ALBERT

Description: Introduction: Nivolumab, a fully human IgG4 monoclonal antibody targeting programmed death receptor-1, has recently been FDA approved for classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous stem cell transplantation (ASCT) and post-transplantation brentuximab vedotin (BV). CheckMate 205 (NCT02181738) is a phase 2, international, multicohort study evaluating nivolumab monotherapy in patients with cHL after failure of ASCT. At minimum 6 months' follow-up of Cohort B (205B) which included patients who had received BV after disease recurrence following ASCT, objective response rate (ORR) per independent radiologic review committee (IRRC) was 66% and 6-month progression-free survival (PFS) was 77%, with an acceptable safety profile (Younes et al. Lancet Oncol 2016; Jul 20 [Epub ahead of print]). Here we report outcomes with longer follow-up (minimum 12-month follow-up) in 205B. Primary results from Cohort A, which enrolled patients who relapsed after ASCT but were BV-naïve, will also be presented for the first time as data were not available at time of abstract submission. Methods: CheckMate 205 was designed to evaluate the efficacy and safety of nivolumab monotherapy in patients with cHL who relapsed after ASCT in 3 cohorts: 205A (BV-naive patients; n = 63); 205B (BV after failed ASCT; n = 80); 205C (BV at any time prior to study drug; n = 100). Nivolumab was given at 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity in 205A and 205B. The primary endpoint was IRRC-assessed ORR. Results: 80 patients were treated in Cohort 205B; the median age was 37 years (range 18-72). Patients had received a median of 4 prior regimens (range 3-15). At data cut-off (April 2016) with median duration of follow-up of 15.4 months (range 1.9-18.5), 43 patients (54%) still remained on therapy. IRRC-assessed ORR for patients in 205B was 68% (95% confidence interval [CI], 56%, 78%). CR and partial response (PR) rates per IRRC were 8% (3%, 16%) and 60% (48%, 71%), respectively. With longer follow-up, the median duration of response was prolonged to 13.1 months (95% CI, 8.7, not reached; range, 0.0+, 14.2+). The median duration of CR (DOCR) was not reached (95% CI, 4.6, not available [NA]; range, 0.7+, 10.4+) and the median duration of PR was 13.1 months (95% CI, 7.79, NA; range, 0.0+, 13.4+) (Table 1). IRRC median PFS was 14.8 months (95% CI, 11.3 months, NA); 12-month PFS was 54.6% (95% CI, 40.9%, 66.4%), and 12-month overall survival (OS) was 94.9% (median OS not reached). Of 37 patients (46%) who discontinued nivolumab, the most common reasons were disease progression (n = 19 [24%]), allogeneic stem cell transplant (n = 7 [9%]) and adverse events (n = 5 [6%]). Seventy-four patients (93%) had drug-related adverse events (AEs) of any grade. The most common drug-related AEs were fatigue (28%), infusion reaction (20%), arthralgia (15%), and rash (15%). 29% of patients had Grade 3-4 drug-related AEs; the most common were increased lipase (8%), neutropenia (5%), and increased aspartate aminotransferase (4%). The most common serious AEs were pyrexia, pneumonia, tumor progression, arrhythmia, infusion reaction, and meningitis (≤4% each). Conclusions: In this report with extended 12-month follow-up, longer remissions are noted following nivolumab monotherapy in relapsed cHL, including durable PRs in heavily pretreated patients. Nivolumab has an acceptable safety profile, similar to previously reported. Primary results following nivolumab monotherapy in BV-naïve patients with cHL who progressed after ASCT (Cohort 205A) will also be presented at the meeting. Study funding: Study funded by Bristol-Myers Squibb. Professional writing assistance was provided by K. Jesien of Caudex and funded by Bristol-Myers Squibb. Disclosures Timmerman: Seattle Genetics, Genmab, Celgene: Consultancy, Honoraria; Bristol-Myers Squibb, Kite Pharma, Valor Biopharmaceuticals, Janssen: Research Funding. Engert:Takeda, BMS: Consultancy, Honoraria, Research Funding. Armand:Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Research Funding; Roche: Research Funding; Infinity Pharmaceuticals: Consultancy; Merck: Consultancy, Research Funding; Sequenta Inc: Research Funding. Collins:Takeda: Consultancy, Honoraria, Speakers Bureau. Kuruvilla:Roche Canada: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Merck: Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria. Cohen:Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Trneny:Roche, Celgene, Takeda, Janssen, Gilead, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Celgene: Research Funding. De Boer:NKI-AVL: Employment. Shipp:Cell Signaling: Honoraria; Merck, Gilead, Takeda: Other: Scientific Advisory Board; Bayer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Rodig:Bristol-Myers Squibb: Honoraria, Research Funding; Perkin Elmer: Membership on an entity's Board of Directors or advisory committees. Kato:Bristol-Myers Squibb: Employment. Sumbul:Bristol-Myers Squibb: Employment. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

