Caelyx · Janssen-Cilag
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ThermoDox · Hepatocellular carcinoma (HCC) ; inoperable – first-line
Development and Regulatory status
Jun 19: CHMP medicines under evaluation June 2019 shows a NDA has been filed, assume for this indication .
Mar 18: Results from the OPTIMA Study, if successful, will provide the basis for a global registration filing and marketing approval .
Apr 16: OPTIMA PIII trial continuing, with first recruitment in China; estimated completion now late 2019 [21,22]
Jan 14: Celsion has been consulting with its clinical advisors and the FDA regarding the study design and statistical plan for its proposed pivotal PIII clinical trial. The Company anticipates initiating a multicenter global trial in the first half of 2014 .
Dec 11: Celsion receives written, scientific advice from the EMA, confirming that the HEAT trial is suitable for submission of a MAA. The EMA also approved Celsion´s manufacturing strategy and technology transfer protocols enabling the company to set up manufacturing facilities to support the marketing of ThermoDox outside of the US, if approved .
Mar 11: Orphan drug status approved in the EU .
Nov 10: EMA has issued a positive opinion on the application for Orphan Drug Designation for ThermoDox® 
Aug 10: The HEAT Study (ThermoDox®, in combination with radiofrequency ablation) has been designated as a Fast Track Development Program by the FDA .
Granted orphan drug status in US in Mar 09 .
Planned to file in US before end 2011 .
Trial or other data
Oct 18: PIII OPTIMA study (NCT02112656) completed in Aug 18; no results posted yet .
Aug 18: OPTIMA PIII study still recruiting. Expected completion Q4 2019 .
Dec 15: Celsion announced Clinical Trial Application (CTA) approval from the China Food and Drug Administration (CFDA) to conduct the ongoing PIII OPTIMA Study at clinical sites in China. The OPTIMA Study is expected to enrol up to 550 pts globally. With the addition of these Chinese clinical sites, it is complete enrolment is expected by the end of 2017 .
Aug 15: Further updated results from the retrospective analysis of the HEAT study of ThermoDox® have been announced. The latest overall survival (OS) analysis (July 2015) of the subgroup of 285 pts with single hepatocellular carcinoma (HCC) lesions of either 3-5 cm or 5-7 cm in size showed that ThermoDox® in combination with optimised RFA (≥45min) provided an average 58% improvement in OS compared to optimised RFA alone (Hazard Ratio (HR) = 0.63 (95% CI 0.43 0.93; p = 0.0198). Median OS for the ThermoDox® group has been reached which translates into a 2.1 year survival benefit over the optimized RFA group. Additional findings from the most recent analysis specific to the Chinese cohort of pts with single lesions (74% of the HEAT Study Chinese pt population) showed a 75% improvement (HR = 0.57; p = 0.08) in OS for the ThermoDox® plus optimized RFA group compared to optimized RFA only group. Pts in the Chinese cohort with single lesions between 3-5 cm showed a doubling of improvement (HR = 0.50; p = 0.06) in OS when treated with ThermoDox® plus optimized RFA .
Feb 15: Updated results from the retrospective analysis of the HEAT Study as of January 15, 2015. The latest quarterly overall survival (OS) analysis demonstrated that in a subgroup of patients (n=285, 41% of the study patients), the combination of ThermoDox® and optimized radiofrequency ablation (RFA) provided a 59% improvement in OS compared to optimized RFA alone. The Hazard Ratio at this analysis is 0.628 (95% CI 0.420 0.939) with a p-value of 0.02.
July 14: Updated overall survival data from HEAT study continued to strongly suggest that ThermoDox® may significantly improve OS compared to a radiofrequency ablation (RFA) control in patients whose lesions undergo RFA treatment for 45 minutes or more. These findings apply to patients with single HCC lesions (64.4% of the HEAT Study population) (n=285). For this group, clinical results indicate a 57% improvement in OS, [HR=0.639, 95% CI 0.419 0.974, and a p=0.037]. 
Jul 14: PIII OPTIMA study is currently recruiting pts. Collection of primary outcome data now expected to be Nov 19 .
