ThermoDox® — Pipeline within a Program
The HEAT Study – Primary Liver Cancer
(Hepatocellular Carcinoma Study of RFA and ThermoDox)
The HEAT Study is a pivotal, 700-patient, double-blind, placebo-controlled, international Phase III study designed to evaluate the safety and efficacy of ThermoDox® in combination with radiofrequency ablation (RFA) in patients with non-resectable hepatocellular carcinoma (HCC or primary liver cancer). The trial is being conducted at 79 clinical sites in the United States, Canada, Italy, China, Taiwan, Hong Kong, Korea, Thailand, Malaysia and the Philippines. The primary endpoint for the study is progression free survival (PFS), with a secondary confirmatory endpoint of overall survival (OS).
Our lead product, ThermoDox® is being evaluated in a Phase III clinical trial for primary liver cancer (the HEAT study) and a Phase II clinical trial for recurrent chest wall breast cancer. ThermoDox® is a liposomal encapsulation of doxorubicin, an approved and frequently used oncology drug for the treatment of a wide range of cancers. Localized heat at mild hyperthermia temperatures (greater than 39.5 degrees Celsius) releases the encapsulated doxorubicin from the liposome enabling high concentrations of doxorubicin to be deposited preferentially in and around the targeted tumor.
On January 31, 2013, we announced that ThermoDox® in combination with radio frequency ablation did not meet the primary endpoint of the HEAT study in patients with hepatocellular carcinoma, also known as primary liver cancer. Specifically, we determined, after conferring with the HEAT study independent Data Monitoring Committee, that the HEAT study did not meet the goal of demonstrating persuasive evidence of clinical effectiveness that could form the basis for regulatory approval in the population chosen for the HEAT study. In the trial, ThermoDox® was well-tolerated with no unexpected serious adverse events. We will continue to follow the patients enrolled in the HEAT study to the secondary endpoint, overall survival.
Following the announcement of the Phase III HEAT study results, the Company has conducted a comprehensive analysis of the clinical data with key principal investigators, data experts and liver cancer experts. Emerging data from the HEAT Study post hoc analysis demonstrates that ThermoDox® markedly improves progression free survival (PFS) and overall survival (OS) in patients who had optimal RFA. The post hoc analysis indicates that if patients’ lesions undergo RFA for 45 minutes or more, they clearly benefitted from ThermoDox®. These findings apply to HCC lesions from both size cohorts of the HEAT Study (3-5 cm and 5-7 cm) and represent a sizable subgroup of approximately 300 patients. This data is subject to further verification and review by the HEAT Study Steering Committee.
As the largest trial ever conducted in intermediate HCC, the HEAT Study has been designed to support registration filings in multiple regions worldwide, including the U.S., countries is the Asia Pacific region and Europe. In the U.S., the trial is being conducted under a Special Protocol Assessment with the FDA, and Celsion has received both Fast Track and Priority Review designations and reached a 505b(2) agreement with the FDA, establishing the potential for an accelerated U.S. regulatory review process. ThermoDox® has also received Orphan Drug designations for HCC in both the U.S. and Europe, which provide for 7 and 10 years, respectively, of marketing exclusivity. In recognition of the desperate need for new treatment options in primary liver cancer, the National Cancer Institute has recognized the HEAT Study as a “Priority Clinical Trial”.
The DIGNITY Study – Breast Cancer
The DIGNITY Study is a multicenter, single-arm open label, dose-escalating Phase I/Phase II trial of ThermoDox® plus hyperthermia in patients with recurrent chest wall (RCW) breast cancer. The trial is designed to establish a safe therapeutic dose in Phase I, and then advance into a Phase II study to evaluate safety and evidence of clinical activity, with a primary endpoint of durable complete local response. Celsion has completed enrollment of the Phase I portion of the study and selected a dose for use in a Phase II trial. The Phase II portion of the DIGNITY Study protocol commenced enrollment in 2012
The DIGNITY Study builds upon promising data from a Phase I dose escalation study conducted at the Duke University Medical Center, in which 16 RCW breast cancer patients treated with ThermoDox® demonstrated evidence of either stable disease, partial response or complete response. Toxicities are consistent with doxorubicin, the active agent in ThermoDox® and a widely used chemotherapeutic with a well established safety profile.
The ABLATE Study — Colorectal Liver Metastases
In 2011, Celsion initiated a Phase II study of ThermoDox® in combination with RFA for the treatment of colorectal liver metastases (The ABLATE Study). The trial is expected to enroll up to 88 patients with colorectal cancer metastasized to the liver. Patients will be randomized to receive either RFA plus ThermoDox® or RFA alone for the treatment of liver tumors. The primary study endpoint is based on one year local tumor recurrence, with secondary endpoints of time to progression and overall survival.
In April, 2013, Celsion discontinued enrollment of the ABLATE study pending the results of ongoing analysis of the HEAT study results.
ThermoDox Plus HIFU
Celsion is exploring ThermoDox in combination with high frequency ultrasound (HIFU) as a non-invasive treatment for a variety of cancers. With the Focused Ultrasound Foundation, the Company is supporting preclinical studies exploring the use of ThermoDox® plus HIFU for the treatment of pancreatic cancer. Most recently, Celsion announced a collaboration with the University of Oxford to begin a clinical study of ThermoDox® plus HIFU to treat metastatic liver cancer.
Additional Development Opportunities
In addition to the current development programs, Celsion is considering additional expansion opportunities for its ThermoDox® pipeline, including other tumor indications for which doxorubicin is currently approved.