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David A. Scheinberg - One of the best experts on this subject based on the ideXlab platform.
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a phase 2 study of Actinium 225 225ac lintuzumab in older patients with previously untreated acute myeloid leukemia aml unfit for intensive chemotherapy
Blood, 2017Co-Authors: Laura Finn, David A. Scheinberg, Dragan Cicic, Moshe Yair Levy, Johnnie J Orozco, Jae H Park, Ehab Atallah, Michael Craig, Alexander E Perl, Gregory BergonioAbstract:Abstract Background: Older patients (pts) unfit for induction chemotherapy have high early death rates and limited overall survival (OS), both of which depend on age, prior MDS, comorbidities, and performance status (PS) (Heaematologica 2012;97:1916). 225Ac-lintuzumab (Actimab-A) is a radioimmunoconjugate composed of 225Ac linked to a humanized anti-CD33 monoclonal antibody. 225Ac emits 4 α-particles and has a 10 day half-life. A Phase 1 trial to evaluate fractionated-doses of 225Ac-lintuzumab in combination with low-dose cytarabine was previously conducted. Responses were seen at doses of ≥1 µCi/kg/fraction, and 2 µCi/kg/fraction was chosen as the phase 2 dose to limit myelosuppression. Responding pts had peripheral blasts Patients and Methods: Pts ≥ 60 years with untreated AML and ECOG PS 0-3 were enrolled. Pts with antecedent hematologic disorders (AHDs) were eligible, including those with prior AHD therapy. Pts 60 to 74 years of age were required to have significant cardiac, pulmonary, renal or hepatic impairment. Any pt ≥ 75 years of age was eligible. Expression of CD33 on > 25% of blasts was required. Pts were required to have a peripheral blast count Results: Thirteen pts were treated, and preliminary data are available on 9 with median age 75 years (range, 65-82) and PS median 2 (0-1 in 2 pts, 2 in 3 pts, & 3 in 2 pts). Six (67%) had prior treatment for AHDs (5 MDS, 1 atypical CML). At baseline, 5 pts had ANC ≥ 500/µL, only 2 had ANC ≥ 1000/µL, and only 1 had platelets > 50,000/µL. Available cytogenetic data were limited, but 1 had intermediate and 3 had adverse cytogenetics by MRC criteria. The median baseline bone marrow blast percentage was 26% (range, 20-88%) with a median CD33 expression of 67% (range, 33-91%). Myelosuppression was seen in all evaluable pts including grade 4 thrombocytopenia with marrow aplasia for > 6 weeks following therapy in 3 pts. The only Grade >3 non-hematologic toxicities reported in ≥1 pt were pneumonia and cellulitis. Veno-occlusive disease did not occur. The 30-day mortality rate was 33% (disease progression, acute on chronic respiratory failure, and post-traumatic intracranial hemorrhage after a fall). Objective responses were documented in 5 of the 9 pts (56%): 2 Complete Remissions with incomplete platelet count recovery (CRp) and 3 Complete Remissions with incomplete hematologic recovery (CRi). Among the responders, 2 pts had adverse cytogenetics including one with t-AML, and 3 pts had no AHD. Two pts had resistant disease. Median time to neutrophil recovery (ANC ≥ 500/µL) was 36 days (range 20-60) from the first dose of 225Ac-lintuzumab. The two pts with CRp had neutrophil recovery at Days 60 and 36. Two of the pts with CRi had not reached ANC ≥ 500/µL when they expired from infection on days 65 and 56, and the third is at day 66+ without ANC recovery. Since pts with AHDs may not have capacity to recover to normal neutrophil production, pts without AHDs may be more informative. Of the 3 pts without AHDs, 1 had ANC recovery at Day 36, 1 had death from infection at Day 56 without ANC recovery, and 1 is pending ANC recovery at Day 66+. No pts reached platelet counts > 20,000/µL without transfusions. Conclusions: Preliminary data from this Phase 2 trial of 225Ac-lintuzumab monotherapy at 2 µCi/kg/fraction document a 56% response rate in older pts unfit for intensive therapy, many with AHDs. As myelosuppression at this dose was considered to be longer than acceptable in this population, accrual to this study will continue at 1.5 µCi/kg/fraction with the goal to shorten recovery times. Data on additional patients treated at that dose will be presented. Disclosures Levy: Actinium Pharmaceuticals: Equity Ownership; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Takeda: Consultancy, Speakers Bureau. Orozco: Actinium Pharmaceuticals: Other: Research Funding to Institution for sponsored Clinical Trials. Park: Amgen: Consultancy. Atallah: ADC Therapeutics: Research Funding. Perl: Novartis: Other: Advisory Board; Asana Biosciences: Other: Scientific advisory board; Arog Pharmaceuticals: Consultancy; Pfizer: Other: Advisory Board; Daiichi Sankyo: Consultancy; Seattle Genetics: Other: Advisory board; Actinium Pharmaceuticals: Other: Scientific Advisory Board; Astellas: Consultancy. Scheinberg: Eureka Therapeutics: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees; Memorial Sloan Kettering Cancer Center: Patents & Royalties: WO2012135854 A2, US Provisional 62/62/395,577; Actinium Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Cicic: Actinium Pharmaceuticals: Employment, Equity Ownership. Bergonio: Actinium Pharmaceuticals: Employment, Equity Ownership. Berger: Actinium Pharmaceuticals: Employment, Equity Ownership. Jurcic: Astellas Pharma, Inc: Research Funding; Daiichi-Sankyo: Research Funding; Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion Pharmaceuticals: Consultancy; Celgene: Research Funding; Forma Therapeutics: Research Funding; Genentech: Research Funding; Incyte: Consultancy; Kura Oncology: Research Funding; Merck: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Syros Pharmaceuticals: Research Funding; Amgen: Consultancy.
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efficient one step radiolabeling of monoclonal antibodies with Actinium 225 for alpha particle radioimmunotherapy of cancer
The Journal of Nuclear Medicine, 2014Co-Authors: William F Maguire, Michael R Mcdevitt, Peter Smithjones, David A. ScheinbergAbstract:1188 Objectives Targeted alpha-particle radiation using the radioisotope Actinium-225 (225Ac) is a promising form of therapy for various types of cancer. A historical obstacle to the use of 225Ac has been the difficulty in finding suitable chelators to stably attach it to targeting proteins and monoclonal antibodies. We initially solved this problem with a procedure involving two chemical steps that has been used as a standard in preclinical studies and clinical trials. However, this procedure involves the loss of 90% of the input 225Ac. A more efficient, economical process is needed to facilitate the more widespread use of 225Ac. Methods We conjugated representative antibodies with two forms of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), as well as other chelators as controls. We developed conditions to radiolabel these constructs in one chemical step and characterized their stability, immunoreactivity, biodistribution, toxicity, and therapeutic efficacy in healthy and tumor-bearing mice. Results DOTA- antibody constructs were labeled to a wide range of specific activities in one chemical step at 37 degrees Celsius. Radiochemical yields were approximately ten-fold higher than with the previous approach. The products had intact immunoreactivity and were stable to serum challenge in vitro and in vivo. Labeling kinetics of DOTA-antibody constructs linked through a benzyl isothiocyanate linkage were more favorable than those linked through a N-hydroxysuccinimide linkage. Tissue distribution was similar but not identical between the constructs. The constructs had limited toxicity at typical therapeutic doses in healthy mice and produced specific therapeutic responses in a mouse model of acute myeloid leukemia. Conclusions We have characterized an efficient, one-step radiolabeling method that produces stable, therapeutically active conjugates of antibodies with 225Ac. We propose that this technology is suitable for future preclinical and clinical use. Research Support The following funding sources contributed to this work: NIH R01 CA55349 to D.A.S. William F. Maguire was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the National Institutes of Health under award number:T32GM007739 to the Weill Cornell/Rockefeller/Sloan- Kettering Tri-Institutional MD-PhD Program.
