Supplemental Appendix (Table S1, Figure S1, Figure S2, Figure S3)

Abstract Objective Compare 30‐day mortality among patients receiving the specific reversal agent andexanet alfa versus replacement prothrombin complex concentrate (PCC) in the management of direct‐acting oral anticoagulant (DOAC)–related bleeds. Methods Two patient‐level datasets were used: ANNEXA‐4, a prospective, single‐arm trial of patients taking apixaban or rivaroxaban who received andexanet alfa and ORANGE, a prospective, observational study of anticoagulated patients in UK hospitals, some of whom received PCC. Patients were propensity score matched based on demographic and clinical characteristics. Subgroup analyses were performed by bleed type (intracranial hemorrhage [ICH], gastrointestinal [GI], other). Relative risk (RR) of all‐cause 30‐day mortality was calculated. Results 322 ANNEXA‐4 patients treated with andexanet alfa (mean age = 77.7 years; 64.9% ICH) were matched with 88 ORANGE patients treated with PCC (mean age = 74.9 years, 67.1% ICH). Adjusted 30‐day mortality for patients treated with andexanet alfa (14.6%) was lower than patients treated with PCC (34.1%; RR, 0.43; 95% CI, 0.29–0.63). In the ICH subgroup, patients treated with andexanet alfa had lower mortality (15.3%) than patients treated with PCC (48.9%; RR, 0.31; 95% CI, 0.20–0.48). Mortality risk was lowest for patients in the GI subgroup but did not differ significantly by treatment (12.2% for andexanet alfa vs 25.0% for PCC; RR, 0.49; 95% CI, 0.21–1.16). Conclusions In this propensity score–matched comparison across 2 independent datasets, adjusted 30‐day mortality rates were lower for patients treated with andexanet alfa than in matched patients receiving PCC. This indirect comparison was limited in that it could not account for several highly predictive variables including GCS score, hematoma volume, and expected survival. Further research is warranted to confirm the mortality differences between reversal/replacement agents for DOAC‐related bleeding.

Background Manual segmentations of intracranial hemorrhage on non-contrast CT images are the gold-standard in measuring hematoma growth but are prone to rater variability. Aims We demonstrate that a convex optimization-based interactive segmentation approach can accurately and reliably measure intracranial hemorrhage growth. Methods Baseline and 16-h follow-up head non-contrast CT images of 46 subjects presenting with intracranial hemorrhage were selected randomly from the ANNEXA-4 trial imaging database. Three users semi-automatically segmented intracranial hemorrhage to measure hematoma volume for each timepoint using our proposed method. Segmentation accuracy was quantitatively evaluated compared to manual segmentations by using Dice similarity coefficient, Pearson correlation, and Bland–Altman analysis. Intra- and inter-rater reliability of the Dice similarity coefficient and intracranial hemorrhage volumes and volume change were assessed by the intraclass correlation coefficient and minimum detectable change. Results Among the three users, the mean Dice similarity coefficient, Pearson correlation, and mean difference ranged from 76.79% to 79.76%, 0.970 to 0.980 ( p < 0.001), and −1.5 to −0.4 ml, respectively, for all intracranial hemorrhage segmentations. Inter-rater intraclass correlation coefficients between the three users for Dice similarity coefficient and intracranial hemorrhage volume were 0.846 and 0.962, respectively, and the corresponding minimum detectable change was 2.51 ml. Inter-rater intraclass correlation coefficient for intracranial hemorrhage volume change ranged from 0.915 to 0.958 for each user compared to manual measurements, resulting in an minimum detectable change range of 2.14 to 4.26 ml. Conclusions We spatially and volumetrically validate a novel interactive segmentation method for delineating intracranial hemorrhage on head non-contrast CT images. Good spatial overlap, excellent volume correlation, and good repeatability suggest its usefulness for measuring intracranial hemorrhage volume and volume change on non-contrast CT images.

Background and Purpose:Andexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH).Methods:ANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding ≤18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as ≤35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days.Results:A total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population).Conclusions:Andexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02329327.

As with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor-induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of andexanet alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P < .05) and ≈82% (P < .05), respectively, compared with placebo. The stoichiometric ratios of andexanet alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of andexanet alfa administration, compared with placebo, were observed when andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).

Life-threatening NOAC related major bleeding is associated with high mortality. Off-label PCC is currently recommended in some guidelines as well as the approved specific antidote, andexanet alfa (andexanet). There are no randomised controlled trials comparing these therapies and hence we undertook

Andexanet alfa (andexanet) is a modified human factor Xa (FXa) approved for anticoagulation reversal in patients with life‐threatening bleeding treated with rivaroxaban or apixaban. Four‐factor prothrombin complex concentrates (4F‐PCCs) are approved for reversal of vitamin K antagonist–induced anticoagulation but not FXa inhibitors. The mechanism and effectiveness of 4F‐PCCs for FXa inhibitor reversal are unclear.

Background Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors. Methods We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2‐hour infusion. The coprimary outcomes were the percent change in anti–factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti–factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin). Results Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti–factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti–factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage. Conclusions In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti–factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA‐4 ClinicalTrials.gov number, NCT02329327.)

