Iomab-ACT: a Pilot Study of 131-I Apamistamab Followed by CD19-Targeted CAR T-Cell Therapy for Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia or Diffuse Large B-Cell Lymphoma

This is a pilot study; patients will receive 131-I apamistamab prior to CAR T-cell infusion in order to determine the maximum tolerated dose of 131-I apamistamab is exceeded at 75 mCi, and if so, to assess the safety of a step-down dose of 50 mCi.

Start Date02 Feb 2021

Sponsor / Collaborator

Memorial Sloan Kettering Cancer Center

NCT02665065 / Active, not recruitingPhase 3

A Multicenter, Pivotal Phase 3 Study of Iomab-B Prior to Allogeneic Hematopoietic Cell Transplant Versus Conventional Care in Older Subjects With Active, Relapsed or Refractory Acute Myeloid Leukemia (AML)

The primary objective of this study is to demonstrate the efficacy of Iomab-B, in conjunction with a Reduced Intensity Conditioning (RIC) regimen and protocol-specified allogeneic hematopoietic stem cell transplant (HCT), versus Conventional Care in patients with Active, Relapsed or Refractory Acute Myeloid Leukemia (AML).

Start Date01 Jun 2016

Sponsor / Collaborator

Actinium Pharmaceuticals, Inc.

100 Clinical Results associated with I-131-Apamistamab

100 Translational Medicine associated with I-131-Apamistamab

100 Patents (Medical) associated with I-131-Apamistamab

Literatures (Medical) associated with I-131-Apamistamab

19 Sep 2024·Journal of clinical oncology : official journal of the American Society of Clinical Oncology

Randomized Phase III SIERRA Trial of ¹³¹I-Apamistamab Before Allogeneic Hematopoietic Cell Transplantation Versus Conventional Care for Relapsed/Refractory AML.

Article

Author: Foran, James ; Law, Arjun Datt ; Munshi, Pashna ; Pagel, John M ; Sabloff, Mitchell ; Tomlinson, Benjamin ; Rowley, Scott D ; Levy, Moshe Y ; Cook, Rachel ; MacDougall, James ; Silverman, Margarida ; Desai, Avinash ; Stiff, Patrick ; Kebriaei, Partow ; Lazarus, Hillard M ; Chen, George ; Schuster, Michael ; Al-Kadhimi, Zaid ; McNamara, Kathleen ; Giralt, Sergio ; Sandmaier, Brenda M ; Reddy, Vijay ; Abhyankar, Sunil ; Hari, Parameswaran ; Abboud, Camille ; Seropian, Stuart ; Koshy, Nebu ; Choe, Hannah ; Nath, Rajneesh ; Haeuber, Elaina ; Pandit-Taskar, Neeta ; Spross, Jennifer ; Litzow, Mark R ; Vusirikala, Madhuri ; Orozco, Johnnie J ; Larkin, Karilyn ; Van Besien, Koen ; Jamieson, Katarzyna ; Nahar, Akash ; Gyurkocza, Boglarka

PURPOSEOlder patients with relapsed or refractory AML (RR AML) have dismal prognoses without allogeneic hematopoietic cell transplantation (alloHCT). SIERRA compared a targeted pretransplant regimen involving the anti-CD45 radioconjugate ¹³¹I-apamistamab with conventional care.METHODSSIERRA (ClinicalTrials.gov identifier: NCT02665065) was a phase III open-label trial. Patients age ≥55 years with active RR AML were randomly assigned 1:1 to either an ¹³¹I-apamistamab-led regimen before alloHCT or conventional care followed by alloHCT if initial complete remission (CR)/CR with incomplete platelet recovery (CRp) occurred. Initial response was assessed 28-56 days after alloHCT in the ¹³¹I-apamistamab group and 28-42 days after salvage chemotherapy initiation; patients without CR/CRp or with AML progression could cross over to receive ¹³¹I-apamistamab followed by alloHCT. The primary end point was durable complete remission (dCR) lasting 180 days after initial CR/CRp. Secondary end points were overall survival (OS) and event-free survival (EFS), assessed hierarchically in the intention-to-treat (ITT) population.RESULTSThe ITT population included 153 patients (¹³¹I-apamistamab [n = 76]; conventional care [n = 77]). In total, 44/77 conventional care arm patients crossed over and 40/77 (52%) received ¹³¹I-apamistamab and alloHCT, with six patients (13.6%) experiencing a dCR. In the ITT population, the dCR rate was significantly higher with ¹³¹I-apamistamab (17.1% [95% CI, 9.4 to 27.5]) than conventional care (0% [95% CI, 0 to 4.7]; P < .0001). The OS hazard ratio (HR) was 0.99 (95% CI, 0.70 to 1.41; P = .96), and the EFS HR was 0.23 (95% CI, 0.15 to 0.34), with HR <1 favoring ¹³¹I-apamistamab. Grade ≥3 treatment-related adverse events occurred in 59.7% and 59.2% of the ¹³¹I-apamistamab and conventional care groups, respectively.CONCLUSIONThe ¹³¹I-apamistamab-led regimen was associated with a higher dCR rate than conventional care in older patients with RR AML. ¹³¹I-apamistamab was well tolerated and could address an unmet need in this population.