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phase i trial of the targeted alpha particle nano generator Actinium 225 225ac lintuzumab anti cd33 in combination with low dose cytarabine ldac for older patients with untreated acute myeloid leukemia aml
Blood, 2013Co-Authors: Joseph G Jurcic, Dragan Cicic, Jae H Park, Farhad Ravandi, John M Pagel, Dan Douer, Elihu H Estey, Hagop M Kantarjian, David A. ScheinbergAbstract:Background Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody’s potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the isotope generator 225Ac (t½=10 days), which yields 4 α-particles, was conjugated to lintuzumab. A phase I trial demonstrated that 225Ac-lintuzumab is safe at doses ≤ 3 μCi/kg and has anti-leukemic activity across all dose levels studied (Jurcic et al. ASH, 2011). We are conducting a multicenter, phase I dose escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC. Patients and Methods Patients ≥ 60 yrs who had untreated AML with poor-prognostic factors, such as an antecedent hematologic disorder (AHD), unfavorable cytogenetic or molecular abnormalities, and significant comorbidities, were eligible. Patients received LDAC 20 mg bid for 10 days every 4-6 weeks. During cycle 1, beginning 4-7 days after LDAC, two doses of 225Ac-lintuzumab were given approximately one week apart. Results Seven patients (median age, 76 yrs; range, 72-80 yrs) were treated, all of whom had AHDs. Five (71%) had intermediate-risk cytogenetics, and two (29%) had unfavorable cytogenetics. The median CD33 expression was 76% (range, 69-95%). Prior therapy for myelodysplastic syndrome included hypomethylating agents (n=4) and allogeneic hematopoietic cell transplantation (n=1). Patients received 225Ac-lintuzumab at doses of 0.5 (n=3) or 1 (n=4) μCi/kg/fraction, two fractions per patient (total administered activity, 68-199 μCi). Dose-limiting toxicity was seen in one patient receiving 1 μCi/kg/fraction who had grade 4 thrombocytopenia in the setting of an aplastic bone marrow that persisted > 6 wks after completing the second fraction of 225Ac-lintuzumab. Other toxicities included grade 3 febrile neutropenia (n=5), bacteremia (n=1), pneumonia (n=1), cellulitis (n=1), transient increase in creatinine (n=1), and generalized weakness (n=1). Bone marrow blast reductions were seen in 4 of 6 evaluable patients (67%) after cycle 1 (mean blast reduction, 58%; range, 34-100%). No CRs, however, were observed. The median number of cycles administered was 2 (range, 1-4), and the median time to progression was 2.5 months (range, 2-7+ months). Conclusions Fractionated-dose 225Ac-linutuzmab in combination with LDAC is feasible, safe, and has anti-leukemic activity. Accrual continues to define the MTD, with planned dose levels up to 2 μCi/kg/fraction. Additional patients will be treated at the MTD in the phase II portion of this trial to determine response rate, progression-free survival, and overall survival. Disclosures: Jurcic: Actinium Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees. Ravandi: Actinium Pharmaceuticals, Inc.: Research Funding. Pagel: Actinium Pharmaceuticals, Inc.: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Park: Actinium Pharmaceuticals, Inc.: Research Funding. Douer: Actinium Pharmaceuticals, Inc.: Research Funding. Estey: Actinium Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees. Cicic: Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Scheinberg: Actinium Pharmaceuticals, Inc.: Ac-225-Lintuzumab, Ac-225-Lintuzumab Patents & Royalties, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.
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Actinium 225 in targeted alpha particle therapeutic applications
Current Radiopharmaceuticals, 2011Co-Authors: David A. Scheinberg, Michael R McdevittAbstract:Alpha particle-emitting isotopes are being investigated in radioimmunotherapeutic applications because of their unparalleled cytotoxicity when targeted to cancer and their relative lack of toxicity towards untargeted normal tissue. Actinium- 225 has been developed into potent targeting drug constructs and is in clinical use against acute myelogenous leukemia. The key properties of the alpha particles generated by 225Ac are the following: i) limited range in tissue of a few cell diameters; ii) high linear energy transfer leading to dense radiation damage along each alpha track; iii) a 10 day halflife; and iv) four net alpha particles emitted per decay. Targeting 225Ac-drug constructs have potential in the treatment of cancer.
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renal uptake of bismuth 213 and its contribution to kidney radiation dose following administration of Actinium 225 labeled antibody
Physics in Medicine and Biology, 2011Co-Authors: Jazmin Schwartz, Michael R Mcdevitt, David A. Scheinberg, J S Jaggi, Joseph A Odonoghue, Shutian Ruan, Steven M Larson, John L HummAbstract:Clinical therapeutic studies using 225Ac-labeled antibodies have begun. Of major concern is renal toxicity that may result from the three alpha-emitting progeny generated following the decay of 225Ac. The purpose of this study was to determine the amount of 225Ac and non-equilibrium progeny in the mouse kidney after the injection of 225Ac-huM195 antibody and examine the dosimetric consequences. Groups of mice were sacrificed at 24, 96 and 144 h after injection with 225Ac-huM195 antibody and kidneys excised. One kidney was used for gamma ray spectroscopic measurements by a high-purity germanium (HPGe) detector. The second kidney was used to generate frozen tissue sections which were examined by digital autoradiography (DAR). Two measurements were performed on each kidney specimen: (1) immediately post-resection and (2) after sufficient time for any non-equilibrium excess 213Bi to decay completely. Comparison of these measurements enabled estimation of the amount of excess 213Bi reaching the kidney (γ-ray spectroscopy) and its sub-regional distribution (DAR). The average absorbed dose to whole kidney, determined by spectroscopy, was 0.77 (SD 0.21) Gy kBq−1, of which 0.46 (SD 0.16) Gy kBq−1 (i.e. 60%) was due to non-equilibrium excess 213Bi. The relative contributions to renal cortex and medulla were determined by DAR. The estimated dose to the cortex from non-equilibrium excess 213Bi (0.31 (SD 0.11) Gy kBq−1) represented ~46% of the total. For the medulla the dose contribution from excess 213Bi (0.81 (SD 0.28) Gy kBq−1) was ~80% of the total. Based on these estimates, for human patients we project a kidney-absorbed dose of 0.28 Gy MBq−1 following administration of 225Ac-huM195 with non-equilibrium excess 213Bi responsible for approximately 60% of the total. Methods to reduce renal accumulation of radioactive progeny appear to be necessary for the success of 225Ac radioimmunotherapy.
Michael R Mcdevitt - One of the best experts on this subject based on the ideXlab platform.
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Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
Nature Communications, 2018Co-Authors: Michael R Mcdevitt, Darren R. Veach, Philip A. Watson, Teja Kalidindi, Tatsuo Gondo, Diane Abou, Daniel L J Thorek, Sai Kiran Sharma, Takeshi Hashimoto, Bradley J. BeattieAbstract:Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa. Alpha-particle irradiation of PCa is prompted by molecularly specific-targeting and internalization of the humanized monoclonal antibody hu11B6 targeting hK2 and further accelerated by inherent DNA-repair that up-regulate hK2 (KLK2) expression in vivo. hu11B6 demonstrates exquisite targeting specificity for KLK2. A single administration of Actinium-225 labeled hu11B6 eradicates disease and significantly prolongs survival in animal models. DNA damage arising from alpha particle irradiation induces AR and subsequently KLK2, generating a unique feed-forward mechanism, which increases binding of hu11B6. Imaging data in nonhuman primates support the possibility of utilizing hu11B6 in man.
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efficient one step radiolabeling of monoclonal antibodies with Actinium 225 for alpha particle radioimmunotherapy of cancer
The Journal of Nuclear Medicine, 2014Co-Authors: William F Maguire, Michael R Mcdevitt, Peter Smithjones, David A. ScheinbergAbstract:1188 Objectives Targeted alpha-particle radiation using the radioisotope Actinium-225 (225Ac) is a promising form of therapy for various types of cancer. A historical obstacle to the use of 225Ac has been the difficulty in finding suitable chelators to stably attach it to targeting proteins and monoclonal antibodies. We initially solved this problem with a procedure involving two chemical steps that has been used as a standard in preclinical studies and clinical trials. However, this procedure involves the loss of 90% of the input 225Ac. A more efficient, economical process is needed to facilitate the more widespread use of 225Ac. Methods We conjugated representative antibodies with two forms of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), as well as other chelators as controls. We developed conditions to radiolabel these constructs in one chemical step and characterized their stability, immunoreactivity, biodistribution, toxicity, and therapeutic efficacy in healthy and tumor-bearing mice. Results DOTA- antibody constructs were labeled to a wide range of specific activities in one chemical step at 37 degrees Celsius. Radiochemical yields were approximately ten-fold higher than with the previous approach. The products had intact immunoreactivity and were stable to serum challenge in vitro and in vivo. Labeling kinetics of DOTA-antibody constructs linked through a benzyl isothiocyanate linkage were more favorable than those linked through a N-hydroxysuccinimide linkage. Tissue distribution was similar but not identical between the constructs. The constructs had limited toxicity at typical therapeutic doses in healthy mice and produced specific therapeutic responses in a mouse model of acute myeloid leukemia. Conclusions We have characterized an efficient, one-step radiolabeling method that produces stable, therapeutically active conjugates of antibodies with 225Ac. We propose that this technology is suitable for future preclinical and clinical use. Research Support The following funding sources contributed to this work: NIH R01 CA55349 to D.A.S. William F. Maguire was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the National Institutes of Health under award number:T32GM007739 to the Weill Cornell/Rockefeller/Sloan- Kettering Tri-Institutional MD-PhD Program.