Description: Background Brentuximab vedotin (BV) is an antibody-drug conjugate directed against CD30, a receptor that engages the CD30 ligand expressed on immune cells in the tumor microenvironment, promoting tumor cell growth (Montanari 2014, Hansen 2014). Through disruption of the microtubule network, BV induces apoptotic cell death, and may initiate an antitumor immune response (i.e., immunogenic cell death) through the induction of endoplasmic reticulum (ER) stress (Gardai 2015). Nivolumab is a fully human monoclonal PD-1 blocking antibody that prevents tumor immune evasion. Both agents have independent high single-agent response rates in patients (pts) with relapsed or refractory (R/R) Hodgkin lymphoma (HL), and when used in combination, may exhibit mechanistic synergy. Given the demonstrated efficacy of both BV and nivolumab, together these agents could yield improved CR rates prior to ASCT in pts with R/R HL, and potentially better long-term outcomes. Methods A phase 1/2 study is ongoing to evaluate the safety and antitumor activity of BV administered in combination with nivolumab as first salvage therapy in pts with R/R classical HL after standard frontline chemotherapy (NCT02572167). Adult pts are treated in 21-day cycles for up to 4 cycles (12 weeks). Pts receive 1.8 mg/kg BV on Cycle 1 Day 1, and 3 mg/kg nivolumab on Cycle 1 Day 8. For cycles 2 through 4, BV and nivolumab are administered on Day 1 of each cycle at the same doses. After completion of the Cycle 4 response assessment, pts are eligible to undergo ASCT. Investigator assessment of lymphoma response and progression is per the Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014). Results Twenty-five pts (60% female) with a median age of 32 years (range, 18-69) have been enrolled to date. Sixty percent of pts have relapsed disease, 36% have primary refractory disease (failure to achieve CR with frontline therapy, or relapse within 3 months of completing frontline therapy), and 1 pt (4%) has unknown status. At the time of enrollment, 32% of pts presented with extranodal disease and 16% with bulky disease. At the time of the data extract, 23 pts had received treatment. An increased incidence of infusion-related reactions (IRRs) was observed at the start of combination treatment in Cycle 2 during the BV infusion leading to 1 dose delay. Premedication with corticosteroids (hydrocortisone 100 mg or equivalent) and antihistamines at Cycles 2-4 was instituted through a protocol amendment. Six pts have completed combination treatment, and all have achieved an objective response (ORR, 100%), with 3 of 6 achieving a complete metabolic response (CmR, 50%). All 6 pts have proceeded directly to ASCT. Median number of CD34+ cells collected was 12.9 x106 cells/kg (range, 5-26) in a mean number of 1.7 apheresis sessions (range, 1-2). Adverse events (AEs) for all pts are summarized prior to ASCT. Eighteen of the 23 treated pts (78%) experienced adverse events (AEs). Fifteen pts (65%) had AEs ≤ Grade 2 in severity and 3 pts (13%) experienced Grade 3 AEs. No pts experienced Grade 4 AEs pre-ASCT. Fatigue was the most common AE occurring in 35% of pts, followed by nausea (26%), rash (22%), dyspnea, myalgia, and pruritus (17% each). One pt experienced a treatment-related serious adverse event (SAE) of dehydration, hypercalcemia, and acute kidney injury. Immune-related adverse events (IrAEs) were experienced by 3 pts; 2 pts who experienced Grade 1 rash treated with topical steroids, and 1 pt who experienced Grade 1 hypothyroidism. No pts have discontinued treatment prematurely. In addition to Reed-Sternberg cells, CD30 is expressed on activated T cells. Preliminary biomarker data indicate a BV-induced decrease in the percentage of CD4+ T regulatory (Treg) cells at C1D8, with no decrease in proliferating CD8+ T cells, and no significant decrease observed in the percentage of CD4+ Th1 cells compared to baseline for 5 of 6 pts (83%). Nivolumab induced a robust expansion of T cells at C1D15. Conclusions Early data suggest the combination of BV and nivolumab is an active and well-tolerated salvage therapy in pts with R/R HL. While an elevated incidence of IRRs has been observed, toxicities with this regimen appear to be tolerable overall. The preliminary antitumor activity suggests this combination may be a promising option for R/R HL pts. Updated results will be shared at the time of presentation. Disclosures Herrera: Pharmacyclics: Research Funding; Merck: Research Funding; Immune Design: Research Funding; Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; Seattle Genetics: Research Funding. Bartlett:Gilead: Consultancy. Moskowitz:BMS: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Feldman:Abbvie/Pharmacyclics/Janssen: Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. LaCasce:Seattle Genetics: Research Funding; Forty Seven Inc.: Consultancy. Ansell:Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; Affimed: Research Funding. Fenton:Seattle Genetics: Employment, Equity Ownership. Kato:Bristol-Myers Squibb: Employment. Fong:Seattle Genetics: Employment, Equity Ownership.

