Medical Device Daily

The ability to engineer smaller drug delivery vessels, liposomes, is enabling med-tech and drug companies to better target commonly used cancer drugs for more effective outcomes. Combine that with technologies such as radiofrequency ablation (RFA) and you get a one-two punch against deadly malignancies.

Such is the current effort by Celsion (Columbia, Maryland) and its nanotechnology-based liver cancer treatment: ThermoDox, to be combined with RFA.

Celsion said it is skipping Phase II trials and moving directly into a 600-patient Phase III study, a move decided upon after the company examined Phase I data indicating that the therapy reduced tumor size. Those results were released this week at the 33rd annual scientific meeting of the Society for Interventional Radiology (Fairfax, Virginia).

Celsion is working with the FDA under a special protocol agreement (SPA) and is skipping to Phase III because, “We believe the doxorubicin’s mechanism of action and safety profile are already well understood by medical and regulatory community,” Michael Tardugno, president/CEO of Celsion told Medical Device Daily.

Celsion has employed 100 nm liposomes to deliver the cancer drug, ultimately creating a new drug, ThermoDox.

Computed tomography images of liver lesions from the Phase I study — treating patients with primary and metastatic liver cancer — were presented at SIR in a program entitled “Imaging Features in Patients undergoing Liver RFA plus Heat Deployed Nanoparticles.” It included images that showed differences in the X-ray appearance and size of tumors following treatment the ThermoDox/RFA treatment, compared to tumors of other patients treated with RFA alone.

Liposomes are nanoparticles, artificial vesicles composed of one or more concentric phospholipid bilayers, used in drug delivery. Many liposomal drugs do not actively target organ-specific tumors.

Celsion obtained an exclusive license from a team at Duke University (Durham, North Carolina) that developed heat-sensitive liposomes that create openings in the liposome, thus allowing faster drug release.

RFA is a common method to treat liver cancer, but it sometimes fails to treat the outer margins of larger tumors because temperatures in the periphery are not high enough to destroy the cancer cells. Thus, cancer recurrence rates are high.

Celsion’s ThermoDox treatment uses RFA’s ability to ablate the center of the tumor while simultaneously thermally activating the ThermoDox liposome to release its encapsulated doxorubicin to kill remaining viable cancer cells throughout the heated region, including tumor margins.

The treatment is intended to deliver the drug directly to the cancer cells that survive RFA.

The Phase III trial will again compare RFA/Thermodox to RFA alone, the primary endpoint being progression-free survival, with secondary endpoints of overall survival, patient-reported outcomes for quality of life, and time to local recurrence, plus safety evaluation. Enrollment is expected to begin in the next few weeks, with trial completion in 34 months, Celsion says.

This Phase I study was carried out under a Cooperative Research and Development Agreement at the National Cancer Institute (NCI) of the National Institutes of Health, and led by Steven Libutti, MD, senior investigator, head, Tumor Angiogenesis Section, Surgery Branch, Center for Cancer Research, NCI, and Bradford Wood, MD, chief, Interventional Radiology Research at the NIH Clinical Center, and separately at Queen Mary Hospital (Hong Kong) with Ronnie Poon, MD, professor of surgery at Queen Mary Hospital, University of Hong Kong.

In that study, a total of 24 primary and metastatic liver cancer patients, with up to four lesions ranging from 3 cm to 7 cm, were treated with ThermoDox/RFA at doses ranging from 20 to 60 mg/m.

“This visual data from our Phase I study may be indicative of ThermoDox clinical activity and this should be conclusively determined in the upcoming Phase III randomized controlled study,” Tardugno said.

Celsion received IRB approval for the U.S. Phase III study and Celsion’s clinical trial authorization application for the Phase III protocol has been accepted by China’s SFDA, with enrollment expected in August. Celsion said that clinical trial applications are being finalized for submissions in Korea, Taiwan, Italy and Canada.

In the U.S., North Shore Hospital-Albert Einstein Medical School (Manhasset, New York), led by principal investigator Thanjavur Ravikumar, MD, is currently screening patients. Queen Mary Hospital, University of Hong Kong also is pre-screening patients for the Phase III study. It will be the lead clinical center in Asia.

Once approved in Italy, Riccardo Lencioni, MD, of the University of Pisa, will be the third regional principal investigator of the European sites.

“Having launched a Phase III study within two months of securing an SPA with the FDA is a significant milestone for Celsion,” Tardugno said. “[A]cceptance of our CTA submission by the Chinese regulatory authority demonstrates the value of our strategic focus and Celsion’s ability to execute a complex global clinical strategy.”

Last summer, Celsion reported the purchase of 659,738 shares of Celsion stock from Boston Scientific (Natick, Massachusetts) for $2.6 million, and Boston Scientific was then no longer a Celsion holder. Boston Scientific had been a sbusiness partner with Celsion, as the U.S. marketer of Prolieve Thermodilatation, Celsion’s system for the treatment of benign prostatic hyperplasia.

In June 2007, Boston Scientific purchased the Prolieve assets from Celsion for $60 million (Medical Device Daily, June 25, 2007).

Tardugno said Celsion has sufficient financing for the Phase III trial, “to the point where we have sufficient data to proceed with a new drug application or not. We’re not looking to raise any capital to fund the clinical program for ThermoDox.”

Celsion is already using ThermoDox for another indication: recurrent breast cancer of the chest wall. Tardugno said results from a Phase I trial being conducted at Duke University are expected to be released in 3Q08. This type of cancer is one that occurs after mastectomy.