Berger, Mark S.

Abstract Background: Several targeted therapies have been recently approved as treatment options for acute myeloid leukemia (AML), however, complete remissions (CR) in relapsed/refractory (R/R) patients remain low. Due to suboptimal responses to standard therapies, most of these patients do not receive an allogeneic hematopoietic cell transplant (HCT). In addition, AML patients ≥55 years have poor tolerance and high morbidity from a myeloablative HCT. The SIERRA trial (Study of Iomab-B in Elderly Relapsed or Refractory AML) has been investigating the use of Iomab-B, an 131I-labeled anti-CD45 monoclonal antibody, to reduce relapse in patients with active, R/R AML who receive HCT as compared to Conventional Care (CC) therapies. With the recent approval of various targeted therapies like BCL-2 inhibitors (e.g., venetoclax), FLT-3 inhibitors (e.g., midostaurin and gilteritinib) and IDH inhibitors (e.g., ivosidenib), the protocol was amended to include patients refractory to these therapies. We are reporting on the success rate of engraftment and tolerability of Iomab-B among the CC patients who cross-over to receive Iomab-B and HCT after failing these agents. Methods: Approximately 150 older patients with R/R AML are to be randomized (1:1) to receive Iomab-B followed by fludarabine, total body irradiation (2 Gy) and allogeneic HCT, or to conventional care (CC). CC patients receive physician's choice of therapy, including targeted therapies, and may proceed to standard of care allogeneic HCT if they achieve CR. CC patients not achieving CR may cross over to Iomab-B-based HCT. Results: Available data for 136 patients (>90% of target enrollment; median age 65) demonstrated they had a median of 3 (range: 1-7) prior lines of AML therapies. Median marrow blast at time of study entry was 25%. Prior to enrollment, 85 (63%) patients received targeted therapies, including BCL-2 inhibitors (62%), FLT-3 inhibitors (18%), IDH inhibitors (7%) and others (13%; e.g., gemtuzumab ozogamicin). Among the 50 evaluable patients in the Iomab-B group that received HCT, all successfully engrafted after a median radiation dose delivered to marrow of 14.7 Gy (range: 4.6 - 44.6) with a median time to neutrophil and platelet engraftment of 14.5 (range: 9-28) and 18 (range: 4-58) days, respectively. Of 63 patients randomized to the CC arm and with data available, 11 (17%) achieved CR and proceeded to standard of care HCT without Iomab-B while 52 (83%) did not respond to CC therapy. Twenty-seven of 63 (43%) CC patients received targeted therapy, of whom 21 received venetoclax with hypomethylating agents (HMA) or low-dose Cytarabine (LDAC). Seven of the 27 (26%) CC patients remission after targeted therapy and received standard of care HCT. Of the 20 patients who did not respond to targeted therapies, 11 (55%) crossed-over and received Iomab-B/HCT with a median radiation dose delivered to marrow of 18 Gy (range: 12.6 - 22.6). Median time to neutrophil and platelet engraftment was 12 (range: 10-27) and 20 (range: 15-38) days, respectively. Safety data are available for 103 transplanted patients in both groups and are presented in table. The incidence of Grade ≥3 febrile neutropenia (FN) was 37% vs 55%, sepsis 5% vs 30%, and mucositis 10% vs 20% in the Iomab-B group compared to all transplanted patients in the CC group. In patients who received targeted therapy and HCT (crossover or standard HCT), incidences of FN, sepsis and mucositis were 39%, 28% and 22%, respectively. Conclusion: SIERRA trial patients not achieving CR with recently approved targeted therapies who then crossed-over to receive HCT with Iomab-B successfully engrafted. Time to engraftment was similar to those who were randomized to receive Iomab-B and HCT. Available data suggest incidences of sepsis and mucositis are lower in the Iomab-B group. (www.sierratrial.com or clinicaltrials.gov NCT02665065) Figure 1 Figure 1. Disclosures Gyurkocza: Actinium Pharmaceutical Inc.: Research Funding. Nath: Actinium: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Litzow: Amgen: Research Funding; Biosight: Other: Data monitoring committee; Jazz: Other: Advisory Board; Pluristem: Research Funding; Astellas: Research Funding; Actinium: Research Funding; Omeros: Other: Advisory Board; AbbVie: Research Funding. Koshy: Astellas; Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium, Speakers Bureau. Stiff: Seagen: Research Funding; Incyte: Research Funding; Gamida Cell: Research Funding; Janssen: Research Funding; CRISPR Therapeutics: Consultancy, Honoraria; Kite, a Gilead Company: Research Funding; Macrogenics: Research Funding; Bristol Myers Squibb: Research Funding; Cellectar: Research Funding; BioLineRX: Research Funding; MorphoSys: Consultancy, Honoraria; Amgen: Research Funding; Karyopharm: Consultancy, Honoraria; Cellectar: Research Funding; Actinium: Research Funding. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. Hari: Karyopharm: Consultancy; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Chen: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium. Sabloff: Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Orozco: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium, Research Funding. Foran: abbvie: Research Funding; revolution medicine: Honoraria; novartis: Honoraria; certara: Honoraria; actinium: Research Funding; OncLive: Honoraria; aptose: Research Funding; trillium: Research Funding; gamida: Honoraria; takeda: Research Funding; boehringer ingelheim: Research Funding; bms: Honoraria; taiho: Honoraria; syros: Honoraria; sanofi aventis: Honoraria; pfizer: Honoraria; servier: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Jamieson: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium. Magalhaes-Silverman: Actinium Pharmaceuticals; Incyte; Marker Therapeutics: Other: Principal Investigator, SIERRA Trial, Actinium, Research Funding. Schuster: Takeda: Consultancy, Speakers Bureau; MorphoSys Ag: Consultancy, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Intellisphere: Consultancy, Speakers Bureau; AbbVie Incorporated: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Epizyme: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium Pharmaceuticals, Research Funding; Rafael Pharmaceuticals: Research Funding; GSK: Research Funding; AlloVir: Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; Celgene: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau. Law: Actinium Pharmaceuticals: Research Funding; Novartis: Consultancy. Levy: Takeda, Celgene, Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals,Janssen.: Consultancy. Lazarus: Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees. Giralt: PFIZER: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Berger: Actinium Pharmaceuticals, Inc: Current Employment. Spross: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Desai: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Reddy: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Pagel: AstraZeneca: Consultancy; MEI Pharma: Consultancy; Epizyme: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; BeiGene: Consultancy; Pharmacyclics/AbbVie: Consultancy; Gilead: Consultancy; Incyte/MorphoSys: Consultancy.

Background: Patients ≥55 years of age with high-risk acute myeloid leukemia (AML) may benefit from an allogeneic hematopoietic cell transplantation (HCT), which is often the only potentially curative therapy available. However, complete remission (CR) is usually a pre-requisite for most centers to perform HCT, as CR predicts an optimal outcome. Many older patients with relapsed/refractory (R/R) AML are not transplanted as they do not achieve the required CR. In addition, due to their advanced age, they are unable to tolerate the myeloablative conditioning required for eradication of disease, while the more tolerable reduced intensity conditioning often exhibits high rates of relapse. The SIERRA trial is a prospective, randomized, phase 3 trial for older patients with R/R AML to address this unmet need. We hypothesized that a targeted delivery of radiation to the marrow, achieved with a limit of 24 Gray (Gy) radiation dose to the liver, via an infusion of a therapeutic dose of Iomab-B enables successful engraftment despite active disease in the marrow. Methods: Eligible patients were ≥55 years with active R/R AML (≥5% blasts), adequate organ function, and related/unrelated 8/8 HLA-matched donors. Patients were randomized (1:1) to the Iomab-B or Conventional Care (CC) arm. Patients randomized to Iomab-B received an outpatient dosimetric dose of Iomab-B followed by nuclear medicine imaging to determine the personalized therapeutic dose that would deliver radiation to the marrow while limiting the delivery of radiation to the liver to 24 Gy. HCT is performed 12-14 days following the infusion of a therapeutic dose of Iomab-B, and a non-myeloablative conditioning backbone of fludarabine (30 mg/m2 x 3) and low-dose Total Body Irradiation (TBI 2 Gy x 1 dose). Patients on the CC arm received investigator's choice of salvage therapy, including newly approved targeted agents, and could proceed to physician's choice of conditioning and HCT if they achieved CR. If CC patients did not achieve CR, the study allowed them to cross-over and receive Iomab-B-based conditioning followed by allogeneic HCT. Results: Preliminary data were available from 106 patients (Table 1). 