ALBERT

Description: Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.

Description: Ivosidenib (AG-120) and enasidenib (AG-221) are targeted, oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.

Description: Background: For patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), low response rates and poor overall survival remain unmet clinical needs. AML cells evade apoptosis through overexpression of antiapoptotic genes and inactivation of p53. The antiapoptotic gene Mcl1 is overexpressed in AML cell lines resistant to venetoclax. Similarly, the sensitivity of AML patients' samples to venetoclax inversely correlates with the presence of a TP53 mutation or low expression of p53. In AML, p53 inactivation more commonly results from overexpression of its negative regulators, Mdmx and Mdm2. BTX-A51 is a novel, oral, direct inhibitor of Casein kinase 1α (CK1α), cyclin dependent kinase 7 (CDK7), and CDK9. CK1α phosphorylates Mdmx and Mdm2 leading to enhanced binding and degradation of p53. CDK7 and CDK9 phosphorylate RNA polymerase II (Pol II) to enable transcriptional initiation and elongation, particularly at large clusters of transcriptional enhancers termed super-enhancers (SE). Preclinical studies have demonstrated that BTX-A51 robustly increased p53 protein levels via CK1a inhibition and Mdm2 downregulation while preferentially decreasing SE transcription of key oncogenes such as Myc andMcl1, enabling selective apoptosis of leukemia cells. The combination of CK1α, CDK7, and CDK9 inhibition was synergistic and prolonged survival in multiple genetic and patient-derived xenograft AML models. Study Design and Methods: This is an open-label, multi-center, first-in-human Phase 1 study evaluating the safety of BTX-A51 in patients with R/R AML or high-risk MDS. The trial will be performed in two phases, a dose escalation (phase 1a) and dose expansion (phase 1b). Phase 1a utilizes a hybrid accelerated titration with single patient cohorts and a Bayesian optimal interval (BOIN) design to assess 8 potential dosing cohorts. The maximum tolerated dose (MTD) will be the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate of 0.3. Up to a maximum of 35 patients will be enrolled in the dose escalation phase of the study at Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and City of Hope Cancer Center. Following determination of the MTD, 15 patients will be enrolled in the dose expansion phase for further evaluation of dose-limiting toxicities (DLTs) and for preliminary evidence of efficacy. BTX-A51 will be dosed 3 weeks on drug, followed by 1 week off drug over a 28-day cycle. For the first cycle, patients will receive tumor lysis syndrome prophylaxis with allopurinol and intravenous fluids and be closely monitored. Key inclusion criteria are age ³ 18 years, R/R AML or R/R high-risk MDS, Eastern Cooperative Oncology Group (ECOG) £ 2 and life expectancy of ³ 6 weeks, and adequate kidney and liver function. Key exclusion criteria are receipt of cancer chemotherapy (other than hydroxyurea) within 2 weeks prior to the start of study drug, transplantation within 3 months prior to screening, active graft-versus-host disease requiring systemic immunosuppressive medications, and a white blood cell count 〉 20 × 109/L. The primary objective for the Phase 1 study is to determine the MTD and recommended Phase 2 dose (RP2D) of BTX-A51. Secondary objectives include evaluating overall response (complete remission, complete remission with incomplete blood count recovery, and partial remission) according to the European LeukemiaNet (ELN) 2017 criteria (Döhner et al. Blood. 2017), survival (overall survival and event-free survival) and pharmacokinetics. Correlative objectives include determining the changes in SEs and SE-driven expression of antiapoptotic genes by chromatin immunoprecipitation and RNA-sequencing. Recruitment is ongoing and this trial is registered on clinicaltrials.gov: NCT04243785 Disclosures Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Borthakur:BioLine Rx: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; FTC Therapeutics: Consultancy; BioTherix: Consultancy; Curio Science LLC: Consultancy; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Polaris: Research Funding; PTC Therapeutics: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy. Murray:Salamandra: Current Employment. Kook:Salamandra: Current Employment. Chan:BioTheryx: Current Employment. Stein:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Biotheryx: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Amgen: Consultancy; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background: Acute myeloid leukemia (AML), a hematologic malignancy characterized by clonal expansion of abnormal myeloid progenitors, is a disease exhibiting a dynamic mutational landscape over time. Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are reported in 6-10% of patients (pts) with AML. Ivosidenib (IVO) is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) and is FDA-approved for the treatment of mIDH1 relapsed/refractory (R/R) AML and newly diagnosed (ND) AML in adults ≥ 75 years (yrs) of age or with comorbidities precluding intensive induction chemotherapy (IC). In an ongoing phase 1b study (NCT02677922), 23 pts (11 male; median age 76 yrs [range 61-88]) with mIDH1 ND AML received IVO 500 mg daily and subcutaneous azacitidine (AZA) 75 mg/m2 on Days 1-7 in 28-day cycles. As of 19Feb2019, median number of treatment cycles was 15 (range 1-30); 10 pts remained on treatment. Overall response rate (complete remission [CR] + CRi [incomplete neutrophil recovery] + CRp [incomplete platelet recovery] + morphologic leukemia-free state [MLFS]) was 78% (18/23): including CR in 61% (14/23) and CR with partial hematologic recovery (CRh) in 9% (2/23). mIDH1 clearance assessed in bone marrow mononuclear cells (BMMCs) by BEAMing digital PCR (detection limit 0.02-0.04%) was observed in 11/16 pts (69%) with CR/CRh, including 10/14 (71%) with CR. Aim: Characterize clonal evolution and resistance in pts with mIDH1 ND AML treated on study with IVO + AZA. Methods: The secondary efficacy endpoint of CRh was sponsor derived and defined as CR with absolute neutrophil count 〉 0.5 X 109/L and platelets 〉 50 X 109/L. Bulk DNA sequencing (DNA-seq, 1400-gene ACE Extended Cancer Panel, 2% variant allele detection limit) was performed on BMMCs and/or peripheral blood mononuclear cells (PBMCs). Single-cell (sc) targeted DNA-seq was performed on PBMCs using a microfluidic platform (Tapestri®) with a 20-gene AML panel capable of detecting rare subclones down to 0.1%. Results: To identify mechanisms of acquired resistance, longitudinal bulk DNA-seq was analyzed for 22/23 pts, including 5 pts with available samples at relapse or disease progression (3 CR and 1 MLFS with morphological relapse; 1 CRh with disease progression). Mutations not detected at baseline but emerging during therapy were categorized into canonical biological pathways (Table). Emerging mutations were observed in 9/22 (41%) pts, including 4 with multiple mutations. 