Description: Background Bu-based conditioning regimens are commonly used prior to autologous hematopoietic stem cell transplantation (ASCT) for lymphoma, but clinical results of an intravenous (IV) Bu-based regimen have been limited to single center studies. This multi-center, single-arm, Phase 2 study prospectively evaluated the safety and efficacy of the IV BuCyE regimen in lymphoma patients undergoing ASCT. Methods The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), transplant-related mortality (TRM) and overall response rate. TRM was defined as a death after transplant due to any cause other than disease progression. Subjects underwent first ASCT for Hodgkin lymphoma (HL) and B-cell non-Hodgkin lymphoma (NHL) that relapsed after initial therapy, was initially refractory to an anthracycline-based chemotherapy, or for high-risk NHL histology in first complete remission (CR) [International Prognostic Index (IPI) score of 4-5, or mantle cell lymphoma (MCL)]. Eligible subjects achieved CR or partial remission (PR) following salvage chemotherapy. The study initially enrolled subjects of 18-80 years, but the protocol was amended to reduce the upper age limit to 65 years due to a high TRM rate at post-transplant 100 days for the subjects 〉65 years. Therefore, we report safety for all the subjects undergoing ASCT (n=203) and efficacy from those 65 years old or younger (n=186). IV Bu doses were individually adjusted based on pre-conditioning test PK results; the area under the concentration-time curve of Bu was targeted to 20,000 mM*min. Bu was given as a 3-hour infusion once daily from Days -8 through Day -5. E (1.4 g/m2) was administered on Day -4, followed by 2.5 g/m2/day of Cy on Days -3 and -2. Results A total of 207 subjects with HL (n=66) or NHL (n=141) were enrolled from 32 centers in the US and Canada between February 2010 and April 2012. Four subjects did not proceed with ASCT due to insurance or eligibility issues; the remaining 203 underwent ASCT. The final TRM rates at Day 100 for all subjects (n=203), for those older than 65 year old (n=17), and for those 65 years old or younger (n=186) were 4.5% (95% confidence intervals (CI) 2.1-8.3%), 23.5% (95% CI; 6.8-49.9%) and 2.7% (95% CI: 0.9-6.2%), respectively. The most common grade (Gr) 3 or 4 adverse events (CTCAE v3.0) observed from Day -8 through Day 100 were febrile neutropenia (Gr 3: 58.1%; Gr 4: 3.0%), stomatitis (Gr 3: 40.9%; no Gr 4), nausea (Gr 3: 8.9%; no Gr 4), and hypophosphatemia (Gr 3:6.9%; Gr 4: 1.0%). There was no instance of seizure or hepatic veno-occlusive disease (VOD) meeting the Baltimore criteria. Efficacy was analyzed for 186 subjects ≤65 years old with HL (n=65) or NHL (n=121), which included diffuse large B-cell lymphoma (DLBCL; n=63), MCL (n=29) and follicular lymphoma (FL; n=23). The median age was 49 year old (range: 19-65); 36 % were female, 87% were white, 76% had a Karnofsky Score ≥90. Majority of the patients had CR2 or higher, or PR at transplant except that 19 MCL patients and three DLBCL patients with IPI score 4 had CR1. In addition, five patients (3 for NHL; 2 for HL) who had refractory disease to initial chemotherapy and required salvage therapy to achieve CR1 also enrolled this study. With median 20 months follow-up, the estimated 2-year PFS was 33% for HL and 58%, 77%, and 43% for DLBCL, MCL, and FL respectively [Fig. 1]. The estimated 2-year OS was 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL respectively [Fig. 2 ]. Conclusions IV BuCyE regimen provided good early disease control with acceptable safety profiles in B-cell NHL lymphoma patients 65 year old or younger, but there were early declines in PFS in HL patients. Additional comparisons of PFS and OS from the BuCyE regimen with a pre-specified, matched-control group of approximately 800 matched cases (1:4 ratio) obtained from the Center for International Blood and Marrow Transplant Research registry data who received carmustine, E, cytarabine, and melphalan (BEAM) conditioning regimen are underway, and updated results will be presented. Disclosures: Off Label Use: Busulfan, Cyclophosphamide and VP-16 for Autologous Hematopoietic Stem Cell Transplantation. Costa:Otsuka: Research Funding. Freytes:Otsuka America Pharmaceutical: Research Funding, Travel funds for scientific presentation Other. Armstrong:Otsuka: Employment. Smith:Otsuka Pharmacetical Development & Commercialization: Employment. Elekes:Otsuka Pharmaceutical: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc: Employment.