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phase i trial of the targeted alpha particle nano generator Actinium 225 225ac lintuzumab anti cd33 hum195 in acute myeloid leukemia aml
Blood, 2011Co-Authors: Joseph G Jurcic, Michael R Mcdevitt, Todd L Rosenblat, Neeta Pandittaskar, Jorge A Carrasquillo, Suzanne Chanel, Mark G Frattini, Kevin Zikaras, P Maslak, Dragan CicicAbstract:Abstract Abstract 768 Background: Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody’s potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the α-emitter bismuth-213 (213Bi) was conjugated to lintuzumab. Substantial clinical activity was seen in phase I and II trials, but the use of 213Bi is limited by its 46-min half-life. The isotope generator, 225Ac (t½=10 days), yields 4 α-emitting isotopes and can be conjugated to a variety of antibodies using DOTA-SCN. 225Ac-labeled immunoconjugates kill in vitro at radioactivity doses at least 1,000 times lower than 213Bi analogs and prolong survival in mouse xenograft models of several cancers (McDevitt et al. Science 2001). Methods: We are conducting a first-in-man phase I dose escalation trial to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab in AML. Results: Fifteen patients (median age, 62 yrs; range, 45–80 yrs) with relapsed (n=10) or refractory (n=5) AML were treated to date. Patients received a single infusion of 225Ac-lintuzumab at doses of 0.5 (n=3), 1 (n=4), 2 (n=3), 3 (n=3), or 4 (n=2) μCi/kg (total administered activity, 23–402 μCi). No acute toxicities were seen. Myelosuppression was the most common toxicity; the median time to resolution of grade 4 leukopenia was 26 days (range, 0–71 days). DLT was seen in 3 patients, including myelosuppression lasting >35 days in 1 patient receiving 4 μCi/kg and death due to sepsis in 2 patients treated at the 3 and 4 μCi/kg dose levels. Febrile neutropenia was seen in 4 patients, and 4 patients had grade 3/4 bacteremia. Extramedullary toxicities were limited to transient grade 2/3 liver function abnormalities in 4 patients. With a median follow-up of 2 mos (range, 1–24 mos), no evidence of radiation nephritis was seen. We analyzed plasma pharmacokinetics by gamma counting at energy windows for 2 daughters of 225Ac, francium-221 (221Fr) and 213Bi. Two-phase elimination kinetics were seen with mean plasma t½-α and t½-β of 1.9 and 35 hours, respectively. These results are similar to other lintuzumab constructs labeled with long-lived radioisotopes. Peripheral blood blasts were eliminated in 9 of 14 evaluable patients (64%), but only at doses of ≥1 μCi/kg. Bone marrow blast reductions were seen in 8 of 12 evaluable patients (67%) at 4 weeks, including 6 patients (50%) who had a blast reduction of ≥50%. Three patients treated with 1, 3, and 4 μCi/kg achieved bone marrow blast reductions to ≤5%. Conclusions: This is the first study to show that therapy with a targeted α-particle generator is feasible in humans. 225Ac-lintuzumab has antileukemic activity across all dose levels. Accrual to this trial continues to define the MTD. Disclosures: Jurcic: Actinium Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees, Research Funding. McDevitt: Actinium Pharmaceuticals, Inc.: Consultancy, Research Funding. Cicic: Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership, Patents & Royalties. Scheinberg: Actinium Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding.
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Actinium 225 in targeted alpha particle therapeutic applications
Current Radiopharmaceuticals, 2011Co-Authors: David A. Scheinberg, Michael R McdevittAbstract:Alpha particle-emitting isotopes are being investigated in radioimmunotherapeutic applications because of their unparalleled cytotoxicity when targeted to cancer and their relative lack of toxicity towards untargeted normal tissue. Actinium- 225 has been developed into potent targeting drug constructs and is in clinical use against acute myelogenous leukemia. The key properties of the alpha particles generated by 225Ac are the following: i) limited range in tissue of a few cell diameters; ii) high linear energy transfer leading to dense radiation damage along each alpha track; iii) a 10 day halflife; and iv) four net alpha particles emitted per decay. Targeting 225Ac-drug constructs have potential in the treatment of cancer.
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renal uptake of bismuth 213 and its contribution to kidney radiation dose following administration of Actinium 225 labeled antibody
Physics in Medicine and Biology, 2011Co-Authors: Jazmin Schwartz, Michael R Mcdevitt, David A. Scheinberg, J S Jaggi, Joseph A Odonoghue, Shutian Ruan, Steven M Larson, John L HummAbstract:Clinical therapeutic studies using 225Ac-labeled antibodies have begun. Of major concern is renal toxicity that may result from the three alpha-emitting progeny generated following the decay of 225Ac. The purpose of this study was to determine the amount of 225Ac and non-equilibrium progeny in the mouse kidney after the injection of 225Ac-huM195 antibody and examine the dosimetric consequences. Groups of mice were sacrificed at 24, 96 and 144 h after injection with 225Ac-huM195 antibody and kidneys excised. One kidney was used for gamma ray spectroscopic measurements by a high-purity germanium (HPGe) detector. The second kidney was used to generate frozen tissue sections which were examined by digital autoradiography (DAR). Two measurements were performed on each kidney specimen: (1) immediately post-resection and (2) after sufficient time for any non-equilibrium excess 213Bi to decay completely. Comparison of these measurements enabled estimation of the amount of excess 213Bi reaching the kidney (γ-ray spectroscopy) and its sub-regional distribution (DAR). The average absorbed dose to whole kidney, determined by spectroscopy, was 0.77 (SD 0.21) Gy kBq−1, of which 0.46 (SD 0.16) Gy kBq−1 (i.e. 60%) was due to non-equilibrium excess 213Bi. The relative contributions to renal cortex and medulla were determined by DAR. The estimated dose to the cortex from non-equilibrium excess 213Bi (0.31 (SD 0.11) Gy kBq−1) represented ~46% of the total. For the medulla the dose contribution from excess 213Bi (0.81 (SD 0.28) Gy kBq−1) was ~80% of the total. Based on these estimates, for human patients we project a kidney-absorbed dose of 0.28 Gy MBq−1 following administration of 225Ac-huM195 with non-equilibrium excess 213Bi responsible for approximately 60% of the total. Methods to reduce renal accumulation of radioactive progeny appear to be necessary for the success of 225Ac radioimmunotherapy.
Joseph G Jurcic - One of the best experts on this subject based on the ideXlab platform.
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clinical studies with bismuth 213 and Actinium 225 for hematologic malignancies
Current Radiopharmaceuticals, 2018Co-Authors: Joseph G JurcicAbstract:Objectives Due to the shorter range and higher linear energy transfer of α-particles compared to β-particles, targeted α-particle therapy may produce more efficient tumor killing while sparing neighboring healthy cells. We will review the clinical studies using α-particle therapy for Acute Myeloid Leukemia (AML). Methods A series of clinical trials were conducted to assess the safety, feasibility, and anti-leukemic effects of lintuzumab, an anti-CD33 humanized monoclonal antibody, labeled with the α-emitters bismuth- 213 (213Bi) and Actinium-225 (225Ac). Results An initial phase I study conducted in 18 patients with relapsed or refractory AML demonstrated the safety and antitumor effects of 213Bi-lintuzumab. Subsequently, 213Bi-lintuzumab produced remissions in AML patients after partial cytoreduction with cytarabine in phase I/II trial. The 46- minute half-life of 213Bi and need for an onsite generator has limited its utility. Therefore, a secondgeneration construct was developed using 225Ac, a radiometal that yields four α-particle emissions. A phase I trial demonstrated that a single infusion of 225Ac-lintuzumab could be given safely at doses up to 111 kBq/kg with anti-leukemic activity across all dose levels studied. In a second phase I study, 28% of older patients with untreated AML had objective responses after receiving fractionated-dose 225Aclintuzumab and low-dose cytarabine. Conclusion Based upon the encouraging results seen in phase I trials of 225Ac-lintuzumab, a phase II study of 225Ac-lintuzumab monotherapy for older patients with untreated AML is now in progress and is also being studied in a subset of patients with CD33-positive multiple myeloma.
