ALBERT

Description: Introduction: Exportin-1 (XPO1), a nuclear transport protein critical for the export of tumor suppressor proteins (TSPs) and select mRNAs to the cytoplasm, is highly expressed in acute myeloid leukemia (AML) and correlates with poor survival. Selinexor, an oral, first-in-class, selective inhibitor of nuclear export, blocks XPO1 function. We previously reported that sequential treatment of AML blasts using the hypomethylating agent decitabine followed by selinexor exhibited strong anti-leukemic effects in vivo by inducing the expression of silenced TSPs that are kept in the nucleus by XPO1 inhibition (Ranganathan, Blood 2015). Methods: Based on these findings, a phase I dose-escalation study was initiated to evaluate the safety, feasibility, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and preliminary clinical activity of selinexor in combination with decitabine in poor-risk AML pts (NCT02093403). Adults with relapsed or refractory (R/R) AML and older (age ≥60) unfit pts with untreated AML were eligible. Pts received 10-day decitabine induction(s) at 20mg/m2 on days 1-10 for up to four 28-day cycles in combination with selinexor once daily, twice weekly beginning on day 11. Pts with

Description: A multitude of somatic genomic alterations contribute to the pathogenesis of acute myeloid leukemia (AML). Despite these important biologic insights, current therapeutic approaches to AML remain limited, particularly in adults ≥ 60. The Leukemia & Lymphoma Society (LLS)-led Beat AML trial was designed to assess whether a multi-center clinical trial could use genetic profiling to assign patients (pts) to molecularly defined, subtype-specific therapies within 7 days, and to delineate the role of new therapies in the first-line treatment of AML, with the goal of improving outcomes in older pts with AML through the use of mechanism based novel therapies. Pt eligibility included age ≥ 60 years with non-APML AML, no CNS leukemia, no prior hypomethylating agent (HMA) therapy and no clinical need for emergent therapy. Eligible pts were profiled using local cytogenetics and next generation sequencing (NGS) assay (Foundation Medicine, Inc.) with all molecular data required for treatment assignment (TA) obtained ≤ 7 days. TA was made centrally using a prioritization schema incorporating cytogenetics [t(8;21], inv(16), MLL rearrangement, complex karyotype ≥ 3 abn) and somatic mutations present in a dominant AML clone with a variant allele frequency (VAF) 〉0.3. If no cytogenetic abnormality or mutation with VAF ≥ 0.3 was observed, VAF ≥ 0.2 was used for TA. The trial opened with 3 arms but currently has 11 treatment arms with 7 novel agents (NA) shown in Table 1. Treatment among different arms include either NA followed by combination of NA + HMA if no response, upfront combination of NA + HMA, or NA + intensive chemotherapy for select groups. Current treatment prioritization and TA based upon enrollment are shown in Table 2. Enrollment began November 2016 with a data cut off of April 30, 2018. At data cutoff, 268 pts have enrolled with a median age of 72 years (range: 60 to 92) and 38% being ≥ 75 years; 43% were female; median WBC was 4.8 x 109/L (range: 0.5 to 194.1) and WBC 〉 50 x 109/L in 9.3%; median Hgb was 8.4 g/dL (range: 3.9 to 15); median platelet count was 61 x 109/L (range: 7 to 649). Of the 268 patients, 210 had AML with TA. 53 pts were ineligible for enrollment, most commonly due to an alternative diagnosis, and 5 pts have a treatment decision pending. All pts had cytogenetic results available by 7 days. We achieved TA within 7 days in 106 of the 109 (97.2%) pts in the feasibility phase, and 200/210 (95.2%) of the overall cohort, meeting feasibility requirements. Of the 10 pts with delayed treatment assignment, 1 pt had suboptimal specimen quality whereas 9 pts had delayed TA due to technical (7/10) or instrumentation failure (2/10). All pts had cytogenetics available by 7 days. TA is shown in Table 2. These data confirm the feasibility of a precision medicine TA trial in newly diagnosed pts with AML. The Beat AML trial is dynamic by design, with different arms opening over time and all trial arms designed to detect for substantive clinical efficacy. As shown in Figure 1, of the 210 eligible AML pts enrolled, 7 pts (3.3%) died during the first 7 days prior to TA, 12 pts (5.7%) received alternative treatments prior to TA and 81 pts (38.6%) received an alternative treatment after TA. At time of analysis, weekly safety calls assessed that 23 pts went on an alternative clinical trial deemed better for them than Beat AML, and 40 pts received other standard-of-care therapies, 13 pts received palliative care and 5 pts were not specified. Special events of interest (disease worsening or progression) were assessed in 19 (9.0%) of pts. Of those going onto treatment, 110 pts (52.4%) received treatment on one of the Beat AML sub-studies. At time of abstract submission, one sub-study had completed phase 2 enrollment with positive results using monotherapy as measured by CR/CRi attainment (Study S3 with enasidenib +/- HMA: 43% CR/Cri rate) and is currently in expansion to further assess efficacy of this NA in newly diagnosed AML. Three additional studies have completed phase 1b dose escalation for combined NA + HMA therapy. An update including overall (for all enrolled pts) survival, sub-study-specific survival, and survival of patients receiving alternative