American Journal of HematologyVolume 94, Issue 4 p. E90-E93 E-ONLY ARTICLEFree Access Efficacy and safety of the dual SYK/JAK inhibitor cerdulatinib in patients with relapsed or refractory B-cell malignancies: Results of a phase I study Paul A. Hamlin, Corresponding Author Paul A. Hamlin hamlinp@mskcc.org orcid.org/0000-0001-9500-1804 Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York Department of Medicine, Weill Cornell Medical College, New York, New York Correspondence Paul A. Hamlin, MD, Medical Director, David H. Koch Cancer Center, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, 1275 York Ave., Box 504, New York, NY 10065. Email: hamlinp@mskcc.orgSearch for more papers by this authorIan W. Flinn, Ian W. Flinn Center for Blood Cancer, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TennesseeSearch for more papers by this authorNina Wagner-Johnston, Nina Wagner-Johnston Division of Oncology, Washington University, St. Louis, MissouriSearch for more papers by this authorJan A. Burger, Jan A. Burger Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TexasSearch for more papers by this authorGreg P. Coffey, Greg P. Coffey Biology and Pharmacology, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorPamela B. Conley, Pamela B. Conley Biology and Pharmacology, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorGlenn Michelson, Glenn Michelson Clinical Development, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorJanet M. Leeds, Janet M. Leeds Drug Metabolism and Pharmacokinetics, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorKenneth Der, Kenneth Der Pharmacokinetics, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorYvonne Kim, Yvonne Kim Regulatory Affairs, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorAlice Sabalvaro-Torres, Alice Sabalvaro-Torres Clinical Operations, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorMatt Birrell, Matt Birrell Corporate Development, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorAnjali Pandey, Anjali Pandey Medicinal Chemistry and Chemical Development, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorJohn T. Curnutte, John T. Curnutte Research and Development, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorManish R. Patel, Manish R. Patel Drug Development Unit, Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FloridaSearch for more papers by this author Paul A. Hamlin, Corresponding Author Paul A. Hamlin hamlinp@mskcc.org orcid.org/0000-0001-9500-1804 Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York Department of Medicine, Weill Cornell Medical College, New York, New York Correspondence Paul A. Hamlin, MD, Medical Director, David H. Koch Cancer Center, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, 1275 York Ave., Box 504, New York, NY 10065. Email: hamlinp@mskcc.orgSearch for more papers by this authorIan W. Flinn, Ian W. Flinn Center for Blood Cancer, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TennesseeSearch for more papers by this authorNina Wagner-Johnston, Nina Wagner-Johnston Division of Oncology, Washington University, St. Louis, MissouriSearch for more papers by this authorJan A. Burger, Jan A. Burger Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TexasSearch for more papers by this authorGreg P. Coffey, Greg P. Coffey Biology and Pharmacology, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorPamela B. Conley, Pamela B. Conley Biology and Pharmacology, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorGlenn Michelson, Glenn Michelson Clinical Development, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorJanet M. Leeds, Janet M. Leeds Drug Metabolism and Pharmacokinetics, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorKenneth Der, Kenneth Der Pharmacokinetics, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorYvonne Kim, Yvonne Kim Regulatory Affairs, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorAlice Sabalvaro-Torres, Alice Sabalvaro-Torres Clinical Operations, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorMatt Birrell, Matt Birrell Corporate Development, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorAnjali Pandey, Anjali Pandey Medicinal Chemistry and Chemical Development, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorJohn T. Curnutte, John T. Curnutte Research and Development, Portola Pharmaceuticals, Inc., South San Francisco, CaliforniaSearch for more papers by this authorManish R. Patel, Manish R. Patel Drug Development Unit, Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FloridaSearch for more papers by this author First published: 27 December 2018 https://doi.org/10.1002/ajh.25387Citations: 14AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat To the Editor: Important clinical advances were made in recent years for the treatment of patients with relapsed/refractory B-cell malignancies with approvals of the B-cell antigen receptor (BCR)-targeted therapies ibrutinib and idelalisib,1 as well as venetoclax.2 Furthermore, inhibition of SYK (which is upstream of BTK and PI3K on the BCR signaling pathway) has demonstrated efficacy in early clinical trials.3 Although outcomes for patients have improved with the introduction of targeted therapies, there remains an unmet need for improved, durable, and complete responses. Hence, novel agents with differentiated mechanisms of action are currently under clinical development. As with other malignancies, tumor B cells interact with their microenvironment and are exposed to pro-inflammatory/oncogenic cytokines that signal in part via Janus kinase (JAK) family members.4 Dual suppression of BCR signaling, as well as supportive cytokine JAK/STAT signaling, may be an effective strategy to treat B-cell malignancies. Cerdulatinib was therefore developed as a first-in-class dual SYK/JAK kinase inhibitor. In preclinical studies, dual SYK/JAK inhibition demonstrated greater antitumor activity in B-cell lymphoma cell lines relative to inhibition of either target alone.5 Consistently, the extent to which cerdulatinib inhibited BCR and B cell IL-4 signaling following oral dosing significantly correlated with tumor response in patients with relapsed/refractory B-cell malignancies.6 Herein, we report the phase I dose-escalation study of cerdulatinib in patients with relapsed/refractory B-cell malignancies, detailing the pharmacokinetics, safety, and initial efficacy. Forty-three patients were dosed with cerdulatinib in the phase I, dose-escalation study between October 2014 and February 2016 at five participating study centers. Of the dosed patients, 8 had chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), 13 had follicular lymphoma (FL; including one transformed FL grade 3B), and 22 had aggressive B-cell non-Hodgkin lymphoma (NHL; diffuse large B-cell lymphoma [DLBCL], n = 16 and mantle cell lymphoma, n = 6). Of the 43 dosed patients, 36 received drug with sufficient duration for pharmacokinetic and efficacy assessments. Baseline patient demographics and characteristics are delineated in Supporting Information Table 1. Escalating QD and BID dose schedules were explored (Figure 1; Supporting Information Table 2). Cerdulatinib demonstrated rapid absorption with a median Tmax of 3 hours. Concentrations rose up to the Tmax of 3 hours and declined thereafter with a terminal T1/2 that averaged 13.4 hours across all patients on Day 1. With QD dosing, the Cmax increased with dose up to 40 mg but did not increase thereafter, up to the highest dose of 100 mg. The steady-state cerdulatinib pharmacokinetic parameters were dose-proportional from 15 to 30 mg, greater than dose-proportional from 30 to 40 mg, and less than dose-proportional at doses >40 mg. For QD doses from 40 to 100 mg, the average steady-state Ctrough was 0.69 μM, and steady-state Cmax was 1.48 μM. Figure 1Open in figure viewerPowerPoint A, Cerdulatinib steady-state concentration-time profiles. Concentration-time profiles for QD and BID dosing cohorts are shown at the end of the first cycle of therapy to reflect steady-state concentrations. Mean (± SD) cerdulatinib concentrations are shown in μM on the y-axis, time in hours on the x-axis. B, Maximum percent change in the sum of target tumor volumes. Left, best percentage change in the sum of target tumor volumes from baseline for patients with CLL/SLL, FL, DLBCL, and mantle cell lymphoma who had evaluable computed tomography/positron emission tomography scans. Right, top images, patient had relapsed within 1 year following a partial response to R-CHOP. On presentation, the patient was found to have transformed double-hit FL (DLBCL, 60%; FL grade 3B, 40%). The tumor was CD20+, CD10-, BCL2 (strong), cMYC (50%), and Ki67 (80%). Partial response (69%) was achieved following two cycles of cerdulatinib 65 mg QD; the patient relapsed after five cycles. Bottom images, patient was diagnosed with FL in 1998 and received prior therapy with chlorambucil (1998), fludarabine/rituximab (1999-2000), and bevacizumab/rituximab (2011-2012) before relapsing in September 2014. The patient began cerdulatinib 45 mg QD in October 2014, and the dose was subsequently reduced to 30 mg QD due to fatigue. The patient had a partial response (56%) after two cycles of cerdulatinib and had 76% nodal reduction after 1 year A physiologic-based pharmacokinetic model suggested pH-dependent drug solubility was likely responsible for the saturation in exposure with QD dosing. BID dosing was therefore explored as a means to increase exposure. This was initiated at 15 mg BID, then 20 mg BID, and finally 45 mg BID. The maximum administered dose was 45 mg BID, which achieved a steady-state Ctrough of 1.09 ± 0.50 μM and, interestingly, more limited maximum exposure (Cmax, 1.19 ± 0.71 μM) relative to QD dosing. For each dose level, percent inhibition of SYK and JAK signaling was estimated as previously described,6 and near complete inhibition of these pathways was achieved at steady-state Ctrough at tolerated exposures (Supporting Information Table S2). The overall median treatment duration was 7.9 weeks (range, 1-165; Supporting Information Table S3). Ten patients underwent dose reduction due to an AE, and 13 had their treatment temporarily interrupted due to an AE. The most common AEs associated with treatment interruption were fatigue (n = 5) and gastrointestinal events (n = 3). Although no clear relationship between dose and the incidence of common treatment-emergent AEs was evident, symptoms typically resolved by temporarily withholding cerdulatinib for up to 2 weeks and resuming therapy at the next lower dose. Twelve patients (most with a diagnosis of CLL or FL) remained on cerdulatinib for >24 weeks, and five patients (all with FL) remained on cerdulatinib for >60 weeks (Supporting Information Figure S1). Across cohorts, patients received the majority of their intended dose (relative dose intensity, mean 90% and median 99%). Overall, the most frequently observed grade 3+ AEs were anemia (16%), fatigue (14%), and diarrhea (9%; Supporting Information Table S4). There were no consistent observations of liver abnormalities or neutropenia. Three dose-limiting toxicities were observed during the study. One patient in the 100-mg QD cohort experienced persistent grade 3 nausea despite optimal management. In the 45-mg BID cohort, one patient experienced grade 3 fatigue and one experienced grade 3 elevated serum amylase and lipase, which was associated with abdominal pain, but a normal CT; events in the 45-mg BID cohort resolved with dose reduction. The 45-mg BID dose was deemed not tolerated and, in consultation with clinical investigators, pharmacokinetic data across all cohorts were used to develop a preliminary model, which showed the 35-mg BID dose resulted in predicted average exposures ~15% lower than that observed with 45 mg BID, with Cmin levels predicted to be 25% lower. The 35-mg BID starting dose, with subsequent permissible dose reductions deemed necessary by the investigator, was reviewed by regulatory authorities prior to the initiation of the phase IIa study. In addition to the dose-limiting toxicities described above, serious AEs considered possibly/probably related to treatment included two cases of Pneumocystis jiroveci pneumonia in patients with CLL (at 30 mg QD [grade 5] and 50 mg QD [grade 4]). Prophylaxis for Pneumocystis pneumonia was instituted following the second case, with no subsequent cases reported. Additionally, one grade 5 lung infection was observed, also in a CLL patient. Hypotension (45-mg QD cohort, n = 1 [grade 3]), pyrexia (65-mg QD cohort, n = 1 [grade 2]), febrile neutropenia (45-mg BID cohort, n = 1 [grade 4]), and pancytopenia (45-mg BID cohort, n = 1 [grade 3]) were also observed. The maximum percent change in tumor volume while on therapy is presented in Figure 1B (left). Two patients with FL who initiated the study at 45 mg BID achieved a complete response to cerdulatinib after dose reduction to 30 and 15 mg BID within the first 2 therapy cycles. Five patients achieved a partial response (CLL, n = 3; FL, n = 1; transformed FL grade 3B, n = 1), with response typically manifesting within the first two therapy cycles. The single evaluable patient with transformed FL grade 3B achieved a partial response and remained on study for 140 days. All three patients with CLL who achieved a response were on therapy for >200 days. Of the five CLL patients who did not respond to cerdulatinib, two withdrew from treatment due to Pneumocystis pneumonia, and two had rapidly progressed on prior ibrutinib therapy and came off study before tumor reassessment. Patients with aggressive NHL tended to be highly refractory, with 50% of patients having progressive disease as best response to their last therapy. These patients were also typically treated at suboptimal cerdulatinib exposures and often did not remain on study through the first scheduled on-treatment CT scan at the end of Cycle 2. The single DLBCL patient who achieved a > 50% reduction in target lesions presented with a new lesion and therefore came off study due to progressive disease. Overall, the greatest clinical response was observed in patients with FL and CLL/SLL. Figure 1B (right) shows representative PET (top; FL grade 3B) and CT (bottom) scans of FL patients prior to (baseline) and following two therapy cycles. In conclusion, this phase I study showed the dual SYK/JAK inhibitor cerdulatinib was generally well tolerated and demonstrated promising antitumor activity in heavily pretreated patients with relapsed/refractory B-cell malignancies. An ongoing phase IIa study is assessing the antitumor activity of cerdulatinib in patients with B-cell or T-cell NHL. ACKNOWLEDGMENTS This study was sponsored by Portola Pharmaceuticals, Inc. We thank the patients who participated in this study, as well as their families and the research staff at each site. Preparation of the manuscript was supported by Iwona Bucior, PhD, of Portola Pharmaceuticals, Inc. Data analysis was supported by Andreas Betz. Medical writing and editorial support were provided by Kimberly Brooks, PhD, CMPP, of SciFluent Communications, and were financially supported by Portola Pharmaceuticals, Inc. CONFLICT OF INTEREST GPC, PBC, GM, JML, KD, YK, AST, MB, AP, AB, and JTC are employees and stockholders of Portola Pharmaceuticals, Inc. PAH received research support and consultant fees from Portola Pharmaceuticals, Inc. The other authors declare no potential conflicts of interest. AUTHOR CONTRIBUTIONS Contributed to the design of the study: All authors equally. Collected data: PAH, IWF, NWJ, JAB, GPC, GM, JML, and MRP. Analyzed and interpreted the data: PAH, IWF, NWJ, JAB, GPC, PBC, GM, JML, KD, MB, AP, JTC, and MRP. Performed statistical analyses: PAH, GPC, GM, JML, KD, MB, and AP. Wrote the first draft: PAH, GPC, GM, and MB. Critically revised the manuscript: All authors equally. Approved the final manuscript: All authors equally. Supporting Information Filename Description AJH_25387-sup-0001-Table S1.docxWord 2007 document , 54.5 KB Table S1. Baseline Patient Characteristics Table S2. Summary of Pharmacokinetic and Pharmacodynamic Results Table S3. Patient Disposition Table S4. Summary of TEAEs Figure S1. Cerdulatinib duration of treatment. Duration of cerdulatinib treatment for patients with MCL, FL, DLBCL, and CLL/SLL are shown, as indicated. Weeks on cerdulatinib is indicated on the x-axis. *Indicates two FL patients who achieved complete remission of disease. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Wiestner A. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia. Haematologica. 2015; 100: 1495- 1507. 2Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016; 17: 768- 778. 3Sharman J, Hawkins M, Kolibaba K, et al. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2015; 125: 2336- 2343. 4Ten Hacken E, Burger JA. Microenvironment interactions and B-cell receptor signaling in chronic lymphocytic leukemia: implications for disease pathogenesis and treatment. Biochim Biophys Acta. 2016; 1863: 401- 413. 5Coffey G, Betz A, DeGuzman F, et al. The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther. 2014; 351: 538- 548. 6Coffey GP, Betz A, Feng J, et al. Cerdulatinib pharmacodynamics and relationships to tumor response following oral dosing in patients with relapsed/refractory B-cell malignancies. Clin Cancer Res. 2018; 130: 2782. Citing Literature Volume94, Issue4April 2019Pages E90-E93 FiguresReferencesRelatedInformation

