Perl, Alexander E.

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

Background: The FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (Gilt) improves survival compared with standard salvage chemotherapy in relapsed/refractory (R/R) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML); however, relapses are common and long-term survival remains poor. Combination therapies of FLT3 tyrosine kinase inhibitors (TKIs) with agents that induce apoptosis have demonstrated preclinical synthetic lethality and enhanced cytotoxicity against FLT3mut+ clones. This may delay or prevent drug resistance. We present updated data from the dose-escalation and expansion cohorts of an ongoing, multicenter, open-label, Phase 1b trial (NCT03625505) of Gilt in combination with B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (Ven) in patients (pts) with R/R FLT3mut+ AML. Methods: Pts with R/R AML with ≥1 prior line of therapy and Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible. The expansion cohort required FLT3mut+ R/R AML at enrollment. Pts received the recommended Phase 2 dose (RP2D) of Ven 400 mg in combination with Gilt 120 mg daily in 28-day cycles, following a 3-day ramp-up of Ven. Pts with prior Gilt were excluded from expansion, and none were enrolled in dose escalation; prior Ven or other FLT3 inhibitor was permitted. Concurrent use of moderate or strong CYP3A4 inhibitor was allowed. Interruptions of Ven or both drugs simultaneously were permitted for management of adverse events (AEs), and subsequent cycles could include dose adjustments to minimize myelosuppression or other drug-related AEs. The primary endpoint was modified composite complete remission (mCRc; complete response [CR] + CR with incomplete platelet recovery [CRp] + CR with incomplete blood count recovery [CRi]) + morphologic leukemia-free state (MLFS). Responses were graded by the International Working Group (IWG) for AML criteria (with adapted CRi criteria as presented in the ADMIRAL trial) for comparison with composite CR (CRc) used in Gilt development. All criteria for response used by IWG were maintained in these response definitions. Secondary endpoints included CR + CR with partial hematologic recovery (CRh) and duration of response (DOR) of mCRc. Results: At data cutoff, April 15, 2020, 39 R/R pts started therapy at the RP2D (internal tandem duplications [ITD] only [n=32]; tyrosine kinase domain [TKD] mutation only [n=5]; both TKD and ITD [n=2]). Median age was 63 years (range 23-85) and the majority had an ECOG status of 1-2 (87.2%). Most pts (n=29; 74.4%) had received ≥2 prior lines of therapy, including ≥1 FLT3 TKI (n=25, 64.1%; midostaurin, n=19; sorafenib, n=5; crenolanib, n=1). Twelve pts (30.8%) had prior stem-cell transplant (SCT); 3 (7.7%) had received prior Ven. Grade ≥3 treatment-emergent AEs (TEAEs) were reported in 37 pts (94.9%), and 28 (71.8%) reported serious AEs. The only Grade 3/4 nonhematologic TEAE reported in >20% of pts was febrile neutropenia (48.7%). Four pts (10.3%) experienced a fatal AE, including colitis, disease progression, multiple organ dysfunction syndrome, and bronchopulmonary aspergillosis (all n=1). AEs leading to Ven and Gilt interruptions occurred in 19 pts (48.7%) and 18 pts (46.2%), respectively, and AEs leading to dose reductions occurred in 2 pts (5.1%) for each treatment. Six pts (15.4 %) and 5 pts (12.8%) discontinued Ven and Gilt, respectively, owing to AEs. mCRc was achieved by 83.8% of pts (n=31/37; Table). With median duration of follow-up of 2.9 (range 0.8−11.0) months in all pts, median event-free survival was 5.1 (95% confidence interval: 2.8, 8.3) months but administrative censoring after short follow-up for a large number of recently enrolled patients limits interpretation; median DOR has not been reached. Eight pts (21.6%), all ITD only, proceeded to SCT. CR + CRh was achieved by 7 pts (18.9%). Conclusions: Ven plus Gilt achieved a very high overall rate of marrow and blood blast elimination and mCRc rate (84%) in this expansion cohort of heavily pretreated FLT3mut+ pts, the majority of whom had prior FLT3 TKI exposure. Using similar response assessment criteria, the high mCRc rate here suggests substantially greater antileukemic activity from Ven plus Gilt compared with single-agent Gilt. Cytopenias were prominent but manageable with dose interruption/modification on subsequent cycles. Nonhematologic toxicities were modest, and the combination was well tolerated. Disclosures Daver: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: 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. Altman:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujifilm: Research Funding; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Agios, Theradex, Abbvie: Other: Advisory Board; Astellas, Agios: Honoraria, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Patents & Royalties: Scientific Advisory Board - no payment accepted; Biosight: Other: No payment but was reimbursed for travel . Levis:Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Research Funding. Ritchie:Abbvie: Honoraria; Sierra Oncology: Honoraria; Incyte: Speakers Bureau; Novartis: Honoraria; Jazz pharmaceuticals: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. McCloskey:Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Smith:Abbvie: Other: Research Support, Research Funding; Sanofi: Honoraria; Astellas Pharma: Honoraria, Other: Research Support, Research Funding; FujiFilm: Other: Research support, Research Funding; Revolution Medicines: Other: Research Support, Research Funding; Daiichi Sanyko: Consultancy, Honoraria. Schiller:Johnson & Johnson: Current equity holder in publicly-traded company; Novartis: Consultancy, Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Genentech-Roche: Research Funding; Geron: Research Funding; DeltaFly: Research Funding; Deciphera: Research Funding; Celator: Research Funding; FujiFilm: Research Funding; Ariad: Research Funding; Constellation: Research Funding; Cyclacel: Research Funding; Jazz Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Astellas Pharma: Honoraria, Research Funding; Actinium: Research Funding; Gamida: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Daiichi Sankyo: Research Funding; Abbvie: Research Funding; Stemline: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Ono Pharma: Consultancy; Forma: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Sanofi: Speakers Bureau. Bradley:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Tiu:Astellas Pharma Global Development: Current Employment; Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Hong:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Tong:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Qin:AbbVie: Current Employment, Other: may hold stock or other options. Dilley:AbbVie Inc.: Current Employment, Other: may hold stock or stock options. Perl:Leukemia & Lymphoma Society.: Other; AbbVie Inc, Astellas, Actinium, Bayer HealthCare Pharmaceuticals, Daiichi Sankyo Inc, FUJIFILM Pharmaceuticals USA Inc: Research Funding; AbbVie Inc, Actinium Pharmaceuticals Inc, Astellas, Daiichi Sankyo Inc, FORMA Therapeutics, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, NewLink Genetics: Other; AbbVie Inc, Arog Pharmaceuticals Inc, Astellas, Daiichi Sankyo Inc: Consultancy; Astellas, AbbVie Inc, Daiichi Sankyo, Actinium, Forma, Syndax, Loxo: Consultancy, Honoraria. OffLabel Disclosure: Venetoclax is a B-cell lymphoma 2 inhibitor approved in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Gilteritinib is a kinase inhibitor indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an FLT3 mutation as detected by an FDA-approved test.