17 Jan 2024·Clinical Cancer Research

Targeted Radiation Delivery before Haploidentical HCT for High-risk Leukemia or MDS Patients Yields Long-term Survivors

Article

Author: Fisher, Darrell R. ; Vo, Phuong T. ; Gopal, Ajay K. ; Gooley, Ted A. ; Haaf, Robyn L. ; Green, Damian J. ; Wilbur, D. Scott ; Sandmaier, Brenda M. ; Matesan, Manuela C. ; Lundberg, Sally J. ; Orozco, Johnnie J. ; Pagel, John M. ; Hamlin, Donald K.

AbstractPurpose:Hematopoietic cell transplantation (HCT) has curative potential for myeloid malignancies, though many patients cannot tolerate myeloablative conditioning with high-dose chemotherapy alone or with total-body irradiation (TBI). Here we report long-term outcomes from a phase I/II study using iodine-131 (131I)-anti-CD45 antibody BC8 combined with nonmyeloablative conditioning prior to HLA-haploidentical HCT in adults with high-risk relapsed/ refractory acute myeloid or lymphoid leukemia (AML or ALL), or myelodysplastic syndrome (MDS; ClinicalTrials.gov, NCT00589316).Patients and Methods:Patients received a tracer diagnostic dose before a therapeutic infusion of 131Ianti-CD45 to deliver escalating doses (12–26 Gy) to the dose-limiting organ. Patients subsequently received fludarabine, cyclophosphamide (CY), and 2 Gy TBI conditioning before haploidentical marrow HCT. GVHD prophylaxis was posttransplant CY plus tacrolimus and mycophenolate mofetil.Results:Twenty-five patients (20 with AML, 4 ALL and 1 high-risk MDS) were treated; 8 had ≥ 5% blasts by morphology (range 9%–20%), and 7 had previously failed HCT. All 25 patients achieved a morphologic remission 28 days after HCT, with only 2 patients showing minimal residual disease (0.002–1.8%) by flow cytometry. Median time to engraftment was 15 days for neutrophils and 23 days for platelets. Point estimates for overall survival and progression-free survival were 40% and 32% at 1 year, and 24% at 2 years, respectively. Point estimates of relapse and nonrelapse mortality at 1 year were 56% and 12%, respectively.Conclusions:131I-anti-CD45 radioimmunotherapy prior to haploidentical HCT is feasible and can be curative in some patients, including those with disease, without additional toxicity.

04 May 2022·Expert Opinion on Biological TherapyQ3 · MEDICINE

Where do we stand with radioimmunotherapy for acute myeloid leukemia?

Q3 · MEDICINE

Article

Author: Walter, Roland B

INTRODUCTIONDespite the approval of several new drugs, deaths from acute myeloid leukemia (AML) remain common. Because of well-defined cell surface antigens, easy accessibility, and radiosensitivity of leukemia cells, there is long-standing interest in radiolabeled antibodies (radioimmunotherapy [RIT]) to complement or replace existing treatments and improve outcomes in AML.AREAS COVEREDTargeting primarily CD33, CD45, or CD66, early RIT efforts have focused on β-emitters, including iodine-131 (¹³¹I) and yttrium-90, mostly to intensify conditioning therapy before allogeneic hematopoietic cell transplantation (HCT). An ¹³¹I-labeled CD45 antibody (Iomab-B [apamistamab-I131]) is currently studied in the registration-type phase 3 SIERRA trial (NCT02665065) for this purpose. Of growing interest as therapeutic payloads are α-particle emitting radionuclides such as actinium-225 (²²⁵Ac) or astatine-211 (²¹¹At) since they deliver substantially higher decay energies over a much shorter distance than β-emitters, rendering them more suitable for precise, potent, and efficient target cell killing while minimizing toxicity to surrounding bystander cells, possibly allowing use outside of HCT. Clinical efforts with ²¹¹At-labeled CD45 antibodies and ²²⁵Ac-labeled CD33 antibodies (e.g. ²²⁵Ac-lintuzumab [Actimab-A]) are ongoing.EXPERT OPINIONA first anti-AML RIT may soon become available. This might propel further work to develop RIT-based treatments for AML, with many such efforts already ongoing.

