This application is being submitted in response to the Cancer Center Support Grant: P30CA016087. In the last 5 years, the Laura and Isaac Perlmutter Cancer Center of NYU Langone (PCC) has entered a period of accelerated growth as a NCI-designated Comprehensive Cancer Center. The recruitment of more than 70 new faculty members, including key leaders in basic and population science and clinical translational research, and recent attainment of Comprehensive status under Center Director Dr. Benjamin Neel has had significant downstream growth effects for the PCC clinical research enterprise. This extraordinary breadth of science provides a rich medium for the growth of clinical/translational activity at PCC. In the 2018 PCC Cancer Center Support Grant, 534 therapeutic accruals were reported, a near doubling of the accrual reported in 2016, and a harbinger of the growth potential for clinical research. PCC will develop multiple centers of excellence focused on human disease including brain, lung, blood, skin and breast cancers, with NYU faculty appointed as leaders for each of these centers. These developments position PCC to make substantial contributions in the clinical research arena. In anticipation of this growth, the Clinical Trial Office (CTO) has established an expansion plan to grow the infrastructure from 99 to 140 FTE. This infrastructure is capable of supporting all research activities required of ET-CTN trials including toxicity monitoring, event reporting, research pharmacy management and data capture. In addition, the PCC possesses state of the art immune analysis and monitoring capabilities, including the Precision Immunology Laboratory shared resource; strengths in systems biology and tumor genomic characterization; and robust tissue collection and biospecimen repositories. PCC leadership clearly recognizes the critical importance of strong mentoring for junior investigators. An important goal of this supplement is to provide an avenue for PCC junior faculty, supported by midlevel and senior investigators, to develop and submit high quality letters of intent for Early Therapeutics Clinical Trials Network (ET-CTN) protocols, such as Dr. Diefenbach’s. Given these developments, the PCC is well positioned to grow its connections and activity within the ET-CTN with increased accrual to ET-CTN sponsored studies and active leadership of new protocol concepts. The specific aims of this supplement are to: 1) to develop and execute early phase (pilot, phase 1, phase 2) clinical trials with novel therapeutic agents sponsored by CTEP and ET- CTN that capitalize on institutional scientific strength; 2) to train and mentor the next generation of investigators in clinical and translational research; and 3) to develop and conduct a Phase 1 clinical trial through the ECTCN evaluating the safety, clinical activity, and immunogenicity in relapsed diffuse large B cell lymphoma (DLBCL) and Hodgkin lymphoma (HL) of a novel treatment platform of an oral DNMT...