Background: Gilteritinib is approved for the treatment of relapsed/refractory (R/R) AML and FLT3-mutation (FLT3mut+). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) enrolled prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or post-transplant FLT3inhibitor (FLT3i) maintenance. Some mechanisms of drug resistance can be shared across FLT3i's, suggesting response to gilteritinib might differ in patients treated with frontline FLT3i. A better understanding of how prior therapy modulates response to gilteritinib is necessary to clarify this novel agent's role in the current FLT3-mutated AML treatment algorithm. Methods: This is an ongoing multi-institutional analysis from 13 US centers identifying patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. Patients who received gilteritinib as a part of an ongoing trial were excluded. Response criteria were identical to the ADMIRAL trial. For patients with available data and a composite complete remission (CRc), we defined clinically measurable residual disease (cMRD) negative status by bone marrow flow cytometry using a cutoff of <1 x 10x105 cells as well as polymerase chain reaction (PCR) for FLT3 mutation with a minimum sensitivity of 5%. Survival from the time of gilteritinib initiation was recorded. Multivariate analysis included all variables collected to determine interaction with patient outcome (CR and survival data). Kaplan-Meier curves and log rank test were used for survival analysis after gilteritinib initiation. Results: 72 patients treated with prior FLT3i exposure received gilteritinib for treatment of R/R FLT3mut+ AML. Patient characteristics are presented in table-1 with 46 (64%) previously receiving midostaurin, 19 (26%) sorafenib, and 7 (10%) other FLT3i. 8 (11%) received more than one prior TKI. NGS at diagnosis were available in 66 patients (92%) and co-mutations in DNMT3A, NPM1 and NRAS were observed in more than 10% of patients. Average duration of gilteritinib therapy was 5.7 months (range: 0.2-25 months). 27 (37.5%) received stem cell transplant (SCT) before gilteritinib and 15 (21%) underwent SCT after gilteritinib. The composite CR rate (CRc, defined as CR + CRi + CRp) was 51.4% (n= 37 patients). With regard to specific FLT3i's, we found no significant difference in median survival (7.1 months and 6.4 months for midostaurin and sorafenib, respectively) or remission rates (CRc 54% and 47% for prior midostaurin and sorafenib, respectively). The CRc rate for patients who received only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. A trend toward higher CRc rate was noted in patients treated with gilteritinib in combination regimens rather than as a single agent (64% vs 43%, respectively, p=0.09 using Chi-square test). No survival advantage for combination therapy was seen over single agent. Survival was longest in patients who obtained a CR, particularly a cMRD negative response; this remained significant after censoring at the time of SCT (figures 1&2). Patients who received SCT after gilteritinib had significantly longer survival than non-transplanted patients (9.3 months vs 5.6 months, respectively, HR 0.44, 95% CI 0.2-0.8)(figure-3). Patients with concurrent mutations of NPM1/DNMT3A had a trend toward a higher CRc compared to FLT3 mutation alone (71% vs 50%, p= 0.2) but similar survival. With regard to mutations associated with drug resistance to other FLT3i's, patients with both FLT3-ITD and FLT3-D835 mutation had similar response and survival to FLT3-ITD alone. However, patients with MAPK pathway activating mutations (e.g. NRAS and PTPN11) had lower CRc (37.5% vs 59.5%) and poorer median survival than other patients (3.3 months vs 7.5 months) (HR 2.2- 95% CI 1.1-4.4) p value <0.01(figure-4). Conclusions: In this multi-center, retrospective analysis, gilteritinib remains a clinically active agent after treatment failure of prior FLT3i's (midostaurin or sorafenib). Mutations activating MAPK pathway have been implicated in secondary gilteritinib resistance but are seldom co-mutated at initial FLT3mut+ AML diagnosis. While further study is required, we hypothesize that their detection after frontline FLT3i therapy may represent treatment-emergent clones with propensity for pan-FLT3i resistance. Disclosures Zeidan: Cardiff Oncology: Consultancy, Honoraria, Other; Trovagene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; MedImmune/Astrazeneca: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Research Funding; CCITLA: Other; Leukemia and Lymphoma Society: Other; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Foran:Agios: Honoraria, Research Funding; H3Biosciences: Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy. Daver:Celgene: 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; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Perl:Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Biomed Valley Discoveries: Research Funding; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Syndax: Consultancy, Honoraria; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other; Bayer HealthCare Pharmaceuticals: Research Funding; New Link Genetics: Honoraria, Other; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; Leukemia & Lymphoma Society, Beat AML: Consultancy; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; Takeda: Honoraria, Other: Travel costs for meeting. Altman:Kartos: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; ImmunoGen: Research Funding; Amgen: Research Funding; Aprea: Research Funding; Amphivena: Research Funding; Genentech: Research Funding; Novartis: Consultancy; Syros: Consultancy; Janssen: Consultancy; Immune Pharmaceuticals: Consultancy; ASH: Consultancy; Bristol-Myers Squibb: Consultancy; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; AbbVie: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding; Theradex: Other: Advisory Board; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; PrIME Oncology: Consultancy; PeerView: Consultancy; Cancer Expert Now: Consultancy; France Foundation: Consultancy; Fujifilm: Research Funding. OffLabel Disclosure: Some of the patients we are reporting on received gilteritinib in combination with other agents which is off-label use.