Abstract Background/Introduction Andexanet alfa (“andexanet”) was developed as a specific reversal agent for patients with major bleeding while using factor Xa (FXa) inhibitors. While thrombotic events (TEs) have been reported in patients receiving andexanet, the scope, nature, and timing of these events have not been fully characterized. Purpose The ANNEXA-4 study was a prospective, single-arm, open-label clinical trial that evaluated the safety and efficacy of andexanet in patients with acute major bleeding. In this secondary analysis, the occurrence of TEs was investigated. Methods Patients presenting with acute major bleeding within 18 hours after their last dose of FXa inhibitor were treated with andexanet. Safety outcomes, including TEs (reviewed by an adjudication committee), were evaluated at 30 days. Results Among 352 patients treated with andexanet, 34 (9.7%) experienced one or more TEs (Table). Strokes and deep vein thromboses were the most frequent TE types. Compared to patients with arterial TEs, patients with venous TEs were more likely to have been originally anticoagulated for venous thromboembolism. Median time to first TE was 10.5 days (Figure); time to event was shorter for arterial TEs than for venous TEs. TEs were nonfatal for most patients. Subgroups by age, bleed type, baseline anti-fXa activity, FXa inhibitor dose, and andexanet dose were not associated with the occurrence of TEs. Of the 34 TE patients, 26 (76.4%) had TEs before restart of any (full or prophylactic) anticoagulation; all first TEs occurred in patients not receiving oral anticoagulation. No TEs occurred after resumption of oral anticoagulation (N=100). Table 1. Thrombotic event characteristics Characteristic Result (n/N [%]) TE type Strokes 14/352 (4.0%) Deep vein thromboses 13/352 (3.7%) Myocardial infarctions 7/352 (2.0%) Pulmonary embolisms 5/352 (1.4%) Transient ischemic attacks 1/352 (0.3%) Bleed type Intracranial 23/227 (10.1%) Gastrointestinal 7/90 (7.8%) Other 4/35 (11.4%) Arterial TEs Anticoagulated for AF 17/22 (77.3%) Anticoagulated for VTE 6/22 (27.3%) Venous TEs Anticoagulated for AF 11/18 (61.1%) Anticoagulated for VTE 8/18 (44.4%) Median time to first TE 10.5 days Arterial 6 days Venous 15 days Outcome Fatal 7/34 (20.6%) Nonfatal 27/34 (79.4%) AF = atrial fibrillation; n = number of patients with TEs; N = total number of patients for each characteristic; TE = thrombotic event; VTE = venous thromboembolism. Figure 1. Thrombotic Events Over Time Conclusions In patients with FXa inhibitor-associated acute major bleeding treated with andexanet, TEs occurred a rate not unexpected given the high thrombotic risk of the population. No factors predictive of TEs were identified. Resumption of anticoagulation was associated with fewer TEs. Acknowledgement/Funding Study funded by Portola Pharmaceuticals, Inc.