treatment will be presented. Our data support the feasibility of a rapid precision medicine approach in older pts with previously untreated AML. The Beat AML trial is a model for dynamic, mechanism- based clinical trials in blood cancers where genomic analysis may inform, accelerate, and improve drug development. Disclosures Levine: Roche: Consultancy, Research Funding; Novartis: Consultancy; Isoplexis: Equity Ownership; Janssen: Consultancy, Honoraria; Prelude: Research Funding; Imago: Equity Ownership; Epizyme: Patents & Royalties; Celgene: Consultancy, Research Funding; C4 Therapeutics: Equity Ownership; Qiagen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Loxo: Consultancy, Equity Ownership. Mims:Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Borate:Agios: Consultancy; Novartis: Consultancy. Stein:Novartis: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Agios: Consultancy. Patel:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; France Foundation: Honoraria; Dava Oncology: Honoraria. Stock:Jazz Pharmaceuticals: Consultancy. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Vergilio:Foundation Medicine Inc: Employment. Brennan:Foundation: Employment, Equity Ownership. Vietz:Foundation Medicine: Employment, Equity Ownership. Druker:ARIAD: Research Funding; Oregon Health & Science University: Patents & Royalties; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties; Celgene: Consultancy; Bristol-Meyers Squibb: Research Funding; McGraw Hill: Patents & Royalties; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Monojul: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beta Cat: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; Henry Stewart Talks: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Fred Hutchinson Cancer Research Center: Research Funding; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Description: *equal contribution of AB, RLL, BD and JCB Background: Acute myeloid leukemia (AML) is common with increasing age, and older adults with AML rarely achieve long-term remission with chemotherapy. Gene discovery studies in older adults with AML have shown that this malignancy is characterized by a multitude of somatic genomic alterations beginning with initiating somatic events followed by acquisition of collaborative transforming mutations. Despite these important biologic insights, current therapeutic approaches to AML remain limited, particularly in adults ≥ 60 years of age. The Beat AML trial was designed to assess the feasibility of using genetic profiling to assign patients (pts) to molecularly defined, subtype-specific therapies within 7 days of the initial diagnosis in a multi-center clinical trial setting, and to delineate the role of molecularly informed first-line treatment of AML with mechanism based novel therapies. Methods: Treatment-naïve patients with AML were enrolled in this prospective trial which offered accelerated cytogenetic and comprehensive mutational testing within 7 days followed by treatment assignment using these molecular data. Pt eligibility included age ≥ 60 years with non-APML AML, no known CNS leukemia, no prior hypomethylating agent (HMA) therapy and no clinical need for emergent therapy. Eligible pts were profiled by local cytogenetics analysis and using a central next generation sequencing (NGS) assay (Foundation Medicine, Inc.) with all molecular data required for treatment assignment (TA) obtained 〈 7 days. TA was made centrally using a pre-determined algorithm considering somatic cytogenetic and molecular alterations in the dominant clone, available targeted therapeutics for specific AML subsets, and the likelihood of cure with intensive chemotherapy. Results: From November 2016 to January 2019, 487 pts with a suspected diagnosis of AML had enrolled at 14 clinical sites; 395 were eligible for the study (77% of the patients not eligible for the study had an alternative diagnosis). The median age of eligible patients was 72 years (range: 60 to 92) with 38% being≥ 75 years and 16% with treatment-related AML. From the 395 eligible patients, 374 (94.7%) were centrally assigned to the different cytogenetic/genomic groups within 7 days. The most common groups were TP53 mutated (19%) and marker negative (18%) molecular groups. The Beat AML trial is dynamic by design, thereby allowing different arms to open over time; all trial arms are designed to evaluate for substantial clinical efficacy in small, molecularly defined patient subsets. As shown in Figure 1, 224 patients (57%) had a TA and consented to a BEAT AML sub-study. Of the remaining 171 patients, 103 received standard therapy defined as induction therapy (7+3) or hypomethylation agent (25 before TA and 78 after TA), 28 received an alternative investigational agent (5 before TA and 23 after TA), 38 received palliative care, and 2 had an unknown treatment status and are grouped with the palliative care patients in subsequent analyses; 9 patients died before TA (2 who received standard therapy and 7 in the palliative care group). Demographic, clinical, performance and molecular characteristics were not largely different between pts who elected targeted therapy as part of the BEAT AML trial versus those who elected standard therapy. As shown in Figure 2, the overall survival was significantly longer for patients enrolled in a targeted therapy arm as part of the BEAT AML trial compared to those who elected standard therapy. (p