Abstract: In the current phase 1 study, the combination of brentuximab vedotin, an antibody‐drug conjugate targeting CD30, and re‐induction chemotherapy (mitoxantrone, etoposide, and cytarabine) was found to be safe for patients with CD30‐expressing relapsed/refractory acute myeloid leukemia. The results suggest that CD30 may be a target of further exploration in this patient population.

Abstract: The intensification of chemotherapy for older patients with acute lymphoblastic leukemia can result in improved outcomes in comparison with historical data. Intensification may be appropriate for sufficiently robust older patients with Philadelphia chromosome–negative acute lymphoblastic leukemia.

Abstract: The aurora kinases play an essential role in regulating mitosis and cell division. Over-expression of aurora kinases A and B has been associated with poor-risk features in acute myeloid leukemia (AML). Preclinical studies suggest that small molecule aurora kinase inhibitors have activity in AML cell lines. Alisertib (MLN8237), a novel Aurora-A kinase inhibitor, has been generally well tolerated in early clinical trials of hematological malignancies, including AML. This study sought to evaluate tolerability of alisertib combined with standard “7+3” induction chemotherapy for AML. In this phase I, 3+3 cohort dose-escalation study, alisertib was administered with standard 7+3 induction for newly diagnosed AML. Those with acute promyelocytic leukemia or with AML and core-binding factor alterations were excluded. All patients received 7+3 induction (continuous infusion cytarabine 200mg/m2 x 7 days and intravenous idarubicin 12mg/m2 x 3 days), after which on day 8, alisertib was administered twice daily (BID) for 7 days. Dose escalation occurred via three cohorts (10mg BID, 20mg BID, 30mg BID). All underwent a mid-induction bone marrow biopsy, following the course of alisertib, to assess for residual disease, which if present, was to be treated with 5+2 re-induction (cytarabine 200mg/m2 x 5 days, idarubicin 12mg/m2 x 2 days) without alisertib. Following induction, up to four cycles of consolidation were allowed, using cytarabine (3g/m2 BID days 1,3,5 for those aged 〈 60 and 2g/m2 daily days 1-5 for those aged ≥60) followed by alisertib, according to dose cohort, on days 6-12. After consolidation, alisertib maintenance was initiated, at cohort dose level, for days 1-7 of 21 day cycles, to be continued for 12 months or until disease progression. Those eligible for stem cell transplant (SCT), following induction and/or consolidation courses, were removed from study for this purpose. Currently, 14 patients are enrolled on study (n=3, 10mg BID; n=7, 20mg BID; n=4, 30mg BID). The median age was 62 (range 43-75); 9 (64%) were male, and all but 3 were Caucasian. One patient (7%) had therapy-related AML and six (43%) had underlying myelodysplasia. FLT3 mutations were detected in 3 (21%), NPM1 mutations in 2 (14%), CEBPA mutations in 2 (14%), and IDH1/IDH2 mutations in 4 patients (28.4%). One patient in cohort 2 died of sepsis, deemed unrelated to study drug, prior to completion of the toxicity assessment period and was replaced. Five patients have gone on to SCT. All patients received induction, 7 patients have undergone first consolidation, 3 a second consolidation, 2 a third consolidation, 1 a fourth consolidation, and 1 patient has started maintenance therapy. Alisertib has been well tolerated. All patients have experienced expected grade 4 toxicities of anemia, thrombocytopenia, and febrile neutropenia seen during the induction phase of treatment. At initial dose of 10mg BID, no dose-limited toxicities (DLTs) were encountered. In the 20mg BID cohort, one DLT was encountered, of delayed thrombocytopenia (G4 at day 40). The final cohort, at 30mg BID, is currently accruing (4 of 6 enrolled). No other DLTs have been detected, and other toxicities on study will be presented. The maximum tolerated dose (MTD) will be established upon completion of this cohort. To date, 11 of 12 (92%) evaluable patients have achieved remission following induction (8 cases of CR and 3 of CRp). During the course of the study, one patient has experienced relapse, and none have died. Thirteen of 14 evaluable patients had an ablated mid-induction marrow biopsy, with the remaining patient showing 6% blasts in a 20% cellular marrow at mid-induction. None of the patients have undergone re-induction with 5+2 at mid-induction. We anticipate that the study will be fully enrolled and closed to further accrual by the time of presentation. Alisertib, a novel aurora A kinase inhibitor, appears to be well tolerated in conjunction with standard induction chemotherapy in newly diagnosed AML. Currently, 13 of 14 treated patients have demonstrated marrow ablation at the mid-induction point of therapy, and none have required re-induction with 5+2. Eleven of 12 evaluable patients have achieved remission following induction. These results suggest that alisertib is well-tolerated and may hold promise as a therapeutic agent in AML, when combined with induction chemotherapy. Ongoing efforts seek to define the MTD and establish appropriate dosing for phase II studies. Disclosures Fathi: Millennium: Research Funding; Seattle Genetics: Advisory Board, Advisory Board Other; Agios: Advisory Board, Advisory Board Other. Attar:Agios: Employment.