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phase i trial of targeted alpha particle therapy with Actinium 225 225ac lintuzumab and low dose cytarabine ldac in patients age 60 or older with untreated acute myeloid leukemia aml
Blood, 2016Co-Authors: Joseph G Jurcic, Moshe Yair Levy, Jae H Park, Alexander E Perl, Farhad Ravandi, John M Pagel, Douglas B Smith, Elihu H Estey, Hagop M Kantarjian, Dragan CicicAbstract:Background:225Ac-lintuzumab is a radioimmunoconjugate composed of 225Ac (t½=10 days), which emits 4 α-particles, linked to a humanized anti-CD33 monoclonal antibody. Short-ranged (50-80 µm), high-energy (~100 keV/µm) α particle-emitting isotopes such as 225Ac may result in more specific tumor cell kill and less damage to normal tissues than β-emitters. An initial phase I trial in 20 patients with relapsed/refractory AML showed that a single infusion of 225Ac-lintuzumab is safe at doses ≤ 3 µCi/kg and has anti-leukemic activity (Jurcic et al. ASH, 2011). We conducted a multicenter, phase I dose-escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC. Patients and Methods: Patients ≥ 60 years with untreated AML not candidates for standard induction therapy (e.g., antecedent hematologic disorder, poor-risk cytogenetic or molecular features, and significant comorbidities) were eligible. Patients received LDAC 20 mg twice a day for 10 days every 4-6 weeks for up to 12 cycles. During Cycle 1, 2 fractions of 225Ac-lintuzumab were given 1 week apart, beginning 4-7 days following completion of LDAC. To prevent radiation-induced nephrotoxicity, patients were given furosemide while receiving 225Ac-lintuzumab then spironolactone for 1 year afterward. Four dose levels of 225Ac-lintuzumab were studied using a 3+3 design. Dose escalation proceeded if Results: Eighteen patients (median age, 77 years; range, 68-87 years) completed therapy. Twelve (67%) had prior myelodysplastic syndrome (MDS), for which 10 (83%) received therapy with hypomethylating agents (n=9) or allogeneic hematopoietic cell transplantation (n=1). One patient (6%) had chronic myeloid leukemia in molecular remission prior to developing AML. Eleven patients (61%) had intermediate-risk and 7 (39%) had poor-risk disease by NCCN criteria. Median CD33 expression was 81% (range, 30-100%). 225Ac-lintuzumab was given at 0.5 (n=3), 1 (n=6), 1.5 (n=3), or 2 (n=6) μCi/kg/fraction. Up to 4 cycles of LDAC were administered. Two patients experienced DLT (grade 4 thrombocytopenia with marrow aplasia for > 6 weeks following therapy), one each in the 1 and 2 µCi/kg/fraction cohorts. Although the MTD was not reached, 2 µCi/kg/fraction was chosen as the phase II dose to limit prolonged myelosuppression. Hematologic toxicities included grade 4 neutropenia (n=5) and thrombocytopenia (n=9). Grade 3/4 non-hematologic toxicities included febrile neutropenia (n=6), pneumonia (n=5), other infections (n=3), atrial fibrillation/syncope (n=1), transient creatinine increase (n=1), generalized fatigue (n=1), hypokalemia (n=1), mucositis (n=1), and rectal hemorrhage (n=1). Thirty- and 60-day mortality rates were 0% and 17%, respectively. Eleven of 14 patients (79%) evaluated after Cycle 1 had bone marrow blast reductions (mean reduction, 66%; range, 19-100%). Objective responses (2 CR, 1 CRp, 2 CRi) were seen in 5 of the 18 patients (28%), but only at doses ≥ 1 µCi/kg/fraction (Table 1). One of the responders received 15 cycles of azacitidine for prior MDS. All responses occurred after 1 cycle of therapy, in contrast to historical data with LDAC alone, where the median time to response was 3 cycles. Median progression-free survival (PFS) for all patients was 2.7 months (range, 1.0-31.8+ months). Median overall survival (OS) was 5.6 months (range, 1.6-32+ months). Median response duration was 5.6 months (range, 4.9-32+ months). Peripheral blood blast counts were a strong predictor of response. Among 38 patients treated in the current and initial phase I trials, responses were seen in 8 of 19 patients (42%) with blast counts Conclusions: Fractionated-dose 225Ac-linutuzmab can be safely combined with LDAC and induce remission in older patients with untreated AML. A phase II trial of 225Ac-lintuzumab monotherapy at 2 µCi/kg/fraction using hydroxyurea, if needed, to lower peripheral blast counts prior toadministration will be undertaken to determine response rate, PFS, and OS in this patient population. Disclosures Jurcic:Forma Therapeutics: Research Funding; Seattle Genetics: Research Funding; Kura Oncology: Research Funding; Celgene: Research Funding; Novartis: Membership on an entity9s Board of Directors or advisory committees; Bayer: Consultancy; Alexion Pharmaceuticals: Consultancy; Merck & Co.: Consultancy; Astellas: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding; Daiichi-Sankyo: Research Funding. Levy:Janssen: Speakers Bureau; Actinium Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Research Funding; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Park:Amgen: Consultancy; Genentech/Roche: Research Funding; Juno Therapeutics: Consultancy, Research Funding. Ravandi:Actinium Pharmaceuticals, Inc.: Research Funding. Perl:Actinium Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Consultancy. Smith:Actinium Pharmaceuticals, Inc.: Research Funding. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Scheinberg:Actinium Pharmaceuticals, Inc.: Equity Ownership, Patents & Royalties: Ac-225-Lintuzumab.