Learning Objectives: Andexanet alfa (coagulation factor Xa [recombinant], inactivated-zhzo) is a recombinant modified human Factor Xa (FXa) protein indicated in the US for reversal of anticoagulation in patients treated with rivaroxaban and apixaban due to major bleeding. Andexanet regimen was informed by a pharmacokinetic (PK)/pharmacodynamics (PD) model developed in phase 2 studies in healthy subjects. This analysis aimed to refine the model and validate andexanet regimen with data from bleeding patients. Methods: In ANNEXA-4, an ongoing open-label study, bleeding patients anticoagulated with a FXa inhibitor received IV andexanet bolus (400 or 800 mg) followed by 120-min infusion (4 or 8 mg/min). Anti-FXa activity was measured before andexanet administration (baseline), at end of bolus (EOB), end of infusion (EOI), and 4, 8, 12 h after infusion. For validation of andexanet regimen, percent reversal of anti-FXa activity in bleeding patients was compared with the predicted reversal determined by the PK/ PD model. The model was refined by assessing intrinsic factors (renal function, age, and body weight) on both FXa and andexanet exposure. Results: Plasma levels from 139 patients (apixaban, 76; rivaroxaban, 63) were analyzed. Mean percent reversal of anti-FXa activity at EOB and EOI for rivaroxaban and apixaban in bleeding patients were similar to the PK/PD model predicted. Observed vs predicted anti-FXa activity reversal at EOB for apixaban was 91.7% vs 94.8%, and for rivaroxaban it was 88.9% vs 87.6%; values at EOI were similarly close. After 4 h, the observed reversal fit closely for rivaroxaban, but not for apixaban (8 h, 30.6% vs 40.2%; 12 h, 32.8% vs 48.6%), possibly due to higher baseline anti-FXa activity levels in some apixaban patients. The revised model, including renal function, age, and body weight, showed similar over-prediction of reversal for apixaban at later time points. Conclusions: The PK/PD model in healthy subjects predicted the level of anticoagulation reversal by andexanet in bleeding patients assessed by anti-FXa activity and, thus, validated andexanet regimen required to reverse anticoagulation by FXa inhibitors. The refined PK/PD model confirmed over-prediction of anticoagulation reversal at later times in bleeding patients with higher levels of anticoagulation markers at baseline.

