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Summary Background Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine (DAC) and deoxyguanosine that is resistant to degradation by cytidine deaminase. Methods This is a first-in-human pharmacokinetic (PK)- and pharmacodynamic (PD)-guided Phase 1 dose-escalation study in adults with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients with MDS or AML refractory to, or relapsed after, standard treatment were randomly assigned to one of two regimens of subcutaneous (SC) guadecitabine: Daily×5 or Once Weekly for three weeks. Stratification was based on disease (MDS vs. AML). Treatment assignment was not blinded. A Twice Weekly for three weeks regimen was later added to the study. All regimens were given in 28-day cycles. The primary objective was the safety profile of all regimens and the recommended dose and schedule for phase 2 by either maximum tolerated dose (MTD) or biologically effective dose (BED). All patients who received at least one treatment were included in the analyses. Enrollment is complete and all patients have finished treatment. This study is registered with ClinicalTrials.gov, number NCT01261312. Findings 93 patients were treated (74 AML and 19 MDS): 44 on Daily×5 (3–125 mg/m2/d), 34 on Once Weekly (6–125 mg/m2/d), and 15 on Twice Weekly (60 and 90 mg/m2/d). Guadecitabine SC produced a longer exposure window and half-life, and lower Cmax, of plasma DAC than intravenous DAC. The MTD was 90 mg/m2 in MDS on the Daily×5 regimen but was not reached in AML or on the other regimens. The most common Grade ≥3 adverse events were febrile neutropenia (38/93, 41%), pneumonia (27/93, 29%), thrombocytopenia and anemia (23/93, 25% each), and sepsis (16/93, 17%). The most common serious adverse events (SAEs) were febrile neutropenia (29/93, 31%), pneumonia (26/93, 28%), and sepsis (16/93, 17%). Potent dose-related DNA demethylation occurred on the daily regimen, reaching a plateau at 60 mg/m2 Daily×5 (designated as BED). Responses were seen in heavily pretreated patients including six responders (two complete response [CR], two CR with incomplete blood count recovery [CRi], one CR with incomplete platelet recovery [CRp], and one partial response [PR]) in AML patients and two marrow complete response (mCR) in MDS patients. Responders showed significantly more demethylation than non-responders. Interpretation Guadecitabine SC at 60 mg/m2 Daily×5 is well-tolerated, easily administered, and biologically and clinically active in both MDS and AML; it warrants testing in phase 2 studies.

A microdissection technique was used to separate differentiated cortical plate (cp) cells from immature ventricular zone cells (vz) in the rat embryonic cortex. The cp population contained >85% neurons (TUJ1(+)), whereas the vz population contained approximately 60% precursors (nestin+ only). The chemotropic response of each population was analyzed in vitro, using an established microchemotaxis assay. Micromolar GABA (1-5 microM) stimulated the motility of cp neurons expressing glutamic acid decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis. In contrast, femtomolar GABA (500 fM) directed a subset of GAD- vz neurons to migrate. Thus, the two GABA concentrations evoked the motility of phenotypically distinct populations derived from different anatomical regions. Pertussis toxin (PTX) blocked GABA-induced migration, indicating that chemotropic signals involve G-protein activation. Depolarization by micromolar muscimol, elevated [K+]o, or micromolar glutamate arrested migration to GABA or GABA mimetics, indicating that migration is inhibited in the presence of excitatory stimuli. These results suggest that GABA, a single ligand, can promote motility via G-protein activation and arrest attractant-induced migration via GABAA receptor-mediated depolarization.

Neither elacytarabine nor any of the seven alternative treatment regimens provided clinically meaningful benefit to these patients. OS in both study arms and for all treatments was extremely poor. Novel agents, novel clinical trial designs, and novel strategies of drug development are all desperately needed for this patient population.