FDA Requests Additional Demonstration of OS Benefit to Support Iomab-B BLA in R/R AML

The FDA has determined that the findings from the phase 3 SIERRA trial (NCT02665065), despite meeting its primary end point of 6-month durable complete response (CR) rate, are not sufficient to support a biologics license application (BLA) filing for Iomab-B for patients with relapsed/refractory acute myeloid leukemia (AML), requesting an additional head-to-head randomized trial demonstrating an improvement in overall survival (OS).¹

Results from SIERRA, which had been previously presented at the 2023 Transplantation & Cellular Therapy Meetings, demonstrated a significant improvement in durable CR lasting 180 days or more with Iomab-B plus bone marrow transplant (BMT) vs physician’s choice of salvage chemotherapy and standard allogeneic BMT, at 22% (n = 13/76) vs 0% (n = 0/77), respectively (95% CI, 12.29%-34.73%; P < .0001).1,2 The 6-month event-free survival rate was also improved in the investigational arm, at 26% vs 0.2% with the control (HR, 0.22; 95% CI, 0.15-0.34; P < .0001).2 However, OS, which was a secondary end point, was not met in the intention-to-treat (ITT) analysis.¹

The FDA’s announcement was made after Actinium Pharmaceuticals concluded its clinical and chemistry, manufacturing, and controls discussions with the FDA regarding the BLA pathway for Iomab-B. The FDA is now recommending Actinium conduct a study comparing allogeneic BMT using Iomab-B plus a reduced-intensity conditioning (RIC) regimen of fludarabine and total-body irradiation with allogeneic BMT using RIC comprised of cyclophosphamide plus fludarabine and total-body irradiation. Additionally, the proposed study design will not allow crossover unlike the prior SIERRA trial, in which approximately 60% of patients crossed over to the investigational arm from the control arm, confounding OS results in the ITT population.¹

“While this is not the outcome we expected, we will work with the FDA to further discuss specifics of the proposed randomized head-to-head clinical study to determine its strategic feasibility. The 12 oral presentations of the SIERRA results at prestigious BMT, hematology, and nuclear medicine medical conferences in the United states [US] and [European Union] are an attestation of the strong interest from the transplant community for better conditioning regimens due to the high unmet need,” Avinash Desai, MD, chief medical officer of Actinium, said in a news release.

The SIERRA trial, which enrolled 153 patients aged 55 years or older with relapsed/refractory AML, was designed based on guidance set forth from an end-of-phase-2 meeting with the FDA, which stated that durable CR would be an acceptable end point to support an Iomab-B BLA filing.^1,2

Additional results from the trial indicated that the rate of CR/CR with partial hematologic recovery was 74.6% (n = 44) with Iomab-B (n = 59) vs 6.3% (n = 4) with the control (n = 64).

Furthermore, when investigators excluded patients who crossed over from the control arm, Iomab-B (n = 76) demonstrated an improvement in OS at 6.4 months (95% CI, 5.1-7.9) vs 3.2 months (95% CI, 1.6-7.0) with the control (n = 33). The 1-year OS rates with Iomab-B and the control in this population were 26.1% (95% CI, 16.7%-36.4%) and 13.1% (95% CI, 4.2%-27.4%), respectively. In the crossover cohort, the median OS was 7.1 months (95% CI, 5.2-9.2), and the 1-year OS rate was 35.8% (95% CI, 22.0%-49.8%).²

“We are grateful to the patients, their families, as well as the study investigators and their staff who participated in the SIERRA trial. As a first-of-its-kind study, SIERRA broadened the investigation of Iomab-B as a targeted induction and conditioning agent from a single center to 24 leading BMT centers in North America, demonstrating its potential for the first time in a randomized, controlled study. Through the conduct of SIERRA, Actinium also built strong relationships with key thought leaders. This track record will provide a solid foundation to work with a partner on a subsequent Iomab-B trial, and we look forward to finalizing the path forward for Iomab-B in the US with the FDA,” Desai added.¹

“We are disappointed that the positive results from the SIERRA trial are not deemed adequate by the FDA to support a BLA filing despite meeting the primary end point with statistical significance and producing positive efficacy and safety outcomes on several measures,” Sandesh Seth, CEO and chairman of Actinium, said in the news release. “SIERRA represented a first-of-its-kind radiotherapeutic trial and demonstrated Actinium’s ability to execute seamlessly across manufacturing, supply chain, clinical development, and operations. We intend to leverage these capabilities as we continue to advance our highly differentiated antibody-radiation conjugate pipeline for cell and gene therapy conditioning, hematology therapeutics, and solid tumor candidates. We are committed to establishing the best development path forward for Iomab-B in the US and finding a partner while keeping internal resources and strategic priorities in focus.”

Actinium intends to further consider additional details of the proposed clinical trial, which the regulatory agency suggested could be performed in all adult patients with AML.

References

1. Actinium provides regulatory update on planned BLA filing and future plans for Iomab-B in the US. News release. Actinium Pharmaceuticals, Inc. August 5, 2024. Accessed August 5, 2024. https://ir.actiniumpharma.com/press-releases/detail/486/actinium-provides-regulatory-update-on-planned-bla-filing
2. Gyurkocza B, Choe H, Abboud C, et al. Efficacy and safety results of the SIERRA trial: a multicenter, pivotal phase 3 study of Iomab-B prior to allogeneic hematopoietic cell transplantation versus conventional care in older patients with active, relapsed or refractory acute myeloid leukemia (R/R AML). 2023 Transplantation and Cellular Therapies Meeting. February 15-19, 2023. Orlando FL. Abstract LBA3
3. Iomab-B SIERRA trial. Phase 3 results. Actinium Pharmaceuticals, Inc. February 18, 2023. Accessed August 5, 2024. https://d1io3yog0oux5.cloudfront.net/_e867432f4d7e6dd09397644109efb94f/actiniumpharma/db/206/1110/pdf/Actinium_SIERRA_Data_Webcast_vFINAL_02.18.2023.pptx+for+webinar.pdf