This report is the first description of dosing procedures, pharmacokinetics, biochemical action, and general tolerability of the antiaging drug rapamycin in the common marmoset, a small and short-lived monkey. Eudragit-encapsulated rapamycin was given orally to trained marmosets in a short-term (3 weeks) and a long-term (14 months) study. Circulating trough rapamycin levels (mean = 5.2 ng/mL; 1.93-10.73 ng/mL) achieved at roughly 1.0 mg/kg/day was comparable to those reported in studies of rodents and within the therapeutic range for humans. Long-term treated animals (6/8) indicated a reduction in mammalian target of rapamycin complex 1 signaling as noted by a decrease in the phospho rpS6 to total rpS6 ratio after 2 weeks of treatment. All long-term treated subjects had detectable concentrations of rapamycin in liver (4.7-19.9 pg/mg) and adipose tissue (2.2-32.8 pg/mg) with reduced mammalian target of rapamycin signaling in these tissues. There was no evidence of clinical anemia, fibrotic lung changes, or mouth ulcers. The observed death rate in the long-term study was as expected given the animals' ages. The ability to rapidly and reliably dose socially housed marmosets with an oral form of rapamycin that is well tolerated and that demonstrates a suppression of the mammalian target of rapamycin pathway leads us to conclude that this species offers a viable model for rapamycin testing to establish safety and efficacy for long-term antiaging intervention.

Parkinson’s disease is a chronic neurodegenerative disorder with the core motor features of resting tremor, bradykinesia, rigidity, and postural instability. Non-motor symptoms also occur, and include cognitive dysfunction, mood disorders, anosmia (loss of smell), and REM sleep disturbances. As the development of medications and other therapies for treatment of non-motor symptoms is ongoing, it is essential to have animal models that aid in understanding the neural changes underlying non-motor PD symptoms and serve as a testing ground for potential therapeutics. We investigated several non-motor symptoms in 10 adult male marmosets using the MPTP model, with both the full (n = 5) and partial (n = 5) MPTP dosing regimens. Baseline data in numerous domains were collected prior to dosing; assessments in these same domains occurred post-dosing for 12 weeks. Marmosets given the partial MPTP dose (designed to mimic the early stages of the disease) differed significantly from marmosets given the full MPTP dose in several ways, including behavior, olfactory discrimination, cognitive performance, and social responses. Importantly, while spontaneous recovery of PD motor symptoms has been previously reported in studies of MPTP monkeys and cats, we did not observe recovery of any non-motor symptoms. This suggests that the neurochemical mechanisms behind the non-motor symptoms of PD, which appear years before the onset of symptoms, are independent of the striatal dopaminergic transmission. We demonstrate the value of assessing a broad range of behavioral change to detect non-motor impairment, anosmia, and differences in socially appropriate responses, in the marmoset MPTP model of early PD.

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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.

7048 Background: The SIERRA trial is a prospective, randomized, phase 3, open-label, ongoing multicenter trial for patients aged ≥55 years with active, relapsed/refractory (R/R) AML evaluating allogeneic hematopoietic cell transplantation (HCT) versus conventional care (CC). Recent preliminary data demonstrated robust donor engraftment in all patients treated with Iomab-B (Blood 2018 132:1017) despite active disease. We hypothesize that successful engraftment was due to rapid disease reduction with Iomab-B. Methods: Patients are randomized to receive Iomab-B and HCT or to a CC therapy including approved targeted agents followed by HCT if in remission. Majority of patients (79%) in the CC arm did not achieve CR and the study allowed crossover to receive Iomab-B. Results: Data were evaluated for the first 25% of patients (N=38). Twenty-nine patients received Iomab-B, either directly (N=19) or via crossover (N=10). Median baseline marrow blasts were 30% (4-74) for Iomab-B and 24% (6-70%) for CC, which increased to 45% (10-70%) at crossover. Peripheral blast data was available in 16 patients (Iomab 7, Crossover 9). By day 3 post-Iomab, blasts were reduced by 98% with 100% reduction by day 8 (assuming 0% blasts due to lack of differential at WBC 0.1; Table). All patients engrafted with ANC at a median of 13 days (9-22 days). Conclusions: Targeted re-induction radioimmunotherapy with single agent Iomab-B rapidly decreases peripheral blasts in chemotherapy refractory AML. This significant reduction of leukemia burden followed by successful engraftment after HCT is encouraging in this underserved population. Clinical trial information: NCT02665065. [Table: see text]