Apr 14: Updated results from the 701 patient HEAT study post-hoc analysis as of 31 Mar 14. For the subgroup, treated for >45minutes results indicate a 50% improvement in overall survival (HR 0.666 [95% CI 0.434 - 1.022], p= 0.06.) The median overall survival for this subgroup has not yet been reached 
Apr 14: NCT02112656 (OPTIMA) is a PIII randomized, double blind, dummy-controlled study of ThermoDox in 550 patients with HCC using standardized radiofrequency ablation treatment time ≥ 45 minutes for solitary lesions ≥ 3 cm to ≤ 7 cm. The primary outcome is overall survival. The study starts Jun 14 and is due to complete Jan 18 (primary data collection Jul 15) 
Jan 14: Data from 4 quarterly reviews of overall survival of patients in the PIII HEAT study have been evaluated since the announcement of top line PFS data in Jan 13. This post-hoc analysis suggests that ThermoDox(R) may significantly improve OS vs control, in patients whose lesions undergo RFA treatment for 45 minutes or more. These findings apply to patients with single HCC lesions (64.4% of the HEAT study population) from both size cohorts (3-5 cm and 5-7 cm) and represent a subgroup of 285 patients (41% of the patients in the HEAT study). In the patient subgroup treated in the ThermoDox arm whose RFA procedure was> 45 minutes, results indicate a 55% improvement in OS (HR 0.64 [95% CI 0.41 -- 1.00], p=0.0495). For those whose RFA procedure was < 45 minutes (167 patients or 37% of single lesion patients) the HR was 1.12 [0.68 -- 1.86]; p=0.66. Median overall survival for these subgroups has not yet been reached .
Sept 2013: Most recent overall survival data from HEAT post-hoc analysis presented at International Liver Cancer Assoc 7th annual conference. In the patient subgroup treated in the ThermoDox arm whose RFA procedure lasted >45 mins and was completed within 90 mins (40% of single lesion patients) Overall Survival improved by 71% when compared to the control arm. In the patient subgroup treated in the ThermoDox arm whose RFA procedure lasted >90 mins (23% of single lesion patients), Overall Survival improved by similar 71% when compared to the control arm. When combined, these two subgroups show clinical results that indicate a 61% improvement in Overall Survival, a Hazard Ratio of 0.623 and a P-value = 0.058. In contrast, patients whose RFA procedure lasted <45mins in duration (37% of single lesion pts), indicated that the control arm had a slightly improved OS benefit. Hazard Ratio reported are not statistically significant and HEAT study has not reached its medican point for OS. 
Apr 13: Celsion has conducted an analysis of data from the PIII HEAT Study with key principal investigators after reporting in Jan 13 that ThermoDox® + radiofrequency ablation (RFA) did not meet the study´s primary endpoint. Emerging data demonstrate that ThermoDox® improves PFS and OS in patients who had optimal RFA. The analysis indicates that if patients´ lesions undergo RFA for ≥45 minutes 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) .
Jan 13: Celsion announces that ThermoDox plus radiofrequency ablation did not meet its primary endpoint of improved progression-free survival in the PIII HEAT study. HEAT was designed to show a 33% improvement in PFS with 80% power and a p-value = 0.05. Celsion is considering following currently enrolled pts to the secondary endpoint, overall survival, & is conducting additional analyses of data to assess the future strategic value of ThermoDox. .
Apr 12: The DMC completed a review of 652 pts & recommended that the trial continue as planned. Final planned analysis is expected to occur in late 2012 .
Feb 11: The DMC has reviewed data from 482 randomized patients in the HEAT study and recommended that the trial continue enrollment. However, the DMC has maintained its recommendation to continue withholding enrollment of additional patients in Japan following a review of safety data from 18 Japanese patients .
Sept 10: After reviewing data from 401 patients enrolled in its pivotal Phase III HEAT study for primary liver cancer, the Data Monitoring Committee (DMC) has unanimously recommended that the trial continue to enroll patients with the goal of reaching the 600 patients required to complete the study. 
Aug 10: Consensus recommendations of the National Cancer Institute Clinical Trials Planning Meeting for Hepatocellular Carcinoma have been published in the August 2010 issue of Journal of Clinical Oncology. In addition to evaluating the current standard of care, the NCI panel also recommended Celsion´s Phase III ThermoDox ® HEAT Study as a priority clinical trial for HCC 
NCT00617981is a PIII randomized, double-blinded, dummy-controlled study of the efficacy and safety of ThermoDox in combination with radiofrequency ablation (RFA) compared to RFA-alone in the treatment of non-resectable hepatocellular carcinoma. The study, which started Feb 08 is enrolling 600 patients. The primary outcome is progression free survival. The study is expected to complete Feb 13, but has a primary completion date of Mar 10. In the study RFA will be started about 15 minutes after the 30 minute infusion and should be completed within 3 hours. The total length of the RFA procedure is proportional to the size of the tumor(s) involved (12 to 60 minutes for each lesion). The study is being conducted under a FDA Special Protocol Assessment. [1,2]