53 patients (median age 64) were randomized to Iomab-B and received allogeneic transplant. All Iomab-B patients engrafted, despite a pre-therapy median of 26% marrow blasts. After randomization, 83% (44/53) CC patients failed salvage therapy, including 45% (24/53) who received targeted agents. 26 of 44 (60%) CC patients, with a median 33% marrow blasts, crossed over and received Iomab-B followed by allogeneic HCT. Patient age, donor type (MRD, MUD), bone marrow cellularity, blast percentage, type of donor, stem cell dose, administered Iomab-B activity (mCi), and absorbed radiation dose to the marrow (Gy), were analyzed for time to engraftment among each group. Median time to neutrophil and platelet engraftment were 14 days (range 9-22) and 17 days (range 4-39) respectively, with 91% of evaluable patients achieving full donor chimerism (>95% by day 100, Table 1). Neither the radiation dose delivered to the marrow (median 14.7 Gy; range, 4.6-32 Gy; Table 1) nor the total administered activity (median 632 mCi; range, 354-1027 mCi) showed correlation with the time to either neutrophil (p value=0.525) or platelet engraftment (p value=0.952). Regression analyses, considering all of the variables individually, did not indicate a statistically significant correlation (p > 0.1) between days to engraftment and radiation dose delivered to the marrow. These results were consistent for the Iomab-B cross-over group as well. Furthermore, the marrow absorbed dose did not show a significant correlation with % chimerism at day 28 in patients on the Iomab-B arm or in cross-over patients. Conclusion: Dosimetry to determine a patient-specific therapeutic dose of Iomab-B of 24 Gy to the liver provided absorbed marrow radiation doses that allowed for reliable engraftment after allogeneic HCT in older patients with R/R AML, despite a heavy leukemia burden with median bone marrow blasts of 26% prior to HCT (Iomab-B arm). There was no relationship between total administered activity or radiation dose delivered to the marrow with the speed of engraftment. The SIERRA trial is currently enrolling patients (www.sierratrial.com or clinicaltrials.gov NCT02665065). Disclosures Gyurkocza: Actinium: Research Funding. Nath:Daiichi Sankyo: Consultancy, Honoraria; Actinium: Consultancy, Honoraria; Astellas: Consultancy, Honoraria. Stiff:Kite, a Gilead Company: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Macrogenics: Research Funding; Delta-Fly: Research Funding; Amgen: Research Funding. Hari:Takeda: Consultancy; BMS: Consultancy; GSK: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Incyte Corporation: Consultancy. Al-Kadhimi:Actinium Pharmaceuticals Inc.: Research Funding; Genzyme: Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; Gilead Science: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Novavax: Current equity holder in publicly-traded company. Abboud:BMS: Current equity holder in publicly-traded company; AbbVie Inc: Current equity holder in publicly-traded company; Forty Seven Inc: Research Funding; Abbott Labs: Current equity holder in publicly-traded company; AlloVir: Research Funding; Ryvu: Research Funding; Actinium Pharmaceuticals Inc.: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Pfizer: Research Funding. Magalhaes-Silverman:Incyte: Research Funding; Kadmon Holdings: Research Funding; Actinium Pharmaceuticals: Research Funding. Foran:BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; H3Biosciences: Research Funding; Agios: Honoraria, Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; Revolution Medicine: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Schuster:Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Kebriaei:Amgen: Other: Research Support; Pfizer: Other: Served on advisory board; Ziopharm: Other: Research Support; Jazz: Consultancy; Novartis: Other: Served on advisory board; Kite: Other: Served on advisory board. Levy:Karyopharm: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau; Baylor University Med Center: Current Employment. Giralt:ACTINUUM: Consultancy, Research Funding; MILTENYI: Consultancy, Research Funding; KITE: Consultancy; TAKEDA: Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding; OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding. Liang:Actinium Pharmaceuticals: Current Employment. Berger:Actinium Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company. Reddy:Actinium Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company.

