Abstract: Background: Pev (TAK-924/MLN4924), a novel investigational NAE inhibitor, enhances the anti-leukemic effects of aza in AML cell lines and murine xenografts (Smith et al, Blood 2011). Single-agent pev activity was confirmed in relapsed/refractory AML pts (Swords et al, Br J Haematol 2015). This open-label, multi-center, dose-escalation study (NCT01814826) investigated pev + aza in treatment-naïve older AML pts. Dose-limiting toxicities (DLTs)includedG2 hyperbilirubinemia and G4 AST elevation (n=1 each) at pev 30 mg/m2. The maximum tolerated dose (MTD) for the combination was pev 20 mg/m2 + aza 75 mg/m2 (Swords et al, ASH 2014).We present updated safety/efficacy results for the MTD cohort (fully enrolled). Methods: Primary objectives included safety and tolerability assessments of pev + aza in addition to defining the MTD. Secondary objectives included pharmacokinetics (PK) and disease response assessments. Treatment-naïve pts ≥60 yrs unlikely to benefit from standard induction therapy (defined by ≥1 of: antecedent hematologic disease; known adverse cytogenetic risk; ECOG PS 2; ≥75 yrs), received pev 20 or 30 mg/m2 IV on d 1, 3 and 5, + fixed-dose aza (75 mg/m2 IV/SC) on d 1-5, 8 and 9, every 28 d until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed per NCI-CTCAE v4.03; response per IWG criteria for AML. Bone marrow samples were collected at screening to assess cytogenetic risk (CALGB) and mutation profile; serial samples for PK analysis were drawn in cycle 1. Results: Demographics:As of May 17 2016, 61 pts (median age 75 yrs [range 61-89]; 54% male; 77% ECOG PS 0/1, 23% ECOG PS 2; 57% de novo, 43% secondary AML; median marrow blasts 36% [range 5-92] ) had received pev 20 mg/m2, of whom 48% had intermediate-, 30% adverse-, and 3% favorable-risk cytogenetics. Safety/PK: Pts received a median of 4 cycles (range 1-33), and 23/61 pts (38%) received ≥6 cycles of pev + aza. The most common AEs were constipation (46%), nausea (44%), fatigue (43%), and anemia (39%). Fifty pts (82%) experienced ≥G3 AEs; the most frequent (≥15%) were anemia, febrile neutropenia (each 28%), thrombocytopenia (21%), neutropenia (18%), and pneumonia (15%). ≥G3 AST/ALT elevations were reported in 5% of pts. Forty-one pts (67%) experienced serious AEs; the most frequent (≥10%) were febrile neutropenia, neutropenia (each 25%), and pneumonia (11%). Two pts discontinued due to pev related toxicity (G3 febrile neutropenia). There were 11 on-study deaths unrelated to study therapy. In the MTD expansion phase (n=55), 2 pts experienced DLTs of transient G3/4 transaminase elevations, and were successfully re-challenged following dose reduction to remain on study. Pev PK was not altered by the addition of aza. Responses: Overall response rate (ORR) in 52 response-evaluable pts was 60% (18CR, 5CRi, 8PR; Figure 1), with a median duration of remission of 8.3 mos (95% CI: 5.75, 12.06); 19/31 (61%) responses occurred within the first 2 cycles.Of the 23 pts with CR/CRi, 14 had responses lasting ≥4 cycles, 2 went on to have allogeneic stem cell transplant, 9 had intermediate-, 7 adverse-, and 1 favorable-risk cytogenetics. ORR was: 64% (14/22; 7CR, 3CRi, 4PR) vs 57% (17/30; 11CR, 2CRi, 4PR) for pts with low- ( 〈 30%) vs high- (≥30%) marrow blasts; 58% (18/31; 11CR, 3CRi, 4PR) vs 62% (13/21; 7CR, 2CRi, 4PR) for de novo vs secondary AML pts; 61% (14/23; 8CR, 1CRi, 5PR) vs 50% (8/16; 5CR, 2CRi, 1PR) for intermediate- vs adverse-risk cytogenetic pts; 83% (19/23; 14CR, 2CRi, 3PR) vs 41% (12/29; 5CR, 3CRi, 4PR) for pts who received ≥6 cycles vs 〈 6 cycles of aza, respectively. Responses were seen in pts with typically refractory disease; 7/11 pts with TP53 mutations achieved either a CR/CRi (n=3) or PR (n=4); 