Learning Objectives: The use of Impella percutaneous ventricular assist devices is associated with both thrombotic and hemorrhagic complications. Despite these risks, the optimal therapeutic range for heparin for patients on Impella support remains unknown. Both interpatient variability in heparin requirements and the general practice of administering systemic heparin in addition to a heparin purge solution complicate efforts to design safe and effective anticoagulation protocols for these patients. This single-center study characterizes the heparin doses required to achieve target anti-Xa levels in patients on Impella support, and describes associated rates of bleeding and thrombosis. Methods: We performed a retrospective observational study of patients receiving Impella support from July 2016 to September 2017 in the cardiac care ICU or the cardio-thoracic surgical ICU at a single institution. Patients received heparin to target anti-Xa levels of 0.3–0.7 IU/mL, with patients at a higher risk of bleeding targeted to 0.3–0.5 IU/mL. Patients whose bleeding risk precluded heparin therapy were excluded from this analysis. Heparin doses required to reach goal anti-Xa levels were analyzed for the first 72 hours of Impella placement. Safety outcomes including bleeding and thrombosis rates were recorded. Results: A total of 79 patients with Impella devices were identified during the study period, with 50 patients meeting inclusion criteria. The average systemic heparin dose required to maintain therapeutic anti-Xa levels was 10 ± 5.0 IU/kg/hr. Anti-Xa levels were therapeutic 44% and 88% of the time at 24 and 72 hours following device placement, respectively. Three patients (6%) experienced thrombosis whereas 20 patients (40%) had clinically significant bleeding events. Patients with anti-Xa levels >0.5 at 24 hours following Impella placement had more major bleeding events compared to those with anti-Xa levels <0.5 (53% vs. 19%; p=0.027). Conclusions: We present the largest study to date examining heparin requirements in patients on Impella support. In this study, thrombotic events were uncommon whereas bleeding rates were high, especially for patients with anti-Xa levels >0.5 at 24 hours. Our results suggest that conservative anticoagulation goals for patients on Impella support may reduce bleeding complications without increasing thrombotic risk, although future studies are needed. CCMCritical Care MedicineCrit Care Med0090-3493Lippincott Williams & WilkinsHagerstown, MDCCM

