Treatment with iodine (131I) apamistamab (Iomab-B) conditioning led to a 100% bone marrow transplant rate and engraftment in patients with active relapsed/refractory acute myeloid leukemia who are older than 55 years old, according to results of a single ad hoc interim analysis of the phase 3 SIERRA study.
Treatment with iodine (131I) apamistamab (Iomab-B) conditioning for bone marrow transplant (BMT) led to a 100% BMT rate and engraftment in patients with active relapsed/refractory acute myeloid leukemia (AML) who are older than 55 years old, according to results of a single ad hoc interim analysis of the phase 3 SIERRA study.1
Results of the trial, which are from the first 75% of patients, showed that 100% of patients who received Iomab-B proceeded to transplant and achieved engraftment compared with 16% of patients on the control arm, which was physician's choice of salvage therapies.
An independent Data Monitoring Committee (DMC) completed the analysis, said Actinium Pharmaceuticals, the developer of Iomab-B.
In the DMC's review of unblinded data, it was recommended that the study continue as planned to the full enrollment of 150 patients. The company has not received the study's unblinded primary and secondary end point efficacy data.
The single ad hoc analysis, which conducted in April 2020, was consistent with the study's design that allowed for up to 2 ad hoc analyses between 70 to 110 patients. Currently, the SIERRA trial is over 75% enrolled.
"We are encouraged by the DMC's recommendation to continue the SIERRA trial as planned and that there continues to be no safety concerns from the Iomab-B arm. All of us at Actinium are intensely focused on completing the final portion of patient enrollment in the SIERRA trial," said Mark Berger, MD, chief medical officer of Actinium. "With the large difference in the number of patients advancing to BMT with Iomab-B and those potentially evaluable for [durable complete remission] compared to the control arm through seventy-five percent of enrollment, we remain strongly optimistic about the ultimate success of SIERRA. We look forward to capitalizing on the positive momentum resulting from ASH and from our recent senior personnel additions in medical affairs and clinical development in order to complete enrollment as quickly as possible in 2021."
Iomab-B is a radioactive iodine (131I)—labeled anti-CD45 antibody that targeted radiation directly to leukemic cells for a targeted antitumor effect. The agent has been evaluated for efficacy and safety in 271 patients in phase 1 and 2 trials.
In the randomized, controlled SIERRA study, investigators compared the outcomes of patients receiving Iomab-B and a BMT with those on the control arm who received physician's choice of salvage therapies, including venetoclax (Venclexta), who may proceed to BMT if they achieve a required complete remission (CR). The primary end point was durable CR (dCR) of at least 180 days.
Patients with active, relapsed or refractory AML are randomized 1:1 to receive either conditioning with Iomab-B followed by allogeneic HCT versus conventional chemotherapy of physician’s choice. Patients achieving CR with conditioning chemotherapy are allowed to receive transplant or physician’s choice of therapy. Patients who do not have a CR with the control are allowed to crossover and receive Iomab-B. dCR rate is defined as morphologic CR lasting at least 180 days; the secondary end point is overall survival at 1 year from randomization.
The control arm involves initial dosimetry using trace amounts of Iomab-B (range, 7-20 mCi)2 in the outpatient setting to assess radiation exposure to the marrow, spleen, and nontarget organs. Individual patients received a personalized therapeutic dose based on the upper limit of 24 Gy to the liver. After a therapeutic dose, patients are required to have 4 to 5 days of radiation isolation. Patients then undergoing nonmyeloablative condition with fludarabine at 30 mg/m2 daily followed by total body irradiation and HCT.
To be included on the trial, patients need to have marrow blast count of at least 5% of the presence of peripheral blasts, be at least 55 years of age, have a Karnofsky score of 70 or higher, and have 8/8 allele level unrelated or related hematopoietic stem cell donor matching a human leukocyte antigen (HLA)-A, HLA-B, HLA-C, and DRB-1.
Active, relapsed or refractory AML was defined as disease: with primary induction failure following ≥2 cycles of therapy, which could include either chemotherapy or 2 more cycles of venetoclax (Venclexta) in combination with azacitidine or decitabine; occurring after first early relapse following a CR lasting ≤6 months; relapsed/refractory to salvage combination chemotherapy with high-dose cytarabine; or which is second or subsequent relapse.
Regarding baseline characteristics, patients on Iomab-B had an average age of 65 years (range, 56-77) compared with 64 years (range, 56-76) for the control arm. The majority of patients in the experimental and control arms had adverse cytogenetic and molecular risk (66% each) and primary induction failure at randomization (57% vs 47%, respectively). The median number of prior therapies was 3 (range, 1-5) for both groups.
Prior to enrollment, 85% of patients had failed 2 or more regimens and 33% had failed targeted therapies such as FLT3 and IDH1/2 inhibitors. Therapies received in the conventional-care arm included targeted therapies, venetoclax plus a hypomethylating agent or low-dose cytarabine, and standard-of-care HCT in patients who received venetoclax and achieved remission.
Prior results of SIERRA, which were presented at the 2020 Transplant & Cellular Therapies Meeting, induced a CR rate of 84% in patients with active AML who could then go on to receive allogeneic hematopoietic transplant vs 18% of those on the control arm.2
1. Actinium announces successful pre-planned ad hoc interim analysis of phase 3 SIERRA trial. Actinium Pharmaceuticals. News release. December 29, 2020. Accessed December 29, 2020. https://bit.ly/38O3HCg
2. Gyurkocza B, Nath R, Stiff PF, et al. Targeted conditioning with ant-cd45 iodine (131I) apamistamab [Iomab-B] leads to high rates of allogeneic transplantation and successful engraftment in older patients with active, relapsed, or refractory AML after failure of chemotherapy and targeted agents: preliminary midpoint results from the prospective, randomized phase 3 SIERRA trial. Presented at: 2020 Transplantation & Cellular Therapy Meetings; February 19-23, 2020; Orlando, FL. Abstract 285. https://bit.ly/3c1TWBs.