Abstract Introduction: Midostaurin was the first multikinase inhibitor approved in combination with daunorubicin and cytarabine induction and high-dose cytarabine (HiDAC) consolidation chemotherapy for the treatment of adults with newly diagnosed FLT3-mutation-positive (mut+) acute myeloid leukemia (AML). Approval was largely based on the results from the phase 3 RATIFY trial; patients who received midostaurin had significantly improved overall and event-free survival than those who received placebo (Stone et al, N Engl J Med, 2017). RADIUS-X (NCT02624570) is an expanded treatment protocol (ETP) designed to provide access to midostaurin during the US Food and Drug Administration's review process and to extend the understanding of the safety and tolerability of midostaurin in patients with newly diagnosed FLT3-mut+ AML. The safety profile of midostaurin in preliminary data from RADIUS-X was consistent with that in the RATIFY study (Roboz et al, Blood, 2017 [abstract 1338]). Here we report updated safety data for midostaurin during induction and consolidation and safety data during the maintenance phase. Methods: In this open-label, single-arm ETP, patients (aged ≥18 years) received 1-2 cycles of induction therapy (cytarabine plus daunorubicin [60-90 mg/m2/day] or idarubicin [12 mg/m2/day]) and up to 4 cycles of HiDAC consolidation chemotherapy plus midostaurin (50 mg twice daily [bid] on days 8-21 of each 28-day cycle), followed by up to 12 months of single-agent midostaurin (50 mg bid on days 1-28). Patients could enroll at any point before completion of a second cycle of consolidation. Patients achieving complete remission (CR) or CR with incomplete hematologic recovery (CRi) after induction proceeded to consolidation; patients who maintained a response were eligible to proceed to maintenance. The primary endpoints were safety and tolerability of midostaurin. Results: Of 111 patients screened, 103 were enrolled in the study: 47 during induction (46%) and 56 during consolidation (54%) (Figure). The median age was 58 y (range, 19-79 y); all patients were FLT3-mut+ (Table). Of 47 patients enrolled during induction, 15 received daunorubicin and 32 received idarubicin as the anthracycline. Of 35 patients who completed consolidation and entered maintenance, 9 had completed the protocol treatment and 3 remained on therapy at the data cutoff date (March 30, 2018). The CR/CRi rate for the induction phase was 74% (57% CR, 17% CRi). The relapse rate was 14% overall. The most common reason for study discontinuation was proceeding to transplant (overall, 52%; induction, 11%; consolidation, 42%; maintenance, 34%). The median duration of midostaurin exposure was 35 days (range, 3-426 days). Dose adjustment or interruption due to adverse events (AEs) occurred in 26 patients, most commonly due to febrile neutropenia (n=9) and gastrointestinal disorders (n=6). No new safety events were observed with longer follow-up. Most patients (99%) experienced ≥1 any-grade AE, mostly during induction and/or consolidation. Due to the timing of patient enrollment (up to the second cycle of consolidation), hematologic AEs were lower than reported in comparable studies. The most common AEs occurring in ≥20% of patients were febrile neutropenia (53%), nausea (42%), diarrhea (37%), anemia (36%), platelet count decreased (31%), fatigue (23%), headache (22%), and vomiting (22%). Serious AEs occurred in 50% of patients overall, most commonly febrile neutropenia (37%). AEs during induction were generally similar, regardless of anthracycline received. Overall, 9 patients discontinued due to AEs: 5 during induction (febrile neutropenia, blood bilirubin increased, electrocardiogram QT prolonged, renal impairment, and respiratory distress), 1 during consolidation (sepsis), and 1 during maintenance (leukocytosis). During maintenance, 16 of 35 patients (46%) reported any-grade AEs with midostaurin monotherapy; the most common any-grade and grade 3/4 AEs occurring in >1 patient were platelet count decrease (11% and 3%), nausea (9% and 0%), and oropharyngeal pain (6% and 0%).The rate of death during the study was low, with 1 death reported (disease progression). Conclusions: Midostaurin continued to demonstrate a manageable safety profile with longer follow-up and was associated with high transplant and low relapse rates. Maintenance therapy with midostaurin was well tolerated; no new safety signals were observed. Disclosures Perl: Daiichi Sankyo: Consultancy; Arog: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees. Sweet:Agios: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Incyte: Research Funding; Bristol Myers Squibb: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Speakers Bureau. Roboz:Novartis: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Eisai: Consultancy; Janssen Pharmaceuticals: Consultancy; Argenx: Consultancy; Orsenix: Consultancy; Aphivena Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Jazz Pharmaceuticals: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Otsuka: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy; Janssen Pharmaceuticals: Consultancy; Bayer: Consultancy; Astex Pharmaceuticals: Consultancy; Eisai: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy. Strickland:Astellas Pharma: Consultancy; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis Pharmaceuticals: Consultancy, Research Funding; Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bonifacio:Novartis: Employment. Haines:Novartis: Employment. Barbera:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals Corporation: Employment.