Background: Despite recently approved novel targeted therapies, most patients with high-risk acute myeloid leukemia (AML) still require allogeneic hematopoietic cell transplantation (HCT) to achieve long-term survival. However, older patients with relapsed/refractory (R/R) AML are often unable to undergo HCT due to the toxicity of myeloablative pre-conditioning. Since higher doses of chemotherapy and radiation are associated with prolonged myelosuppression or infectious complications, targeted radiotherapy with Iomab-B, employed in the SIERRA trial, was designed to minimize toxicities in a patient population unable to tolerate standard high-dose myeloablative HCT pre-conditioning. We hypothesize that Iomab-B, which spares non-hematologic organs such as the GI tract, exhibits a favorable toxicity profile with respect to mucositis, febrile neutropenia (FN), and sepsis. Methods: The SIERRA trial is a prospective trial for patients ≥55 years of age with R/R AML (≥5% blasts) and 8/8 HLA-matched related or unrelated donors. Patients were randomized (1:1) to Iomab-B or Conventional Care (CC). Those in the Iomab-B group received a dosimetric infusion of Iomab-B followed by nuclear imaging to determine the personalized therapeutic dose to be delivered to the bone marrow and to other sites of disease. Therapeutic dose calculations, utilizing the Olinda software (Version 2.1, Hermes Medical) to determine the delivery of a maximum of 24 Gray (Gy) dose to the liver, were performed based on the imaging results. HCT is performed 12-14 days following the infusion of a therapeutic dose of Iomab-B, and a non-myeloablative conditioning backbone of fludarabine (30 mg/m2 x 3) and low-dose Total Body Irradiation (TBI 2 Gy x 1 dose). CC patients received the investigator's choice of salvage therapy. Safety data was evaluated from randomization and up to 100 days after HCT in the patients randomized to the Iomab-B group. We specifically evaluated AE variables of mucositis (Gr 2-4), FN (Gr3,4) and sepsis. An analysis was performed with both total activity of Iomab-B as well as with the radiation dose delivered to the bone marrow, stomach wall, small and large intestinal walls. For each of the 3 AEs of interest, a multivariate analysis was performed, allowing each of the predictor variables to be included in the model. Results: A total of 106 patients were randomized at the time of analysis. For those randomized to Iomab-B, data is available for 45 patients that received a therapeutic dose of Iomab-B and HCT. The median dose of Iomab-B administered was 603 mCi (range 313-1027 mCi) and the median radiation dose delivered to the marrow in the Iomab-B group was 14.7 Gy (range 4.6 - 32 Gy). All patients (median age 64) treated with a therapeutic dose of Iomab-B achieved neutrophil engraftment after a median of 14 days post-HCT (range 9-22), despite presenting with a median 26% marrow blasts prior to initiation of therapy. Rates of mucositis, FN, and sepsis are shown in Table 1. No correlation between AEs (FN, mucositis, sepsis) and administered Iomab-B activity (p=0.08), nor with dose delivered to GI tract (p=0.09) was observed. Furthermore, these AEs were not related to the dose of radiation received by the small intestine (median 2.7 Gy range 1.1-6.8 Gy) large intestine (median 2.6 Gy range 0.9-6.5 Gy), nor an average of all 4 GI sites (median 2.8 Gy range 1.6-6.8 Gy). Conclusions: Unlike cases involving treatment with cytotoxic chemotherapy and external beam radiation where mucositis, infections and sepsis increase along with the administered dose, targeted myeloablative conditioning with Iomab-B resulted in low incidences of severe mucositis, FN, and sepsis. These AEs do not appear to be related to the total dose of Iomab-B administered nor to the specific radiation dose delivered to the bone marrow. Furthermore, a low dose of radiation (2.8 Gy) was received by the GI tract compared to the larger dose of radiation (14.7 Gy) delivered to the marrow. Taken together, these results represent potentially significant improvements in the safe delivery of myeloablative therapy with high-dose targeted radioimmunotherapy, prior to HCT in older patients with R/R AML. This SIERRA trial is currently enrolling patients (www.sierratrial.com or clinicaltrials.gov NCT02665065). Disclosures Gyurkocza: Actinium: Research Funding. Nath:Actinium: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria. Stiff:Kite, a Gilead Company: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Delta-Fly: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Hari:Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy. Al-Kadhimi:Actinium Pharmaceuticals Inc.: Research Funding; Genzyme: Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; Gilead Science: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Novavax: Current equity holder in publicly-traded company. Abboud:Ryvu: Research Funding; Actinium Pharmaceuticals Inc.: Research Funding; Pfizer: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company; Abbott Labs: Current equity holder in publicly-traded company; AbbVie Inc: Current equity holder in publicly-traded company; AlloVir: Research Funding; Forty Seven Inc: Research Funding. Magalhaes-Silverman:Kadmon Holdings: Research Funding; Actinium Pharmaceuticals: Research Funding; Incyte: Research Funding. Foran:Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy; Agios: Honoraria, Research Funding; H3Biosciences: Research Funding. Schuster:Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Kebriaei:Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Amgen: Other: Research Support; Ziopharm: Other: Research Support; Novartis: Other: Served on advisory board; Jazz: Consultancy. Levy:Karyopharm,Takeda, BMS: Consultancy, Honoraria, Speakers Bureau. Giralt:KITE: Consultancy; NOVARTIS: Consultancy, Honoraria, Research Funding; OMEROS: Consultancy, Honoraria; ACTINUUM: Consultancy, Research Funding; MILTENYI: Consultancy, Research Funding; TAKEDA: Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding. Liang:Actinium Pharmaceuticals: Current Employment. Berger:Actinium Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company. Reddy:Actinium Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company.

