Children’s National Health System and the Celsion Corporation (Lawrenceville, NJ) have recently announced a Phase I clinical trial in the US to determine a safe and tolerable dose of ThermoDox in conjunction with non-invasive magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU). The trial is aimed on young adults and children with recurring solid tumors.
ThermoDox technology consists of liposomes loaded with doxorubicin, a conventional chemotherapeutic drug. Liposomes are small lipid structures which can be used to encapsulate and deliver drugs through the bloodstream. While liposomal doxorubicin formulations have been available for a while, what makes ThermoDox special is that the liposomes are thermosensitive, and can release their drug payload if exposed to small temperature elevations above body temperature. This permits for highly localized release of the drug at the tumor site, which could enhance the drug effectiveness and reduce side-effects. ThermoDox is delivered into the bloodstream of the patient while the tumor site is visualized and undergoes non-invasive and localized heating using the MR-HIFU system. When the liposomes arrive at the heated tumor through the blood they rapidly release their drug payload.
Medgadget had the opportunity to discuss the clinical trial and the ThermoDox technology with the Principal Investigator for the study AeRang Kim, MD, PhD, an oncologist and a member of the solid tumor faculty at the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Health System.
Conn Hastings, Medgadget: Can you give us a brief overview of the proposed trial design and the hospitals and institutions that are involved?
AeRang Kim, Children’s National Health System: This is a Phase I study of lyso-thermosensitive liposomal doxorubicin (LTLD) with MR-HIFU in children and young adults with relapsed or refractory solid tumors. This will be a dose escalation study to determine the recommended pediatric dose of LTLD combined with MR-HIFU. Once a dose is recommended, we will evaluate LTLD with MR-HIFU induced mild hyperthermia. This is a single institution study performed at Children’s National Health System, and the first study of LTLD in children.
Medgadget: Will the trial focus on certain types of cancer, or is any solid tumor potentially eligible for treatment?
AeRang Kim: Any malignant solid tumor is eligible, which may include but is not limited to rhabdomyosarcoma and other soft tissue tumors, Ewing sarcoma, osteosarcoma, neuroblastoma, Wilms Tumor, hepatic tumors, and germ cell tumors. Patients must have at least one lesion in areas accessible to HIFU.
Medgadget: This Phase I trial focuses on children and young adults with difficult to treat tumors. Given the potential side-effects of chemotherapy, should enhanced tumor targeting technologies that can reduce off-target effects be used more commonly, and not just for patients with recurrent or refractory tumors? Do you think these kinds of technologies will become more common in the future?
AeRang Kim: Yes for both of these questions. It is my belief that the only way we can advance therapy for pediatric cancers is to develop treatments that are more specific with less side effects. I do believe that these types of technologies for more targeted precision medicine are becoming more common now and this will continue in the future. If this treatment is tolerated and we find a safe dose, we hope we can incorporate promising therapies such as LTLD and HIFU into upfront treatment protocols.
Medgadget: Previous clinical trials with ThermoDox have employed radiofrequency ablation as the source of heat to trigger drug release at the tumor site. Have there been any trials using the MR-HIFU technology? How does it compare with radiofrequency ablation as an effective trigger for ThermoDox?
AeRang Kim: There is a Phase I adult study evaluating ultrasound guided focused ultrasound in patients with liver cancer. The study is too early to have reported any results. The principles of heat application would be hypothesized to be the same, but the advantages of HIFU as a heating method over radiofrequency ablation (RFA) are that it is completely non-invasive (no RFA needle); it allows for ablation of large volumes; there is no ionizing radiation used for guidance, and other heating modalities such as hyperthermia can be used.
Medgadget: Previous clinical trials of ThermoDox in conjunction with radiofrequency ablation have met with mixed results, with the best results coming when radiofrequency ablation was applied in an optimal manner. Will this influence the way that treatment is applied in this new trial?
AeRang Kim: What is fantastic about MR-HIFU is that we can actually quantify in real time the temperature of heating and the duration of heat so that we can provide optimal heating in conjunction with LTLD.
Medgadget: Does the HIFU treatment result in localized destruction of the tumor tissue, through the heating effect, or does the major therapeutic effect come from the action of the released doxorubicin?
AeRang Kim: MR-HIFU ablative therapy will result in localized destruction of tumor tissue through heating effect, but when combined with LTLD the doxorubicin will be released in the heated tumor margins and in any areas within the tumor that were not completely ablated, thus increasing the likelihood of complete tumor necrosis and hopefully minimize the possibility of tumor recurrence.
The ThermoDox concept, as applied to a variety of cancers, is illustrated in the following video:
Link: ThermoDox info page…