Abstract Background: Older patients (pts) with AML unfit for intense induction chemotherapy have a poor prognosis with a 5 year survival of <10%. 225Ac-lintuzumab is composed of 225Ac linked to a humanized anti-CD33 monoclonal antibody. Data were previously presented on the initial 13 pts who received 2.0 µCi/kg/dose on Days 1 and 8 (ASH, 2017, Abstract 616). Although that dose resulted in a high response rate of 69%, there were 6 pts with Grade 4 thrombocytopenia lasting >6 weeks and 5 CRi patients did not reach an ANC of ≥ 500/µL. Therefore, the activity level was reduced to 1.5 µCi/kg/dose for further evaluation. Methods: This study enrolled older pts with untreated AML who were considered to be unfit for standard induction chemotherapy. Pts aged 60 to 74 years were required to have significant co-morbidities, while all pts ≥ 75 years were eligible. Other eligibility criteria included ECOG PS 0-2, CD33 expression on > 25% of blasts, and a peripheral blast count <200/µL within 10 days of the first dose to optimize targeting of bone marrow (BM) blasts. Hydroxyurea was used to lower peripheral blast counts. 1.5 µCi/kg of 225Ac-lin were administered IV on Days 1 and 8. G-CSF was given starting 10 days after the 2nd dose and spironolactone was given for up to 1 year to minimize the risk of radiation-induced nephrotoxicity. Pts were evaluated for the CD33 splicing polymorphism SNP rs12459419. Results: 18 pts were included in this prespecified Interim Analysis. An additional 9 pts were treated at this dose and will be included in an updated analysis at the ASH meeting. The median age of the 18 pts was 73.5 years (range 60-87) and median ECOG Performance Status was 1 (0 in 3 pts, 1 in 9 pts, & 6 in 2 pts). 11 pts had prior AHDs (6 MDS, 2 CMML, 2 NHL, 1 myelofibrosis), and 9 had prior treatment for AHDs. Of the pts with known cytogenetic and molecular genetic results, 1 had favorable-risk, 3 had intermediate-risk, and 5 had adverse-risk AML using NCCN guidelines. The median baseline BM blast % was 40.5% (range, 22-66%) with a median CD33 expression of 62% (range, 26-100%) of AML cells. Objective responses were seen in 4 pts (22%): 3 complete remissions with incomplete platelet count recovery (CRp) and 1 complete remission with incomplete hematologic recovery (CRi). Among the responders with known cytogenetics, 1 pt had adverse genetics and 1 had Intermediate-risk genetics.Of the pts with remission, 3 had CT genotype for the CD33 splicing polymorphism SNP rs12459419 (including 2 CRp) and 1 had CC genotype. 3 of the responders are in follow up at Days 59, 169 and 266 without further treatment. Myelosuppression was seen in all pts including Grade 4 thrombocytopenia with marrow aplasia for > 6 weeks after the first dose in 4 pts. 1 pt with prior MDS had pancytopenia for > 4 months. The 3 pts with CRp achieved an ANC ≥ 1000/µL at Days 28, 38, and 40 from the first dose of 225Ac-lin. The pt with CRi did not reach an ANC of 500/µL. Non hematologic Grade ≥3 Treatment-Emergent adverse events (AEs) that were at least possibly related were 4 patients with febrile neutropenia, as well as 1 patient each with fungal pneumonia, acute respiratory failure, pulmonary edema, chest pain, sepsis, gastric hemorrhage, generalized muscle weakness, atrial fibrillation with rapid ventricular response and typhilitis. No pts had an infusion-related reaction requiring dose interruption. Veno-occlusive disease did not occur. The 30-day mortality rate was 16.7% (1 cardiac arrest and 2 with multi organ failure). Conclusions: Preliminary data from this Interim Analysis of 225Ac-lin monotherapy in older AML pts unfit for intensive therapy indicate a lower rate of myelosuppression at 1.5 µCi/kg/dose but also a lower response rate than was seen at 2.0 µCi/kg/dose. Although the study met the prespecified response criteria for continuing enrollment, it will be closed to further accrual in recognition that targeted radiation, like other therapies, will likely have the best outcomes when used in combination with other therapies in pts with active AML. An extensive development program in AML, MDS, and multiple myeloma is planned. One study will utilize 225Ac-lin in combination with salvage chemotherapy and another with venetoclax. 225Ac-lin will be used as a single agent for AML postremission therapy. In addition, 225Ac-lin will be used as targeted conditioning prior to hematopoietic stem cell transplant in pts with MDS with a complex karyotype and as a conditioning agent prior to autologous transplant in MM. Table. Table. Disclosures Atallah: Jazz: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; BMS: Consultancy. Orozco:Actinium Pharmaceuticals: Research Funding. Craig:Novartis: Research Funding; Actinium Pharmaceuticals: Research Funding; Celgene: Research Funding. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Finn:Ochsner Clinic Foundation: Employment. Perl:NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; Astellas: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees. Park:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Consultancy, Research Funding; Shire: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. Roboz:Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Celltrion: Consultancy; Celgene Corporation: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Pfizer: Consultancy; Argenx: Consultancy; Roche/Genentech: Consultancy; AbbVie: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Bayer: Consultancy; Sandoz: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Astex Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy; Argenx: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Eisai: Consultancy; Orsenix: Consultancy; Cellectis: Research Funding; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Celltrion: Consultancy. Tse:Brown Cancer Center, University of Louisville School of Medicine: Employment; Jazz: Consultancy; Amgen: Consultancy; Amgen: Honoraria; Amgen: Honoraria. Mawad:Swedish Cancer Institute: Employment. Rizzieri:Novartis: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Berger:Actinium Pharmaceuticals: Employment, Equity Ownership. Jurcic:Astellas: Research Funding; Daiichi-Sankyo: Research Funding; Incyte: Consultancy; Celgene: Research Funding; AbbVie: Consultancy, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Syros Pharmaceuticals: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Genetech: Research Funding; Kura Oncology: Research Funding.