4 stayed on study for 〉 10 cycles. After a median follow-up of 16.4 mos, 6-mo survival was 52%. Median overall survival was: 7.0 mos for the MTD cohort; 8.5 vs 5.2 mos for pts with low- ( 〈 30%) vs high- (≥30%) marrow blasts (Figure 2); 5.6 vs 11.2 mos for de novo vs secondary AML pts (Figure 3); and 16.1 vs 5.3 mos for pts aged 65-74 vs ≥75 yrs, respectively. Conclusion: Pev + aza was well tolerated. Response rates and durable remissions were observed with limited additional toxicity beyond what is expected for aza alone. The timing and frequency of responses suggests benefit from the addition of pev compared to aza alone (Dombret et al, Blood 2015). At the time of writing, a randomized phase 2 study in low-blast AML/high-risk myelodysplastic syndromes is ongoing. Disclosures Coutre: Janssen: Consultancy; Pharmacylics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Zeidner:Tolero: Research Funding; Merck: Research Funding; Takeda: Research Funding; Otsuka: Consultancy; Agios: Honoraria. Foran:medscape: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; novartis: Honoraria; pfizer: Honoraria; karyopharm: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Cruz:Millennium Pharmaceuticals, Inc.: Honoraria; Millennium Pharmaceuticals, Inc.: Speakers Bureau. Erba:Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Juno: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Sunesis: Consultancy; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Ariad: Consultancy; Jannsen: Consultancy, Research Funding. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Tam:Millennium Pharmaceuticals, Inc.: Consultancy. Vardhanabhuti:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dobler:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faessel:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dash:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Sedarati:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dezube:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Savona:Takeda: Research Funding; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

Abstract: RP2D of PEV 20 mg/m2 in PEV/AZA combo did not alter toxicity profile of AZA; dose-limiting toxicities were transiently elevated AST/ALT. In treatment-naive older AML patients, the intent-to-treat ORR was 50%.

Abstract: Background: Treatment of elderly AML patients considered unfit for conventional chemotherapy is inadequate and hypomethylating agents are commonly used alternatives. In the case of azacitidine, responses are typically seen after 3–6 cycles of therapy, and a recent large randomized trial in elderly unfit patients reported a complete response (CR)/CR with incomplete blood count recovery rate of 28% (Dombret et al, EHA 2014). Pevonedistat (MLN4924) is an investigational, first-in-class NEDD8-activating enzyme (NAE) inhibitor. A phase 1 trial previously reported pevonedistat single-agent clinical activity in relapsed/refractory AML patients. Preclinical studies of pevonedistat and azacitidine identified synergistic lethality in AML cell lines and murine xenografts. The current phase 1b dose-escalation study evaluated the safety and tolerability of pevonedistat combined with azacitidine in elderly AML patients considered unfit for conventional chemotherapy. Methods: The primary objective was to assess the safety and tolerability of pevonedistat combined with azacitidine. Secondary objectives included assessment of pevonedistat pharmacokinetics (PK) and clinical activity. Treatment-naïve AML patients aged ≥60 years who were considered unfit for standard induction therapy received pevonedistat via 1-hour IV infusion on days 1, 3, and 5 of 28-day cycles. Dose escalation began at 20 mg/m2 and used an adaptive Bayesian continual reassessment method. Azacitidine 75 mg/m2 was administered (IV or SC) on days 1–5 and 8–9. Patients were treated until disease progression or unacceptable toxicity. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Responses were assessed according to International Working Group response criteria for AML. Serial blood samples were obtained for PK analysis following dosing on days 1 and 5 of cycle 1. Results: As of May 30, 2014, 25 patients (median age 75.0 years [range 63–85]; 16 [64%] male) had received pevonedistat 20 mg/m2 (n=22) and 30 mg/m2 (n=3). Primary diagnoses were 16 (64%) de novo AML and 9 (36%) secondary AML. Fourteen (56%) patients had intermediate- and 6 (24%) had adverse-risk cytogenetics (5 [20%] undetermined). During dose escalation, dose-limiting toxicity (DLT) at the 30 mg/m2 pevonedistat dose level included reversible grade 2 increased bilirubin (n=1) and grade 3/4 increased transaminases (n=1) without clinical sequelae. In 1 of the 22 patients treated at the maximum tolerated dose (20 mg/m2 pevonedistat plus 75 mg/m2 IV/SC azacitidine), 1 additional DLT (grade 4 AST/ALT elevation) was seen in the expansion cohort. This patient was successfully re-challenged with a reduced pevonedistat dose. The most common all-grade AEs are shown in table 1. Twelve (48%) patients experienced drug-related grade ≥3 AEs (table 1). The nature and frequency of the reported toxicities (excluding DLTs) were similar to previous reports for azacitidine alone. Preliminary PK data showed that addition of azacitidine did not alter the known PK profile of single-agent pevonedistat. In the 18 response-evaluable patients, there were 6 (33%) CRs and 4 (22%) PRs (table 2), for an overall response rate of 56%. Nine of the 10 responses occurred within the first two cycles of therapy and included 1 patient with bone marrow blasts 〉 80%. Conclusions: Combination therapy with pevonedistat and azacitidine was generally well-tolerated. The characteristics of the observed responses suggest added benefit from the addition of pevonedistat compared with azacitidine alone. Table 1 Common all-grade AEs n (%) Most frequent (≥10%) drug-related grade ≥3 AEs n (%) Febrile neutropenia 9 (36) Febrile neutropenia 4 (16) Constipation 8 (32) Thrombocytopenia 3 (12) Decreased appetite 7 (28) – – Thrombocytopenia 7 (28) – – Table 2 Responders* Tumor Type Cytogenetic Risk Group Current Status Response Molecular CR 1st Response 1st CR 1 De novo AML Adverse C12 C4 – – 2 Undetermined C4† C1 C1 Y 3 Adverse C9 C1 C1 Y 4 Undetermined C5‡ C1 C2 Y 5 Intermediate C5† C1 C2 N 6 Intermediate C7 C1 C4 Y 7 Intermediate C2 C2 – – 8 Secondary AML Undetermined C4 C2 C2 – 9 Normal C4 C1 – – 10 De novo AML – C1 C1 – – Molecular CR, complete remission confirmed by molecular studies *All received 20 mg/m2 pevonedistat except #4, who started on 30 mg/m2 and had a dose reduction to 20 mg/m2. †Patient off study ‡Patient off treatment and in follow-up Disclosures Swords: Novartis: Consultancy; KaloBios Pharmaceuticals, Inc.: Consultancy; Millennium: The Takeda Oncology Company: Consultancy. Savona:Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Erba:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding. Foran:Takeda Pharmaceuticals International Co.: Research Funding. Hua:Takeda Pharmaceuticals International Co.: Employment. Faessel:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Dash:Takeda Pharmaceuticals International Co.: Employment. Sedarati:Takeda Pharmaceuticals International Co.: Employment. Dezube:Takeda Pharmaceuticals International Co.: Employment. Medeiros:Millennium: The Takeda Oncology Company: Consultancy, Honoraria; Takeda Pharmaceuticals International Co.: Research Funding.