Description: Abstract 3080 Background: Salvage therapeutic options are limited for multiple myeloma (MM) patients who relapse after autologous hematopoietic stem cell transplantation (ASCT). A second ASCT using a different conditioning regimen may provide long-term disease control. We report efficacy and safety of daily intravenous busulfan (IV Bu) conditioning given with bortezomib for second ASCT. Materials and Methods: In this prospective, multicenter, Phase IIa study, thirty MM patients who relapsed ≥ 1 year after initial ASCT and were candidates for second ASCT were enrolled at eleven centers in the US and Canada. Patients received a test dose of IV Bu (0.8 mg/kg) over 2 hours between Days -12 and -9 prior to ASCT. Pharmacokinetic (PK) analysis from test dose determined Bu exposure as area under the concentration-time curve (AUC). This analysis was used to determine individualized Bu PK-directed dosing for the conditioning regimen in order to achieve a total regimen AUC of 20,000 mM*min. IV Bu was administered over 3 hours once daily from Day -5 to Day -2. Confirmatory PK analysis was conducted in all patients on Day -5. Bu doses were adjusted on Days -3 and -2, if needed. Bortezomib (1.3 mg/m2 QD) was administered as an IV bolus injection on Day -1. Disease response was evaluated prior to the ASCT and at 3 and 6 months post-transplant, based on the International Myeloma Working Group uniform response criteria in 2006. Results: Patient Demographics: Median age at second ASCT was 59 years (range: 48–73). All patients had previously been treated with bortezomib (86.7%), thalidomide (46.7%), and/or lenalidomide (66.7%). All subjects underwent first ASCT with high-dose melphalan. Median time from first ASCT to second ASCT was 28.0 months (range: 12–119). The disease status at second ASCT was seven very good partial response (VGPR; 23.3%), twelve partial response (PR; 40.0%), two stable disease (SD; 6.7%); and nine progressive disease (PD; 30.0%). Safety: The most common grade 3 or 4 adverse event (CTCAE v3.0) was febrile neutropenia in 15 patients (50.0%), followed by stomatitis in 13 patients (43.3%), nausea in four (13.3%) and hypokalemia in three (10.0%). One transplant-related death due to pulmonary complications was reported for a patient with Parkinsonism on post-transplant Day 20. There was no instance of seizure, worsening neuropathy, or hepatic veno-occlusive disease (VOD) meeting the Baltimore criteria. Efficacy: 28 patients had evaluable disease response at least at one time point after second ASCT. Disease response at 3 months were two complete responses (CR; 6.7%), five VGPR (16.7%), four PR (13.3%), eight SD (26.7%), nine PD (30.0%), and two cases without evaluable assessment (6.7%). Two patients who achieved CR at 3 months had PD and VGPR prior to ASCT, respectively. Disease response at 6 months were one stringent CR (sCR; 3.3%), one CR (3.3%), four VGPR (13.3%), seven SD (23.3%), fourteen PD (46.7%), and three cases without evaluable assessment (10.0%). Median progression-free survival was 191 days, while median overall survival has not been reached yet. PK: 40.0% (n=12/30) of patients had AUC outside the expected range from pre-transplant test dose, 0.8 mg/kg of IV Bu: eleven cases with AUC 1,500 μM*min. If only weight was used (e.g. 3.2 mg/kg daily) to determine the dose without considering difference in individual busulfan metabolism, this 40% would have been dosed outside the total target AUC range. Based on test PK, IV Bu dosing for conditioning was individualized ranging between 1.99 and 4.73 mg/kg, which resulted in 93.3% of patients (n=28/30) falling between 16,000 and 24,000 μM*min as a total target AUC without any further dose alteration during conditioning. Only 2 patients (6.7%) needed dose reduction on Days -3 and -2. Mean Bu clearance for test dose and on Day -5 were comparable, 3.00 and 2.92 ml/min/kg, respectively. Conclusions: Disclosures: Stadtmauer: Millenium: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Off Label Use: IV busulfan and bortezomib-based conditioning regimen prior to transplant for myeloma. Freytes:Otsuka Pharmaceuticals: Research Funding. Shaughnessy:Otsuka: Honoraria, Speakers Bureau. White:Otsuka: Honoraria, Research Funding. Rodriguez:Otsuka: Consultancy, Research Funding, Speakers Bureau; Millennium: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; SOBI: Consultancy, Speakers Bureau. Sun:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Armstrong:Otsuka: Employment. Smith:Otsuka Pharmaceutical Development & Commercialization, Inc: Consultancy. Elekes:Otsuka Pharmaceutical Development & Commercialisation., Inc.: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Reece:Otsuka: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Millinneum Pharmaceuticals: Research Funding; Merck: Consultancy, Honoraria, Research Funding.

Description: Abstract 813 Background: Published reports indicate that oral or intravenous (IV) busulfan in combination with cyclophosphamide and VP-16 (BuCyVP-16) is an effective conditioning regimen with acceptable safety profile for lymphoma patients prior to autologous hematopoietic stem cell transplantation (ASCT). Since the therapeutic window of Bu is narrow, it is important to standardize the systemic exposure during conditioning. Although the IV formulation of Bu eliminates the problem of variable drug absorption, unpredictable systemic exposure can still occur due to interpatient differences in Bu clearance. Therefore, tighter control of systemic Bu exposure using pharmacokinetics (PK) may lead to improved efficacy and further decrease in toxicity. The aim of this multi-center, single-arm, Phase II study was to prospectively evaluate the safety and efficacy of IV BuCyVP-16 regimen in lymphoma patients undergoing ASCT, after optimizing Bu exposure using PK-directed dosing. Methods: Patients with chemosensitive, relapsed or primary-refractory Hodgkin and B-cell non-Hodgkin lymphoma undergoing the first ASCT received a test dose of IV Bu (0.8 mg/kg) given as a 2-hour infusion 11 to 14 days before transplant. Bu exposure was determined as area under the concentration-time curve (AUC) using six serial blood samples after the test dose administration. Doses for the conditioning regimen were then calculated to result in total AUC (conditioning + test) of 20,000 mM*min. One-fourth of the resulting calculated Bu dose was given as a 3-hour infusion on Day -8, followed by a second, confirmatory PK analysis. The same daily Bu dose was administered on the next 3 days, unless the confirmatory PK analysis showed that this would result in total AUC outside the target range (〉24,000 mM*min or 1,500 μM*min) in five patients (2.6 %) and lower AUC (

Description: Background: The tumor suppressor p53, encoded by the TP53 gene, is negatively regulated by murine double minute 2 (MDM2), an E3 ubiquitin ligase. Deregulation of MDM2 results in the degradation of p53, leading to cessation of the protein's multiple tumor-suppressive functions, including the induction of apoptosis and reactivation of aberrantly silenced genes. Although TP53 is not frequently mutated in AML, p53 pathway dysfunction is prevalent, with MDM2 overexpression being frequently observed. Disrupting MDM2's negative regulatory effect to reactivate functional p53 is a promising strategy for the treatment of AML. Milademetan (DS-3032b) is a small-molecule MDM2 inhibitor that disrupts the p53-MDM2 interaction and has demonstrated single-agent activity in preclinical and clinical studies of AML. Survival rates are poor for patients with relapsed/refractory (R/R) AML or high-risk MDS which underpins the rationale for combination treatments to build on the efficacy of available agents. AZA, a hypomethylating agent, is part of the standard of care for AML and MDS. Reactivation of p53-inducible genes with milademetan combined with hypomethylation and direct cytotoxicity with AZA has shown activity in preclinical models of AML. Study Design and Methods: This open-label, 2-part, multicenter, phase 1 dose-escalation and -expansion study (NCT02319369) evaluates milademetan in combination with AZA in patients with R/R AML or high-risk MDS. Key inclusion criteria comprise a diagnosis of R/R AML or high-risk MDS; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2; and adequate renal, hepatic, and clotting functions. Additional inclusion criteria for newly diagnosed patients is ineligibility for intensive induction chemotherapy due to advanced age (≥ 75 years), congestive