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ThermoDox^® - doxorubicin dramatically enhanced with lysolipid thermally sensitive liposomes (LTSL)

First on the horizon, developed in partnership with Duke University, Celsion has encapsulated doxorubicin, a proven and frequently used cancer drug, in its heat-activated liposome to create ThermoDox. ThermoDox is an investigational new drug being studied for efficacy and safety for both hepatocellular carcinoma (HCC, or primary liver cancer) and recurrent breast cancer at the chest wall (RCW).

In hepatocellular carcinoma

Celsion's lead indication is primary liver cancer (hepatocellular carcinoma, or HCC).

HCC incidence and treatment

Radio Frequency Ablation (RFA) has become an increasingly common method for treating liver cancer. However, while RFA uses extremely high temperatures (80º-100º C) to ablate tumors, it may fail to treat the outer margins of larger tumors since temperatures in the periphery are not high enough to destroy the cancer cells. Recurrence rates typically correlate with the size and number of lesions, and are high especially for tumors greater than 3 centimeters (1 inch) in diameter or for patients with multiple liver tumors.

Celsion's ThermoDox treatment approach is designed to deliver high concentrations of anti-cancer drugs directly to those cancer cells that survive RFA. In conjunction with ablating the center of the tumor, RFA simultaneously activates ThermoDox to release its encapsulated doxorubicin, killing the remaining viable cancer cells throughout the heated region, including the tumor margins. Our approach, while increasing the delivery of the drug at the desired tumor site has the potential to reduce drug exposure distant to the tumor site and associated side effects.

HCC Phase I Trial

A Phase I single dose escalation study that investigated ThermoDox in combination with RFA for the treatment of liver cancer is complete. The study was performed at the National Cancer Institute (NCI), which is part of the National Institutes of Health (NIH), and at Queen Mary Hospital, an affiliate of the University of Hong Kong, in Hong Kong.

In this trial, a total of 24 primary and metastatic liver cancer patients, with up to 4 lesions ranging from 3 to 7 centimeters, were treated with ThermoDox in combination with radiofrequency ablation at doses ranging from 20 to 60 mg/m2. Enrollment in the trial has been completed and clinical data is currently being assembled for analysis and eventual submission to the FDA.

Evidence of clinical activity was presented at the 2008 IHPBA Conference, Mumbai India. In single-dose treatment, a maximum tolerated dose (MTD) of 50 mg/m2 with no unanticipated serous adverse events was experienced.

Dr. Ronnie Poon's presentation

While the Phase I trial has been designed to determine the maximum safe dose and safety profile of ThermoDox, evidence of clinical activity was noted, specifically with reference to a potential dose-response relationship.

HCC Phase III Clinical Trial

Celsion, through Special Protocol Assessment Guidance, has reached agreement with the US FDA for a pivotal Phase III clinical trial program in the treatment of HCC. This global trial with sites in the USA, Hong Kong, Canada, Taiwan, Korea, China and Italy is currently enrolling approximately 600 patients in the study designed to demonstrate the efficacy and safety of ThermoDox with RFA compared with RFA alone in HCC.

The primary endpoint of this trial is progression-free survival and will allow for an accelerated study with conditional marketing approval. Final approval will be based on the survival data derived later in the study from the same population. Secondary endpoints are: time to local recurrence, overall survival, and Patient Reported Outcome score. Recruitment is currently underway, pending enrollment completion by late 2010. Our projected marketing approval in the United States is late 2011. Celsion believes this Phase I to Phase III transition in 2008 is fully supported by the drug's proposed mechanism of action, safety data that has been generated to date, and end point discussions based on progression-free survival with the FDA.

See a complete list of Celsion clinical trials

In recurrent chest wall breast cancer (RCW)

Investigations by Celsion have focused on the use of proprietary heating devices alone and in combination with radiation and chemotherapy. More recently, studies at Duke University have indicated that heat may improve the therapeutic action of non-temperature sensitive liposomal doxorubicin formulations. Based on this work, Celsion has commissioned a study for the use of ThermoDox in combination with heat to treat a population of advance breast cancer patients with loco-regional chest wall disease (RCW).

Occasionally RCW can be referred to by several different terms. Some of these include inflammatory breast disease, inflammatory breast cancer, chest wall breast cancer, local-regional recurrence, chest wall recurrence.

Additionally, Celsion has also reached agreement with FDA for an open label, pivotal Phase II study evaluating the efficacy of ThermoDox in combination with mild heat energy for the treatment of RCW. Approval in the US, which is dependent on compelling results with a primary endpoint of an objective durable complete response, is projected to be late 2010 to early 2011.

RCW incidence and treatment

RCW Phase I Trial

An open label Phase I trial of ThermoDox in combination with heat in patients with RCW cancer to determine the maximum tolerated dose (MTD) in a multi-cycle treatment is being conducted at Duke University. This program is expected to advance to a Phase II trial in 4Q08 and receive marketing approval by the end of 2011.

Interim results from the Phase I trial were presented at the International Congress of Hyperthermic Oncology in April 2008 and in 2007 at the Society for Thermal Medicine and the European Society for Hyperthermic Oncology. The interim trial results, under the direction of Dr. Kimberly Blackwell, Associate in Medicine, Duke University Medical Center, were presented by Dr. Zeljko Vujaskovic and Dr. Ellen Jones, Associate Clinical Professors at Duke University, who reported at the lower dosing cohorts all evaluable patients showed early signs of clinically meaningful activity with two patients having a complete response in the treated area.

View trial details

Such results are unusual at this early stage in a study, and complete responses at such low doses indicate a biological proof of principle in these patients for whom there is no recognized standard of care. The researchers further reported that the patients tolerated ThermoDox well and did not exhibit any unexpected reactions.