Abstract: Allogeneic hematopoietic cell transplantation (HCT) after high-dose conditioning regimens imposes prohibitively high risks of morbidity and mortality for patients with high-risk acute myeloid leukemia (AML) who are older or have comorbid conditions. Here, we examined outcomes after nonmyeloablative allogeneic HCT in such patients. Patients and Methods Two hundred seventy-four patients (median age, 60 years) with de novo or secondary AML underwent allogeneic HCT from related (n = 118) or unrelated donors (n = 156) after conditioning with 2 Gy of total-body irradiation (TBI) with or without fludarabine. A calcineurin inhibitor and mycophenolate mofetil were used for postgrafting immunosuppression. Results With a median follow-up of 38 months in surviving patients, the estimated overall survival at 5 years was 33%. The estimated 5-year relapse/progression and nonrelapse mortality rates were 42% and 26%, respectively. The cumulative incidences of grades 2, 3, and 4 acute graft-versus-host disease (GVHD) were 38%, 9%, and 5%, respectively. The cumulative incidence of chronic GVHD at 5 years was 44%. Patients in first and second complete remission had better survival rates than patients with more advanced disease (37% and 34% v 18%, respectively). Patients with HLA-matched related or unrelated donors had similar survivals. Unfavorable cytogenetic risk status was associated with increased relapse and subsequent mortality. Chronic GVHD was associated with lower relapse risk. Conclusion Allogeneic HCT from related or unrelated donors after conditioning with low-dose TBI and fludarabine, relying almost exclusively on graft-versus-leukemia effects, can result in long-term remissions in older or medically infirm patients with AML.

Abstract: We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities. Patients and Methods Patients received low-dose total-body irradiation ± fludarabine before HCT from HLA-matched related (n = 611) or unrelated (n = 481) donors, followed by mycophenolate mofetil and a calcineurin inhibitor to aid engraftment and control GVHD. Median patient age was 56 years (range, 7 to 75 years). Forty-five percent of patients had comorbidity scores of ≥ 3. Median follow-up time was 5 years (range, 0.6 to 12.7 years). Results Depending on disease risk, comorbidities, and GVHD, lasting remissions were seen in 45% to 75% of patients, and 5-year survival ranged from 25% to 60%. At 5 years, the nonrelapse mortality (NRM) rate was 24%, and the relapse mortality rate was 34.5%. Most NRM was a result of GVHD. The most significant factors associated with GVHD-associated NRM were serious comorbidities and grafts from unrelated donors. Most relapses occurred early while the immune system was compromised. GVT effects were comparable after unrelated and related grafts. Chronic GVHD, but not acute GVHD, further increased GVT effects. The potential benefit associated with chronic GVHD was outweighed by increased NRM. Conclusion Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.

Abstract: Patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) have a short life expectancy. The aim of this study was to analyze the outcome of patients with advanced CLL when treated with nonmyeloablative conditioning and hematopoietic cell transplantation (HCT). Patients and Methods Sixty-four patients diagnosed with advanced CLL were treated with nonmyeloablative conditioning (2 Gy total-body irradiation with [n = 53] or without [n = 11] fludarabine) and HCT from related (n = 44) or unrelated (n = 20) donors. An adapted form of the Charlson comorbidity index was used to assess pretransplantation comorbidities. Results Sixty-one of 64 patients had sustained engraftment, whereas three patients rejected their grafts. The incidences of grades 2, 3, and 4 acute and chronic graft-versus-host disease were 39%, 14%, 2%, and 50%, respectively. Three patients who underwent transplantation in complete remission (CR) remained in CR. The overall response rate among 61 patients with measurable disease was 67% (50% CR), whereas 5% had stable disease. All patients with morphologic CR who were tested by polymerase chain reaction (n = 11) achieved negative molecular results, and one of these patients subsequently experienced disease relapse. The 2-year incidence of relapse/progression was 26%, whereas the 2-year relapse and nonrelapse mortalities were 18% and 22%, respectively. Two-year rates of overall and disease-free survivals were 60% and 52%, respectively. Unrelated HCT resulted in higher CR and lower relapse rates than related HCT, suggesting more effective graft-versus-leukemia activity. Conclusion CLL is susceptible to graft-versus-leukemia effects, and allogeneic HCT after nonmyeloablative conditioning might prolong median survival for patients with advanced CLL.

