Celsion Corporation will continue to follow patients with hepatocellular carcinoma enrolled on the phase 3 OPTIMA trial examining ThermoDox® in combination with radiofrequency ablation for overall survival.
Celsion Corporation will continue to follow patients with hepatocellular carcinoma (HCC) enrolled on the phase 3 OPTIMA trial examining ThermoDox® in combination with radiofrequency ablation for overall survival (OS), according to a recent announcement.1
The unexpected and marginally crossed futility boundary, suggested by the Kaplan-Meier analysis at the time of the second interim analysis conducted on July 9, 2020, may have been due to a data maturity issue, according to the oncology company. Twenty-six consecutive patient deaths represented in the second analysis “behave far differently from the balance of the patients who have died as of this date,” according to Celsion.
When the 26 consecutive patient deaths, which occurred between September 2019 and March 2020, are removed from the pre-planned interim analysis, the OS pattern in the OPTIMA trial is comparable to that observed in the prospective HEAT trial subgroup. Moreover, following the second interim analysis, 8 deaths occurred in a 3:1 ratio of the control arm to the investigational arm, which further supports the concern for data maturity, according to Celsion.
Additionally, investigators in China and Vietnam, who enrolled 37% of the total patient population, joined the OPTIMA trial after the trial was initiated, at 12 months and 18 months, respectively. Notably, the Kalan-Meier curves for both geographies suggest a potential issue with regard to data maturity versus the behavior observed in the HEAT study subgroup and other OPTIMA testing site regions.
Specifically, a negative Kaplan-Meier curve was observed with regard to the China sites, although a 56% improvement in the median time to death was observed in the investigational arm. At the Vietnamese sites, a marginal Kaplan-Meier benefit was observed, with a 45% improvement in the median time to death. “This dichotomy must be reconciled, most probably with longer follow up, before it can determine the study’s direction,” noted Celsion.
Data from OPTIMA, including Chemistry, Manufacturing, and Controls information, has been sent to the National Institutes of Health (NIH) to undergo independent analysis. Computed tomography scans will also be sent to the NIH to be evaluated for progression-free survival. Celsion noted that based on trends observed during the OS follow-up period, the company could decide to discontinue OPTIMA at any time.
Last month, July 2020, an independent data monitoring committee (DMC) recommended that the company consider stopping the phase 3 trial. The recommendation followed data yielded from the second preplanned interim analysis, which had been reviewed on July 9, 2020. Results had revealed that the prespecified boundary of 0.900 for stopping the trial for futility had been crossed, with an actual value of 0.903 reported. However, because the 2-sided P value of 0.524 provided uncertainty, the committee left the final choice up to the company.
“Last month’s DMC recommendation to consider discontinuation of the OPTIMA study based on the 2nd 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. We believe, therefore, that Celsion is obligated to undertake this rigorous evaluation of the data and the trial’s recruitment trends,” Michael H. Tardugno, chairman, president, and chief executive officer of Celsion, stated in a press release.
“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,” added Tardugno. “We appreciate the ongoing support and confidence from our research investigators and clinical advisors.”
In the trial, patients were randomized to receive ThermoDox® in combination with standardized radiofrequency ablation using standardized treatment dwell time for solitary HCC lesions 3.0 cm or greater to 7.0 cm or less or standardized radiofrequency ablation alone.2 Overall survival (OS), as defined from the date of randomization to the death date, served as the primary end point of the trial, while the secondary end point was progression-free survival (PFS), as defined as the time from the date of randomization until the date of investigator-assessed radiological disease progression or death because of any cause.
To enroll on the trial, patients had to be aged 18 years or older and diagnosed with a single HCC lesion of 3.0 cm or greater but 7.0 cm or less in maximum diameter based on diagnosis at screening. Patients must also have been eligible to receive radiofrequency ablation as a medically indicated treatment. Additionally, to be eligible for enrollment, patients must have had a left ventricular ejection fraction of 50% or greater, an ECOG performance status of 0, and Child-Pugh Class A disease without current encephalopathy or ascites.
Patients were not eligible to enroll if were scheduled for liver transplantation, had an expected ablation volume of greater than 30% of total liver volume or removal of 3 hepatic segments, more than 1 lesion identified during baseline, or have received prior treatment for HCC outside of the study protocol. Additionally, patients with serious medical illnesses such as congestive heart failure, myocardial infarction, or cerebral vascular accident within 6 months before the study start were not permitted to participate.
The statistical plan for the phase 3 trial was composed of 2 interim efficacy analyses conducted by the DMC. The first analysis was announced in November 2019 following an August 2019 data lock, which occurred after the prescribed minimum number of 128 patient events had been reached. The second analysis was conducted in July 2020 following an April 2020 data lock after the prescribed minimum number of 158 events had been reported.
Previous data from a retrospective analysis of the HEAT trial of ThermoDox® in combination with radiofrequency ablation in 701 patients with HCC revealed an average 54% risk improvement in OS versus optimized radiofrequency ablation alone in a large, well-bounded patient subgroup (n = 285; 41% of the entire study population; HR, 0.65; 95% CI, 0.45-0.94; P = .02).3 Moreover, the median OS in the experimental arm had been reached; this translated to a survival benefit of 2 years over what had been reported in the comparator arm.
Additionally, of the 223-patient subgroup, 154 patients with single lesions who received optimized radiofrequency ablation for 45 minutes or more experienced a risk improvement of 53% in OS (HR, 0.66) with ThermoDox® compared with optimized radiofrequency ablation alone. The clinical benefit observed in the intent-to-treat cohort further confirmed the importance of radiofrequency ablation heating time, according to Celsion, as 72% of patients in the large cohort received treatment with optimized radiofrequency ablation.