Background: Patients ≥55 years of age with rel/ref AML who have failed to achieve complete remission (CR) after standard induction & salvage therapies do not routinely undergo allogeneic hematopoietic cell transplantation (HCT) due to inability to receive myeloablative conditioning and lack of efficacy. With the advent of recently approved targeted therapies (e.g. venetoclax, IDH inhibitors) more patients achieve CR, however durable responses in heavily pre-treated patient populations remain unsatisfactory with very few patients being transplanted. The SIERRA (Study of Iomab-B in Elderly Relapsed or Refractory AML) trial is a prospective, randomized, phase 3 trial designed to address this unmet need. We present the preliminary analysis of the first 50% of patients and analyze the proportion of patients who fail standard chemo and targeted therapies that can then successfully undergo HCT with Iomab-B-based conditioning. Study continues to enroll (N=150), primary end-point durable CR of ≥180 days. Methods: Eligible patients are ≥ 55 years with rel/ref AML (≥5% blasts), adequate organ function, and related/unrelated 8/8 HLA-matched donors. Patients are randomized (1:1) to receive Iomab-B followed 12-14 days later by reduced intensity conditioning (fludarabine(FLU)/TBI) and HCT, or to conventional care (CC). CC patients may receive investigator's choice of salvage therapy, including newly approved targeted agents such as venetoclax, IDH Inhibitors and may proceed to standard HCT if they achieve CR. If patients do not achieve CR, the study allows cross-over (CO) to Iomab-B with HCT. Results: Preliminary data are available from the first 75 patients enrolled on the SIERRA trial. Median age of 64 years (range: 55-77). All patients had active measurable disease (Table 1). Patients in this trial were heavily pretreated with 85% failing ≥2 induction therapies and 33% failing targeted therapies. Molecular and cytogenetics was 68% adverse risk. (NCCN, v1.2018) Following therapeutic dose of Iomab-B as a single agent, there was significant reduction of circulating blasts by day 3 (99%, p<0.0001), and peripheral blasts became undetectable by day 8 prior to FLU. All patients transplanted on the Iomab-B arm with data available showed median days to engraftment of ANC at 14 (range: 9-22) and platelets at 16 (range: 4-30) (Table 1). After randomization, 82% (31/38) patients in the CC arm failed salvage therapy and did not proceed to standard HCT. Significantly, 32% (12/38) of these patients received targeted therapy. 73% (8/11) of the patients receiving venetoclax with HMA or cytarabine did not adequately respond and did not proceed to standard HCT, 45% (5/11) crossed over to Iomab-B and received HCT. Following standard chemotherapies, 85% (22/26) were evaluated for CO. In total, 63% (19/30) received Iomab-B and HCT. The most common reason preventing crossover was disease progression. All crossover (Iomab-B) patients showed similar engraftment (Table 1). CC patients showed increased incidence of febrile neutropenia with grade 3 prior to CO evaluation or HCT, compared to Iomab-B patients prior to HCT (CC: 34%, Iomab-B: 8%). Iomab-B administration was generally well-tolerated with no grade 4 and 1 grade 3 infusion reaction. There were no Iomab-B-related deaths or 100 day non-relapse transplant related mortality deaths in patients on the Iomab-B arm (Table 1). Conclusion: 100% of the patients receiving HCT on the Iomab-B arm engrafted, despite a median of 29% BM blasts pre-Iomab-B. 82% of the patients on the CC arm failed to be eligible for standard of care transplant, including a high percentage of those receiving targeted therapies. On the CC arm, 63% of eligible patients crossed over to Iomab-B/HCT with robust engraftment despite a median of 35% BM blasts pre-Iomab-B. The incidence of grade 3 febrile neutropenia was higher in patients treated on the conventional care arm with salvage therapy vs. those treated on the Iomab-B arm prior to HCT. In conclusion, despite advanced age, active disease and heavily pre-treated patients, 68% (50/74) of all patients enrolled in the SIERRA trial were able to undergo HCT after reinduction and targeted conditioning with Iomab-B. These results show significant improvements in the current rates of transplantation in this patient population. This SIERRA trial is currently enrolling. For full study details see www.sierratrial.com or clinicaltrials.gov (NCT02665065). Disclosures Gyurkocza: Actinium Pharmaceuticals: Research Funding. Nath:Astellas: Consultancy; Actinium: Consultancy; Daiichi Sankyo: Consultancy. Stiff:Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Unum: Research Funding; Cellectar: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding. Tomlinson:Actinium Pharmaceuticals, Inc: Other: Travel Support. Abhyankar:Incyte: Speakers Bureau; Therakos: Other: Consulting, Speakers Bureau. Hari:AbbVie: Consultancy, Honoraria; Cell Vault: Equity Ownership; Sanofi: Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria. Al-Kadhimi:Seattle Genetics: Other: Stocks; Celldex Biotech: Other: Stocks. Foran:Agios: Honoraria, Research Funding. Orozco:Actinium Pharmaceuticals: Research Funding. Van Besien:Miltenyi Biotec: Research Funding. Sabloff:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding. Kebriaei:Pfizer: Honoraria; Kite: Honoraria; Jazz: Consultancy; Amgen: Research Funding; Pfizer: Honoraria; Kite: Honoraria; Jazz: Consultancy; Amgen: Research Funding. Levy:Takeda (Millennium Pharmaceuticals): Consultancy. Lazarus:Adaptive Biotechnologies: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Actinium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva Pharmaceuticals: Speakers Bureau; Biosight: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Pluristem Therapeutics, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Genentech: Speakers Bureau. Giralt:Novartis: Consultancy; Actinium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Kite: Consultancy; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy. Berger:Actinium Pharmaceuticals, Inc: Employment, Equity Ownership. Reddy:Actinium Pharmaceuticals: Employment. Pagel:Pharmacyclics: Consultancy; AstraZeneca: Consultancy; Gilead Sciences: Consultancy.

Abstract Background: Older patients (pts) with AML unfit for intense induction chemotherapy have a poor prognosis with a 5 year survival of <10%. 225Ac-lintuzumab is composed of 225Ac linked to a humanized anti-CD33 monoclonal antibody. Data were previously presented on the initial 13 pts who received 2.0 µCi/kg/dose on Days 1 and 8 (ASH, 2017, Abstract 616). Although that dose resulted in a high response rate of 69%, there were 6 pts with Grade 4 thrombocytopenia lasting >6 weeks and 5 CRi patients did not reach an ANC of ≥ 500/µL. Therefore, the activity level was reduced to 1.5 µCi/kg/dose for further evaluation. Methods: This study enrolled older pts with untreated AML who were considered to be unfit for standard induction chemotherapy. Pts aged 60 to 74 years were required to have significant co-morbidities, while all pts ≥ 75 years were eligible. Other eligibility criteria included ECOG PS 0-2, CD33 expression on > 25% of blasts, and a peripheral blast count <200/µL within 10 days of the first dose to optimize targeting of bone marrow (BM) blasts. Hydroxyurea was used to lower peripheral blast counts. 1.5 µCi/kg of 225Ac-lin were administered IV on Days 1 and 8. G-CSF was given starting 10 days after the 2nd dose and spironolactone was given for up to 1 year to minimize the risk of radiation-induced nephrotoxicity. Pts were evaluated for the CD33 splicing polymorphism SNP rs12459419. Results: 18 pts were included in this prespecified Interim Analysis. An additional 9 pts were treated at this dose and will be included in an updated analysis at the ASH meeting. The median age of the 18 pts was 73.5 years (range 60-87) and median ECOG Performance Status was 1 (0 in 3 pts, 1 in 9 pts, & 6 in 2 pts). 11 pts had prior AHDs (6 MDS, 2 CMML, 2 NHL, 1 myelofibrosis), and 9 had prior treatment for AHDs. Of the pts with known cytogenetic and molecular genetic results, 1 had favorable-risk, 3 had intermediate-risk, and 5 had adverse-risk AML using NCCN guidelines. The median baseline BM blast % was 40.5% (range, 22-66%) with a median CD33 expression of 62% (range, 26-100%) of AML cells. Objective responses were seen in 4 pts (22%): 3 complete remissions with incomplete platelet count recovery (CRp) and 1 complete remission with incomplete hematologic recovery (CRi). Among the responders with known cytogenetics, 1 pt had adverse genetics and 1 had Intermediate-risk genetics.Of the pts with remission, 3 had CT genotype for the CD33 splicing polymorphism SNP rs12459419 (including 2 CRp) and 1 had CC genotype. 3 of the responders are in follow up at Days 59, 169 and 266 without further treatment. Myelosuppression was seen in all pts including Grade 4 thrombocytopenia with marrow aplasia for > 6 weeks after the first dose in 4 pts. 1 pt with prior MDS had pancytopenia for > 4 months. The 3 pts with CRp achieved an ANC ≥ 1000/µL at Days 28, 38, and 40 from the first dose of 225Ac-lin. The pt with CRi did not reach an ANC of 500/µL. Non hematologic Grade ≥3 Treatment-Emergent adverse events (AEs) that were at least possibly related were 4 patients with febrile neutropenia, as well as 1 patient each with fungal pneumonia, acute respiratory failure, pulmonary edema, chest pain, sepsis, gastric hemorrhage, generalized muscle weakness, atrial fibrillation with rapid ventricular response and typhilitis. No pts had an infusion-related reaction requiring dose interruption. Veno-occlusive disease did not occur. The 30-day mortality