Thermodox + MR-HIFU for Cancer

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

Trial Summary

What is the purpose of this trial?

This trial uses a heat-activated drug and a non-invasive heating technology to treat patients with hard-to-treat or recurring tumors. The drug is activated by heat, and then higher heat is used to destroy the tumor cells.

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.

What data supports the idea that Thermodox + MR-HIFU for Cancer is an effective treatment?

The available research shows that Thermodox combined with MR-HIFU is effective in increasing the concentration of the cancer-fighting drug doxorubicin directly in tumors. In a study with rabbits, this combination resulted in significantly higher levels of doxorubicin in tumors compared to using the drug alone. Another study in rats demonstrated that the treatment effectively released the drug at the target site when heated, showing a good correlation between the drug uptake and the temperature increase. These findings suggest that Thermodox + MR-HIFU can deliver more of the drug to the tumor, potentially making it more effective than traditional methods. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Thermodox + MR-HIFU for cancer?

Research shows that using Thermodox (a heat-sensitive form of the chemotherapy drug doxorubicin) with MR-HIFU (a focused ultrasound technique) can increase the concentration of the drug in tumors, leading to better tumor control. In studies with animals and some human trials, this combination has shown improved effectiveness compared to using the drug alone. ^{1 2 3 4 5}

What safety data is available for Thermodox + MR-HIFU treatment?

The safety data for Thermodox (Lyso-thermosensitive Liposomal Doxorubicin, LTLD) combined with MR-HIFU includes several studies. A Phase I feasibility study in breast cancer patients aims to increase local doxorubicin levels without increasing systemic toxicity. Another Phase I study focused on determining the maximum tolerated dose and dose-limiting toxicity of LTLD during radiofrequency ablation for hepatic malignancies. These studies suggest that LTLD can be safely administered with hyperthermia techniques like MR-HIFU, with a focus on optimizing local drug delivery while minimizing systemic side effects. ^{1 3 5 6 7}

Is Thermodox + MR-HIFU safe for humans?

Thermodox (Lyso-thermosensitive Liposomal Doxorubicin) combined with MR-HIFU has been studied in clinical trials, and the main goal was to find a safe dose and understand its side effects. The research suggests that this treatment can be safely administered, as it aims to increase drug delivery to tumors without increasing overall side effects. ^{1 3 5 6 7}

Is the drug Lyso-thermosensitive Liposomal Doxorubicin a promising treatment for cancer?

Yes, Lyso-thermosensitive Liposomal Doxorubicin (ThermoDox) is a promising treatment for cancer. It uses heat to release the drug directly into tumors, increasing its concentration where it's needed most. This targeted approach can improve the drug's effectiveness while reducing side effects. Studies have shown that longer heating times can significantly increase the amount of drug delivered to the tumor, enhancing its therapeutic effect. ^{4 5 8 9 10}

What makes ThermoDox + MR-HIFU treatment unique for cancer?

ThermoDox + MR-HIFU is unique because it uses heat-sensitive liposomes to deliver chemotherapy directly to tumors when heated by focused ultrasound, allowing for targeted drug release and minimizing side effects elsewhere in the body. ^{4 5 8 9 10}

Research Team

AeRang Kim, MD, PhD

Principal Investigator

Children's National Research Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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 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]

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 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]

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]

References

1. India 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. [2022]

2. Netherlands 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. [2022]

3. England 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. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Hyperthermia-mediated doxorubicin release from thermosensitive liposomes using MR-HIFU: therapeutic effect in rabbit Vx2 tumours. [2022]

5. Netherlands 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. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Drug development of lyso-thermosensitive liposomal doxorubicin: Combining hyperthermia and thermosensitive drug delivery. [2022]

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

Phase I study of heat-deployed liposomal doxorubicin during radiofrequency ablation for hepatic malignancies. [2023]

8. England 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. [2020]

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

Magnetic resonance guided high-intensity focused ultrasound mediated hyperthermia improves the intratumoral distribution of temperature-sensitive liposomal doxorubicin. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Large-Volume Hyperthermia for Safe and Cost-Effective Targeted Drug Delivery Using a Clinical Ultrasound-Guided Focused Ultrasound Device. [2021]