heart failure, or ECOG PS of 3 that is not related to leukemia. Key exclusion criteria include acute promyelocytic leukemia, central nervous system leukemia, unresolved toxicity from previous anticancer therapy, mean QTcF interval 〉450 ms for males or 〉470 ms for females, or prior treatment with an MDM2 inhibitor. During part 1 (dose escalation), patients with R/R AML or high-risk MDS receive single-agent milademetan (part 1; completed) or milademetan in combination with AZA at different dose schedules (part 1A; ongoing). Milademetan is administered as a single agent on days 1-21 of each 28-day cycle (21/28 schedule) at a starting dose of 60 mg and escalating to 90, 120, 160, and 210 mg. Less frequent dosing schedules will also be evaluated, starting with the maximum tolerated dose (MTD) determined from the 21/28 schedule. In part 1A, AZA will be administered at 75 mg/m2 subcutaneously or intravenously on days 1-7 of each 28-day cycle, with milademetan treatment on days 5-14 or 8-14. The primary objectives of part 1 are to assess safety and tolerability, determine the MTD of single-agent milademetan and in combination with AZA, and identify the recommended dose for expansion (RDE) for milademetan plus AZA. During part 2 (dose expansion), 3 cohorts of patients with either (1) R/R AML, (2) newly diagnosed AML, or (3) high-risk MDS will receive milademetan in combination with AZA at the RDE. The primary objectives of part 2 are to confirm safety and tolerability, evaluate response to combination treatment, and identify a recommended phase 2 dose. Pharmacokinetics and pharmacodynamics of milademetan as a single agent and in combination with AZA will be evaluated in both parts. Approximately 80 patients are planned to be enrolled in part 1, and up to 40 patients are planned to be enrolled for each cohort in part 2. This study is currently recruiting in the United States. Disclosures DiNardo: agios: Consultancy, Honoraria; medimmune: Honoraria; celgene: Consultancy, Honoraria; syros: Honoraria; jazz: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria. Olin:Spectrum: Research Funding; Revolution Medicine: Consultancy; Mirati Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Research Funding; Ignyta: Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding; Astrazeneca: Research Funding; Daiichi Sankyo: Research Funding; Clovis: Research Funding. Ishizawa:Daiichi Sankyo: Patents & Royalties: Joint submission with Daiichi Sankyo for a PTC patent titled "Predictive Gene Signature in Acute Myeloid Leukemia for Therapy with the MDM2 Inhibitor DS-3032b," United States, 62/245667, 10/23/2015, Filed. Sumi:Daiichi Sankyo, Inc.: Employment. Xie:Daiichi Sankyo, Inc.: Employment. Kato:Daiichi Sankyo, Inc.: Employment; Celgene: Employment, Equity Ownership. Kumar:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Andreeff:NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; BiolineRx: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy.

Description: Platelet interaction with exposed adhesive ligands at sites of vascular injury is required to initiate a normal hemostatic response and may become a pathogenic factor in arterial diseases leading to thrombosis. We report a targeted disruption in a key receptor for collagen-induced platelet activation, glycoprotein (GP) VI. The breeding of mice with heterozygous GP VI alleles produced the expected frequency of wild-type, heterozygous, and homozygous genotypes, indicating that these animals had no reproductive problems and normal viability. GP VInull platelets failed to aggregate in response to type I fibrillar collagen or convulxin, a snake venom protein and known platelet agonist of GP VI. Nevertheless, tail bleeding time measurements revealed no severe bleeding tendency as a consequence of GP VI deficiency. Ex vivo platelet thrombus formation on type I collagen fibrils was abolished using blood from either GP VInull or FcR-γnull animals. Reflection interference contrast microscopy revealed that the lack of thrombus formation by GP VInull platelets could be linked to a defective platelet activation following normal initial tethering to the surface, visualized as lack of spreading and less stable adhesion. These results illustrate the role of GP VI in postadhesion events leading to the development of platelet thrombi on collagen fibrils.