Abstract: We have shown safety of unrelated donor hematopoietic cell transplantation (HCT) using nonmyeloablative conditioning with fludarabine (FLU, 90 mg/m2) and 2 Gy total body irradiation (TBI) and post-HCT immunosuppression with MMF (15 mg/kg) and cyclosporine (CSP 5–6.25 mg/kg) both given BID (Maris Blood 2003 Vol 102, No 6). The graft rejection rate in the first 89 pts was 23% and more frequent for marrow (8/18; 44%) than PBSC (13/71; 18%) recipients. Multivariate analysis identified recipients of marrow grafts and those without preceding chemotherapy at highest risk for graft rejection (p=0.006 for each). The t½ of mycophenolic acid, the active metabolite of MMF, was 3 hours, and its binding to IMPDH II rapidly reversible. This led to the hypothesis that exclusive use of PBSC grafts and TID dosing of MMF might result in higher engraftment and lower acute GVHD rates. The current protocol (MMF TID) was identical to the original one (MMF BID) except that all pts received PBSC and were given MMF TID. The protocol’s primary goal was to achieve graft rejection 〈 10% and 〈 20% for pts with and without prior chemotherapy, respectively, and its secondary goal to reduce the incidence of acute GVHD. Pts with malignant diseases (n=103), matched with their donors for HLA-A, -B, -C antigens and -DRB1 and -DQB1 alleles, were entered on study. Median donor T cell chimerism at day 28 was 92% compared to 75% for 71 PBSC recipients given MMF BID on the prior protocol (p=0.02). When BID and TID MMF pts were considered together, donor T cell chimerism 〈 50% was highly predictive for graft rejection (p 〈 0.0001). The durable engraftment rate for pts given MMF TID versus BID was 95% (98/103) compared to 82%, respectively (p=0.004). For pts with and without prior chemotherapy given MMF TID versus BID, rejection rates were 3% compared to 10% (p=0.08) and 17% compared to 53% (p=0.05), respectively. Cumulative probabilities of grades II, III and IV acute and chronic extensive GVHD were 39%, 10%, 2%, and 45%, respectively, and were similar to rates in BID MMF pts, suggesting further improvements in GVHD prevention are needed. For the 103 pts given MMF TID, 1-year overall survival, progression-free survival, relapse/progression, and non-relapse mortality were 64%, 54%, 27%, and 19%, respectively. Kaplan-Meier 1-year survivals were as follows: acute leukemia (n=24) 79%, B cell malignancies (n=47: CLL, n=13; Hodgkin disease, n=8; NHL, n=27) 63%, multiple myeloma (n=11) 55%, CML (n=5) 100%, MDS/myeloproliferative syndromes (MPS) (n=12) 50%, and RCC 50%. Kaplan-Meier 1-year progression free survivals were as follows: acute leukemia 71%, B cell malignancies 61%, multiple myeloma 46%, CML 60%, MDS/MPS 33%, and RCC 25%. The use of unrelated donor PBSC grafts and administration of MMF TID after nonmyeloablative conditioning significantly improved donor T cell chimerism and engraftment rates over the preceding protocol. However, further improvements in immunosuppression after HCT are needed to reduce acute GVHD rates.

Abstract: Background: SL-401 is a novel targeted therapy directed to the interleukin-3 receptor (CD123), a target overexpressed on acute myeloid leukemia (AML) blasts and AML cancer stem cells (CSCs), and a variety of additional hematologic malignancies. While conventional chemotherapy can induce remission in a majority of treatment-naive AML patients, relapse rates remain high. Outcomes are particularly poor when minimal residual disease (MRD), as determined by genetic and/or flow cytometric analyses, remains after therapy, with high rates of relapse and short disease-free survival. Conceivably, a therapy directed at lowering MRD burden may improve long-term outcomes. Given the association of MRD with CD123+ AML CSCs, SL-401 is being evaluated in patients with AML in first or second complete remission (CR1 or CR2, respectively) with high risk of relapse including persistent MRD. Preliminary results are reported here. Methods & Results: This multicenter, single-arm Phase 2 trial of AML patients in CR1 or CR2 with high risk of relapse includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients (MRD+ or MRD-) receive SL-401 as a daily IV infusion at 7, 9, or 12 ug/kg/day for days 1- 5 of a 28 day