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phase i trial of targeted alpha particle therapy with Actinium 225 225ac lintuzumab and low dose cytarabine ldac in patients age 60 or older with untreated acute myeloid leukemia aml
Blood, 2016Co-Authors: Joseph G Jurcic, Moshe Yair Levy, Jae H Park, Alexander E Perl, Farhad Ravandi, John M Pagel, Douglas B Smith, Elihu H Estey, Hagop M Kantarjian, Dragan CicicAbstract:Abstract Background: 225Ac-lintuzumab is a radioimmunoconjugate composed of 225Ac (t½=10 days), which emits 4 α-particles, linked to a humanized anti-CD33 monoclonal antibody. Short-ranged (50-80 µm), high-energy (~100 keV/µm) α particle-emitting isotopes such as 225Ac may result in more specific tumor cell kill and less damage to normal tissues than β-emitters. An initial phase I trial in 20 patients with relapsed/refractory AML showed that a single infusion of 225Ac-lintuzumab is safe at doses ≤ 3 µCi/kg and has anti-leukemic activity (Jurcic et al. ASH, 2011). We conducted a multicenter, phase I dose-escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC. Patients and Methods: Patients ≥ 60 years with untreated AML not candidates for standard induction therapy (e.g., antecedent hematologic disorder, poor-risk cytogenetic or molecular features, and significant comorbidities) were eligible. Patients received LDAC 20 mg twice a day for 10 days every 4-6 weeks for up to 12 cycles. During Cycle 1, 2 fractions of 225Ac-lintuzumab were given 1 week apart, beginning 4-7 days following completion of LDAC. To prevent radiation-induced nephrotoxicity, patients were given furosemide while receiving 225Ac-lintuzumab then spironolactone for 1 year afterward. Four dose levels of 225Ac-lintuzumab were studied using a 3+3 design. Dose escalation proceeded if Results: Eighteen patients (median age, 77 years; range, 68-87 years) completed therapy. Twelve (67%) had prior myelodysplastic syndrome (MDS), for which 10 (83%) received therapy with hypomethylating agents (n=9) or allogeneic hematopoietic cell transplantation (n=1). One patient (6%) had chronic myeloid leukemia in molecular remission prior to developing AML. Eleven patients (61%) had intermediate-risk and 7 (39%) had poor-risk disease by NCCN criteria. Median CD33 expression was 81% (range, 30-100%). 225Ac-lintuzumab was given at 0.5 (n=3), 1 (n=6), 1.5 (n=3), or 2 (n=6) μCi/kg/fraction. Up to 4 cycles of LDAC were administered. Two patients experienced DLT (grade 4 thrombocytopenia with marrow aplasia for > 6 weeks following therapy), one each in the 1 and 2 µCi/kg/fraction cohorts. Although the MTD was not reached, 2 µCi/kg/fraction was chosen as the phase II dose to limit prolonged myelosuppression. Hematologic toxicities included grade 4 neutropenia (n=5) and thrombocytopenia (n=9). Grade 3/4 non-hematologic toxicities included febrile neutropenia (n=6), pneumonia (n=5), other infections (n=3), atrial fibrillation/syncope (n=1), transient creatinine increase (n=1), generalized fatigue (n=1), hypokalemia (n=1), mucositis (n=1), and rectal hemorrhage (n=1). Thirty- and 60-day mortality rates were 0% and 17%, respectively. Eleven of 14 patients (79%) evaluated after Cycle 1 had bone marrow blast reductions (mean reduction, 66%; range, 19-100%). Objective responses (2 CR, 1 CRp, 2 CRi) were seen in 5 of the 18 patients (28%), but only at doses ≥ 1 µCi/kg/fraction (Table 1). One of the responders received 15 cycles of azacitidine for prior MDS. All responses occurred after 1 cycle of therapy, in contrast to historical data with LDAC alone, where the median time to response was 3 cycles. Median progression-free survival (PFS) for all patients was 2.7 months (range, 1.0-31.8+ months). Median overall survival (OS) was 5.6 months (range, 1.6-32+ months). Median response duration was 5.6 months (range, 4.9-32+ months). Peripheral blood blast counts were a strong predictor of response. Among 38 patients treated in the current and initial phase I trials, responses were seen in 8 of 19 patients (42%) with blast counts Conclusions: Fractionated-dose 225Ac-linutuzmab can be safely combined with LDAC and induce remission in older patients with untreated AML. A phase II trial of 225Ac-lintuzumab monotherapy at 2 µCi/kg/fraction using hydroxyurea, if needed, to lower peripheral blast counts prior toadministration will be undertaken to determine response rate, PFS, and OS in this patient population. Download : Download high-res image (84KB) Download : Download full-size image Disclosures Jurcic: Forma Therapeutics: Research Funding; Seattle Genetics: Research Funding; Kura Oncology: Research Funding; Celgene: Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees; Bayer: Consultancy; Alexion Pharmaceuticals: Consultancy; Merck & Co.: Consultancy; Astellas: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding; Daiichi-Sankyo: Research Funding. Levy: Janssen: Speakers Bureau; Actinium Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Research Funding; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Park: Amgen: Consultancy; Genentech/Roche: Research Funding; Juno Therapeutics: Consultancy, Research Funding. Ravandi: Actinium Pharmaceuticals, Inc.: Research Funding. Perl: Actinium Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Consultancy. Smith: Actinium Pharmaceuticals, Inc.: Research Funding. Cicic: Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Scheinberg: Actinium Pharmaceuticals, Inc.: Equity Ownership, Patents & Royalties: Ac-225-Lintuzumab.
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phase i trial of targeted alpha particle immunotherapy with Actinium 225 225ac lintuzumab anti cd33 and low dose cytarabine ldac in older patients with untreated acute myeloid leukemia aml
Blood, 2015Co-Authors: Joseph G Jurcic, Moshe Yair Levy, Jae H Park, Alexander E Perl, Farhad Ravandi, John M Pagel, Douglas B Smith, Elihu H Estey, Hagop M Kantarjian, Dennis EarleAbstract:Background: The use of short-ranged (50-80 µm), high-energy (~100 keV/µm) α particle-emitting isotopes for radioimmunotherapy may result in more specific tumor cell kill and less damage to normal tissues than β-emitters. 225Ac-lintuzumab consists of a radiometal that emits four α-particles linked to an anti-CD33 antibody. A phase I trial showed that 225Ac-lintuzumab is safe at doses ≤ 3 µCi/kg and has anti-tumor activity against relapsed/refractory AML across all dose levels studied (Jurcic et al. ASH, 2011). We are conducting a multicenter, phase I dose-escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC. Patients and Methods: Patients ≥ 60 years with untreated AML not suitable for standard induction chemotherapy (e.g., antecedent hematologic disorder, unfavorable cytogenetic or molecular abnormalities, and significant comorbidities) were eligible. Patients received LDAC 20 mg twice daily for 10 days every 4-6 weeks for up to 12 cycles. During Cycle 1, two fractions of 225Ac-lintuzumab were given one week apart, beginning 4-7 days following completion of LDAC. To prevent radiation-induced nephrotoxicity, patients were given furosemide while receiving 225Ac-lintuzumab and spironolactone for one year afterward. 225Ac doses were escalated using a 3+3 design. Four dose levels were studied with a total accrual of up to 24 patients. In planned analyses, dose escalation proceeded if Results: Fourteen patients (median age, 77 years; range, 68-87 years) completed therapy. An additional patient received only one of two planned fractions of 225Ac-lintuzumab due to technical issues and is excluded from analysis. Nine (64%) had prior myelodysplastic syndrome, for which seven received prior therapy with hypomethylating agents (n=6) or allogeneic hematopoietic cell transplantation (n=1). One patient (7%) had chronic myeloid leukemia in molecular remission prior to development of AML. Nine patients (64%) had intermediate-risk and five (36%) had unfavorable cytogenetics. Median CD33 expression was 81% (range, 45-100%). 225Ac-lintuzumab was given at 0.5 (n=3), 1 (n=6), 1.5 (n=3), or 2 (n=2) μCi/kg/fraction. Up to 4 cycles of LDAC were administered. DLT was seen in one patient at 1 µCi/kg/fraction who had grade 4 thrombocytopenia with marrow aplasia for more than 6 weeks following therapy. Hematologic toxicities included grade 4 neutropenia (n=4) and thrombocytopenia (n=6). Grade 3/4 non-hematologic toxicities included febrile neutropenia (n=7), pneumonia (n=4), bacteremia (n=1), cellulitis (n=1), transient creatinine increase (n=1), hypokalemia (n=1), rectal hemorrhage (n=1), and generalized weakness (n=2). Eight of 11 patients (73%) evaluated after Cycle 1 had bone marrow blast reductions (mean reduction, 72%; range, 34-100%). Seven (64%) had blast reductions of at least 50%. Objective responses (1 CR, 1 CRp, 2 CRi) were seen in four of the 14 patients (29%) after one cycle of therapy (Table 1). Responses were seen only at doses ≥ 1 µCi/kg/fraction (4 of 11 patients, 36%). Median progression-free survival (PFS) was 2.7 months (range, 1.7-16.9 months). Median overall survival (OS) was 5.5 months (range, 2.2-24 months). Conclusions: Fractionated-dose 225Ac-linutuzmab can be safely combined with LDAC and produce remission in older patients with untreated AML. Dose escalation continues to define the MTD. Additional patients will be treated at the MTD in the phase II portion of this trial to determine response rate, PFS, and OS. Disclosures Jurcic:Ambit Biosciences: Research Funding; Astellas Pharma US, Invc.: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Sunesis Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy; Bayer Pharmaceuticals: Consultancy; Merck and Co.: Consultancy; Celgene Corp.: Research Funding; Actrinium Pharmaceuticals, Inc.: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Off Label Use: Ac-225-lintuzumab is an investigational agent being developed for the treatment of acute myeloid leukemia.. Pagel:Actinium Pharmacetuicals, Inc.: Equity Ownership. Park:Actinium Pharmaceuticals, Inc.: Research Funding; Juno Therapeutics: Consultancy. Levy:Takeda: Consultancy. Perl:Actinium Pharmaceuticals, Inc.: Research Funding. Earle:Actinium Pharmaceuticals, Inc.: Employment. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Scheinberg:Actinium Pharmaceuticals, Inc.: Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties.