Description: Key Points BV and Nivo were well-tolerated in patients with R/R HL, with less than 10% of patients treated with systemic steroids for immune-related AEs. The complete response rate was 61% (82% objective response rate), and patients were able to undergo stem cell transplant without adverse impact.

Description: Introduction: Allo-HSCT is a potentially curative option for patients (pts) with classical Hodgkin lymphoma (cHL) who relapse after autologous (auto)-HSCT. Nivolumab (nivo) is approved in the US for treatment of relapsed or progressive cHL after auto-HSCT and post-transplant brentuximab vedotin. Nivo was studied in pts with relapsed cHL in ph 1 (CheckMate 039, NCT01592370) and multicohort ph 2 (CheckMate 205, NCT02181738) studies. Response rate in 95 heavily pretreated cHL pts across those studies was 65%, with an estimated median duration of response of 8.7 mo. Decision to proceed to allo-HSCT after nivo was not restricted within the studies and was at the discretion of treating clinicians; some pts were referred and elected to undergo subsequent allo-HSCT. Allo-HSCT-related immune complications, including graft vs host disease (GVHD) after prior exposure to PD-1 blockade have been reported (Nivolumab US PI; 2016). Here we report safety outcomes in HL pts from these 2 studies who received nivo and subsequent allo-HSCT. Methods: Pts from the CheckMate 039 cHL monotherapy cohort (n=23) and all CheckMate 205 cohorts (n=243) who underwent allo-HSCT after study treatment are included in this post hoc analysis. Basic post-allo-HSCT outcomes (transplant date, GVHD, disease status) were prospectively collected in CheckMate 205. Further details from CheckMate 205 (stem cell source, preparative regimen, additional post-allo-HSCT safety data) and all post-allo-HSCT data from CheckMate 039 were collected retrospectively. Non-relapse mortality (NRM) was defined as death without disease relapse. Steroid-responsive febrile syndrome (SRFS) was defined as steroid-responsive, non-infectious fever that could be accompanied by skin, joint, or liver symptoms. Results: This analysis includes pts from CheckMate 039 (n=5) and 205 (n=12) who underwent allo-HSCT. Median age at time of allo-HSCT was 33 y (range 18-56). Pts had received a median of 9 nivo doses (range 4-16); 16 underwent allo-HSCT without disease progression or intervening therapy between nivo and allo-HSCT; the remaining pt had disease progression on nivo and received combination chemotherapy before allo-HSCT. Median interval between last nivo dose and allo-HSCT was 29 d (range 11-94). Stem cell source was peripheral blood (n=14) or bone marrow (n=3). Donors were HLA-matched sibling (n=3), single-antigen mismatched related (n=1), haploidentical (n=5), matched unrelated (n=7), and mismatched unrelated (n=1). Reduced-intensity conditioning (RIC) was used in 15 pts and myeloablative conditioning (MAC) in 2. Acute GVHD occurred in 14 pts (82%): grade (g)2-4 in 10 pts (59%) and g3-4 in 5 (29%). Among those 14 pts, organs involved were skin (3 g1, 4 g2, 4 g4, 1 g unknown), gut (1 g2, 1 g3, 4 g4), liver (4 g4), and lung (1 g unknown). Median time to onset of g3-4 acute GVHD was 22 d (range 13-139). Two pts had hyperacute GVHD (onset ≤14 d post-transplant). One pt with hepatic veno-occlusive disease died due to multiorgan GVHD. Five pts had SRFS (onset 0-53 d post-allo-HSCT). Two pts experienced g3 encephalitis: 1 lymphocytic encephalitis case without an identified infectious cause resolved on corticosteroids, and 1 suspected viral encephalitis case resolved on antiviral therapy. There were 6 deaths among 17 pts; all 6 were NRM-related: 5 due to GVHD in pts who had received RIC allo, and 1 due to pulmonary injury in a pt who had received MAC. Median time from allo-HSCT to death was 119 d (range 39-440). There were no deaths due to disease progression. Follow-up is ongoing and additional results will be presented. Conclusions: Results of this small cohort indicate that severe GVHD with rapid onset and unique complications such as SRFS, and NRM may occur in pts with prior exposure to PD-1 blockade. Although the data set is small and follow-up is limited, results support a hypothesis that prior anti-PD-1 exposure could potentially magnify the risk of