AbstractPurpose: Preclinical studies suggest SYK and JAK contribute to tumor-intrinsic and microenvironment-derived survival signals. The pharmacodynamics of cerdulatinib, a dual SYK/JAK inhibitor, and associations with tumor response were investigated. Patients and Methods: In a phase I dose-escalation study in adults with relapsed/refractory B-cell malignancies, cerdulatinib was administered orally to sequential dose-escalation cohorts using once-daily or twice-daily schedules. The study enrolled 8 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 13 with follicular lymphoma, 16 with diffuse large B-cell lymphoma (DLBCL), and 6 with mantle cell lymphoma. Correlation of tumor response with pharmacodynamic markers was determined in patients with meaningful clinical responses. Results: Following cerdulatinib administration, complete SYK and JAK pathway inhibition was achieved in whole blood of patients at tolerated exposures. Target inhibition correlated with serum cerdulatinib concentration, and IC50 values against B-cell antigen receptor (BCR), IL2, IL4, and IL6 signaling pathways were 0.27 to 1.11 μmol/L, depending on the phosphorylation event. Significant correlations were observed between SYK and JAK pathway inhibition and tumor response. Serum inflammation markers were reduced by cerdulatinib, and several significantly correlated with tumor response. Diminished expression of CD69 and CD86 (B-cell activation markers), CD5 (negative regulator of BCR signaling), and enhanced expression of CXCR4 were observed in 2 patients with CLL, consistent with BCR and IL4 suppression and loss of proliferative capacity. Conclusions: Cerdulatinib potently and selectively inhibited SYK/JAK signaling at tolerated exposures in patients with relapsed/refractory B-cell malignancies. The extent of target inhibition in whole-blood assays and suppression of inflammation correlated with tumor response. (ClinicalTrials.gov ID:NCT01994382).

Background: Despite recent advances, follicular lymphoma (FL) remains incurable for most patients. Relapsed/refractory (r/r) FL is associated with decremental treatment responses, accumulating toxicity, and poor survival among early failures of 1st line chemoimmunotherapy. Underscored by the recent approvals of idelalisib, copanlisib, and duvelisib, targeting B-cell receptor (BCR) signaling produces ORR of ~50% in r/r patients; however, new agents with a better therapeutic index over long-term administration are needed. SYK is a key regulator of BCR signaling (upstream of BTK and PI3K), and its inhibition results in clinical activity in FL. Compared with unaffected nodes, lymph nodes from FL patients have greater numbers of follicular helper T cells that express high levels of IL-4, which may support the tumor via the JAK1/3 pathway. Cerdulatinib, an oral, reversible inhibitor of SYK and JAK kinases (JAK1, JAK3, TYK2), previously reported a ~45% overall response rate (ORR) in r/r FL as a single agent. Xenograft studies suggest cerdulatinib may combine with rituximab to enhance antitumor activity. We report updated results from a phase 2a study of single-agent cerdulatinib and initial results in combination with rituximab in r/r FL. Methods: This phase 2a study confirmed the safety and efficacy of cerdulatinib 30 mg BID in r/r B- and T-cell lymphoma patients. Dose reductions were permitted to 15 mg BID. Response was assessed by Lugano criteria. Results: A planned interim analysis was performed on July 18, 2019, in which enrollment was 40 patients in the single-agent cohort and 19 patients in the rituximab combination cohort. For the single-agent cohort, median age (range) was 64 (42-81) years and median prior therapies (range) was 3 (1-9). Ninety-five percent of patients had prior anti-CD20 therapy, and 25% had prior therapy with BCR pathway inhibitors. For the combination cohort, median age (range) was 67 (47-85) years and median prior therapies (range) was 3 (1-10). Eighty-eight percent of patients had prior anti-CD20 therapy, and 32% had prior therapy with BCR pathway inhibitors. The safety profile appeared similar in both cohorts. The most common treatment-emergent grade 3+ adverse events in ≥5% of patients for both cohorts were lipase increase (27%), neutropenia (18%), diarrhea (12%), amylase increase (10%), hypertension (8%), nausea (7%), and pneumonia (5%). Grade 3+ infections occurred in 17.5% of single-agent cohort patients and 15.8% of combination cohort patients. Amylase and lipase increases generally were not associated with abdominal pain or pancreatitis. In addition, to date there has been no evidence of cumulative toxicity. The ORR was 45% as a single agent (12.5% complete response [CR], 32.5% partial response [PR], with 25% stable disease [SD] and 5% progressive disease [PD] in 40 evaluable patients) and 59% in the combination cohort (11.7% CR, 47% PR, with 27.8% SD and no PD in 17 evaluable patients). Responses typically occurred after 2 cycles, generally improved over time, and were durable in the single-agent cohort, with 10 patients on drug for >1 year. Enrollment in the combination cohort is ongoing. Updated safety and efficacy will be presented. Conclusion: The recommended cerdulatinib phase 2 dose of 30 mg BID was tolerable and efficacious in heavily pretreated r/r FL. The cerdulatinib + rituximab combination appears to be well tolerated, with tumor reductions in all evaluable patients. The safety profile and unique mechanism of action of cerdulatinib support further combination studies in FL. Disclosures Smith: Pharmacyclics: Research Funding; Denovo Biopharma: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Acerta Pharma BV: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Ignyta (spouse): Research Funding; Ayala (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding. Munoz:AstraZeneca: Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Stevens:Astellas: Consultancy. Smith:Portola Pharmaceuticals: Research Funding. Feldman:Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Roche: Research Funding; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Ye:MingSight: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Takeda: Research Funding; AbbVie: Research Funding; Portola Pharmaceuticals: Research Funding. de Vos:Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Miller:Verastem: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau. Birrell:Portola Pharmaceuticals: Employment, Equity Ownership. Leeds:Portola Pharmaceuticals: Employment, Equity Ownership. Coffey:Portola Pharmaceuticals: Employment, Equity Ownership, Research Funding. Conley:Portola Pharmaceuticals: Employment, Equity Ownership. Michelson:Portola Pharmaceuticals: Employment, Equity Ownership. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership.