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phase i trial of alpha particle therapy with Actinium 225 225ac lintuzumab anti cd33 and low dose cytarabine ldac in older patients with untreated acute myeloid leukemia aml
Journal of Clinical Oncology, 2015Co-Authors: Joseph G Jurcic, Moshe Yair Levy, Jae H Park, Farhad Ravandi, John M Pagel, Douglas B Smith, Dan Douer, Elihu H Estey, Hagop M Kantarjian, Dennis EarleAbstract:7050 Background: 225Ac-lintuzumab consists of a radiometal that emits 4 α-particles linked to an anti-CD33 antibody. A phase I trial showed safety and efficacy of 225Ac-lintuzumab in relapsed AML. We are conducting a multicenter, phase I trial to determine the maximum tolerated dose (MTD), toxicity, and activity of fractionated-dose 225Ac-lintuzumab combined with LDAC. Methods: Patients ≥ 60 yrs with untreated AML not suitable for standard induction were eligible. Patients received LDAC 20 mg BID for 10 d every 4-6 wks for up to 12 cycles. During Cycle 1, 2 doses of 225Ac-lintuzumab were given one week apart, 4-7 d following LDAC. 225Ac doses were escalated using a 3+3 design. Results: Twelve patients (median age, 77 yrs; range, 68-87 yrs) were treated. Eight (67%) had prior myelodysplastic syndrome, for which 6 (75%) received hypomethylating agents (n = 5) or allogeneic stem cell transplant (n = 1). One (8%) had chronic myeloid leukemia in molecular remission prior to AML. Nine patients (75%) had interme...
George Sgouros - One of the best experts on this subject based on the ideXlab platform.
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dosimetric impact of ac 227 in accelerator produced ac 225 for alpha emitter radiopharmaceutical therapy of patients with hematological malignancies a pharmacokinetic modeling analysis
EJNMMI Physics, 2021Co-Authors: George Sgouros, Dale L Ludwig, Nitya Ray, E C FreyAbstract:Actinium-225 is an alpha-particle emitter under investigation for use in radiopharmaceutical therapy. To address limited supply, accelerator-produced 225Ac has been recently made available. Accelerator-produced 225Ac via 232Th irradiation (denoted 225/7Ac) contains a low percentage (0.1–0.3%) of 227Ac (21.77-year half-life) activity at end of bombardment. Using pharmacokinetic modeling, we have examined the dosimetric impact of 227Ac on the use of accelerator-produced 225Ac for radiopharmaceutical therapy. We examine the contribution of 227Ac and its daughters to tissue absorbed doses. The dosimetric analysis was performed for antibody-conjugated 225/7Ac administered intravenously to treat patients with hematological cancers. Published pharmacokinetic models are used to obtain the distribution of 225/7Ac-labeled antibody and also the distribution of either free or antibody-conjugated 227Th. Based on our modeling, the tissue specific absorbed dose from 227Ac would be negligible in the context of therapy, less than 0.02 mGy/MBq for the top 6 highest absorbed tissues and less than 0.007 mGy/MBq for all other tissues. Compared to that from 225Ac, the absorbed dose from 227Ac makes up a very small component (less than 0.04%) of the total absorbed dose delivered to the 6 highest dose tissues: red marrow, spleen, endosteal cells, liver, lungs and kidneys when accelerator produced 225/7Ac-conjugated anti-CD33 antibody is used to treat leukemia patients. For all tissues, the dominant contributor to the absorbed dose arising from the 227Ac is 227Th, the first daughter of 227Ac which has the potential to deliver absorbed dose both while it is antibody-bound and while it is free. CONCLUSIONS: These results suggest that the absorbed dose arising from 227Ac to normal organs would be negligible for an 225/7Ac-labeled antibody that targets hematological cancer.
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abstract 3052 combining α particle radiopharmaceutical therapy using Actinium 225 and immunotherapy with anti pd l1 antibodies in a murine immunocompetent metastatic breast cancer model
Cancer Research, 2016Co-Authors: Anders Josefsson, Jessie R Nedrow, Sunju Park, Sagar Ranka, George SgourosAbstract:The programmed cell death ligand 1 (PD-L1) plays an essential role in suppressing immune recognition of cancer. PD-L1 is expressed on a variety of cells including tumor cells, tumor associated macrophages (TAMs) and other cells within the microenvironment of the tumor. When PD-L1 binds to the programmed death 1 (PD-1) receptor it inhibits CD8+ T-cell effector function. By upregulating the expression levels of PD-L1, tumor cells and TAMs are capable of avoiding T-cell immune recognition. Immunotherapy using anti-PD-L1 antibody (Ab) has shown promising anti-tumor effect against a number of cancers including breast cancer, and is currently used in several clinical trials. Furthermore, studies have shown that anti-PD-L1 Ab targeted immunotherapy synergizes with radiation therapy. The aim of this study was to investigate a possible gain in therapeutic efficacy when combining targeted α-particle radiopharmaceutical therapy using 225Ac with anti-PD-L1 Ab immunotherapy in a murine immunocompetent metastatic breast cancer model. 6-8 week old healthy female neu-N mice were injected in the left cardiac ventricle (LCV) with 50,000 NT2.5 (endogenously derived) tumor cells to create highly aggressive widespread breast cancer metastases. Groups (n = 8) of mice were injected intravenously (i.v.) in the tail vein 72 h after the LCV injection with either 1) a single dose of 300 or 400 nCi 225Ac-DOTA-anti-PD-L1 Ab (0.15 mg/kg), 2) a single dose of 100 times (100x) anti-PD-L1 Ab (15.9 mg/kg) or 3) a 400 nCi single dose 225Ac-DOTA-anti-PD-L1 Ab (0.15 mg/kg) in combination with a single dose of 100x anti-PD-L1 Ab (16.1 mg/kg). The mice in the control group were injected i.v. in the tail vein with 100 μl of saline. The 225Ac-DOTA-anti-PD-L1 conjugate was radiolabeled having a specific activity of 0.137 μCi/μg with a radiochemical purity >95%. The group receiving the single dose of 100x anti-PD-L1 Ab had the highest median survival of 44 days (p = 0.0007) followed by the 400 nCi 225Ac-DOTA-anti-PD-L1 Ab group with 39.5 days (p = 0.0413) compared with the control group 31.5 days. The survival for other treatment groups were not significant compared with the control group. Furthermore, the survival from the single dose of 100x anti-PD-L1 Ab treatment was significantly higher than the single dose treatment of 400 nCi 225Ac-DOTA-anti-PD-L1 Ab (p = 0.0308). The highest survival rate was the mice treated with 100x anti-PD-L1 Ab. The combination treatment using 400 nCi 225Ac-DOTA-anti-PD-L1 Ab and 100x anti-PD-L1 Ab showed a significant lower survival compared to each treatment by itself. However, the combination treatment was only performed with one dose and the injection was at the same time, different concentrations and time spaced injections could possibly favor the combined treatment method over the single modality treatments. Citation Format: Anders Josefsson, Jessie R. Nedrow, Sunju Park, Sagar Ranka, George Sgouros. Combining α-particle radiopharmaceutical therapy using Actinium-225 and immunotherapy with anti-PD-L1 antibodies in a murine immunocompetent metastatic breast cancer model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3052.
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dosimetric analysis of Actinium 225 labeled anti pd l1 alpha particle radioimmunotherapy of melanoma cancer in an immunocompetent mouse model
The Journal of Nuclear Medicine, 2016Co-Authors: Anders Josefsson, Jessie R Nedrow, Sunju Park, Sagar Ranka, George SgourosAbstract:635 Objectives In the immune checkpoint system the Programmed cell Death Ligand 1 (PD-L1) is co-opted by tumor cells to suppress immune recognition of cancer. PD-L1 is expressed on tumor cells, tumor associated macrophages and other cells in the tumor microenvironment, which can inhibit the T-cell effector function. We have recently shown that anti-PD-L1 antibodies can be modified for radionuclide imaging in an immunocompetent pre-clinical model. The aim of this study was to investigate combined anti-PD-L1 immunotherapy and radionuclide therapy using the alpha particle emitting radionuclide Actinium-225 (225Ac) for melanoma cancer in a immunocompetent mouse model and to perform dosimetric analysis of tumor and limiting normal tissues. Methods Immunocompetent C57BL/6 mice were injected with one million B16F10 melanoma tumor cells in the right flank 10 days prior to treatment. The mice were injected in the tail vein with 18.9 kBq 225Ac labeled anti-PD-L1 antibodies (225Ac-anti-PD-L1) and euthanized 1, 24 and 72 hours post injection (p.i.). Tumors and normal tissues were removed and measured in a gamma well counter for the dosimetric analysis. In addition, tumor and normal tissues were frozen, cryo-sectioned and imaged using the α-Camera a quantitative digital autoradiography image system to determine the distribution and activity concentration of 225Ac-anti-PD-L1 on sub organ/tumor levels. Results The calculated mean absorbed radiation dose (from alpha-particle emissions) to the tumor was 3.8 Gy from 225Ac-anti-PD-L1. For the kidneys, which probably is the limiting normal tissue the calculated mean absorbed radiation dose (from alpha-particle emissions) was 2.0 Gy, with 1.3 Gy originating from 225Ac-anti-PD-L1 and 0.65 Gy from the unbound daughter radionuclide Bismuth-213 (213Bi). The α-Camera images showed 1 hour p.i. that the majority of 225Ac-anti-PD-L1 was located within the pelvis region of the kidneys, with a small uptake in medially situated proximal tubules. In the tumor a few hot spots were detected 1 hour p.i. with activity concentrations up to 2.5 times higher than compared with the average of the whole tumor. Hematological toxicity was not observed and the maximum tolerable dose (MTD) for tumor-free mice was greater than 18.9 kBq. Conclusions A relative high mean absorbed radiation dose was calculated to the tumor from 225Ac-anti-PD-L1 and in combination with the anti-PD-L1 immunotherapy could be an effective combination treatment. Concerning normal tissues a low mean absorbed radiation dose was calculated to the kidneys, but a heterogeneous activity distribution in combination with the alpha particles high relative biological effectiveness (RBE) could lead to later toxicity at the high administered activity used in this study.
