Abstract: 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 〈 33% of patients in a cohort experienced dose-limiting toxicity (DLT). 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. Table 1. Objective Responses Response Dose Level (μCi/kg/fraction) Total (n=14) 0.5 (n=3) 1 (n=6) 1.5 (n=3) 2 (n=2) CR 0 0 1 (33%) 0 1 (7%) CRp 0 0 0 1 (50%) 1 (7%) CRi 0 1 (17%) 1 (33%) 0 2 (14%) Overall Response 0 1 (17%) 2 (67%) 1 (50%) 4 (29%) Abbreviations: CR, complete remission; CRp, CR with incomplete platelet recovery; CRi, CR with incomplete count recovery. Disclosures Jurcic: Ambit Biosciences: Research Funding; Astellas Pharma US, Invc.: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Sunesis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's 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 entity's 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 entity's Board of Directors or advisory committees, Patents & Royalties.

Abstract: 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.

Abstract: 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.

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.

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 〈 33% of patients in a cohort experienced dose-limiting toxicity (DLT). 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 〈 200/µL, compared with 0 of 17 patients with blast counts ≥ 200/µL (P=0.002). This difference is likely due to decreased marrow targeting in patients with higher circulating blast counts when the subsaturating antibody doses used in this trial are given. 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 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.