Introduction: Direct oral FXa inhibitors (DOACs, e.g., apixaban [Apix] and rivaroxaban [Riva]) exert their anticoagulant activity by specifically targeting FXa with subnanomolar affinities. Reversal of DOAC-induced anticoagulation can be achieved by immediate and effective sequestration of the inhibitors to relieve inhibition of FXa activity and restore normal thrombin generation (TG). Andexanet alfa (AnXa) is a modified human FXa protein approved in the US and EU for patients treated with Apix or Riva, when reversal of anticoagulation is needed due to life-threatening bleeding. Factor replacement therapies (e.g., 4 factor-PCCs [4F-PCCs]) have demonstrated clinical benefit for vitamin K antagonist-anticoagulated patients by replacing factors II, VII, IX, and X rendered deficient by the anticoagulant. In contrast, the effectiveness and clinical benefit of 4F-PCCs are unclear for reversing DOACs because PCCs do not affect anti-FXa activity. In the present study, we evaluated the effect of individual coagulation factors (FIX, FX, FII), as well as 4F-PCCs on TF-initiated TG (TF-TG) in human platelet poor plasma (PPP), with or without Apix or Riva, and compared it with AnXa under the same conditions. Methods: TF-TG was measured using a calibrated automated thrombogram (CAT, 5 pM TF, Diagnostica Stago). Purified plasma proteins (FIX, FX, FII), PPP, and a commercially available 4F-PCC (Kcentra/Beriplex) were used. 4F-PCC was used with or without pretreatment with the heparinase cup (Haemonetics Corporation) at room temperature for 30 minutes. TF-TG was measured in PPP spiked with purified plasma proteins, 4F-PCC (0-1.0 IU/mL), 4F-PCC + Riva or Apix (0-250 ng/mL), or PPP with AnXa (0-4 μM) + Riva or Apix (0-2000 ng/mL). For comparison, reversal of warfarin anticoagulation by 4F-PCC was performed under similar conditions using individual plasma from warfarin-treated patients (INR = 1.5-6.9) spiked with 4F-PCC (0-1.0 IU/mL). Five CAT parameters were collected, and the endogenous thrombin potential (ETP) and Peak thrombin (Peak) were used for the comparisons. Results: In normal PPP, addition of FX (up to 1.0 IU/mL) had minimal effect on TF-TG parameters, whereas FIX (1.0 IU/mL) mainly increased Peak (~60%). In contrast, FII (1.0 IU/mL) increased both the ETP (~2x) and Peak (~50%). These observations are consistent with the relative plasma concentration and affinity of these coagulation factors as the substrate for the respective enzyme complexes, demonstrating the predominant role of prothrombinase activity in the TF-TG. Addition of 4F-PCC (1.0 IU/mL, equivalent to the therapeutic dose of 50 IU/kg) to PPP caused similar increases of ETP (~2.4x) and Peak (~40%). However, individual plasma protein (FIX, FX, FII) or 4F-PCC up to 1.0 IU/mL was unable to restore normal ETP or Peak in the presence of Apix or Riva (75-250 ng/mL). ETP and Peak increased only when the inhibitor concentrations were sufficiently low (<75 ng/mL), leading to less inhibition of FXa and increased FIIa formation, likely due to an increased FII level from 4F-PCC addition. Similar results were obtained with or without preincubation of 4F-PCC with heparinase prior to spiking in plasma. In contrast, AnXa (0-4.0 μM) dose-dependently reversed Apix- and Riva- (up to 2000 ng/mL) induced inhibition of TF-TG. In the same TF-TG assay, 4F-PCC dose-dependently reversed warfarin anticoagulation in warfarin-treated patients' plasma spiked with 4F-PCC. Conclusions: Specific reversal agents are effective for restoration of TF-TG by either direct sequestration of the FXa inhibitor and restoration of FXa activity (in the case of AnXa with FXa inhibitors) or by replacement of inactive factors due to warfarin treatment (in the case of 4F-PCCs). Addition of coagulation factors or use of 4F-PCCs had limited effect on restoration of normal TG in the presence of a FXa inhibitor. These data demonstrate that AnXa can normalize TF-TG over a wide range of FXa inhibitor concentrations (0-2000 ng/mL), in particular over the range observed in bleeding patients in the ANNEXA-4 study, where 77% of bleeding patients had inhibitor levels ≥75 ng/mL at baseline. In contrast, 4F-PCCs were only able to restore normal TF-TG at low inhibitor levels (<75 ng/mL). These in vitro data are consistent with ANNEXA-4, where AnXa demonstrated >90% immediate reversal of anti-FXa activity and >80% hemostatic efficacy with a wide range of FXa inhibitor levels and multiple bleed types. Disclosures Lu: Portola Pharmaceuticals: Employment, Equity Ownership. Lin:Portola Pharmaceuticals, Inc: Employment, Equity Ownership. Bui:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership. Conley:Portola Pharmaceuticals: Employment, Equity Ownership.

Acute major bleeding secondary to trauma is a significant complication of anticoagulated patients. In patients taking Factor Xa (FXa) inhibitors, major bleeding events can be life-threatening in the absence of a specific reversal agent.

e19532 Background: Pre-clinical data suggest a role for SYK and JAK signaling pathways as oncogenic drivers in PTCL. Most compelling is the frequent demonstration of SYK expression (not expressed in normal T-cells) in PTCL and that transgenic expression of SYK in mouse T cells drives a lethal lymphoproliferative disorder. Frequent activating mutations to JAK/STAT pathways are also observed. Cerdulatinib is a small molecule reversible ATP competitive inhibitor of SYK and JAK1, JAK3 and TYK2. Methods: Eighteen relapsed/refractory PTCL patients were enrolled as part of a phase 2a study, receiving 30 mg cerdulatinib orally BID. Response was assessed by Lugano classification criteria at the end of 2 months and every 3 cycles thereafter. Results: Patients included PTCL-NOS (7), AITL (6), ALCL (2), HSTCL (1), Gamma-delta TCL (1), and EITL (1); median age 70 [48-84]; prior transplant 28%; and 44% refractory to last therapy. Eleven patients were evaluated for clinical response, 3 discontinued prior to evaluation (2 due to progression; 1 withdrew consent), and 4 patients have yet to be evaluated. Six patients have responded (ORR 43%). Of these, 4 achieved a CR after 2 cycles, 2 achieved a PR, and 2 SD. Four responding patients remain on drug: 1 for 11+ months and the remaining for 3-7 months. A patient with CR was referred to allogeneic transplant and censored after cycle 2. An additional patient achieved complete remission of target lesions, but discontinued therapy due to a new lesion. The majority of responses were observed in PTCL-NOS and AITL. Importantly, CRs and PRs occurred in patients who failed multiple lines of therapy, including pralatrexate, romidepsin, belinostat, and an investigational PI3K inhibitor. The most common AEs of any grade were diarrhea (33%), fatigue (22%), lipase increase (17%), and nausea (17%). Grade 3+ AEs occurring in ≥2 patients are neutropenia (4), diarrhea (3), lipase increase (2), and pneumonia (2). The target PK range was achieved with an average SSCmin of ~0.8 µM. Conclusions: These data suggest that cerdulatinib is well tolerated and capable of generating durable complete responses in heavily pre-treated PTCL. Clinical trial information: NCT01994382.

7511 Background: Cerdulatinib is a selective, potent inhibitor of SYK, JAK1, JAK3, and TYK2. Preclinical and clinical data suggest that combined SYK/JAK inhibition may have activity in B- and T-cell NHL. SYK is a key regulator of BCR signalling (upstream of BTK and PI3K), and is also expressed in T-cell lymphomas. Preclinical studies suggest it may be an oncogenic driver in PTCL. Frequent activating JAK/STAT mutations are observed in B and T cell NHL. A phase 1 dose escalation study of cerdulatinib in 43 patients with r/r CLL and NHL was completed in 2016. Complete inhibition of SYK and JAK was well tolerated and consistent antitumor activity was seen in CLL and FL. Methods: This phase 2a study intended to confirm the safety and efficacy of cerdulatinib dosed 30 mg orally BID in patients with r/r B- and T-cell lymphoma. Dose reductions were permitted to a minimum of 15mg BID. Response was assessed by Lugano Classification criteria. Results: 99 patients enrolled (FL: 36, CLL/SLL: 28, PTCL: 18, marginal zone lymphoma: 8, aggressive: 5, Waldenstrom’s macroglobulinemia: 4). Median age is 68 (42-93) and median # of prior therapies is 3 (1–13). 30 patients had prior BTK, PI3K or BCL-2 inhibitor therapy. The most common AEs of any grade are diarrhea (42%), fatigue (36%), and nausea (32%). Grade 3+ AEs occurring in ≥5% patients are neutropenia (18%), lipase increase (15%), pneumonia (12%), diarrhea (10%), and fatigue (7%). 5 patients have had Grade 5 infections considered related to study drug (3 of 5 in the CLL cohort). The target PK range has been achieved with an average SSCmin of ~0.8 µM. Broad activity seen: 61% ORR in CLL/SLL, 50% in FL, and 43% in PTCL (4 CRs, 2 PRs in 14 patients). The first PTCL patient achieved a CR and is on drug at 11 months. Responses typically occurred after 2 cycles of treatment. Durable PRs have occurred in patients who relapsed on BTK inhibitor (CLL, 5+ months, WM, 7+ months, FL, 12 months), venetoclax (SLL, 18+ months), and tenalisib (PTCL, 3+ months) therapy. Updated PK/PD, safety and efficacy will be presented. Conclusions: The cerdulatinib phase 2 dose of 30 mg BID demonstrates good tolerability and efficacy in heavily pre-treated r/r B and T cell NHL. Clinical trial information: NCT01994382.