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Actinium 225 treatment of ovarian cancer metastases
The Journal of Nuclear Medicine, 2008Co-Authors: Yahel Harel, Andrew Prideaux, Hong Song, George SgourosAbstract:557 Objectives: Ovarian cancer metastases are initially confined to the intraperitoneal (ip) space. This work examines the feasibility of targeting these tumors locally using immunoliposomal targeting of 225Ac. Methods: 225Ac was actively loaded into Herceptin-immunoliposomes (HIL) using the ionophore calcimycin. Stability and retention of 225Ac was determined by incubation at 37°C in growth media. Nude mice were injected ip with SKOV3-NMP2 ovarian carcinoma cells, an aggressive variant of SKOV3 cells that develops tumor nodules on organs in the ip space. Ten days post tumor inoculation 225Ac-HIL or 225Ac-Herceptin (H) was injected ip. Mice were sacrificed at 1, 6, 24, 72, 120, and 240h and blood, heart, kidneys, liver, lungs, stomach, intestine, spine, femur, spleen, and tumor were extracted for gamma counting. Tumor-free mice were also injected ip with 225Ac-HIL or 225Ac-H to determine the maximal tolerated dose (MTD). Results: Active loading yielded 83±5% encapsulation efficiency, significantly higher than passive encapsulation. Stability studies showed 70-90% retention of initial activity over a 30 day period. 225Ac-HIL uptake was observed primarily in the tumor and spleen, with some uptake in the peritoneal organs (kidneys, liver, stomach, and intestine). The absorbed dose to kidneys and tumor was 1.4 and 0.25 Gy/kBq, respectively, for 225Ac-H and 0.90 and 0.11 Gy/kBq, respectively, for 225Ac-HIL-injected mice. The 213Bi dose contribution to kidneys from 225Ac-HIL was half of that from 225Ac-H. The MTD was >1 μCi and Conclusions: Immunoliposomal targeting of peritoneal disease with the α-emitter 225Ac provides advantages over antibody-delivery in terms of decreased toxicity, and greater delivery of α-particles to the targeted tumor. Efficacy studies are pending.
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enhanced retention of the α particle emitting daughters of Actinium 225 by liposome carriers
Bioconjugate Chemistry, 2007Co-Authors: Stavroula Sofou, Michael R Mcdevitt, Jaspreet Singh Jaggi, David A. Scheinberg, Barry J Kappel, George SgourosAbstract:Targeted α-particle emitters hold great promise as therapeutics for micrometastatic disease. Because of their high energy deposition and short range, tumor targeted α-particles can result in high c...
Dennis Earle - One of the best experts on this subject based on the ideXlab platform.
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phase i trial of targeted alpha particle immunotherapy with Actinium 225 225ac lintuzumab anti cd33 and low dose cytarabine ldac in older patients with untreated acute myeloid leukemia aml
Blood, 2015Co-Authors: Joseph G Jurcic, Moshe Yair Levy, Jae H Park, Alexander E Perl, Farhad Ravandi, John M Pagel, Douglas B Smith, Elihu H Estey, Hagop M Kantarjian, Dennis EarleAbstract:Background: The use of short-ranged (50-80 µm), high-energy (~100 keV/µm) α particle-emitting isotopes for radioimmunotherapy may result in more specific tumor cell kill and less damage to normal tissues than β-emitters. 225Ac-lintuzumab consists of a radiometal that emits four α-particles linked to an anti-CD33 antibody. A phase I trial showed that 225Ac-lintuzumab is safe at doses ≤ 3 µCi/kg and has anti-tumor activity against relapsed/refractory AML across all dose levels studied (Jurcic et al. ASH, 2011). We are conducting a multicenter, phase I dose-escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC. Patients and Methods: Patients ≥ 60 years with untreated AML not suitable for standard induction chemotherapy (e.g., antecedent hematologic disorder, unfavorable cytogenetic or molecular abnormalities, and significant comorbidities) were eligible. Patients received LDAC 20 mg twice daily for 10 days every 4-6 weeks for up to 12 cycles. During Cycle 1, two fractions of 225Ac-lintuzumab were given one week apart, beginning 4-7 days following completion of LDAC. To prevent radiation-induced nephrotoxicity, patients were given furosemide while receiving 225Ac-lintuzumab and spironolactone for one year afterward. 225Ac doses were escalated using a 3+3 design. Four dose levels were studied with a total accrual of up to 24 patients. In planned analyses, dose escalation proceeded if Results: Fourteen patients (median age, 77 years; range, 68-87 years) completed therapy. An additional patient received only one of two planned fractions of 225Ac-lintuzumab due to technical issues and is excluded from analysis. Nine (64%) had prior myelodysplastic syndrome, for which seven received prior therapy with hypomethylating agents (n=6) or allogeneic hematopoietic cell transplantation (n=1). One patient (7%) had chronic myeloid leukemia in molecular remission prior to development of AML. Nine patients (64%) had intermediate-risk and five (36%) had unfavorable cytogenetics. Median CD33 expression was 81% (range, 45-100%). 225Ac-lintuzumab was given at 0.5 (n=3), 1 (n=6), 1.5 (n=3), or 2 (n=2) μCi/kg/fraction. Up to 4 cycles of LDAC were administered. DLT was seen in one patient at 1 µCi/kg/fraction who had grade 4 thrombocytopenia with marrow aplasia for more than 6 weeks following therapy. Hematologic toxicities included grade 4 neutropenia (n=4) and thrombocytopenia (n=6). Grade 3/4 non-hematologic toxicities included febrile neutropenia (n=7), pneumonia (n=4), bacteremia (n=1), cellulitis (n=1), transient creatinine increase (n=1), hypokalemia (n=1), rectal hemorrhage (n=1), and generalized weakness (n=2). Eight of 11 patients (73%) evaluated after Cycle 1 had bone marrow blast reductions (mean reduction, 72%; range, 34-100%). Seven (64%) had blast reductions of at least 50%. Objective responses (1 CR, 1 CRp, 2 CRi) were seen in four of the 14 patients (29%) after one cycle of therapy (Table 1). Responses were seen only at doses ≥ 1 µCi/kg/fraction (4 of 11 patients, 36%). Median progression-free survival (PFS) was 2.7 months (range, 1.7-16.9 months). Median overall survival (OS) was 5.5 months (range, 2.2-24 months). Conclusions: Fractionated-dose 225Ac-linutuzmab can be safely combined with LDAC and produce remission in older patients with untreated AML. Dose escalation continues to define the MTD. Additional patients will be treated at the MTD in the phase II portion of this trial to determine response rate, PFS, and OS. Disclosures Jurcic:Ambit Biosciences: Research Funding; Astellas Pharma US, Invc.: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Sunesis Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy; Bayer Pharmaceuticals: Consultancy; Merck and Co.: Consultancy; Celgene Corp.: Research Funding; Actrinium Pharmaceuticals, Inc.: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Off Label Use: Ac-225-lintuzumab is an investigational agent being developed for the treatment of acute myeloid leukemia.. Pagel:Actinium Pharmacetuicals, Inc.: Equity Ownership. Park:Actinium Pharmaceuticals, Inc.: Research Funding; Juno Therapeutics: Consultancy. Levy:Takeda: Consultancy. Perl:Actinium Pharmaceuticals, Inc.: Research Funding. Earle:Actinium Pharmaceuticals, Inc.: Employment. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Scheinberg:Actinium Pharmaceuticals, Inc.: Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties.
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phase i trial of alpha particle therapy with Actinium 225 225ac lintuzumab anti cd33 and low dose cytarabine ldac in older patients with untreated acute myeloid leukemia aml
Journal of Clinical Oncology, 2015Co-Authors: Joseph G Jurcic, Moshe Yair Levy, Jae H Park, Farhad Ravandi, John M Pagel, Douglas B Smith, Dan Douer, Elihu H Estey, Hagop M Kantarjian, Dennis EarleAbstract:7050 Background: 225Ac-lintuzumab consists of a radiometal that emits 4 α-particles linked to an anti-CD33 antibody. A phase I trial showed safety and efficacy of 225Ac-lintuzumab in relapsed AML. We are conducting a multicenter, phase I trial to determine the maximum tolerated dose (MTD), toxicity, and activity of fractionated-dose 225Ac-lintuzumab combined with LDAC. Methods: Patients ≥ 60 yrs with untreated AML not suitable for standard induction were eligible. Patients received LDAC 20 mg BID for 10 d every 4-6 wks for up to 12 cycles. During Cycle 1, 2 doses of 225Ac-lintuzumab were given one week apart, 4-7 d following LDAC. 225Ac doses were escalated using a 3+3 design. Results: Twelve patients (median age, 77 yrs; range, 68-87 yrs) were treated. Eight (67%) had prior myelodysplastic syndrome, for which 6 (75%) received hypomethylating agents (n = 5) or allogeneic stem cell transplant (n = 1). One (8%) had chronic myeloid leukemia in molecular remission prior to AML. Nine patients (75%) had interme...
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phase i trial of alpha particle therapy with Actinium 225 225ac lintuzumab anti cd33 and low dose cytarabine ldac in older patients with untreated acute myeloid leukemia aml
Journal of Clinical Oncology, 2015Co-Authors: Joseph G Jurcic, Moshe Yair Levy, Jae H Park, Farhad Ravandi, John M Pagel, Douglas B Smith, Dan Douer, Elihu H Estey, Hagop M Kantarjian, Dennis EarleAbstract:7050 Background: 225Ac-lintuzumab consists of a radiometal that emits 4 α-particles linked to an anti-CD33 antibody. A phase I trial showed safety and efficacy of 225Ac-lintuzumab in relapsed AML. We are conducting a multicenter, phase I trial to determine the maximum tolerated dose (MTD), toxicity, and activity of fractionated-dose 225Ac-lintuzumab combined with LDAC. Methods: Patients ≥ 60 yrs with untreated AML not suitable for standard induction were eligible. Patients received LDAC 20 mg BID for 10 d every 4-6 wks for up to 12 cycles. During Cycle 1, 2 doses of 225Ac-lintuzumab were given one week apart, 4-7 d following LDAC. 225Ac doses were escalated using a 3+3 design. Results: Twelve patients (median age, 77 yrs; range, 68-87 yrs) were treated. Eight (67%) had prior myelodysplastic syndrome, for which 6 (75%) received hypomethylating agents (n = 5) or allogeneic stem cell transplant (n = 1). One (8%) had chronic myeloid leukemia in molecular remission prior to AML. Nine patients (75%) had interme...
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phase i trial of alpha particle therapy with Actinium 225 225ac lintuzumab anti cd33 and low dose cytarabine ldac in older patients with untreated acute myeloid leukemia aml
Journal of Clinical Oncology, 2015Co-Authors: Joseph G Jurcic, Moshe Yair Levy, Jae H Park, Farhad Ravandi, John M Pagel, Douglas B Smith, Dan Douer, Elihu H Estey, Hagop M Kantarjian, Dennis EarleAbstract:7050 Background: 225Ac-lintuzumab consists of a radiometal that emits 4 α-particles linked to an anti-CD33 antibody. A phase I trial showed safety and efficacy of 225Ac-lintuzumab in relapsed AML. ...
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phase i trial of targeted alpha particle therapy using Actinium 225 225ac lintuzumab anti cd33 in combination with low dose cytarabine ldac for older patients with untreated acute myeloid leukemia aml
Blood, 2014Co-Authors: Joseph G Jurcic, Jae H Park, Farhad Ravandi, John M Pagel, Douglas B Smith, Dan Douer, Elihu H Estey, Hagop M Kantarjian, Richard L Wahl, Dennis EarleAbstract:Background: Lintuzumab, a humanized anti-CD33 monoclonal antibody, targets myeloid leukemia cells but has only modest activity in AML. To increase the antibody’s potency yet avoid nonspecific cytotoxicity of β-emitting isotopes, 225Ac (t½=10 d), a radiometal that yields 4 α-particles, was conjugated to lintuzumab. A phase I trial showed that 225Ac-lintuzumab is safe at doses ≤ 3 µCi/kg and has anti-leukemic activity across all dose levels studied (Jurcic et al. ASH, 2011). We are conducting a multicenter, phase I dose-escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC. Patients and Methods: Patients ≥ 60 yrs who had untreated AML with poor prognostic factors, e.g. , an antecedent hematologic disorder, unfavorable cytogenetic or molecular abnormalities, and significant comorbidities, were eligible. Patients received LDAC 20 mg twice daily for 10 d every 4-6 wks for up to 12 cycles. During Cycle 1, beginning 4-7 days after completion of LDAC, two doses of 225Ac-lintuzumab were given approximately one week apart. To prevent radiation-induced nephrotoxicity, patients were given furosemide while receiving 225Ac-lintuzumab and spironolactone for one year afterward. Results: Nine patients (median age, 76 yrs; range, 73-81 yrs) were treated. Seven patients (78%) had a history of myelodysplastic syndromes (MDS), for which five (56%) received prior therapy with hypomethylating agents (n=4) or allogeneic hematopoietic cell transplantation (n=1). One patient (11%) had chronic myeloid leukemia in a molecularly undetectable state at the time of AML diagnosis. Six patients (67%) had intermediate-risk cytogenetics, and three (33%) had unfavorable cytogenetics. The median CD33 expression was 76% (range, 45-100%). Patients received 225Ac-lintuzumab at doses of 0.5 (n=3) or 1 (n=6) μCi/kg/fraction. Total administered activity ranged from 68-199 μCi. The median number of cycles administered was 2 (range, 1-4). Dose-limiting toxicity was seen in one patient receiving 1 µCi/kg/fraction who had grade 4 thrombocytopenia with bone marrow aplasia persisting > 6 wks after receiving 225Ac-lintuzumab. Hematologic toxicities included grade 4 neutropenia (n=1) and thrombocytopenia (n=3). Grade 3/4 non-hematologic toxicities included febrile neutropenia (n=6), pneumonia (n=2), bacteremia (n=1), cellulitis (n=1), transient increase in creatinine (n=1), hypokalemia (n=1), and generalized weakness (n=1). Bone marrow blast reductions were seen in 5 of 7 patients (71%) evaluated after Cycle 1. Mean blast reduction was 61% (range, 34-100%). Three of the 7 patients (43%) had marrow blast reductions of ≥ 50%; however, no remissions were observed. Median progression-free survival (PFS) was 2.5 mos (range, 1.7-15.7+ mos). Median overall survival (OS) from study entry was 5.4 mos (range, 2.2-24 mos). For the 7 patients with prior MDS, median OS was 9.1 mos (range 2.3-24 mos). Conclusions: Fractionated-dose 225Ac-linutuzmab in combination with LDAC is feasible, safe, and has anti-leukemic activity. Dose escalation continues to define the MTD, with planned doses up to 2 µCi/kg/fraction. Additional patients will be treated at the MTD in the phase II portion of this trial to determine response rate, PFS, and OS. Disclosures Ravandi: Actinium Pharmaceuticals, Inc.: Research Funding. Pagel: Actinium Pharmaceuticals, Inc.: Equity Ownership, Research Funding. Park: Actinium Pharmaceuticals, Inc.: Research Funding. Wahl: Actinium Pharmaceuticals, Inc.: Research Funding. Earle: Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Cicic: Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Scheinberg: Actinium Pharmaceuticals, Inc.: Equity Ownership, Research Funding.