Abstract Introduction: ASP2215, a new tyrosine kinase inhibitor with activity against FMS-like receptor tyrosine kinase-3 (FLT3) and AXL receptor tyrosine kinase, is currently in development for the treatment of acute myeloid leukemia (AML). Methods: In an ongoing, first-in-human Phase 1/2, dose-escalation/dose-expansion study, the pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of ASP2215 were evaluated under fasting conditions in patients with relapsed or refractory AML (R/R AML). Patients who met study criteria were assigned to treatment in the dose-escalation cohorts or were randomized to an open dose level in the dose-expansion cohorts. The dose-escalation cohort was a modified 3+3 with accelerated titration design that evaluated ascending oral doses of ASP2215 (20-450 mg), the dose-expansion cohort was a parallel, multi-dose-expansion cohort. Blood samples were collected and safety/tolerability assessments, including 12-lead electrocardiogram, were evaluated at protocol-specified time points for both cohorts. Effect of increasing ASP2215 exposure on inhibition of FLT3 phosphorylation, assessed via plasma inhibitory assay (PIA), was evaluated using an inhibitory PK/PD Emaxmodel. PK/PD analyses were performed to evaluate the relationship between ASP2215 exposure and changes from baseline in QTcF intervals (ΔQTcF) and changes from baseline in clinical laboratory values (e.g., creatinine kinase [ΔCK], aspartate aminotransferase [ΔAST]). Results: Data from an interim analysis of the dose-escalation/dose-expansion study were available from 215 subjects (n=23 [dose escalation], n=192 [dose expansion]). The ASP2215 PK parameters across the dose range (20-450 mg), evaluated after both single- and multiple-dose administration, are presented (Table); statistical analyses suggest the ASP2215 PK parameters are dose proportional from 20-450 mg. Median time to maximal concentration (Tmax) was observed between 2 hr and 6 hr after single and repeated oral dosing. The estimated median half-life (t1/2) ranged from approximately 45 hr to 159 hr based on the accumulation ratio; ASP2215 accumulation was extensive after multiple dose administration as reflected by the accumulation index (Rac) ranging from approximately 3.2-10. A strong correlation was shown for ASP2215 exposure-related inhibition of FLT3 phosphorylation, with >90% FLT3 inhibition observed by Day 8 at ASP2215 doses of ≥80 mg. Although a positive slope was observed between ΔQTcF and ASP2215 exposure, only 5% of the study population were reported as having a maximum post-baseline QTcF interval >500 msec. A similar trend was observed with ASP2215 concentration-related increases in ΔCK and ΔAST; however, <10% of all subjects experienced a Grade ≥3 shift from baseline in CK or AST concentrations. Conclusions: ASP2215 has demonstrated exposure-related FLT3 inhibition and a pharmacokinetic profile that support once-daily oral administration for the treatment of AML in subjects who relapsed after, or are refractory to, induction or salvage treatment. Table. ASP2215 Pharmacokinetic Parameters after Multiple-Dose Administration 20 mg (n=4) 40 mg (n=3) 80 mg (n=3) 120 mg (n=3) 200 mg (n=2) 300 mg (n=3) 450 mg (n=3) Cmax(ng/mL) 45.6 (30.5, 137) 106 (76.7, 140) 396 (217, 516) 282 (248, 593) 1460 (886, 2040) 1260 (1040, 2280) 1150 (776, 1530) Tmax(hr) 4.01 (4.00, 6.00) 3.87 (0.500, 6.00) 4.33 (4.00, 4.42) 2.02 (1.95, 5.75) 6.03 (6.00, 6.07) 6.05 (4.08, 6.07) 5.00 (4.07, 5.93) AUC0-24(ng·h/mL) 926 (543, 2480) 2460 (1750, 2800) 6280 (4160, 10600) 6190 (4200, 11300) 31500 (16500, 46600) 28700 (22300, 43300) 11500 (8070, 14900) t1/2 (hr) 52.8 (39.7, 83.1) 83.7 (68.5, 243) 91.5 (60.9, 108) 45.3 (30.5, 63.3) 143 (99.7, 186) 159 (83.3, 187) 56.9 (51.5, 62.3) Rac 3.70 (2.92, 5.51) 5.55 (4.64, 15.1) 6.02 (4.18, 7.02) 3.25 (2.38, 4.33) 9.08 (6.51, 11.7) 10.1 (5.53, 11.7) 3.94 (3.62, 4.27) Data are presented as median (minimum, maximum). AUC0-24, area under the concentration-time curve between 0-24 hr; Cmax, maximal concentration; t1/2, elimination half-life; Tmax, time to maximal concentration; Rac, accumulation ratio. Disclosures Smith: Astellas: Research Funding; Plexxikon: Research Funding. Off Label Use: ASP2215 is an investigational product for the treatment of AML. Perl:Astellas US Pharma Inc.: Consultancy; Ambit/Daichi Sankyo: Consultancy; Arog Pharmaceuticals: Consultancy; Asana Biosciences: Consultancy; Actinium Pharmaceuticals: Consultancy. Altman:Novartis: Other: Advisory board; BMS: Other: Advisory board; Seattle Genetics: Other: Advisory board; Spectrum: Other: Advisory board; Ariad: Other: Advisory board; Astellas: Other: Advisory board; assistance with abstract preparation. Gill:Astellas Pharma US, Inc: Employment. Kadokura:Astellas Pharma Global Development: Employment, Other: Personal fees. Yuen:Astellas Pharma, Inc.: Employment. Fisniku:Astellas: Employment. Liu:Astellas: Employment. Nagase:Astellas: Employment. Sargent:Astellas Pharma US, Inc: Employment. Bahceci:Astellas Pharma Global Development: Employment.

