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CaelyxBaxter Healthcare Limited

Baxter Healthcare Limited
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15 November 2021
London MI Service

New Medicines

ThermoDoxInoperable hepatocellular carcinoma (HCC) – first-line


New formulation

Development and Regulatory status

Sep 21Development discontinued. The Company provides a final update on the PIII OPTIMA Study and the decision to stop following patients. Independent analyses conducted by a global biometrics contract research organization and the NIH, did not find any evidence of significance or factors that would justify continuing to follow patients for OS. Therefore, the Company notified all clinical sites to discontinue following patients. While the analyses did identify certain patient subgroups that appear to have had a clinical benefit, Celsion concluded that it would not be in its best interest to pursue these retrospective findings as the regulatory hurdles supporting further discussion would be significant [30].
Sep 19Data from the OPTIMA study will be reviewed as it matures up to two interim analyses expected to be conducted in H2 19 and H1 20. Celsion expects that the final efficacy analysis, if necessary, will be completed in H1 21. If the study proves to provide a clinically meaningful improvement in overall survival, Celsion will immediately apply for marketing authorisation in the US, Europe and China [27].
Mar 18Results from the OPTIMA Study, if successful, will provide the basis for a global registration filing and marketing approval [25].
Apr 16OPTIMA PIII trial continuing, with first recruitment in China; estimated completion now late 2019 [21,22].
Jan 14Celsion 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 [14].
Dec 11Celsion 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 [9].
Mar 11Orphan drug status approved in the EU [8].
Nov 10EMA has issued a positive opinion on the application for Orphan Drug Designation for ThermoDox® [6].
Aug 10Planned to file in US before end 2011 [3].
Aug 10The HEAT Study (ThermoDox®, in combination with radiofrequency ablation) has been designated as a Fast Track Development Program by the FDA [4].
Mar 09Granted orphan drug status in US [3].


Heat-activated liposomal formulation of doxorubicin. ThermoDox® releases the encapsulated doxorubicin when heated through microwave thermotherapy, or radiofrequency ablation, to a temperature of 38.5-42°C.
Inoperable hepatocellular carcinoma (HCC) – first-line
Intravenous infusion

Trial or other data

Feb 21Following independent analysis, the company decided to discontinue patient follow up for overall survival in the OPTIMA study, with the study database of 556 patients frozen at 185 patient deaths [29].
Sep 20During the second interim analysis of the OPTIMA study, an unexpected and marginally crossed futility boundary was noted thought to be associated with a data maturity issue. The company has hired independent statisticians to further evaluate the trial data, the statistical plan, and the hypothesis generating data from the earlier HEAT Study, as well as, supplying data to the NIH for independent analysis and recommendation. The company expects to announce its plans for the OPTIMA Study before year end [28].
Nov 19An independent Data Monitoring Committee (DMC) recommended to continue the PIII OPTIMA study as per the protocol, following evaluation of safety and data integrity from 556 patients. The pooled PFS data is consistent with what was observed in the pooled HEAT Study subgroup data (a median PFS of 16.8 months), while the latest pooled OPTIMA study data demonstrates medium PFS of 17.3 months. Median follow-up for OS is only 25 months at this which is too early for estimates. A 2nd pre-planned interim efficacy analysis is projected for Q2 2020 following 158 patient deaths [26].
Oct 18PIII OPTIMA study (NCT02112656) completed in Aug 18; no results posted yet [24].
Aug 18OPTIMA PIII study still recruiting. Expected completion Q4 2019 [23].
Dec 15Celsion 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 [20].
Aug 15Further 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 [19].
Feb 15Updated 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. [19].
Jul 14Updated 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] [18].
Jul 14PIII OPTIMA study is currently recruiting pts. Collection of primary outcome data now expected to be Nov 19 [17].
Apr 14Updated 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 [16].
Apr 14NCT02112656 (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) [15].
Jan 14Data 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 [14].
Sep 13Most 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 [13].
Apr 13Celsion 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) [12].
Jan 13Celsion 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 [11].
Apr 12The DMC completed a review of 652 pts & recommended that the trial continue as planned. Final planned analysis is expected to occur in late 2012 [9].
Feb 11The 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 [7].
Sep 10After 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 [5].
Aug 10Consensus 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 [2].
Aug 10NCT00617981is 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].