News (Medical) associated with I-131-Apamistamab

18 Nov 2024

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Actinium Pharmaceuticals Highlights Antibody Radiation Conjugate Program Developments and Reports Financial Results for the Third Quarter 2024

- Aligned with FDA on operationally seamless Phase 2/3 trial for Actimab-A + CLAG-M in relapsed/refractory acute myeloid leukemia - Actimab-A selected for National Cancer Institute's recently opened myeloMATCH precision medicines program for patients with acute myeloid leukemia and myelodysplastic syndromes - Two Iomab-ACT INDs cleared by FDA: Commercial CAR-T trial at University of Texas Southwestern and sickle cell transplant trial at Columbia University; proof-of-concept safety and efficacy data expected in 2025 - Actinium seeking U.S. strategic partner for Iomab-B to conduct dose optimization and head-to-head Phase 3 trial based on FDA guidance in adult patients with active relapsed or refractory acute myeloid leukemia - Accomplished biopharma industry executive June Almenoff, M.D., Ph.D., appointed to Actinium's Board of Directors - Cash and cash equivalents of approximately $78.6 million as of September 30, 2024, is expected to fund operations into 2027 NEW YORK, Nov. 18, 2024 /PRNewswire/ -- Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company), a leader in the development of Antibody Radiation Conjugates (ARCs) and other targeted radiotherapies, today highlighted recent regulatory and development updates for its Iomab-B, Actimab-A and Iomab-ACT ARC clinical programs as well as its financial results for the third quarter ended September 30, 2024. Iomab-B is a first in class CD45 targeted conditioning agent to enable bone marrow transplant (BMT) and has been studied in over four hundred patients including the completed Phase 3 SIERRA trial for patients with relapsed or refractory acute myeloid leukemia (r/r AML). Actimab-A is a targeted radiotherapeutic that uses the Actinium-225 (Ac-225) isotope payload directed against CD33 with broad potential for development in AML and other myeloid indications including in collaboration with the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement (CRADA). Iomab-ACT is a next-generation CD45 targeted conditioning agent being developed for cell and gene therapies for both malignant and non-malignant hematologic indications. Actinium is executing cutting-edge R&D focused on ARCs and other targeted radiotherapies for blood cancer and solid tumor indications leveraging its strong intellectual property portfolio of 230 patents and patent applications including several patents related to the manufacture of the isotope Ac-225 in a cyclotron. Sandesh Seth, Actinium's Chairman and CEO, stated, "During the third quarter and over the last several weeks, we have made significant progress with our three ARC clinical programs. Actinium is now positioned to advance exciting clinical trials for Actimab-A and Iomab-ACT in large indications with high unmet needs that can deliver impactful clinical data in 2025. Actimab-A's backbone therapy potential is poised to be realized with the operationally seamless Phase 2/3 trial following alignment with the FDA, additional clinical trials being planned under the NCI CRADA including the myeloMATCH program and via our R&D efforts to further elucidate Actimab-A's mutation agnostic mechanism of action. The clinical data anticipated from Iomab-ACT in 2025 from the commercial CAR-T and sickle cell transplant trials has the potential to establish Iomab-ACT as a best-in-class targeted conditioning agent for both malignant and non-malignant hematology indications. In addition, our recent meeting with the FDA regarding Iomab-B established a clear development pathway, which will be incredibly valuable in securing a U.S. strategic partner. Finally, I am delighted to welcome Dr. June Almenoff to our Board of Directors, who brings over 25 years of biopharma industry experience with a proven track record of leading drug development through approvals and executing value enhancing business development transactions." Actimab-A Regulatory and Development Update Actinium met with the FDA in the third quarter and aligned with the FDA on an operationally seamless randomized Phase 2/3 trial to study Actimab-A + CLAG-M In the Phase 2 portion of the study, the Actimab-A dose will be optimized in combination with CLAG-M The Phase 3 portion will study the optimized dose of Actimab-A + CLAG-M versus CLAG-M alone in patients with r/r AML Operationally seamless trial design is expected to reduce the required time and resources compared to separate Phase 2 and Phase 3 trials Actinium continues to evaluate and develop additional Actimab-A clinical trials under its CRADA with the NCI, investigator initiated, or Actinium sponsored studies Actimab-A selected by NCI for recently opened myeloMATCH precision medicine program for patients with AML and myelodysplastic syndrome (MDS) Iomab-ACT Program Update In the third quarter, the FDA cleared the investigational new drug (IND) applications for both the commercial CAR-T study led by the University of Texas Southwestern (UTSW) and the sickle cell trial being led by Columbia University The UTSW commercial CAR-T trial expected to initiate patient enrollment in 1Q 2025 with proof-of-concept clinical data expected by year end Commercial CAR-T sales exceeded $3.5 billion in 2023 with multiple CAR-T therapies approved for patients with lymphomas, leukemias and multiple myeloma Columbia University sickle cell transplant trial to study Iomab-ACT for targeted conditioning prior to BMT for the first time in a non-malignant hematology setting, which is a rapidly growing indication for BMT; patient enrollment expected to commence in the first half of 2025 Iomab-B Regulatory Status and Program Update Actinium is seeking a U.S. strategic partner to advance clinical development of Iomab-B including the Phase 3 trial Actinium met with the FDA in the fourth quarter and aligned on the patient population for the head-to-head Phase 3 trial to evaluate allogeneic BMT using Iomab-B plus a reduced intensity conditioning regimen of fludarabine