Abstract Background: Gilteritinib (ASP2215) is a novel, highly selective, potent oral FLT3/AXL inhibitor with preclinical activity against FLT3-ITD activating and FLT3-D835 resistance mutations. The objectives of this phase 1/2 study were to assess gilteritinib safety/tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles after single- and multiple-day dosing, and antileukemic effects in patients with R/R AML. Methods: This open-label study (NCT02014558) enrolled patients (≥18 yr) into 1 of 7 dose-escalation cohorts (20-450 mg once daily [QD]) or concomitant dose-expansion cohorts. While confirmed FLT3 mutation was not an inclusion criterion, each expanded dose level enrolled ≥10 patients with FLT3 mutations (FLT3mut+); 120 and 200 mg dose levels were further expanded with ≥40 FLT3mut+ patients. The choice to expand these dose cohorts was based upon FLT3 inhibition in correlative assays and clinical activity seen during dose escalation. Safety and tolerability were primary endpoints; blood samples were drawn from patients in the dose-escalation cohorts to evaluate gilteritinib PK parameters and PD effects. Antileukemic response rates (eg, complete remission [CR], CR with incomplete platelet recovery [CRp], CR with incomplete hematological recovery [CRi], overall response rate [ORR]) were secondary endpoints. Results: Patients (N=252; 129M:123F, median age 62 yr [range: 21-90]) enrolled between October 2013 and August 2015 received ≥1 dose of gilteritinib. The study population was heavily pretreated: 70% (n=177) had ≥2 prior AML therapies, 29% (n=73) had a prior stem cell transplant, and 25% (n=63) had prior TKI treatment with sorafenib most commonly used. Across the study, 194 patients had a locally confirmed FLT3 mutation (ITD, n=159; D835, n=13; ITD-D835, n=16; other, n=6). For all enrolled patients, progressive disease (n=75), lack of efficacy (n=44), adverse events (n=34), and death (n=29) were the most common reasons for treatment discontinuation. Seven deaths were considered possibly/probably related to treatment: pulmonary embolism, respiratory failure, hemoptysis, intracranial bleed, ventricular fibrillation, septic shock, and neutropenia (all n=1). Maximum tolerated dose was determined to be 300 mg when 2 of 3 patients in the 450 mg cohort experienced diarrhea and/or hepatic transaminase elevation as dose-limiting toxicities. Diarrhea (16%) and fatigue (15%) were the most commonly reported treatment-related adverse events of any grade. Less than 5% of patients (11/252) had a maximum post-baseline QTcF interval >500 msec. Gilteritinib concentrations were generally dose proportional and showed both a long-elimination half-life (45-159 h) and substantial accumulation (3.2-10 fold) by day 15. An exposure-related increase in the inhibition of FLT3 phosphorylation with increasing doses of gilteritinib was also observed. Gilteritinib showed strong antileukemic activity in FLT3mut+ patients (ORR=49%); response was observed less frequently in patients with wild-type FLT3 (ORR=12%). While CR, CRi, and CRp occurred at all doses, responses were enriched among FLT3mut+ patients with gilteritinib steady-state trough concentrations ≥100 ng/mL, which correlated with potent FLT3 inhibition in PD assays and corresponded to doses ≥80 mg. The ORR in 169 FLT3mut+ patients receiving ≥80 mg was 52% (Table); median overall survival in this patient population was ~31 wk (range: 1.7-61; Figure) and median duration of response was 20 wk (range: 1.1-55). Clinical responses occurred in FLT3mut+ patients with -ITD, -D835, and both mutations (ORR: 55%, 17%, and 62%, respectively) as well as in FLT3mut+ patients with or without prior TKI treatment (ORR: 42% vs 56%, respectively). Conclusions: This PD-driven, first-in-human study shows that gilteritinib was well tolerated and generated frequent, prolonged, clinically important responses in FLT3mut+ patients with R/R AML. Antileukemic responses were enriched in FLT3mut+ patients treated at doses that consistently and potently inhibited FLT3 phosphorylation. The survival of these patients appears better than expected for this patient population when treated with standard therapy. Our data suggest that FLT3 inhibition may improve survival in patients with FLT3mut+R/R AML; as such, phase 3 testing of oral gilteritinib 120 mg QD in patients with FLT3mut+R/R AML after first-line therapy is underway (NCT02421939). Disclosures Perl: Astellas US Pharma Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Asana Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Altman:Janssen: Other: advisory board; BMS: Membership on an entity's Board of Directors or advisory committees; Spectrum: Other: advisory board; Ariad: Other: advisory board; Seattle Genetics: Other: advisory board; Syros: Other: advisory board. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Smith:Astellas: Research Funding. Erba:Jannsen: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Agios: Research Funding; Juno: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Daiichi Sankyo: Consultancy; Ariad: Consultancy; Amgen: Consultancy, Research Funding; Astellas: Research Funding; Gylcomimetics: Other: DSMB; Seattle Genetics: Consultancy, Research Funding; Sunesis: Consultancy; Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy. Gill:Astellas: Employment. Goldberg:Bristol Myers Squibb, Novartis: Speakers Bureau; Novartis: Consultancy; COTA Inc: Employment; Pfizer: Honoraria; Neostem: Equity Ownership. Jurcic:Astellas: Research Funding. Larson:Astellas: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Liu:Astellas: Employment. Ritchie:Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Consultancy, Research Funding; Astellas Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; NS Pharma: Research Funding. Schiller:Incyte Corporation: Research Funding. Strickland:Celator: Research Funding; Cyclacel: Research Funding; Karyopharm Therapeutica: Research Funding; GlaxoSmithKline: Research Funding; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Ambit: Consultancy; Alexion Pharmaceuticals: Consultancy; Astellas Pharma: Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Sanofi: Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Research Funding. Stuart:Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Agios: Research Funding; Incyte: Research Funding; Bayer: Research Funding; Celator: Research Funding; Astellas: Research Funding. Martinelli:Ariad: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Roche: Consultancy, Speakers Bureau; MSD: Consultancy; Genentech: Consultancy; Novartis: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Bahceci:Astellas: Employment. Levis:Millennium: Consultancy, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Abstract Introduction: ASP2215 is a highly selective inhibitor of AXL and FMS-like tyrosine kinase-3 (FLT3) receptors. ASP2215 is active against both FLT3 internal tandem duplication [ITD] and D835 mutations. Prior analyses of an open-label, dose-escalation/dose-expansion study in subjects with relapsed or refractory acute myeloid leukemia (R/R AML) show ASP2215 was well tolerated from 20-300 mg and associated with antileukemic activity in FLT3 mutation-positive (FLT3+) patients at ≥80 mg with minimal activity observed in wild-type FLT3 subjects. Here we describe the tolerability and potent activity of ASP2215 in a large cohort of FLT3+ patients. Methods: Patients (≥18 years) with R/R AML were assigned to treatment in dose-escalation cohorts or were randomized to an open dose level in the dose-expansion cohorts. Although FLT3 mutation was not an inclusion criterion, each expanded dose level enrolled ≥10 FLT3+ subjects; 120 mg and 200 mg dose levels were further expanded with ≥40 FLT3+ subjects. Tolerability was assessed by adverse event (AE) monitoring. Response assessment was based on modified Cheson criteria and duration of response and overall survival were calculated using Kaplan-Meier estimates. Results: As of June 19, 2015,215 patients with a median age of 61 yr (range: 21-90) had received ≥1 dose of ASP2215 (safety population). Across the safety population, 65% of subjects received ≥2 prior lines of AML therapy, 29% had a hematopoietic stem cell transplant prior to ASP2215 treatment, and 23% had prior tyrosine kinase inhibitor (TKI) treatment. Approximately 73% of patients were FLT3+, of which 137 had FLT3-ITD mutation, 7 were FLT3-D835+, and 9 had both FLT3-ITD and D835. Treatment-related AEs of all Grades, reported in ≥10% of the safety population were diarrhea (16%), fatigue (13%), and increased AST (11%); <2% of subjects reported a Grade ≥3 QTc prolongation. Activity was assessed in the 133 FLT3+ patients treated with ASP2215 ≥80 mg. Overall response rate (ORR; composite complete [CRc] plus partial remission [PR]) for all FLT3+ subjects was 55% (Table). Median overall survival for FLT3+ patients receiving ASP2215 ≥80 mg was ~29 weeks (95% CI: 22-32) and was similar for patients who achieved CRc or PR (Figure). Treatment with ≥80 mg ASP2215 was associated with an ORR of 60% in FLT3-ITD subjects; ORR for the other FLT3 populations was 29% (Table). No difference was observed in median ORR of ASP2215 (≥80 mg) in TKI-naïve patients (55%) and patients with prior TKI treatment (55%). Conclusions: ASP2215, a novel AXL/FLT3 TKI, was well tolerated in subjects with R/R AML and demonstrated a strong antileukemic activity in FLT3+ subjects. Importantly, the ASP2215 response rate in these FLT3+ patients was independent of prior TKI treatment. Even in this heavily pretreated population, the survival of R/R FLT3+ AML patients who received ≥80 mg ASP2215 was longer than prior reports of cytotoxic chemotherapy or other FLT3 inhibitors. Table. ASP2215 Response Assessment 80 mg 120 mg 200 mg 300 mg 450 mg Total All FLT3+ Subjects Population, n 12 52 57 10 2 133 CRc, n (%) 5 (42) 25 (48) 28 (49) 3 (30) 0 61 (46) PR, n (%) 3 (25) 3 (6) 3 (5) 3 (30) 0 12 (9) ORR, n (%) 8 (67) 28 (54) 31 (54) 6 (60) 0 73 (55) Subjects with FLT3-ITD Only Population, n 10 46 50 8 0 114 CRc, n (%) 4 (40) 23 (50) 26 (52) 3 (38) 0 56 (49) PR, n (%) 3 (30) 3 (7) 3 (6) 3 (38) 0 12 (11) ORR, n (%) 7 (70) 26 (57) 29 (58) 6 (75) 0 68 (60) Subjects with FLT3-D835 and Subjects with FLT3-ITD and FLT3-D835 Population, n 2 5 5 1 1 14 CRc, n (%) 1 (50) 1 (20) 2 (40) 0 0 4 (29) PR, n (%) 0 0 0 0 0 0 ORR, n (%) 1 (50) 1 (20) 2 (40) 0 0 4 (29) CRc, composite complete remission (complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete hematologic recovery); ORR, overall response rate; PR, partial response. NR, no response. Subjects with non-evaluable data (N=8) were not included in this curve. Figure 1. Overall Survival by Best Overall Response Achieved with ASP2215 ≥80 mg Across All FLT3+ Subjects Figure 1. Overall Survival by Best Overall Response Achieved with ASP2215 ≥80 mg Across All FLT3+ Subjects Disclosures Altman: BMS: Other: Advisory board; Novartis: Other: Advisory board; Spectrum: Other: Advisory board; Ariad: Other: Advisory board; Seattle Genetics: Other: Advisory board; Astellas: Other: Participation in an advisory board December 2013. Off Label Use: ASP2215 is currently under investigation for the treatment of AML and is not yet approved.. Perl:Arog Pharmaceuticals: Consultancy; Asana Biosciences: Consultancy; Actinium Pharmaceuticals: Consultancy; Ambit/Daichi Sankyo: Consultancy; Astellas US Pharma Inc.: Consultancy. Cortes:Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Levis:Arog: Research Funding; Ambit: Research Funding; Takeda: Research Funding; Astellas: Consultancy. Smith:Plexxikon: Research Funding; Astellas: Research Funding. Claxton:NCI: Research Funding; Medimmune, Inc: Research Funding; Ambit Biosciences Corp: Research Funding; Incyte Corporation: Research Funding; Merck Sharp & Dohme Corp: Research Funding; Astellas Pharma: Research Funding. Erba:Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Ariad: Consultancy; Celgene: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; GlycoMimetics: Other: Data Safety and Monitoring Committees ; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Amgen: Consultancy, Research Funding; Celator: Research Funding; Millennium/Takeda: Research Funding; Astellas: Research Funding; Sunesis: Consultancy; Celator: Research Funding; Pfizer: Consultancy; Astellas: Research Funding; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees ; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Daiichi Sankyo: Consultancy. Gill:Astellas Pharma US, Inc: Employment. Goldberg:Cyclacel: Research Funding; Celetor: Research Funding; Pfizer: Research Funding; Ambit: Research Funding; Astellas: Research Funding. Jurcic:Astellas Pharma: Research Funding. Larson:Astellas: Consultancy, Research Funding. Lui:Astellas Pharma US, Inc: Employment. Ritchie:Incyte: Speakers Bureau; Novartis: Speakers Bureau; Ariad: Other: Advisory Board; Celgene: Speakers Bureau; Onyx: Speakers Bureau. Sargent:Astellas Pharma US, Inc: Employment. Schiller:Sunesis: Honoraria, Research Funding. Strickland:Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation; Alexion Pharmaceuticals: Other: Advisory Board Particpation; Amgen: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation. Wang:Immunogen: Research Funding. Stuart:Sunesis: Honoraria, Other: Advisory Board, Research Funding; Astellas Pharma, Inc: Research Funding. Baldus:Novartis: Research Funding. Martinelli:MSD: Consultancy; ARIAD: Consultancy; BMS: Speakers Bureau; Pfizer: Consultancy; Novartis: Speakers Bureau; Roche: Consultancy. Bahceci:Astellas Pharma Global Development: Employment.

Abstract Abstract 788 FLT3 mutations are common in AML and are associated with poor prognosis. Lestaurtinib is a multi-targeted kinase inhibitor with potent activity against FLT3. In an attempt to definitively establish whether or not there is clinical benefit for FLT3 inhibition in the relapse setting, we conducted a randomized trial of chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Patients were randomized to receive either chemotherapy alone, consisting of mitoxantrone, etoposide, and cytarabine (MEC) or high-dose cytarabine (HiDAc) depending on the duration of CR1) or chemotherapy followed by 80 mg lestaurtinib orally BID. Patients on the chemotherapy only arm were eligible for crossover if they were refractory to therapy. Patients on the lestaurtinib arm received the drug for up to 112 days on study (they could continue to receive the drug through a separate extension protocol). The primary objective was complete remission (CR/CRp). Secondary objectives included overall survival (OS), safety, and tolerability. From January 2004 through December 2008, 224 patients at 52 different centers were enrolled and randomized, with 220 patients actually receiving therapy. Blood samples from patients on the lestaurtinib arm were obtained at baseline, on Day 15, and on Day 42 for pK studies and for determination of in vivo FLT3 inhibition and measurement of plasma FLT3 ligand (FL) and alpha-1 acid glycoprotein (AGP) levels. The median age for all patients enrolled was 55 years (53.5 in the control arm, 58.5 in the lestaurtinib arm), with 88% having FLT3/ITD mutations, 8% having D835 mutations, and 4% having both. The duration of CR1 was less than 6 months in 47% of patients in each arm. On the lestaurtinib arm, 107 patients received at least 1 week of lestaurtinib (mean 60.1 days, range 8-418), with 17 of these patients receiving drug on the extension protocol. On the chemotherapy only arm, 7 patients crossed over to receive lestaurtinib, and 31 patients went on to receive lestaurtinib on the extension protocol after outcome evaluation. Lestaurtinib was generally well tolerated following chemotherapy, with 104 Grade 3/4 adverse events in the lestaurtinib arm versus 99 in the control arm. There were 61 serious adverse events in the lestaurtinib arm versus 49 in the control arm. Early death (by Day 42) occurred in 22 lestaurtinib patients (2 progressive leukemia, 14 infectious, 6 organ failure) and16 control patients (6 progressive leukemia, 5 infectious, 5 organ failure). By intention to treat analysis, there were 29 CR/CRp in the lestaurtinib arm and 23 in the control arm (26% versus 21%; p = 0.35), with no difference in OS (4.73 months versus 4.57 months) between the two arms. Blood samples from 79 of the 107 lestaurtinib-treated patients obtained on Day 15 were analyzed for FLT3 inhibitory activity (plasma inhibitory activity [PIA] assay), as well as FLT3 ligand (FL), lestaurtinib, and AGP concentrations. Mean lestaurtinib plasma concentration was 12 uM at Day 15 and fell to 7.5 uM on Day 42. Mean lestaurtinib concentration at Day 15 was 13.3 uM in patients achieving CR/CRp and 11.5uM in non-responders. A target of >85% inhibition of FLT3 maintained at trough (pre-dose) was defined from previous studies. Of the 79 patients tested, 46 (58%) achieved this degree of FLT3 inhibition on Day 15. FL concentrations rose from baseline (15.6 pg/mL) to Day 15 (1148 pg/mL), and AGP concentrations rose by an average of 52% over the same period, both of which may have reduced the degree of FLT3 inhibition. Of the 46 patients with target FLT3 inhibition on Day 15, 18 (39%) achieved CR/CRp, while only 3 (9%) of the 32 patients with below target FLT3 inhibition achieved CR/CRp. Thus, in patients with FLT3 mutant AML at first relapse, pharmacokinetic factors and possible physiologic factors (FL and AGP) limit lestaurtinib's ability to effectively inhibit FLT3. FLT3 inhibition by lestaurtinib, when achieved, correlates with better CR rates, but in this trial that benefit was negated by a poor CR rate in those patients for whom the drug did not reach the target level of FLT3 inhibition. Overall, lestaurtinib treatment following re-induction chemotherapy failed to increase response rates or prolong survival of patients with FLT3 mutant AML in first relapse. Disclosures: Levis: Cephalon: Clinical Advisory Board member. Ravandi:Cephalon: Honoraria, Member, clinical advisory board, Research Funding. Erba:Cephalon: Research Funding, Speakers Bureau. Baccarani:Novartis Pharma, Bristol Myers Squibb, Merck Sharp & Dome, Pfizer: Consultancy, Speakers Bureau. Stone:Cephalon: ad hoc consultancy; Novartis: Research Funding, ad hoc consultancy. Advani:Cephalon: Research Funding. Douer:Cephalon: Honoraria, Research Funding, Speakers Bureau. Litzow:Cephalon: Research Funding. Tremmel:Cephalon: Employment, Equity Ownership. Bensen-Kennedy:cephalon: Employment. Smith:Cephalon: Research Funding.