cycle in a 3x3 design. In stage 2, patients (MRD+ only) receive SL-401 at the dose determined in stage 1. Presence of MRD for eligibility requires either molecular (by cytogenetics, FISH, PCR, or next-generation sequencing of AML-associated mutations) or multiparameter flow cytometry (MFC) evidence of persistent abnormalities in the setting of morphologic CR. In stage 2, MRD assessment will include MFC of bone marrow aspirates conducted at a central laboratory for uniformity. Objectives include characterization of SL-401 safety with determination of the maximum tolerated or tested dose, and preliminary assessment of efficacy including changes in MRD burden and response duration. As of 7/27/16, stage 1 has been completed and stage 2 is open for enrollment. Nine patients (stage 1) received SL-401 (7 ug/kg, n=3; 9 ug/kg, n=3; 12ug/kg, n=3). The median age was 63 years (range: 51-78 years); 6 males and 3 females were treated; 8 patients were in CR1 and 1 patient was in CR2 at enrollment. The 12 ug/kg dose level was the highest tested dose with no DLTs; MTD was not reached. The most common treatment-related AEs, all grades, were thrombocytopenia (3/9; 33%) and hypoalbuminemia (3/9; 33%); the most common ≥ grade 3 treatment-related AE was thrombocytopenia (1/9; 11%); there was no DLT. Patients treated at all doses received 1+ to 5+ cycles (ongoing) of SL-401, including 3 MRD+ patients treated at 7 ug/kg (n=1) or 9 ug/kg (n=2) who received 1-5 cycles, and 1 MRD+ patient treated at 12 ug/kg who is receiving ongoing SL-401 for 4+ cycles. For all 3 patients treated at 12 ug/kg (MRD+, n=1; MRD-, n=2), 2 patients remain on SL-401 and have received 1+ and 4+ cycles (both ongoing); one other patient treated at 12 ug/kg discontinued the study because of infection unrelated to study drug. Notably, the one MRD+ patient treated at 12 ug/kg (ongoing at 4+ cycles) had marked MRD reduction as determined by MFC at the local institution; this patient is being considered for stem cell transplant (SCT). Conclusions: Stage 1 is complete without DLT or MTD, and stage 2 (expansion) is open to enroll AML patients in CR1 or CR2 who are MRD+ at the highest tested dose of 12 ug/kg. The safety profile has been similar to that observed in other SL-401 clinical studies, with no unexpected AEs. Targeting MRD with SL-401 has the potential to reduce this chemo-resistant cell population and offer improved long-term outcomes for AML patients in remission with high risk of relapse. Updated data will be presented. Clinical trial information: NCT02270463. Disclosures Lane: N-of-1: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Pfizer: Speakers Bureau; Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau. Wang:Immunogen: Research Funding; Incyte: Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Carraway:Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Lindsay:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Stone:Novartis: Consultancy; Juno Therapeutics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Karyopharm: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

Abstract: Background Post-remission therapies for patients with AML such as high-dose cytarabine (HiDAC) and allogeneic stem cell transplant (alloSCT) have led to improved outcomes for younger patients, but disease recurrence remains prevalent with ~40% 5-year OS. CD33 is a cell surface receptor expressed in ~90% of AML, representing a promising target for therapy. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Methods This phase 1b dose-escalation study (NCT02326584) evaluates the safety and anti-leukemic activity of 33A in combination with consolidation therapy (HiDAC) or as a single agent for maintenance therapy. AML patients (ECOG status 0-1) must be in 1st remission (CR or CRi) after standard induction therapy and be able to receive HiDAC (consolidation cohort) or be in 1st remission and have completed planned post-remission therapies, either chemotherapy and/or alloSCT (maintenance cohort). For maintenance post-alloSCT, patients were between Day 60 and 100 post-transplant without significant GVHD. Prior to HiDAC administration (3 gm/m2 q12h Day 1, 3, 5), 33A is given on Day 1 for up to 4 cycles (28-day cycle). For maintenance therapy, 33A