and total body irradiation (Flu/TBI) versus allogeneic BMT using reduced intensity conditioning comprised of cyclophosphamide plus Flu/TBI Head-to-head Phase 3 trial to enroll adult patients aged 18 and above with active AML with blasts counts greater than 5% and less than 20%, representing a broader patient population than that in the SIERRA trial Dose optimization trial to be completed prior to initiating the head-to-head Phase 3 trial to determine the dose for Iomab-B based on radiation to the bone marrow rather than the maximum tolerable dose of 24 Gy of radiation to the liver as was done in the SIERRA trial based on several interactions with the FDA before starting the SIERRA trial Mr. Seth added, "We are excited by our recent progress and committed to delivering on several milestones in the near-term and throughout 2025. Our current balance sheet provides strong runway into 2027, which enables us to deliver important clinical data and further realize our vision of being a leading fully integrated specialty radiopharmaceutical company." Third Quarter 2024 Financial Results Cash and cash equivalents of approximately $78.6 million as of September 30, 2024. Based on Actinium's current operating plan, cash and cash equivalents are expected to fund operations into 2027. Research and Development Expense, net of reimbursements Research and development expenses of $9.8 million for the three months ended September 30, 2024 decreased $1.8 million from $11.6 million for the three months ended September 30, 2023. The decrease is primarily a result of a decline in Chemistry, manufacturing and controls, or CMC, expenses of $5.5 million and lower consulting expenses of $0.5 million, both due to lower activity in 2024 related to Iomab-B. These declines were partially offset by increased preclinical expenses of $3.9 million. General and administrative expense General and administrative expenses of $2.8 million for the three months ended September 30, 2024 increased by $0.1 million from $2.7 million for the three months ended September 30, 2023, primarily due to higher non-cash stock compensation expense of $0.5 million, partially offset by lower compensation expense of $0.3 million due to lower headcount. In the third quarter of 2024, our overall headcount reduced by approximately twenty percent, with a majority of these former employees being from our clinical and CMC groups. As a result of these departures, we expect our personnel expenses to be reduced by approximately $3.7 million in 2025, which may be offset by additional hires or consultants. We do not expect these departures to have a material impact on our operations or ability to execute our operating plan and we are actively seeking a strategic partner for Iomab-B in the U.S. to advance the clinical development activity for Iomab-B including the planned Phase 3 trial. Other income Other income is comprised of net interest income in both reporting periods. The amount for the three months ended September 30, 2024 and 2023 of $1.0 million in each reporting period was virtually unchanged from the same time period in the prior year. Net loss Net loss of $11.6 million for the three months ended September 30, 2024 decreased by $1.7 million from $13.3 million for the three months ended September 30, 2023 due to lower research and development expenses partially offset by higher general and administrative expenses. About Actinium Pharmaceuticals, Inc. Actinium develops Antibody Radiation Conjugates (ARCs) and other targeted radiotherapies intended to meaningfully improve outcomes for people who have failed existing oncology therapies. The company continues to advance its development for product candidate Actimab-A, a therapeutic agent that has demonstrated potential activity in r/r AML patients. In addition, Actinium is engaged with the National Cancer Institute (NCI) under the Cooperative Research and Development Agreement (CRADA) for development of Actimab-A in AML and other myeloid malignancies. Iomab-ACT, Actinium's next generation conditioning candidate, is being developed with the goal of improving patient access and outcomes for potentially curative cell and gene therapies. Iomab-B is an induction and conditioning agent prior to bone marrow transplant in patients with relapsed and refractory acute myeloid leukemia (r/r AML), which Actinium is seeking a potential strategic partner for in the U.S. In addition, the company's R&D efforts are primarily focused on advancing several preclinical programs for solid tumor indications. Actinium holds 230 patents and patent applications including several patents related to the manufacture of the isotope Ac-225 in a cyclotron. For more information, please visit: Forward-Looking Statements This press release may contain projections or other "forward-looking statements" within the meaning of the "safe-harbor" provisions of the private securities litigation reform act of 1995 regarding future events or the future financial performance of the Company which the Company undertakes no obligation to update. These statements are based on management's current expectations and are subject to risks and uncertainties that may cause actual results to differ materially from the anticipated or estimated future results, including the risks and uncertainties associated with preliminary study results varying from final results, estimates of potential markets for drugs under development, clinical trials, actions by the FDA and other governmental agencies, regulatory clearances, responses to regulatory matters, the market demand for and acceptance of Actinium's products and services, performance of clinical research organizations and other risks detailed from time to time in Actinium's filings with the Securities and Exchange Commission (the "SEC"), including without limitation its most recent annual report on form 10-K, subsequent quarterly reports on Forms 10-Q and Forms 8-K, each as amended and supplemented from time to time. Investors: [email protected] SOURCE Actinium Pharmaceuticals, Inc. 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Phase 3Financial StatementPhase 2Radiation Therapy

20 Sep 2024

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Actinium Pharmaceuticals Announces Publication of Results from the Phase 3 SIERRA Trial of Iomab-B in the Journal of Clinical Oncology

Iomab-B is the first CD45 targeted radiotherapy for conditioning in development to enable potentially curative bone marrow transplant and represents an alternative to chemotherapy-based approaches SIERRA achieved durable Complete Remission primary endpoint and Event-Free Survival secondary endpoint with high statistical significance Iomab-B was well tolerated in the older, heavily pretreated relapsed/refractory AML patients with active disease enrolled in the SIERRA trial Actinium to seek strategic partner for Iomab-B for further development in the U.S. following completion of interactions with FDA for additional head-to-head clinical trial to demonstrate overall survival benefit NEW YORK, Sept. 20, 2024 /PRNewswire/ -- Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company), a leader in the development of Antibody Radiation Conjugates (ARCs) and other targeted radiotherapies, today announced the publication of the Phase 3 SIERRA results of Iomab-B in the peer-reviewed Journal of Clinical Oncology (JCO). The article, titled, "Randomized Phase III SIERRA Trial of 131I-Apamistamab Before Allogeneic Hematopoietic Cell Transplantation vs Conventional Care for Relapsed/Refractory Acute Myeloid Leukemia" and is available online on the ASCO Journal of Clinical Oncology website HERE. The Phase 3 SIERRA ( Study of Iomab-B in Elderly Relapsed Refractory AML) trial was a randomized, multi-center, controlled trial that enrolled 153 patients aged 55 and above with active relapsed or refractory Acute Myeloid Leukemia (r/r AML), including heavily pre-treated patients and those with high-risk characteristics such as a TP53 mutation. The SIERRA trial compared outcomes of patients receiving Iomab-B (Iodine-131-apamistamab) and a bone marrow transplant (BMT) to physician's choice of salvage chemotherapy and standard allogeneic BMT in the control arm. The SIERRA trial met the primary endpoint of durable Complete Remission (dCR) of 6-months following initial complete remission after BMT with high statistical significance (p-value of <0.0001) with 22% of patients (13/76) achieving dCR in the Iomab-B arm compared to 0% of patients (0/77) in the control arm. A significant improvement in Event Free Survival (EFS), a secondary endpoint of the SIERRA trial with a Hazard Ratio = 0.22 (p-value <0.0001) was also achieved. SIERRA did not meet the secondary endpoint of overall survival (OS) on an intent to treat basis analysis due to the high crossover rate with nearly 60% of control arm patients receiving Iomab-B followed by a BMT. The Phase 3 SIERRA results were first presented in a late-breaker presentation at the Transplantation & Cellular Therapy (TCT) Tandem Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and the Center for International Blood & Marrow Transplant Research (CIBMTR) in February 2023. Since TCT, the results of the SIERRA trial have been presented in several oral presentations at leading BMT, hematology, nuclear medicine and nursing meetings and congresses in the U.S. and EU. Supplemental analyses of the SIERRA results have shown improved survival outcomes in patients with a TP53 mutation, which is associated with poor outcomes, as well as increased 1-and 2-year overall survival in patients aged 65 and above. Dr. Sergio Giralt, Deputy Division Head, Division of Hematological Malignancies and Attending Physician, Adult BMT Service at the Memorial Sloan Kettering Cancer Center, and leading SIERRA Trial investigator and corresponding author, said, "The SIERRA trial was important for the field of transplant and demonstrated for the first time in a randomized study that the CD45 antibody-radioconjugate Iomab-B can provide patients with improved access to a potentially curative hematopoietic stem cell transplant, and improved outcomes compared to current chemotherapy-based regimens. Importantly, Iomab-B demonstrated a statistically significant improvement in key efficacy endpoints including durable Complete Remission and event-free survival. The SIERRA trial was conducted as multiple new therapies gained approval and was designed to address the nuances and difficulty of treating this patient population including allowing physician's choice of care in the control arm given the heterogeneity of treatment across institutions and the crossover design to provide best patient care. Despite multiple drug approvals for patients with AML, there remains no curative options for older patients with relapsed or refractory disease and outcomes for these patients also remain dismal. My fellow investigators and I are disappointed that the SIERRA trial will not support the approval of Iomab-B despite the positive results and significant unmet medical need of this patient population. However, there is continued significant interest from the transplant community to participate in the upcoming phase 3 study with Iomab-B to provide patients access to this important drug candidate." On August 05, 2024, Actinium announced that after concluding both its clinical and Chemistry, Manufacturing and Controls ("CMC") interactions with the FDA regarding the BLA pathway for Iomab-B, the FDA determined that demonstrating an overall survival benefit in a randomized head-to-head trial is required for a BLA filing, and the SIERRA trial alone will not be adequate for BLA filing. Sandesh Seth, Actinium's Chairman and CEO, stated, "We are excited that the SIERRA results have been published in the peer-reviewed Journal of Clinical Oncology. We believe the SIERRA trial was a major advancement for the field of BMT and targeted radiotherapeutics but most importantly for patients with relapsed and refractory AML. We look forward to completing our interactions with the FDA to finalize the specifics of the additional Phase 3 randomized trial and working to secure a U.S. partner for Iomab-B. In doing so, we hope to accelerate Iomab-B reaching patients with high unmet need that can benefit from a bone marrow transplant." About Actinium Pharmaceuticals, Inc. Actinium develops targeted radiotherapies to meaningfully improve survival for people who have failed existing oncology therapies. Advanced pipeline candidates Iomab-B, an induction and conditioning agent prior to bone marrow transplant, and Actimab-A (National Cancer Institute CRADA pivotal development path), a therapeutic agent, have demonstrated potential to extend survival outcomes for people with relapsed and refractory acute myeloid leukemia. Actinium plans to advance Iomab-B for other blood cancers and next generation conditioning candidate Iomab-ACT to improve cell and gene therapy outcomes. Actinium holds more than 230 patents and patent applications including several patents related to the manufacture of the isotope Ac-225 in a cyclotron. For more information, please visit: Forward-Looking Statements This press release may contain projections or other "forward-looking statements" within the meaning of the "safe-harbor" provisions of the private securities litigation reform act of 1995 regarding future events or the future financial performance of the Company which the Company undertakes no obligation to update. These statements are based on management's current expectations and are subject to risks and uncertainties that may cause actual results to differ materially from the anticipated or estimated future results, including the risks and uncertainties associated with preliminary study results varying from final results, estimates of potential markets for drugs under development, clinical trials, actions by the FDA and other governmental agencies, regulatory clearances, responses to regulatory matters, the market demand for and acceptance of Actinium's products and services, performance of clinical research organizations and other risks detailed from time to time in Actinium's filings with the Securities and Exchange Commission (the "SEC"), including without limitation its most recent annual report on form 10-K, subsequent quarterly reports on Forms 10-Q and Forms 8-K, each as amended and supplemented from time to time. Investors: [email protected] SOURCE Actinium Pharmaceuticals, Inc. 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Phase 3Clinical Result