Abstract: Unlike the significant advances seen with intensive chemotherapy for pediatric acute lymphoblastic leukemia (ALL) over the last two decades, long-term outcomes among patients over age 50 remain poor, with median survival less than one year. This contrast has been attributed to high-risk chromosomal features, decreased compliance with and tolerance of effective therapies, and exposure to less intensive multi-agent regimens among adults with ALL. In recent years, more intensive chemotherapeutic paradigms, derived from pediatric protocols, have been studied in adult ALL. The purpose of the current study was to determine the efficacy of an intensified multi-agent approach, derived from a completed DFCI consortium pediatric regimen used in younger adults, in an older (age 〉 50) population of patients with ALL. For this study, modifications of the pediatric regimen included incorporation of clofarabine in consolidation, adjustment to dose and scheduling of PEG asparaginase and steroids, as well as inclusion of stem cell transplant (SCT) for eligible patients. The primary endpoint was survival rate at 1 year, with the goal of improving from the 33% historical control to 53%. Adults, aged 51-75 years, with newly diagnosed ALL or lymphoblastic lymphoma, were eligible. During induction, patients received multi-agent chemotherapy with vincristine, prednisone, doxorubicin, and PEG asparaginase. Imatinib was instituted if cytogenetics confirmed the presence of the Philadelphia chromosome. Patients received prophylactic intrathecal therapy with induction, and those with CNS involvement underwent additional IT therapy. Prednisone was administered for 21 days for those aged less than 60 and for 7 days for those aged 60 and above. Following induction, cycle one of consolidation included treatment with clofarabine, prednisone, and PEG asparaginase. After induction and first consolidation course, eligible patients proceeded to allogeneic SCT. Patients without matched sibling donors could receive unrelated donor or cord blood transplants. While those eligible under age 60 could undergo ablative conditioning regimens, those 60 and older received reduced intensity regimens. Those not eligible for SCT, went on to receive CNS, consolidation and continuation phases of treatment, as per protocol, which incorporated treatment with cycles of vincristine, doxorubicin, 6-mercaptopurine, and dexamethasone. PEG asparaginase was incorporated into the induction, consolidation I, CNS phase, and consolidation II phases of therapy. As of the most current analysis, 30 patients have been enrolled. A total of 19 of 29 evaluable patients (66%) have achieved a complete remission (CR). Three patients were refractory to induction therapy, four discontinued treatment during induction due to toxicity, of which three died, and nine patients have experienced relapse following remission. Nine patients have undergone SCT. A total of 15 patients have died on study out of 27 evaluated, and the overall survival, calculated by the method of Kaplan and Meier, at one year was 62% [95% CI, 41%-77%] (Figure 1), while disease-free survival for the 18 patients who achieved a CR following induction therapy at one year was 77% [95% CI, 49%-90%] . In total, for evaluable patients with at least one year of follow-up, the proportion surviving at one year was 61% [two-sided 80% CI, 47-75%] (16/26), significantly higher than the historical rate (33% used for this analysis, one-sided 90% exact CI) among such patients. Overall survival is also shown for Ph+ and Ph- groups (Figure 2). The most common grade 3/4 toxicities included transaminitis and hyperbilirubinemia, cytopenias, hypophosphatemia, hyperglycemia, and neutropenic fever. The major toxicity of liver injury, thought related to PEG asparaginase, prompted an amendment to the protocol to reduce the dose. Additionally, PEG asparaginase administration was limited to only those with Philadelphia chromosome-negative disease, to decrease risk of severe hepatotoxcity in patients receiving concurrent imatinib and PEG asparaginase. These data suggest that intensive multi-agent chemotherapy is tolerable in older patients with ALL, and can result in improved outcomes when compared to historical data. Additional study of similarly intensive regimens, incorporating novel therapies and alternative formulations of asparaginase, are warranted in older populations of ALL. Disclosures Fathi: Seattle Genetics: Research Funding; Seattle Genetics: Advisory Board, Advisory Board Other. Stone:Novartis: Research Funding.

