Data Monitoring Committee Recommends Potential Stop of OPTIMA Trial in HCC

The independent data monitoring committee (DMC) has recommended that Celsion Corporation consider stopping the global, phase 3 OPTIMA trial examining ThermoDox^® in combination with radiofrequency ablation for the treatment of patients with hepatocellular carcinoma (HCC), according to a recent announcement.¹

The recommendation came after data from the second pre-planned interim safety and efficacy analysis were reviewed by the DMC on July 9, 2020. The analysis revealed that the prespecified boundary of 0.900 for stopping the trial for futility was crossed with an actual value of 0.903. However, because the 2-sided P value of 0.524 for this analysis provides uncertainty, the DMC has left the final decision up to Celsion, the developer of the ThermoDox^® platform. The company plans to conduct a thorough analysis of the unblinded data from the trial before making a final decision. Notably, no safety concerns were reported during the interim analysis.

“We are surprised and disappointed that the OPTIM study results were not found to be more robust at this analysis. 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,” Michael H. Tardugno, chairman, president, and chief executive officer of Celsion, commented in a press release issued by the company.

He added that the new is inconclusive and difficult for the medical community, for patients with the disease, and for shareholders, and underscores the complexity of HCC and the challenge of treatment. “We will conduct additional analyses of the unblinded data from the trial to better understand the results and to develop our plan going forward,” he added.

In the phase 3 trial, investigators set out to identify whether ThermoDox^®, a thermally sensitive liposomal doxorubicin, has efficacy in the treatment of patients with nonresectable HCC when used in combination with standardized radiofrequency ablation.

For the trial, patients were randomized to receive ThermoDox® plus standardized radiofrequency ablation using standardized treatment dwell time for solitary HCC lesions ≥3.0 cm to ≤7.0 cm or standardized radiofrequency ablation alone.² The primary end point of the trial was overall survival (OS) as defined from the date of randomization to the death date, while the secondary end point of the trial 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.

In order to be eligible for enrollment, patients had to be aged ≥18 years, diagnosed with a single HCC lesion of ≥3.0 cm but ≤7.0 cm in maximum diameter based on diagnosis at screening. They must also have been appropriate candidates for receiving radiofrequency ablation as a medically indicated treatment. Additionally, patients must have had a left ventricular ejection fraction of ≥50%, an ECOG performance status of 0, and Child-Pugh Class A disease without either current encephalopathy or ascites.

If patients were scheduled for liver transplantation, had an expected ablation volume of >30% of total liver volume or removal of 3 hepatic segments, more than 1 lesion detected during baseline, or have previously received treatment for HCC outside the study protocol, they were not eligible to participate on the trial. Additionally, those who had serious medical illnesses such as congestive heart failure, myocardial infarction, or cerebral vascular accident within 6 months prior to study start were not permitted to enroll.

The statistical plan for OPTIMA was comprised of 2 interim efficacy analyses by the DMC. The first analysis was announced in November 2019 following data lock in August 2019, which occurred after the prescribed minimum number of 128 patient events had been reached. The second analysis was conducted in July 2020 following data lock in April 2020 after the prescribed minimum number of 158 events had been reached.

“The present development had never been anticipated by the Company or our advisors based on both the first pre-planned efficacy analysis and on tracking against the subgroup analysis of the company’s earlier HEAT study upon which the OPTIMA study was based,” added Tardugno.

Previously, results from a retrospective analysis of the 701-patient HEAT trial of ThermoDox^® in combination with radiofrequency ablation in patients with HCC showed revealed an average 54% risk improvement in OS compared with optimized radiofrequency ablation alone in a large, well-bounded subgroup of patients (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, translating into a 2-year survival benefit over what had been observed in the comparator arm.

Additionally, of the 223-patient subgroup, data with 154 patients with single lesions who received optimized radiofrequency ablation for 45 minutes or more showed a 53% risk improvement in OS (HR, 0.66) with ThermoDox^® versus optimized radiofrequency ablation alone. The company reported that the clinical benefit observed in the intent-to-treat cohort further confirmed the importance of radiofrequency ablation heating time, as 72% of patients in the large cohort received treatment with optimized radiofrequency ablation.

References

1. Celsion Corporation receives recommendation from independent data monitoring committee to consider stopping the phase III OPTIMA study. News release. Celsion Corporation. July 13, 2020. Accessed July 13, 2020. bit.ly/3el8NGR.
2. Study of ThermoDox with standardized radiofrequency ablation (RFA) for treatment of hepatocellular carcinoma (HCC) (OPTIMA). ClinicalTrials.gov. Updated October 24, 2018. Accessed July 13, 2020. https://clinicaltrials.gov/ct2/show/NCT02112656.
3. Celsion Corporation announces final overall survival data from the HEAT study of ThermoDox® in primary liver cancer. News release. Celsion Corporation. August 15, 2016. Accessed July 13, 2020. bit.ly/3eqLcEE.