05 Aug 2024

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Actinium Provides Regulatory Update on Planned BLA Filing and Future Plans for Iomab-B in the U.S.

FDA determined that the Phase 3 SIERRA trial is not adequate to support a BLA filing for Iomab-B despite its statistically significant primary endpoint Additional head-to-head randomized clinical trial demonstrating overall survival benefit with Iomab-B is required by FDA to support a BLA filing Actinium to request a meeting with the FDA to further discuss specifics of additional trial Actinium will seek strategic partner for Iomab-B in the U.S. following completion of FDA interactions and focus development efforts on Actimab-A, Iomab-ACT and preclinical programs NEW YORK, Aug. 5, 2024 /PRNewswire/ -- Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium" or the "Company"), a leader in the development of Antibody Radiation Conjugates ("ARCs") and other targeted radiotherapies, today announced a regulatory update on the Company's planned Biologics License Application ("BLA") filing for Iomab-B in patients with active relapsed or refractory acute myeloid leukemia ("r/r AML"). Iomab-B is an induction and conditioning targeted radiotherapy agent comprised of an anti-CD45 monoclonal antibody and Iodine-131 radioisotope payload. The Company announced that it has now concluded both its clinical and Chemistry, Manufacturing and Controls ("CMC") interactions with the FDA regarding the BLA pathway for Iomab-B. Despite the SIERRA trial meeting the primary endpoint of durable Complete Remission ("dCR") with statistical significance (p-value<0.0001) and other positive secondary endpoints including Event Free Survival ("EFS") and safety, the FDA has now determined that demonstrating an overall survival benefit in a randomized head-to-head trial is required for a BLA filing. The FDA has advised Actinium to conduct a study to evaluate allogeneic bone marrow transplant ("BMT") using Iomab-B plus a reduced intensity conditioning regimen of fludarabine and total body irradiation ("Flu/TBI") versus allogeneic BMT using reduced intensity conditioning comprised of cyclophosphamide plus Flu/TBI, a difference from the SIERRA trial, which had allowed physician's choice of salvage therapies and heterogenous conditioning regimens in the control arm. Additionally, the proposed new study will not allow patients to crossover from the control arm which was allowed in the SIERRA trial and confounded the overall survival analysis in the intent to treat ("ITT") patient population, as nearly 60% of patients crossed over from the control arm. The Phase 3 SIERRA trial enrolled 153 patients with r/r AML and compared outcomes of patients receiving Iomab-B and BMT to patients receiving physician's choice of care with salvage chemotherapy and standard allogeneic BMT in the control arm. In February 2023, Actinium announced that the SIERRA trial met the primary endpoint with statistical significance as 22% of patients (13/76) on the Iomab-B arm achieved dCR compared to 0% of patients (0/77) on the control arm resulting in a p-value of <0.0001. The SIERRA trial was conducted in accordance with guidance from the End of Phase 2 meeting with the FDA, which stated that positive results for dCR as the primary endpoint would be an acceptable endpoint to support an Iomab-B BLA filing. SIERRA did not meet the secondary endpoint of overall survival on an intent to treat basis analysis due to the high crossover rate with nearly 60% of control arm patients receiving Iomab-B followed by a BMT. Over the last several years, a majority of therapies for patients with AML have been approved based on achieving a positive overall survival endpoint. Actinium presented several additional analyses from the SIERRA study to the FDA including long-term follow-up that demonstrated a trend towards improved overall survival and evidence of survival benefit in patients with high-risk TP53 mutations to support Iomab-B's impact on overall survival. The SIERRA trial data were presented in 12 oral presentations at several leading bone marrow transplant, hematology and nuclear medicine conferences in both the U.S. and Europe, which Actinium believes demonstrates the high unmet medical need and scientific importance of Iomab-B's ability to provide improved access and outcomes for patients with active r/r AML to the transplant community. However, the FDA has now determined that the analyses from the SIERRA trial do not adequately support a BLA filing for Iomab-B and requires an additional clinical study. Actinium expects the safety and efficacy data from the SIERRA trial will provide supportive evidence for a future Iomab-B BLA filing . Key Outcomes and Implications of FDA Interactions Phase 3 SIERRA trial results are not adequate to support a BLA filing for Iomab-B in patients with active r/r AML FDA is requiring an additional randomized head-to-head trial to demonstrate an overall survival benefit evaluating allogeneic BMT using Iomab-B plus a reduced intensity conditioning regimen of fludarabine and total body irradiation (Flu/TBI) to allogeneic BMT using reduced intensity conditioning comprised of cyclophosphamide plus Flu/TBI Proposed additional clinical trial to evaluate Iomab-B plus Flu/TBI compared to a single regimen comprised of cyclophosphamide plus Flu/TBI which differs from the SIERRA trial that allowed physician's choice of salvage therapy and heterogenous conditioning regimens in the control arm The proposed additional clinical trial will not allow crossover, which was allowed in SIERRA, and confounded the overall survival analysis in the intent to treat (ITT) patient population as nearly 60% of patients crossed over from the control arm Actinium intends to further discuss the specifics of the additional clinical trial including the patient population, which the FDA has suggested could include all adult AML patients Upon conclusion of its interactions with the FDA, Actinium will seek a strategic partner for Iomab-B for the U.S. Dr. Avinash Desai, Actinium's Chief Medical Officer, said, "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 bone marrow transplant, hematology and nuclear medicine medical conferences in the U.S. and EU are an attestation of the strong interest from the transplant community for better conditioning regimens due to the high unmet need. 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 twenty-four leading bone marrow transplant 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 U.S. with the FDA." Sandesh Seth, Actinium's Chairman and CEO, said, "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 endpoint with statistical significance and producing positive efficacy and safety outcomes on several measures. 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 & gene therapy conditioning, hematology therapeutics and solid tumor candidates. We are committed to establishing the best development path forward for Iomab-B in the U.S. and finding a partner, while keeping internal resources and strategic priorities in focus." About Actinium Pharmaceuticals, Inc. Actinium develops Antibody Radiation Conjugates ("ARCs") and other targeted radiotherapies intended to meaningfully improve outcomes for people who have failed existing oncology therapies. Iomab-B is an induction and conditioning agent prior to bone marrow transplant in patients with relapsed and refractory acute myeloid leukemia ("r/r AML"), which Actinium plans to advance with a potential strategic partner in the U.S. following completion of FDA interactions. The company continues to advance its development for product candidate Actimab-A, a therapeutic agent that has demonstrated potential activity in r/r AML patients. In addition, Actinium is engaged with the National Cancer Institute ("NCI") under the Cooperative Research and Development Agreement ("CRADA") for development of Actimab-A in AML and other myeloid malignancies. Iomab-ACT, Actinium's next generation conditioning candidate, is being developed with the goal of improving patient access and outcomes for potentially curative cell and gene therapies. In addition, the company's R&D efforts are primarily focused on advancing several preclinical programs for solid tumor indications. Actinium holds more than 235 patents and patent applications including several patents related to the manufacture of the isotope Ac-225 in a cyclotron. For more information, please visit: Forward-Looking Statements This press release may contain projections or other "forward-looking statements" within the meaning of the "safe-harbor" provisions of the private securities litigation reform act of 1995 regarding future events or the future financial performance of the Company which the Company undertakes no obligation to update. These statements are based on management's current expectations and are subject to risks and uncertainties that may cause actual results to differ materially from the anticipated or estimated future results, including the risks and uncertainties associated with preliminary study results varying from final results, estimates of potential markets for drugs under development, clinical trials, actions by the FDA and other governmental agencies, regulatory clearances, responses to regulatory matters, the market demand for and acceptance of Actinium's products and services, performance of clinical research organizations and other risks detailed from time to time in Actinium's filings with the Securities and Exchange Commission (the "SEC"), including without limitation its most recent annual report on form 10-K, subsequent quarterly reports on Forms 10-Q and Forms 8-K, each as amended and supplemented from time to time. Investors: [email protected] SOURCE Actinium Pharmaceuticals, Inc.

Clinical ResultPhase 3Radiation Therapy

100 Deals associated with I-131-Apamistamab

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Refractory acute myeloid leukemia	Phase 3	CA	Actinium Pharmaceuticals, Inc.	01 Jun 2016
Refractory acute myeloid leukemia	Phase 3	US	Actinium Pharmaceuticals, Inc.	01 Jun 2016
Relapsing acute myeloid leukemia	Phase 3	US	Actinium Pharmaceuticals, Inc.	01 Jun 2016
Relapsing acute myeloid leukemia	Phase 3	CA	Actinium Pharmaceuticals, Inc.	01 Jun 2016

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


SNMMI2024	Not Applicable	-	-	Iomab-B	ahuxpxnsrk(wjaskbrwzp) = jehwkgmikh pwmyxrqsla (skamjymjhn )	-	09 Jun 2024
NCT02665065 (SIERRA, EHA2024) Manual	Phase 3	Acute Myeloid Leukemia	153	Iomab-B with fludarabine and total bodyirradiation (2 Gy)	(mquybwhvic) = okbjkghhbi yudjivtubc (mjopjdfagl ) View more	Positive	14 May 2024
				Conventional Care	(mquybwhvic) = yxnoyatjmw yudjivtubc (mjopjdfagl ) View more
NCT02665065 (SIERRA, EHA2024) Manual	Phase 3	Acute Myeloid Leukemia CD45	153	Iomab-B + fludarabine	(enteslfdme) = jfufoahxeq kvmvjbuzyb (doywwyfgoc ) View more	Positive	14 May 2024
				physician’s choice of conventional care	(enteslfdme) = sodiokmdgo kvmvjbuzyb (doywwyfgoc ) View more
NCT02665065 (SIERRA, EBMT2024) Manual	Phase 3	Acute Myeloid Leukemia	153	Iomab-B	(gzizclozgu) = alwdqewwba kghvpppxbo (qamepsxkpd )	Positive	17 Apr 2024
NCT02665065 (SIERRA, Biospace) Manual	Phase 3	Acute Myeloid Leukemia	54	Iomab-B	(zawtrwfjmw) = pqdqxcfzal offowmlucj (btmwgsxqot ) View more	Positive	26 Feb 2024
				Crossover	(zawtrwfjmw) = actfdnecrl offowmlucj (btmwgsxqot ) View more
NCT02665065 (SIERRA, Tandem Meetings ASTCT and CIBMTR2024) Manual	Phase 3	Acute Myeloid Leukemia	153	Iomab-B with fludarabine and total body irradiation	(eqcatknviq) = htjvrjvfoc zfnmwgfbcg (prfacsftxy ) View more	Positive	01 Feb 2024
				Conventional Care	(eqcatknviq) = cjsxsfzmox zfnmwgfbcg (prfacsftxy ) View more
SIERRA (Biospace) Manual	Phase 3	Acute Myeloid Leukemia	153	Iomab-B (Crossover + TP53 Mutation)	(xrpofsduwk) = miimxclaaf wiblbpqovr (gsrxpoachc ) View more	Positive	11 Dec 2023
				Control Arm (TP53 Mutation)	(xrpofsduwk) = uusxilydxu wiblbpqovr (gsrxpoachc ) View more
NCT02665065 (SIERRA, EHA2023)	Phase 3	Acute Myeloid Leukemia	153	Iomab-B with fludarabine and total body irradiation	(idyltnhytq) = ofngrncora ftitngtcgy (ewriktvjdl ) View more	-	08 Jun 2023
				IOMAB-B (Physician's choice of conventional care)	(idyltnhytq) = nxrpfavpmt ftitngtcgy (ewriktvjdl ) View more
NCT02665065 (SIERRA, EBMT2023) Manual	Phase 3	Acute Myeloid Leukemia Second line	153	Iomab-B	(elbdanajxh) = ywjzoxafbm zdjzpteehn (yfgjsraaji ) View more	Positive	26 Apr 2023
				Conventional Care	(elbdanajxh) = rrcbjvdcry zdjzpteehn (yfgjsraaji ) View more
NCT02665065 (SIERRA, EBMT2023)	Phase 3	Acute Myeloid Leukemia CD45	153	Iomab-B based conditioning followed by HCT	(gcsqzkeeji) = khziaeywzi kgvezpgdzg (rhjhtqbkrf, 12.29 - 34.73) View more	Positive	23 Apr 2023
				Iomab-B	(kioqsetgal) = hdltcqhptp kxcbtybbbl (omnmgqmntd ) View more

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