rate was 16.7% (1 cardiac arrest and 2 with multi organ failure). Conclusions: Preliminary data from this Interim Analysis of 225Ac-lin monotherapy in older AML pts unfit for intensive therapy indicate a lower rate of myelosuppression at 1.5 µCi/kg/dose but also a lower response rate than was seen at 2.0 µCi/kg/dose. Although the study met the prespecified response criteria for continuing enrollment, it will be closed to further accrual in recognition that targeted radiation, like other therapies, will likely have the best outcomes when used in combination with other therapies in pts with active AML. An extensive development program in AML, MDS, and multiple myeloma is planned. One study will utilize 225Ac-lin in combination with salvage chemotherapy and another with venetoclax. 225Ac-lin will be used as a single agent for AML postremission therapy. In addition, 225Ac-lin will be used as targeted conditioning prior to hematopoietic stem cell transplant in pts with MDS with a complex karyotype and as a conditioning agent prior to autologous transplant in MM. Table. Table. Disclosures Atallah: Jazz: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; BMS: Consultancy. Orozco:Actinium Pharmaceuticals: Research Funding. Craig:Novartis: Research Funding; Actinium Pharmaceuticals: Research Funding; Celgene: Research Funding. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Finn:Ochsner Clinic Foundation: Employment. Perl:NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; Astellas: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees. Park:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Consultancy, Research Funding; Shire: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. Roboz:Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Celltrion: Consultancy; Celgene Corporation: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Pfizer: Consultancy; Argenx: Consultancy; Roche/Genentech: Consultancy; AbbVie: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Bayer: Consultancy; Sandoz: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Astex Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy; Argenx: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Eisai: Consultancy; Orsenix: Consultancy; Cellectis: Research Funding; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Celltrion: Consultancy. Tse:Brown Cancer Center, University of Louisville School of Medicine: Employment; Jazz: Consultancy; Amgen: Consultancy; Amgen: Honoraria; Amgen: Honoraria. Mawad:Swedish Cancer Institute: Employment. Rizzieri:Novartis: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Berger:Actinium Pharmaceuticals: Employment, Equity Ownership. Jurcic:Astellas: Research Funding; Daiichi-Sankyo: Research Funding; Incyte: Consultancy; Celgene: Research Funding; AbbVie: Consultancy, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Syros Pharmaceuticals: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Genetech: Research Funding; Kura Oncology: Research Funding.

Abstract Background: Patients ≥55 years of age with active, relapsed or refractory acute myeloid leukemia (R/R AML) who have failed standard induction therapies most often receive salvage therapy with a wide variety of agents, but very few achieve remission. These patients do not routinely undergo allogeneic hematopoietic cell transplantation (HCT) due to lack of efficacy using a standard HCT approach. The SIERRA trial is a prospective, randomized, phase 3, open-label, ongoing multicenter trial designed to address this significant unmet need in R/R AML. This trial compares Iomab-B, an 131I-radiolabeled anti-CD45 antibody as targeted conditioning prior to HCT against standard conventional care therapies with an accrual goal of 150 patients. We have performed a preliminary safety analysis, validating the initial feasibility of this multi-center trial. Methods: Eligible patients are ≥ 55 years of age with active, R/R AML, adequate organ function, and related/unrelated matched donor. Patients are randomized (1:1 ratio) to receive dosimetry directed Iomab-B followed 12 days later by HCT with fludarabine 30 mg/m2 x 3 days and 2 Gy of total body irradiation as transplant conditioning, or to a Conventional Care (CC) arm. Patients randomized to CC, may receive investigator's choice of salvage induction chemotherapy including approved targeted agents as well as Venetoclax (in combination with a hypomethylating agent) and proceed to standard HCT if they achieve complete remission (CR). If patients do not achieve CR, the study allows optional cross-over to the Iomab-B arm, evaluated between days 28-42 after CC therapy. The primary efficacy endpoint for the study is durable complete remission (dCR) of 6 months. The secondary efficacy objective is to evaluate overall survival at 1 year. Results: Forty patients have been enrolled to date and data are available for 38 patients (19 = Iomab-B, 19 = CC) as of July 5th, 2018. The median age was 63 years (range: 55-76). All patients had active disease at the time of enrollment with median bone marrow (BM) blasts of 30% in the Iomab-B arm and 47% in the crossover arm prior to receiving Iomab-B (Table 1). Of the patients in the CC arm, 88% did not achieve a CR and 65% of those crossed-over to receive Iomab-B. The most common reason preventing crossover was declining performance status. Time to HCT was not increased in the crossover patients receiving Iomab-B compared to those that underwent a standard of care transplant after achieving CR (median 65 vs 75 days), while the Iomab-B arm patients were transplanted at a median of 27 days after randomization. Iomab-B therapy was well-tolerated with no grade 3 or 4 infusion-related reactions reported. The median activity of Iomab-B was 626 mCi (range: 397-1027). All patients randomized to Iomab-B (N=13) engrafted, with median days to engraftment of ANC at 13 (range: 9-22) and platelets at 17 (range: 13-26). All patients who received Iomab-B after crossover (N=9) also engrafted with time to engraftment similar to patients initially randomized to the Iomab-B arm (Table 1). Donor chimerism (≥95%), within 100 days after HCT, was found in 9 of 10 patients in the Iomab-B arm and 8 of 9 patients in those that crossed over to receive Iomab-B, with two patient exceptions having mixed donor chimerism at day 28. A preliminary safety analysis for all randomized patients on either study arm showed the most frequent non-hematologic adverse events ≥ grade 3 occurring in >10% patients were febrile neutropenia (34.2%), stomatitis (15.8%), malnutrition (13.2%), epistaxis, sepsis, hypotension, hypobilirubinemia and fatigue (all 10.5%). There were no Iomab-B-related deaths. Interpretation: Preliminary safety analysis demonstrates the feasibility of delivering targeted conditioning with Iomab- B for HCT in R/R AML patients who have active disease and a high BM blast burden (median: ≥ 30%) prior to transplantation. All patients who received Iomab-B, including those crossed over after failing to achieve CR on CC salvage therapy, engrafted ANC within 13 days, despite active disease prior to transplant. In addition, the time to HCT from randomization was not increased in patients receiving Iomab-B after cross-over compared to those who underwent standard of care HCT after achieving CR on the CC arm. This study is currently enrolling and for full study details see www.sierratrial.com or clinicaltrials.gov (NCT02665065). Disclosures Tomlinson: Foundation Medicine: Consultancy. Foran:Xencor, Inc.: Research Funding; Agios: Research Funding. Chen:Bellicum Pharmaceuticals: Research Funding. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Lazarus:Pluristem Ltd.: Consultancy. Berger:Actinium Pharmaceuticals: Employment, Equity Ownership. Reddy:Actinium Pharmaceuticals: Employment, Equity Ownership; Pharmacyclics: Employment. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.

Abstract Lapatinib (GW572016) is a selective inhibitor of both epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases. Here, we explore the therapeutic potential of lapatinib by testing its effect on tumor cell growth in a panel of 31 characterized human breast cancer cell lines, including trastuzumab-conditioned HER-2-positive cell lines. We further characterize its activity in combination with trastuzumab and analyze whether EGFR and HER-2 expression or changes induced in the activation of EGFR, HER-2, Raf, AKT, or extracellular signal-regulated kinase (ERK) are markers of drug activity. We report that concentration-dependent antiproliferative effects of lapatinib were seen in all breast cancer cell lines tested but varied significantly between individual cell lines with up to 1,000-fold difference in the IC50s (range, 0.010-18.6 μmol/L). Response to lapatinib was significantly correlated with HER-2 expression and its ability to inhibit HER-2, Raf, AKT, and ERK phosphorylation. Long-term in vivo lapatinib studies were conducted with human breast cancer xenografts in athymic mice. Treatment over 77 days resulted in a sustained and significant reduction in xenograft volume compared with untreated controls. For the combination of lapatinib plus trastuzumab, synergistic drug interactions were observed in four different HER-2-overexpressing cell lines. Moreover, lapatinib retained significant in vitro activity against cell lines selected for long-term outgrowth (&gt;9 months) in trastuzumab-containing (100 μg/mL) culture medium. These observations provide a clear biological rationale to test lapatinib as a single agent or in combination with trastuzumab in HER-2-overexpressing breast cancer and in patients with clinical resistance to trastuzumab. (Cancer Res 2006; 66(3): 1630-9)