OPTIMA Trial Will Continue to Follow Patients With HCC Treated With ThermoDox Combo

Patients with hepatocellular carcinoma (HCC), or primary liver cancer, treated with ThermoDox plus radiofrequency ablation (RFA) in the phase 3 OPTIMA clinical trial (NCT02112656) will continue to be followed for overall survival (OS), although an unexpected and marginally crossed futility boundary was observed in the second interim analysis, which may be associated with a data maturity issue, Celsion Corporation announced in a press release.¹

The company also noted that 26 consecutive patient deaths, occurring between September 2019 and March 2020, behaved differently in the second analysis compared with the balance of patients who have died to date. The OS pattern appears similar to the findings of the prospective HEAT Study subgroup that the OPTIMA study is based on when the 26 consecutive patient deaths are removed.

Subsequent to the second interim analysis, which was conducted on July 9, 2020, 8 patient deaths occurred in a 3:1 ratio of the control arm to treatment arm patients. This further supports the concerns for data maturity.

Study investigators from China and Vietnam, who enrolled approximately 37% of the patient population in the OPTIMA trial, joined 12 to 18 months following initiation of the study. According to the Kaplan-Meier curves for both geographies, a potential data maturity issue was observed when compared with the behavior of the HEAT Study subgroup and other OPTIMA study testing regions.

China sites had a negative Kaplan-Meier curve, but a 56% improvement in the treatment arm was observed in the median time to death. The Vietnamese sites had a marginal benefit on the Kaplan-Meier curve, with a median time to death improvement of 45%. Celsion states that this dichotomy must be reconciled, most likely with longer follow-up, before the direction of the study can be determined.

Data from the trial were sent to the National Institutes of Health (NIH) for independent analysis. All CT scans are being prepared to be sent to the NIH as well for evaluation of the progression-free survival (PFS).

The company announced in July 2020, that the independent Data Monitoring Committee (DMC) had recommended that Celsion consider stopping the trial. Because the pre-specified boundary for stopping the trial for futility of 0.900 was crossed marginally with an actual value of 0.903, the final decision is up to the company. The p-value for this analysis was 0.524, which provided further uncertainty.

“Last month’s DMC recommendation to consider discontinuation of the OPTIMA Study based on the second interim data was never anticipated, nor was it supported by the science, independent clinical evaluation of the HEAT Study subgroup or prospective preclinical research conducted by Celsion and our consultants to support the OPTIMA Study,” said Michael H. Tardugno, chairman, president and chief executive officer, Celsion, in a statement. “We believe, therefore, that Celsion is obligated to undertake this rigorous evaluation of the data and the trial’s recruitment trends.”

The global, randomized, double-blind, placebo-controlled OPTIMA study is evaluated the efficacy of ThermoDox, a lyso-thermosensitive liposomal doxorubicin, in combination with standard RFA for a minimum of 45 minutes for a lesion of 3 to 7 cm in size compared with RFA on its own. The trial enrolled 554 patients across 65 clinical sites in North America, Europe, China, and Asia Pacific.

The primary end point of the study is OS, while key secondary end points include PFS, time to disease progression, and safety.

As of August 2019, the median PFS was 17.3 months, which compared favorably with the median of 16.8 months observed in the HEAT Study subgroup. OS was consistent with what has been observed in the HEAT Study subgroup, which was an international randomized phase 3 of ThermoDox plus RFA in patients with intermediate, unresectable HCC. The hazard ratio for success at 158 events in the first analysis was 0.70 in the OPTIMA study, compared with 0.65 in the HEAT Study subgroup.²

To be included in the study, patients had to have a confirmed diagnosis of a single HCC lesion of ≥3.0 cm but ≤7.0 cm in diameter and 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 also were eligible for the study 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. 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.

“While the trial outcome as predicted by the second interim analysis may not change, and as unlikely as it may be, in the event we see substantial clinical benefit while continuing to monitor patients, we will carefully review our options with the 14 regulatory agencies that have allowed the OPTIMA Study to be conducted,” Tardugno stated.¹ “We appreciate the ongoing support and confidence from our research Investigators and clinical advisors.”

_Reference

_{1. Celsion Corporation to Continue Following Patients in Phase III OPTIMA Study for Overall Survival. News Release. August 4, 2020. Accessed August 5, 2020. https://bit.ly/3i89kyi}

_{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 August 5, 2020. https://bit.ly/2Caj23L}