Abstract: Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients & gt;60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%] , while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

Abstract: Background: Aurora kinases play essential roles in regulating cell division, and increased expression has been noted in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We previously conducted a phase I study of alisertib combined with "7+3" induction chemotherapy in untreated patients with AML, and found the combination to have an adverse event profile similar to 7+3 alone, with promising efficacy, particularly for patients with high-risk disease, such as those who were older, with high-risk molecular features, or with secondary AML. These patients collectively have a historically grim prognosis, with an approximate rate of remission, in trials, of 45%. CPX-351, a liposomal daunorubicin-cytarabine product, was recently approved for use in secondary AML after it was demonstrated to be superior to 7+3 induction, with a median survival of 9.6 months versus 5.9 months among older patients, in a phase 3 trial. We recently completed accrual to a phase II study of alisertib plus induction chemotherapy in patients with untreated, high-risk AML. Methods: Patients were eligible if they had AML defined by WHO 2016 and either an adverse-risk karyotype (European Leukemia Net Guidelines), secondary (post-MDS/MPN) AML, therapy-related AML, or age ≥ 65 vears. We used a Simon two-stage design, assuming a null composite remission rate (complete remission [CR] and CR with incomplete count recovery [CRi] ) of 45%. Patients could be enrolled prior to cytogenetic classification, but those without adverse-risk karyotype who lacked other eligibility criteria were removed before day 8 and replaced. All patients received continuous infusion cytarabine 100mg/m2 on days 1-7 [D1-7] and idarubicin 12mg/m2 [or daunorubicin 60mg/m2] D1-3 (7+3). On D8 through D15, alisertib at 30mg BID orally (PO) was administered. All underwent a mid-induction marrow biopsy to assess for residual disease, which if present, was treated with 5+2 re-induction without alisertib. Following remission, patients could receive up to 4 consolidation cycles with cytarabine (3g/m2 BID D1,3,5 for age 〈 60 and 2g/m2 daily D1-5 for age ≥60) with alisertib PO at 30mg BID, D6-12, and alisertib maintenance at 30mg BID PO (D1-7 of 3 week cycles) thereafter for 12 months. Patients who pursued stem cell transplant (SCT) were followed for EFS and OS. Results: 39 eligible patients were enrolled. The median age was 67 (range 33-83); 25 (64%) were male, and 33 (85%) were Caucasian. 22 patients (56%) had secondary AML (16 with antecedent MDS, 2 with antecedent CMML, 1 with antecedent MPN, and 3 with therapy-related AML). 13 (33%) exhibited adverse risk karyotype. FLT3 mutations were seen in 7 (18%), NPM1 in 7 (18%), IDH1 in 5 (13%), IDH2 in 5 (13%), CEBPA in 3 (8%), and TP53 mutations in 4 (10%) patients. 33 patients (85%) demonstrated an ablated marrow at mid-treatment, and six (15%) received re-induction at mid-treatment. 8 patients (21%) were refractory to induction, and five (13%) died prior to response assessment due to infection or bleeding. The 30-day and 60-day mortality rates were 8% and 13%, respectively. Patients experienced expected grade 4 toxicities of leukopenia, anemia, thrombocytopenia, and febrile neutropenia; no new attributable safety signals were detected. The CR+CRi rate was 64% (2-stage 95% CI 48-79%) with 20 patients (51%) achieving CR and 5 (13%) achieving Cri. The CR+CRi rate was 59% (13 of 22) in those with secondary AML, 67% (18 of 27) in those aged ≥ 65, 77% (10 of 13) in those with adverse risk karyotype, and 75% (3 of 4 patients) in patients with TP53 mutations. One (3%) patient achieved a partial remission. Based on the composite remission rate of 64%, the combination was deemed effective per study design. 5 patients have relapsed to date. 10 have received at least 1 cycle of consolidation, 16 patients (41%) have gone on to SCT. With a median follow-up of 14 months (Figure), the 12-month overall survival (OS) is 51% (37-65%). Although the data continues to mature, median OS is 12.2 months (90% CI 8.8-NA). In the subset of patients achieving a CR+CRi, the 12-month relapse-free survival was 52% (90% CI 34-67%). Conclusions: Alisertib, a novel aurora A kinase inhibitor, combined with conventional induction, is efficacious and demonstrates a promising rate of remission and survival among patients with previously untreated high-risk AML. Larger randomized studies are under consideration to better assess the promise of this novel combination. Figure. Figure. Disclosures Brunner: Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. DeAngelo:Glycomimetics: Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Shire: Honoraria; BMS: Consultancy; Amgen: Consultancy; Pfizer Inc: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; ARIAD: Consultancy, Research Funding; Amgen: Consultancy; Takeda: Honoraria; Blueprint Medicines: Honoraria, Research Funding. Amrein:Takeda: Research Funding. Steensma:Acceleron: Consultancy; Amphivena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; H3 Biosciences: Research Funding; Janssen: Consultancy, Research Funding; Kura: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Otsuka: Membership on an entity's Board of Directors or advisory committees; Syros: Research Funding; Takeda: Consultancy. Garcia:Celgene: Consultancy. Rosenblatt:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees. Chen:Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Fathi:Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding; Jazz: Honoraria.