is given as a single agent on Day 1 for up to 8 cycles (6-wk cycle). Results Consolidation cohort: 21 patients (57% male) with a median age of 52 years (range, 21-64) were treated with 5, 10, or 20 mcg/kg of 33A with HiDAC. Patients received a median of 2 cycles (range, 1-4). As anticipated, all patients experienced Grade 4 myelosuppression. At 20 mcg/kg, 1 DLT (lack of recovery of platelets [25K] and/or ANC [500] by Day 42) occurred in Cycle 1. At 10 mcg/kg, no DLTs were observed but delay of subsequent cycles of treatment occurred in 4 of 10 patients, primarily due to thrombocytopenia. No DLTs were observed in the 8 patients treated at 5 mcg/kg and 1 non-hematologic-related dose delay was reported (otitis externa). Non-hematologic treatment-emergent adverse events (AE) in ≥25% of patients regardless of relationship included nausea (38%) and fatigue (33%). No infusion-related reactions (IRRs) or events of veno-occlusive disease were reported. The 30- and 60-day mortality rates were 0%. Of the 19 efficacy evaluable patients, 15 (79%) have maintained remission, 18 patients are alive and 3 patients (14%) remain on treatment. Reasons for treatment discontinuation were completion of planned consolidation therapy (38%), AE (thrombocytopenia, 14%), leukemic relapse (5%), and other non-AE (29%). Nine patients (43%) went on to receive an alloSCT. Maintenance cohort: 22 patients (41% male) with a median age of 45.5 years (range, 23-71) have been treated with 5 mcg/kg of 33A. Patients were a median of 6.2 months from diagnosis (range, 3.4-21.5); 12 patients completed chemotherapy-based treatment alone and 10 patients completed standard chemotherapy with an alloSCT in 1st remission. Patients received a median of 3 cycles (range, 1-6); no DLTs were reported. AEs reported in ≥15% of patients were fatigue (41%), neutropenia (41% [36% ≥G3]), nausea (36%), thrombocytopenia (36% [27% ≥G3] ), diarrhea, dyspnea, headache, and vomiting (18% each); no IRRs were observed. Of the 20 efficacy evaluable patients, 15 (75%) have maintained remission. Reasons for treatment discontinuation were AEs (41%, primarily myelosuppression), leukemic relapse (14%), completion of planned therapy (9%), and other non-AE reasons (19%); 4 patients (18%) remain on treatment. Median OS is not yet reached and 19 patients are alive. Pharmacokinetic data in patients receiving post-remission therapy with 33A demonstrate that exposure appears to be greater than in patients with active disease, possibly due to a decrease in target-mediated disposition. Conclusions 33A can be safely administered in combination with HiDAC and as monotherapy in the post-remission setting. In combination with HiDAC, non-hematologic toxicities of 33A were consistent with effects reported with HiDAC alone. As a single agent, 33A administered as maintenance post-chemotherapy and/or alloSCT results in predictable on-target myelosuppression, with mild non-hematologic adverse effects. Disclosures Yang: Seattle Genetics: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Advani:Seattle Genetics: Consultancy, Research Funding. Walter:Emergent Biosolutions: Consultancy; Seattle Genetics: Research Funding; CSL Behring: Research Funding; Celator Pharmaceuticals: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Covagen AG: Consultancy; Agios: Consultancy; Arog: Research Funding. Faderl:Seattle Genetics: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Celator Pharmaceuticals: Research Funding; BMS: Research Funding; Ambit Bioscience: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; JW Pharma: Consultancy; Amgen: Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Erba:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Gylcomimetics: Other: DSMB; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Celator: Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Bexalata: Other: Advisory Board participation. Levy:Amgen: Speakers Bureau; Jansen: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Research Funding. Wood:Pfizer: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement; Juno: Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement. Feldman:Seattle Genetics: Employment, Equity Ownership. Voellinger:Seattle Genetics: Employment, Equity Ownership.

