03749850

Study Details | NCT03749850 | Image-guided Targeted ... In this phase I feasibility study, the investigators evaluate the combination of lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox) with local ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6073884/

Safety and feasibility of ultrasound-triggered targeted drug ... We aimed to assess the safety and feasibility of targeted release and enhanced delivery of doxorubicin to solid tumours from thermosensitive liposomes ...