immune-related complications after transplantation. While these data should not be interpreted as showing that allo-HSCT is contraindicated, they highlight a need for caution when considering allo-HSCT after PD-1 blockade. Studies of larger cohorts with longer follow-up and immunologic analyses should be pursued to confirm and understand these results. Funding: BMS. Writing support F. Beebe, Caudex. Disclosures Armand: Infinity Pharmaceuticals: Consultancy; Sequenta Inc: Research Funding; Roche: Research Funding; Merck: Consultancy, Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Zinzani:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Collins:Takeda: Consultancy, Honoraria, Speakers Bureau. Cohen:Bristol-Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Halwani:Abbvie: Consultancy, Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding; Pharmacyclics: Consultancy, Research Funding; Immune Design: Research Funding; Seattle Genetics: Research Funding; Kyowa Hakko Kirin: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Carlo-Stella:Boehringer Ingelheim: Consultancy; Rhizen Pharmaceuticals: Research Funding. Millenson:Janssen: Other: Spouse's employment/salary. Kato:Bristol-Myers Squibb: Employment. Popa McKiver:Bristol-Myers Squibb: Employment, Equity Ownership. Sumbul:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Santoro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; ArQule: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

Description: Convulxin (CVX), a C-type lectin derived from the venom of Crotalus durissus terrificus, is a potent activator of human platelets, binding predominantly to platelet glycoprotein (GP) VI, but also to GP Ibα. Native CVX is an octamer composed of four αβ-heterodimers. It has been speculated that multimer size contributes greatly to CVX function, but proof of this hypothesis has not yet been reported. Additionally, two different native sequences have been reported (GenBank protein accession numbers CAA76182 and AAQ11362), one bearing lysine (K), the other glutamic acid (E), at β chain residue 89, but the physiological relevance of this difference is unknown. In an earlier report, we have described the production of monomeric recombinant CVX (rCVX) heterodimers using the Drosophila S2 system. We now employ this recombinant protein and site-directed mutagenesis to evaluate the influence of multimer size and the substitution βK89E on CVX function. By flow cytometry, native CVX (αβ)4 and both recombinant forms of CVX (αβ89K and αβ89E) bind to CHO cells expressing human recombinant GPVI (hrGPVI) and to human platelets in whole blood. Surface plasmon resonance (BIAcore) was employed to assess the kinetics of the interaction between hrGPVI and native or recombinant CVX. The calculated equilibrium dissociation constants (KD) were: for rCVX αβ89K, 11.3 x 10−8 M; for rCVX αβ89E, 9 x 10−8 M; and for native CVX (αβ)4, 2.8 x 10−8 M. These results indicate that the affinities of the two rCVX forms for hrGPVI are essentially the same and that the relative affinity of native CVX is about three-fold higher. Next, aggregation of human PRP was used to assess the relative function of the CVX forms. The minimum concentration of native CVX that induces platelet aggregation (70 picomolar) is roughly 400-fold lower than that of either rCVX αβ89K or rCVX αβ89E (each, 29 nanomolar). Based on these findings, it is apparent that: 1) There is little, if any difference, in the affinity or activity of the two recombinant forms of CVX; 2) the octameric form of native CVX results in roughly a three-fold increase in affinity for GPVI; and 3) this increase in affinity of the octameric form of native CVX cannot account for the substantial increase in its ability to induce platelet aggregation relative to the recombinant forms. These results are consistent with the hypothesis that the ability of native CVX octamer to cluster mobile GPVI molecules within the platelet membrane may be the single most important factor that contributes to the efficiency with which CVX is able to induce signal transduction and platelet activation. Moreover, smaller forms of CVX, such as the rCVX heterodimers, may prove to be efficient inhibitors of platelet activation by native CVX and other GPVI agonists.