Abstract: Background For patients who are less than 65 years with newly diagnosed AML, standard induction treatment is continuous infusion cytarabine for 7 days and an anthracycline for 3 days (7+3). Although a high percentage of patients achieve an initial CR by morphologic criteria, some requiring a 2nd induction, a significant number of patients are either primarily resistant to treatment or achieve a morphologic CR but with flow cytometric or molecular evidence of minimal residual disease (MRD). CD33, a cell surface antigen, is expressed in approximately 90% of AML, representing a promising target of therapy regardless of genetic or mutational heterogeneity. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. Addition of 33A to 7+3 chemotherapy could result in enhanced and deeper (MRD negative) remissions, resulting in reduced relapse rates and improved overall survival. Methods This phase 1b study (NCT02326584) evaluated the safety and antileukemic activity of escalating doses of 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m2 and daunorubicin 60 mg/m2). AML patients (ECOG status 0-1) must be eligible to receive induction therapy. 33A is given on Days 1 and 4 concomitantly with the combination treatment. Response assessments occur on Days 15 and 28; investigator assessment of response is per IWG criteria (Cheson 2003). A 2nd induction regimen and post-remission therapies were per investigator choice and did not include additional administration of 33A. MRD was assessed centrally by bone marrow examination using a multi-parametric flow cytometric assay at Days 15 and Day 28. Results To date, 42 patients (36% male) with a median age of 45.5 years (range, 18-65) have been treated with 10+10 (n=4) and 20+10 (n=38) mcg/kg of 33A. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by MRC criteria and 17% of patients had secondary AML. As expected, all patients experienced Grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from Day 1 of therapy was 33 days for neutrophils (≥1K) and 35 days for platelets (≥100K). Three DLTs (lack of recovery of platelets [25K] and/or ANC [500] by Day 42) occurred at the 20+10 mcg/kg dose level, which was determined to be the maximum tolerated dose (MTD) of 33A in combination with 7+3. No non-hematologic treatment emergent adverse events (AEs) ≥Grade 3 were reported in 〉 15% of patients; Grade 1 or 2 non-hematologic AEs occurring in 〉 15% of patients were nausea (55%), diarrhea (33%), constipation (31%), decreased appetite (19%), fatigue (19%), and vomiting (17%); no infusion-related reactions occurred. No veno-occlusive disease (VOD) or significant hepatotoxicity was observed. The 30- and 60-day mortality rates were 0% and 7%, respectively. Of the 40 efficacy evaluable patients, best responses include 24 CR (60%), 7 CRi (18%), and 4 morphologic leukemia-free state (10%) with a CR+CRi (CRc) rate of 78%; 94% of CR or CRi responses occurred with 1 cycle of induction therapy. Twenty-three of 31 (74%) patients attaining CR or CRi achieved MRD negative status. Median OS is not yet reached; 36 patients were alive at the time of this data cut with 6 patients (14%) still on treatment. Pharmacokinetic data demonstrate rapid elimination of 33A. Conclusions 33A can be safely combined with 7+3 with acceptable count recovery and the recommended phase 2 dose is 20+10 mcg/kg on Days 1 and 4. An alternate schedule of single-day dosing on Day 1 is under investigation and enrollment continues. Extramedullary AEs, including hepatic toxicity, and induction mortality rates were similar to reported rates for 7+3 alone in this AML population. A high remission rate within the 1st induction cycle was observed, the majority of which were MRD negative. Disclosures Erba: Sunesis: Consultancy; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy; Amgen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Jannsen: Consultancy, Research Funding; Gylcomimetics: Other: DSMB; Agios: Research Funding; Astellas: Research Funding; Juno: Research Funding. Levy:Millennium: Speakers Bureau; Amgen: Speakers Bureau; Jansen: Speakers Bureau; Seattle Genetics: Research Funding. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Bexalata: Other: Advisory Board participation. Advani:Seattle Genetics: Consultancy, Research Funding. Faderl:JW Pharma: Consultancy; Amgen: Speakers Bureau; Karyopharm: Consultancy, Research Funding; Ambit Bioscience: Research Funding; BMS: Research Funding; Celator Pharmaceuticals: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Celgene: Consultancy, Research Funding. Smith:Seattle Genetics: Research Funding; Celgene: Consultancy, Speakers Bureau. Wood:Juno: Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement; Pfizer: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement. Walter:Covagen AG: Consultancy; Astra-Zeneca: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Research Funding; Amgen: Research Funding; Celator Pharmaceuticals: Research Funding; CSL Behring: Research Funding; Seattle Genetics: Research Funding; Emergent Biosolutions: Consultancy; Agios: Consultancy; Arog: Research Funding. Yang:Seattle Genetics: Research Funding. Feldman:Seattle Genetics: Employment, Equity Ownership. Voellinger:Seattle Genetics: Employment, Equity Ownership. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding.