Data Monitoring Committee Recommends Stopping Phase 3 OPTIMA Trial in Hepatocellular Carcinoma

The independent Data Monitoring Committee (DMC) has recommended Celsion Corporation consider stopping the global phase 3 OPTIMA clinical trial (NCT02112656), which is evaluating the combination of ThermoDox with radiofrequency ablation for the treatment of patients with hepatocellular carcinoma (HCC) or primary liver cancer.¹

The recommendation was based on findings from the second pre-planned interim safety and efficacy analysis, which was conducted on July 9, 2020, by the DMC. In this analysis, the pre-specified boundary for stopping the trial for futility was 0.900, and the actual value was 0.903. The 2-sided P value of 0.524 led to uncertainty over the benefit of the regimen; the decision to stop the trial will ultimately be decided by the company.

“We are surprised and disappointed that the OPTIMA Study results were not found to be more robust at this analysis,” said Michael H. Tardugno, chairman, president and CEO, Celsion, in a statement. “Nonetheless, we intend to follow the advice of the DMC and will consider our options either to stop the study or continue to follow patients after a thorough review of the data, and an evaluation of our probability of success. Timing for this decision is made less urgent by the fact that the OPTIMA Study has been fully enrolled since August 2018 and that the vast majority of the trial expenses have already been incurred.”

The study is a global, randomized, double-blind, placebo-controlled trial and is assessing the efficacy of ThermoDox, a lyso-thermosensitive liposomal doxorubicin, in combination with radiofrequency ablation for a minimum of 45 minutes for a lesion of 3 to 7 cm in size, which has become the standard for this combination, compared with radiofrequency ablation on its own.

The trial enrolled 554 patients across 65 clinical sites in North America, Europe, China, and Asia Pacific. The primary end point is overall survival, and key secondary end points include progression-free survival, time to disease progression, and safety.

Two interim efficacy analyses were planned by the DMC, and the first was announced in November 2019 after the prescribed minimum of 128 patient events was reached. The second interim analysis was conducted this month after the prescribed minimum of 158 patient events was reached. No concerning safety signals were observed during this interim analysis.

The DMC recommended unanimously that the OPTIMA trial continue based on the findings of the first interim analysis, according to a press release in November 2019. In this analysis, the patient demographics and risk factors appeared consistent with what the company observed previously in the HEAT Study subgroup and all data quality metrics met expectations for the OPTIMA trial.²

The HEAT study was an international, randomized phase 3 study of ThermoDox plus radiofrequency ablation in patients with intermediate, unresectable HCC. The study did not meet its primary end point of 33% improvement in progression-free survival, a subgroup of 285 patients who received radiofrequency ablation for more than 45 minutes and were followed for at least 3 years demonstrated a 2-year survival benefit. 

The median progression-free survival as of August 2019 was 17.3 months in the OPTIMA study, which compared favorably with the 16.8-month median in the HEAT Study subgroup. Overall survival also appeared consistent with that observed in the HEAT Study subgroup.

The hazard ratio for success at 158 events in the first analysis of OPTIMA was 0.70, and the hazard ratio was 0.65 for the patients in the HEAT Study subgroup.

To be included in the study, patients had to have been diagnosed with a single HCC lesion of ≥3.0 cm but ≤7.0 cm in diameter. They also had to be an appropriate candidate for radiofrequency ablation as a medically indicated treatment based on the position and accessibility of the target lesion and if they were not a candidate for surgical resection. Patients could be enrolled if they had Child-Pugh Class A without current encephalopathy or ascites, left ventricular ejection fraction of ≥50%, and an ECOG performance status of 0.

Patients with a scheduled liver transplant, expected ablation volume of >30%, or more than 1 lesion at baseline were ineligible to enroll in the study. They also could not have previously received treatment for HCC outside the study protocol or have serious medical illnesses, such as congestive heart failure, myocardial infarction or cerebral vascular accident within the last 6 months, or life-threatening cardiac arrhythmias.

Celsion plans to hold a conference call on July 15, 2020, to discuss the current observations from the OPTIMA trial and the DMC’s recommendations to stop the clinical trial.¹

“This, of course, is inconclusive and difficult news for the medical community, [patients with] HCC, and our shareholders, and confirms the complexity and challenge of treating primary liver cancer,” Tardugno concluded.

_Reference

1. _{Celsion corporation receives recommendation from independent data monitoring committee to consider stopping the phase III optima study. News Release. July 13, 2020. Accessed July 13, 2020. https://bit.ly/2ZomTD5}
2. _{Celsion reports unanimous independent data monitoring committee recommendation to continue the phase III optima study of thermodox in primary liver cancer. News Release. November 4, 2019. Accessed July 13, 2020. https://bit.ly/2Caj23L}