Abstract: Cabozantinib is well tolerated by patients with acute myeloid leukemia with a maximum tolerated dose of 40 mg daily, and it may have a unique advantage over other FMS‐like tyrosine kinase 3 inhibitors in targeting the F691 tyrosine kinase domain mutation, which is increasingly being seen as a secondary resistance alteration after initial FMS‐like tyrosine kinase 3 inhibitor therapy.

Abstract: Background: Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) consisting of an antibody specific for human CD30, an anti-microtubule agent monomethyl auristatin E (MMAE), and a protease-cleavable linker attaching MMAE to the antibody. BV is efficacious therapy against certain CD30-expressing malignancies, including classical Hodgkin lymphoma and anaplastic large cell lymphoma, and is currently approved for use in these diseases. We and others previously demonstrated CD30 expression on a sizeable proportion of primary AML samples as well as cell lines. Given this data, we conducted a phase I dose-escalation trial of BV in combination with re-induction chemotherapy (MEC) for patients with relapsed or refractory AML. Methods: In this phase I, 3+3 cohort dose-escalation study, BV was administered 3 days prior to initiation of MEC re-induction for relapsed or refractory AML. Eligibility for enrollment included adults over age 18, adequate organ function, an ECOG performance status of ≤ 2, and a diagnosis of relapsed or refractory AML with 〉 20% CD30 expression (as assessed by immunohistochemistry or flow cytometric analysis). On day 1 of the trial, all enrolled participants were initiated on therapy with BV intravenously using three sequential dosing levels (0.9 mg/kg, 1.2 mg/kg, 1.8mg/kg). On day 3, patients were initiated on MEC re-induction chemotherapy (Mitoxantrone 10mg/m2 IV administration for five days [D3-8], etoposide 100mg/m2 IV D3-8, cytarabine 1000mg/m2 IV D3-8). The period of dose limiting toxicity (DLT) assessment occurred during the period of re-induction (approximately D1-35). Once dose escalation for BV reached a dose of 1.8 mg/kg IV, no further escalation would occur. An additional cohort of ten patients were to be treated at this maximum dose, or if a maximum tolerated dose (MTD) was reached, an additional 10 patients were to be treated at this dose. Thereafter, maintenance therapy with BV could be initiated, and administered IV every 21 days, as per dose level during prior re-induction, and continued for up to 12 months. Those eligible for stem cell transplant (SCT) were removed from study for this purpose. Results: 22 eligible patients were enrolled on study. The median age was 58 (range 23-72); 15 (68%) were male, and 20 (91%) were Caucasian. 7 patients (32%) had secondary AML (6 with antecedent MDS and 1 with therapy related AML). 6 (27%) exhibited adverse risk karyotype. FLT3 mutations were seen in 7 (32%), NPM1 in 4 (18%), and CEBPA in 2 (9%). The median degree of blast CD30 expression in those assessed by flow cytometry was 92% (range 30-98%). 6 patients had refractory disease, while the remaining had relapsed AML at time of enrollment. 10 patients (46%) had undergone prior allogeneic stem cell transplantation (SCT), one of whom had undergone two prior stem cell transplants. Three patients were treated at dose level 1, 5 at dose level 2, and 4 at dose level 3. Two of the patients treated at dose level 2 were removed prior to end of DLT period due to lack of response and were replaced, and 1 patient treated at dose level 3 died due to infectious complications prior to end of DLT monitoring period and was replaced. No new attributable toxicities apart from that expected from MEC re-induction alone were seen with the combination therapy. No DLTs were detected, and the recommended phase 2 dose (RP2D) was deemed to be dose level 3 (1.8 mg/kg). An additional 10 patients were treated at the RP2D. Overall, 4 patients achieved a complete remission (CR) and 4 achieved a complete remission with incomplete hematologic recovery (CRi), for a composite remission rate (CCR) of 36% (8/22). Among the 14 patients treated at the RP2D of 1.8mg/kg, 6 achieved a CR or CRi (CCR 43%). Of the remaining cases, one was replaced prior to response assessment and the others experienced progressive disease. The degree of baseline CD30 expression by flow cytometry did not appear to predict for response in this phase 1 dose escalation study, although study of correlative samples is ongoing. Conclusions: BV is well tolerated when administered in conjunction with conventional re-induction chemotherapy in patients with relapsed-refractory AML, in whom CD30 is an intriguing target. Adverse events on this study were predominantly expected and related to marrow suppression from MEC re-induction. No DLT was identified. Additional and larger studies are needed to more comprehensively assess the efficacy of CD30-targeted therapy in AML. Disclosures Fathi: Jazz: Honoraria; Boston Biomedical: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Emadi:NewLink Genetics: Research Funding. Brunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Amrein:Takeda: Research Funding.