3/22 (14%) pts had emerging IDH2 mutations, with concurrent rise in plasma 2-hydroxyglutarate (2-HG) levels. Within the relapse/progression cases, emerging mutations were observed in 4/5 pts, including 3 where the emerging mutation appeared to be the predominant mutation at relapse/progression (2 CR pts with IDH2 mutations, and 1 CRh pt with a TET2 mutation). To date, from the bulk DNA-seq analysis, no emergence of an IDH1 second-site or receptor tyrosine kinase pathway (FLT3, KRAS, NRAS, PTPN11) mutation has been observed. To further evaluate clonal evolution of clinical response and disease progression, scDNA-seq was performed, with data available for 15 pts (10 CR, 2 CRh, 1 MLFS, and 2 stable disease), including end-of-study time points for 5 relapse/progression pts. In the 2 relapsed pts with an emerging IDH2 mutation observed by bulk DNA-seq, 1 had a minor IDH2 clone present at baseline that expanded independently from IDH1 during therapy (Fig). In a separate case, a subclonal baseline PTPN11 clone evolved to gain both RUNX1 and IDH2 mutations, becoming the predominant clone at relapse. In 2 other cases, scDNA-seq data showed that non-IDH1 clones were selected from baseline clones ancestral (TP53 n = 1) to or emerged separate from mIDH1 (TET2 n = 1). Clonal architecture and evolution from additional pts will be presented. Conclusion: IVO + AZA combination treatment in IC-ineligible ND AML led to deep and durable molecular remissions. Although the dataset is small, IDH2 clones appeared to expand or emerge separate from the IDH1 clone, with no observation of an IDH1 second-site mutation to date. Understanding patterns of emerging mutations/pathways at relapse will allow for comparison with mIDH1 R/R AML and ND AML pts treated with IVO monotherapy. These results underline the importance of mutational testing, particularly at progression to determine optimal salvage therapy. Potential combination or sequential therapies should be evaluated prospectively in future clinical trials. Disclosures Daigle: Agios: Current Employment, Current equity holder in private company. Choe:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. DiNardo:Syros: Honoraria; MedImmune: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Stein:Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Stein:Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotheryx: Consultancy; Bayer: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Seattle Genetics: Consultancy; Abbvie: Consultancy; Amgen: Consultancy; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fathi:Amphivena: Consultancy, Honoraria; Agios: Consultancy, Research Funding; Forty Seven: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Research Funding; Astellas: Consultancy; Takeda: Consultancy; PTC Therapeutics: Consultancy; Novartis: Consultancy; NewLink Genetics: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; TrovaGene: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Blue Print Oncology: Consultancy; Boston Biomedical: Consultancy; Kura: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy; AbbVie: Consultancy. Döhner:Pfizer: Research Funding; Sunesis: Other, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Arog: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding. Martinelli:Celgene: Consultancy, Speakers Bureau; Jazz: Consultancy; Incyte: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Daichii Sankyo: Consultancy, Research Funding; Janssen: Consultancy; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Roche: Consultancy. Patel:France Foundation: Honoraria; DAVA Pharmaceuticals: Honoraria; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy. Tan:AbbVie: Other: Investigator on an AbbVie funded clinical trial; Agios: Research Funding; Janssen: Research Funding; NOHLA Therapeutics: Research Funding; Novartis: Other, Research Funding. Zeidan:Astellas: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Aprea: Research Funding; MedImmune/Astrazeneca: Research Funding; ADC Therapeutics: Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Leukemia and Lymphoma Society: Other; CCITLA: Other; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding. De Botton:Forma Therapeutics: Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; Pierre Fabre: Consultancy; Janssen: Consultancy, Honoraria; Seattle Genetics: Honoraria; Bayer: Consultancy, Honoraria; Servier: Consultancy. Stone:Syntrix: Consultancy; Macrogenics: Consultancy; Hoffman LaRoche: Consultancy; Stemline: Consultancy; AbbVie: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy; Trovagene: Consultancy; Jazz: Consultancy; Otsuka: Consultancy; Novartis: Consultancy, Research Funding; Argenx: Consultancy, Other: Data and safety monitoring board; Biolinerx: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding; Daiichi-Sankyo: Consultancy; Agios: Consultancy, Research Funding; Actinium: Consultancy; Celgene: Consultancy, Other: Data and safety monitoring board; Syros: Consultancy; Syndax: Consultancy; Elevate: Consultancy; Gemoab: Consultancy; Janssen: Consultancy. Frattini:BMS: Current Employment, Current equity holder in private company. Franovic:BMS: Current Employment, Current equity holder in private company. Xu:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Winkler:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Wu:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Vyas:Forty Seven: Research Funding; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Astellas: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau.