ALBERT

Description: Background: Background: Subsets of B cell lymphomas demonstrate a reliance on B-cell receptor (BCR) and/or cytokine JAK/STAT signaling for survival. SYK is positioned upstream of BTK, PI3Kδ, and PLCγ2 on the BCR signaling pathway, making it a potential therapeutic target. Additional survival support appears to be mediated by cytokine-induced JAK/STAT pathways, which can be activated by tumor autocrine signaling loops or by pro-inflammatory cytokines originating from non-malignant infiltrating leukocytes present in the tumor microenvironment. Pre-clinical models demonstrate broad anti-tumor activity with combined SYK and JAK inhibition relative to selective inhibition of these targets alone. Methods: This is a 3+3 dose escalation study with 28-day cycles and doses studied ranging from 15mg to 65mg once daily. PK, PD, and safety were monitored. Clinial response was assessed by standard criteria. The level of inhibition of SYK and JAK was determined by multiple whole blood assays measuring signaling via BCR and receptors for the B-cell antigen, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden - CCL3, CCL4, and other markers of inflammation, were also measured. Results: A total of 36 patients (pt) with CLL/SLL or B cell NHL were dosed. Median age was 67 years (range 23-85) and median prior therapies (tx) was 3 (range 1-8). Treatment emergent AEs of ≥ grade 3 observed deemed related to study drug were: neutropenia (n=2), anemia (n=1), and pneumocystis pneumonia (grade 5, n=1) at 30mg; anemia, AST increase, hypotension, thrombocytopenia (n=1 for each), and fatigue (n=2) at 45mg; anemia, neutropenia, abdominal pain, pneumonia, and fatigue (n=1 for each) at 50mg, and diarrhea and fatigue (n=1 for each) at 65mg. The patient with grade 3 AST had tumor progression to the liver. No dose-limiting toxicities (DLT) have been reported to date and cerdulatinib is generally well tolerated. Saturating inhibition of SYK and JAK in circulating lymphocytes (〉80% inhibition) and serum inflammation markers (e.g., β2M,CRP, CCL4; 50-90% inhibition) occurs at plasma concentrations achieved at Cmin of the 40mg dose ( 0.6-1µM) at steady state. At the 65mg dose, these parameters were 80-90% inhibited on day 1 of cycle 1 indicating a more immediate effect compared to lower doses. At the 65mg dose, steady state Cmin and Cmax concentrations are approximately 1 and 2µM, respectively, sufficient to induce apoptosis in the majority of B cell lymphoma cell lines tested. PK is suitable for once daily dosing with a half-life of 12-16 hours and a 2:1 peak-trough ratio. Partial responses (n=4) were observed at 30mg in a pt with del 17p CLL who had relapsed after 6 prior tx; at 45mg a pt with CLL who had received 4 prior tx, and another pt with FL who had received 3 prior tx; and at 65mg in a pt with a transformed DLBCL (MYC, BCL2, and BCL6 expression by IHC) who had relapsed approximately 1 year after 1 prior tx. Responses occurred after 2 cycles of tx. Seven total patients have remained on cerdulatinib for over 200 days, including 2 who have been on for a year or more. Conclusions: Cerdulatinib continues to demonstrate a favorable PK profile and good tolerability at high levels of SYK and JAK inhibition. The clinical responses seen to date support further development and dose escalation continues to identify the MTD. Phase II expansion cohorts are open or planned for CLL, FL, aggressive NHL (DLBCL), and a combination with rituximab. Disclosures Michelson: Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Pandey:Portola Pharmaceuticals Inc: Employment. Birrell:Portola Pharmaceuticals Inc: Employment. Coffey:Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Leeds:Portola Pharmaceuticals Inc: Employment. Curnutte:Portola Pharmaceuticals Inc: Employment.

Description: Introduction: Andexanet alfa (andexanet) is a modified recombinant human factor Xa (FXa), developed to reverse the anticoagulation effects of both direct and indirect FXa inhibitors. For antithrombin III (ATIII)-dependent FXa inhibitors, such as enoxaparin, andexanet binds to the ATIII-enoxaparin complex with high affinity and reverses the inhibition of coagulation factors Xa and IIa. This study evaluated the ability of andexanet to reverse anticoagulation effects and blood loss due to the indirect FXa inhibitor, enoxaparin, in a rabbit liver laceration model. Methods: In a rabbit model of surgically-induced, acute hemorrhage (liver laceration model), rabbits were randomized to receive enoxaparin (8 mg/kg; subcutaneous bolus) or enoxaparin vehicle. This route of administration and dose of enoxaparin was based on the pharmacokinetic profile of enoxaparin and pharmacodynamic activity in the rabbit (2-fold increase in blood loss relative to non-anticoagulated rabbits). Andexanet (15, 35, or 75 mg per rabbit) or andexanet vehicle was administered to anesthetized rabbits as a 5-minute bolus, 120 minutes after enoxaparin injection (from Time 120 to Time 125 minutes), prior to livery injury. The five treatment groups were enoxaparin vehicle + andexanet vehicle, enoxaparin + andexanet vehicle, or enoxaparin + andexanet (3 dose levels). For liver laceration, a standardized injury (10 1-cm-long and 2- to 3-mm-deep incisions) was made into two liver lobes with 5 incisions in each lobe, and bleeding was allowed to progress for 15 minutes (from Time 125 to Time 140 minutes). Study efficacy endpoints included evaluations of blood loss in rabbits anticoagulated with enoxaparin, and anti-FXa activity in plasma. Results: In rabbits anticoagulated with enoxaparin, andexanet significantly decreased blood loss 2-3 fold, relative to vehicle control (assessed at Time 140 minutes) at all doses of andexanet administered (15, 35, 75 mg per animal) (see Table 1). The mean blood loss in anticoagulated rabbits administered andexanet was similar to that in non-anticoagulated rabbits (enoxaparin vehicle + andexanet vehicle). In enoxaparin-anticoagulated rabbits, andexanet rapidly (5 minutes after the start of andexanet administration; Time 125 minutes) reduced mean anti-FXa activity, and the reduction was significant for the 35-mg and 75-mg doses of andexanet (see Table 1). Anti-FXa activity did not return to baseline levels for the duration of the study from Time 120 to Time 140 minutes. These results are consistent with previous studies in enoxaparin-anticoagulated rats where a similar decrease in anti-FXa activity was sufficient to significantly reduce blood loss. These findings with an indirect (ATIII-mediated) FXa inhibitor enoxaparin are distinct from those with a direct FXa inhibitor (e.g., rivaroxaban), which showed that larger reductions in anti-FXa activity were required for significant reductions in blood loss. Conclusions: Administration of andexanet resulted in reversal of the anticoagulant effects of enoxaparin as well as restoration of hemostasis in enoxaparin-anticoagulated rabbits, suggesting it could be clinically valuable for the management of major bleeding associated with indirect FXa inhibitors. This study suggests a potential difference in the extent of reduction in anti-FXa activity required for significant reduction in blood loss associated with indirect vs. direct FXa inhibitors. Further studies are ongoing to better understand correlations between anti-FXa activity and blood loss following andexanet administration in enoxaparin-anticoagulated animals. Disclosures Pine: Portola Pharmaceuticals: Employment. Lu:Portola: Employment, Patents & Royalties. Canivel:Portola Pharmaceuticals: Employment. Pratikhya:Portola Pharmaceuticals: Employment. DeGuzman:Portola Pharmaceuticals: Employment. Karbarz:Portola Pharmaceuticals: Employment. Takeda:Portola Pharmaceuticals: Employment. Malinowski:Portola Pharmaceuticals: Employment. Leeds:Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding; 3-V Biosciences: Equity Ownership; Sea Lane Biotechnologies: Consultancy. Conley:Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding.

Description: Background: SYK and JAK signaling pathways may be critical mediators in the pathogenesis of peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). SYK expression is observed in these malignant cells, and pre-clinical data suggest it acts as an oncogenic driver possibly by mediating chronic T-cell antigen receptor-independent signaling. Consistently, transgenic expression of constitutively active SYK in CD4+ T cells in mice results in a lethal T-cell proliferative disease, while its expression in B cells did not result in clonal expansion. Moreover, evidence for JAK/STAT pathway involvement in these diseases has been demonstrated by gene expression profiling, and frequent activating mutations to common γ chain, JAK1, JAK3, or STAT5b are observed in PTCL. Malignant T-cell clones from CTCL patients secrete a host of Th2 cytokines (IL-3, IL-4, IL-5, IL-6, IL-10, and IL-13) and exhibit deregulation of the IL-2 receptor signaling pathway. These cytokines induce JAK/STAT signaling, which may promote T-cell proliferation and survival. Overall, the data suggest that dual inhibition of SYK and JAK may perturb multiple and independent survival mechanisms implicated in PTCL and CTCL. Cerdulatinib is a small-molecule reversible ATP competitive inhibitor of SYK and JAK family members. Results of cerdulatinib single-agent 30 mg BID in a phase 2a dose expansion study in patients with PTCL and CTCL are reported here. Methods: Patients with relapsed/refractory PTCL or CTCL who received at least 1 prior systemic therapy were eligible to be treated with cerdulatinib at 30 mg orally BID. These expansion cohorts were enrolled in 2 stages: initially 20 patients accrued and, if ≥3 responses were observed, the cohort was expanded. The primary endpoint is response according to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Patients are treated until progression, intolerance, or response adequate to allow stem cell transplantation. All patients receive antimicrobial prophylaxis (typically sulfamethoxazole and trimethoprim [Bactrim]). Results: An interim analysis of 61 patients with PTCL and 37 with CTCL who received cerdulatinib as a single agent was performed on July 18, 2019. Patient characteristics: median (range) age: PTCL: 65 (21-85) years and CTCL: 62 (24-80) years; median prior systemic therapies: PTCL: 2 (1-12) and CTCL: 5 (1-16); refractory to last therapy: PTCL: 48% and CTCL: 62%. For PTCL and CTCL combined, 41% of patients received prior romidepsin, 5% received prior belinostat, 12% received prior pralatrexate, and 32% received prior brentuximab. In the PTCL cohort, 60 patients were evaluable for response (overall response rate [ORR] of 35%). Responses were primarily seen in AITL/TFH subtype (ORR of 55% [12 of 22], of which 41% of patients achieved a complete response [CR]). Responses have additionally been observed in patients with PTCL-NOS, ATLL, ALCL, and gamma-delta TCL. The ORR in CTCL patients was 35%, with the greatest activity observed in mycosis fungoides (ORR of 45%, of which 9% of patients achieved CR) versus Sezary syndrome (ORR of 17%, with no CR). Rapid improvements in pruritus have been observed in CTCL patients, independent of tumor response. Median duration of response is pending for both cohorts, but several patients have been in response for over a year. Among all patients, the most common (〉5% incidence) treatment-emergent grade 3+ adverse events were lipase increase (21%) and amylase increase (18%), diarrhea (8%), neutropenia (8%), anemia (7%), and fatigue (6%). Grade 3+ infections occurred in 29% of patients, which were generally managed by standard care. The amylase and lipase increases occurred without clinical pancreatitis and resolved irrespective of dose modification. Conclusion: Cerdulatinib has shown good tolerability and clinical activity in PTCL and CTCL. Complete and durable responses across a spectrum of PTCL and CTCL subtypes were observed. Correlative studies are aimed at identifying predictors of response and resistance. This phase 2a study will inform the design of a pivotal trial in T-cell lymphoma. Disclosures Horwitz: Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; ADCT Therapeutics: Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Affimed: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kura: Consultancy; Trillium: Research Funding; Astex: Consultancy; Aileron: Research Funding; Forty-Seven: Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Portola: Consultancy; Forty-Seven: Research Funding; Trillium: Research Funding; Forty-Seven: Research Funding; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; ADCT Therapeutics: Research Funding; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Kyowa Hakko Kirin: Consultancy; Aileron: Research Funding; Aileron: Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Portola: Consultancy; Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Trillium: Research Funding; Kura: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Portola: Consultancy; Affimed: Consultancy. Feldman:Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Roche: Research Funding; Portola Pharma: Research Funding; Pfizer: Research Funding; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding. Khodadoust:Corvus Pharmaceuticals: Research Funding. Kim:Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Research Funding; Elorac: Research Funding; Merck: Research Funding; Galderma: Research Funding; Corvus: Honoraria, Membership on an entity's Board of Directors or advisory committees; miRagen: Research Funding; Medivir: Honoraria, Membership on an entity's Board of Directors or advisory committees; Soligenix: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Trillium: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding; Portola Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Munoz:AstraZeneca: Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Incyte: Research Funding; Portola: Research Funding; Celgene: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Fosunkite: Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Patel:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Phillips:Celgene: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees. Smith:Acerta Pharma BV: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Denovo Biopharma: Research Funding; Genentech: Research Funding; Incyte Corporation: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding; Ignyta (spouse): Research Funding; Ayala (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding. Smith:Portola Pharmaceuticals: Research Funding. Wilcox:Millenium/Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; CTI Biopharma: Research Funding; Incyte: Research Funding. Birrell:Portola Pharmaceuticals: Employment, Equity Ownership. Leeds:Portola Pharmaceuticals: Employment, Equity Ownership. Conley:Portola Pharmaceuticals: Employment, Equity Ownership. Michelson:Portola Pharmaceuticals: Employment, Equity Ownership. Coffey:Portola Pharmaceuticals: Employment, Equity Ownership, Research Funding. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership.

Description: 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.

Description: Introduction: Andexanet alfa (andexanet) is a modified, recombinant human factor Xa (FXa) molecule that acts as a decoy to bind and sequester FXa inhibitors. We previously reported Phase 2 data with apixaban, rivaroxaban, edoxaban, and enoxaparin in healthy volunteers, and demonstrated that andexanet rapidly reversed pharmacodynamic (PD) markers of anticoagulation. Here, we report new clinical data demonstrating the efficacy of andexanet in reversing the anticoagulant activity of betrixaban, a direct FXa inhibitor which has recently completed a large Phase 3 clinical trial in acute medically ill patients (APEX). Methods: In an ongoing, Phase 2, randomized, double-blind study in healthy subjects, andexanet (n=12) or placebo (n=6) was administered intravenously following dosing of 80 mg qd po betrixaban to steady state (7 days). In Cohort 1 (andexanet bolus only), subjects (n=6) received an 800 mg bolus of andexanet 3 hours after the last dose of betrixaban on day 7 or matching placebo (n=3). In Cohort 2 (andexanet bolus plus 2-hour infusion), subjects (n=6) received an 800 mg bolus of andexanet 4 hours after the last betrixaban dose, followed immediately by a 2-hour infusion of andexanet (8 mg/min), or matching placebo (n=3). Study endpoints included assessments of safety and multiple PD markers of anticoagulation reversal, including reduction in anti-FXa activity, decrease in unbound betrixaban plasma concentration, and restoration of thrombin generation. Results: Following treatment with betrixaban in Cohort 1, andexanet rapidly (2 minutes after the bolus) decreased anti-FXa activity from 29.9 ± 11.6 to 6.5 ± 4.5 ng/mL while the anti-FXa levels following placebo were largely unchanged (45.2 ± 44.8 to 43.6 ± 37.7 ng/mL). Unbound betrixaban plasma concentration decreased from 12.3 ± 5.6 to 3.6 ± 2.7 ng/mL with andexanet, but remained constant following placebo administration (18.3 ± 17.9 to 19.3 ± 18.1 ng/mL). Similar results were observed in Cohort 2 following andexanet bolus (2 minutes after the bolus), and the effects were maintained during the 2-hour infusion of andexanet. For Cohort 1, thrombin generation was restored (within the mean pre-anticoagulant value ± 2 standard deviations) in 6/6 (100%) of the andexanet-administered subjects vs. 1/3 (33.3%) of the placebo subjects. For Cohort 2, thrombin generation was restored in 5/6 (83.3%) of the andexanet subjects vs. 1/3 (33.3%) of the placebo subjects. Andexanet was well-tolerated; there were no thrombotic events or other serious/severe adverse events. Conclusions: Andexanet was well-tolerated and rapidly reversed anticoagulation effects of betrixaban in healthy subjects. The results of this and previous studies indicate that andexanet could be a universal antidote for all four direct FXa inhibitors (apixaban, rivaroxaban, edoxaban, and betrixaban) as well as indirect FXa inhibitors. An ongoing Phase 3b/4 study (ANNEXA™-4) study in patients receiving a FXa inhibitor who present with acute major bleeding and require urgent reversal of anticoagulation will provide efficacy and safety information on andexanet in this target patient population. Disclosures Crowther: Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Daichii: Honoraria; Alexion: Consultancy, Speakers Bureau; Celgene: Honoraria; Celgene: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Ortho Clinical Diagnostics: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daichii: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Ortho Clinical Diagnostics: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Ortho Clinical Diagnostics: Honoraria; Ortho Clinical Diagnostics: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daichii: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daichii: Honoraria; Daichii: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Ortho Clinical Diagnostics: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daichii: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daichii: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Alexion: Consultancy, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Daichii: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Alexion: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daichii: Honoraria; Celgene: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daichii: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daichii: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daichii: Honoraria; Daichii: Honoraria; Daichii: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Celgene: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Daichii: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Celgene: Honoraria; Daichii: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Ortho Clinical Diagnostics: Honoraria; Celgene: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lu:Portola: Employment, Patents & Royalties. Leeds:Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding. Lin:Portola Pharmaceuticals: Employment. Conley:Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding. Gold:Portola Pharmaceuticals: Employment. Connolly:Portola Pharmaceuticals: Consultancy. Curnutte:Sea Lane Biotechnologies: Consultancy; 3-V Biosciences: Equity Ownership; Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding.

Description: Introduction: Preclinical studies of the Syk-mediated B-cell receptor pathway and Jak-mediated cytokine pathways have demonstrated a potential therapeutic advantage for the dual inhibition of both Syk and Jak kinases in the treatment of B-cell malignancies. Cerdulatinib (PRT062070) was identified from a chemistry screen as a potent and selective inhibitor of Syk, Jak1, Jak3, and Tyk2, with minimal activity against Jak2. Cerdulatinib is efficacious in rodent models of B-cell lymphoma and autoimmune disease (Coffey et al., ASH 2012) and has demonstrated anti-tumor activity in genetically diverse B-cell lymphoma cell lines that is greater than that of Syk- or Jak- selective inhibitors alone (Ma et al., ASH 2013). Methods: This Phase 1 3+3 dose escalation study is evaluating cerdulatinib, given continuously on either a once daily (QD) or twice daily (BID) schedule, for relapsed/refractory chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin lymphoma (NHL). The primary objective is to determine the maximum tolerated dose (MTD) of cerdulatinib in patients with CLL or NHL. Secondary objectives are to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of cerdulatinib and to make a preliminary assessment of antitumor activity. Toxicity is graded according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4. Clinical response is evaluated according to published criteria (Hallek et al., Blood 2008:111:5446-5456; Cheson et al., J. Clin. Oncol. 2012: 25:579-586). The level of inhibition of Syk and Jak is determined using a variety of whole blood assays measuring signaling via receptors for the B-cell antigen, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden, including CCL3, CCL4, and other markers of inflammation, are also being measured. Results: As of 4 August 2014, twelve patients have been enrolled in once daily dose cohorts of 15 mg QD, 30 mg QD, and 45 mg QD. No dose-limiting toxicities have been reported. Grade ≥3 adverse events (AEs), regardless of causality, were: Grade 3 anemia (n=1), Grade 3 neutropenia (n=1), Grade 3 fatigue (n=1), Grade 3 hypotension (n=1), Grade 3 AST increased (n=1), Grade 3 hematochezia (n=1), and Grade 5 Pneumocystis pneumonia (PCP; n=1). The patient who experienced PCP pneumonia was a 76 year old male with CLL who had received prior therapy with bendamustine and rituximab. Cerdulatinib is well-absorbed with an average terminal elimination half-life at steady state of 14 hours. Selective inhibition of Syk and Jak in whole blood assays was observed post-treatment, with IC25-IC50 (Cmin to Cmax at steady-state) against these targets achieved at the 15 mg dose level, and IC50-IC80 (Cmin to Cmax at steady-state) achieved at the 30 mg and 45 mg doses. Reductions of 〉50% in serum markers of inflammation, as well as in CCL3 and CCL4, were noted at all dose levels post-treatment. Two patients treated at the 15 mg dose (1 CLL, 1 follicular lymphoma [FL]) remained on study for 〉230 and 〉200 days, respectively, with stable disease (SD) prior to disease progression. One patient treated at the 30 mg dose (diffuse large B-cell lymphoma [DLBCL], who did not respond to prior R-CHOP therapy), remained on study with SD for 140 days. One patient treated at the 30 mg dose (CLL) experienced a 〉60% decrease in peripheral lymphocyte count prior to coming off study for PCP pneumonia. Another patient treated at the 30 mg dose (CLL) experienced early lymphocytosis and a 33% reduction in lymph node size at the end of Cycle 2 and remains on study in Cycle 3. One patient treated at the 45 mg dose (FL) experienced a 40% decrease in lymph node size at the end of Cycle 4 and remains on study in Cycle 5. Conclusions: Cerdulatinib has been well tolerated in the initial cohorts of this Phase 1 study, with no dose-limiting toxicities and preliminary evidence of anti-tumor activity. Dose escalation continues and Phase 2 expansion cohorts are planned in CLL, DLBCL and FL. Disclosures Hamlin: Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy; Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding. Strickland:SCRI Development Innovations: Employment. Pandey:Portola Pharmaceuticals, Inc.: Employment; Portola Pharmaceuticals, Inc.: Equity Ownership. Coffey:Portola Pharmaceuticals: Employment, Equity Ownership. Leeds:Portola Pharmaceuticals, Inc.: Employment. Levy:Portola Pharmaceuticals: Employment; University of Michigan: Patents & Royalties. Curnutte:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership; Sea Lane Biotechnologies: Consultancy; 3-V Biosciences: Equity Ownership. Wagner-Johnston:Gilead: Consultancy; Gilead: Speakers Bureau; Celgene: Research Funding. Flinn:Portola Pharmaceuticals, Inc.: Research Funding.

Description: Background: Pre-clinical data suggest a role for SYK and JAK signaling pathways as oncogenic drivers in peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). A published study described a unique translocation in 17% of PTCL specimens resulting in a SYK-ITK fusion protein, in which the kinase domain of SYK was constitutively active. This fusion protein was expressed transgenically in T cells in mice, resulting in a lethal T-cell proliferative disease, while its expression in B cells did not result in clonal expansion. Expression of wildtype SYK in PTCL is frequently observed. Additionally, gene expression profiling implicates JAK/STAT signaling in this disease and frequent activating mutations to common γ chain, JAK1, JAK3, or STAT5b are observed. SYK expression is also reported in Mycosis Fungoides (MF), the most common variant of CTCL. Moreover, malignant T cell clones from CTCL patients secrete a host of Th2 cytokines (IL3, IL4, IL5, IL6, IL10, and IL13) and exhibit deregulation of the IL2 receptor signaling pathway. These cytokines mostly signal via JAK/STAT and promote T-cell proliferation and survival, and are potential mediators of pruritus. Overall, the data suggest that dual inhibition of SYK and JAK may perturb multiple and independent survival mechanisms in PTCL and CTCL. Cerdulatinib is a small-molecule reversible ATP competitive inhibitor of SYK and JAK family members. In a phase 1 study in patients (pts) with B-cell malignancies, the recommended phase 2 dose was identified with a favorable safety profile and initial evidence of clinical activity. Subsequently, disease-specific phase 2a expansion cohorts were opened. The results of expansion cohorts in PTCL and CTCL are reported below. Methods: Pts with relapsed/refractory PTCL or CTCL who had received at least 1 prior systemic therapy were eligible to be treated with cerdulatinib at 30 mg orally BID. These expansion cohorts were enrolled in 2 stages: initially 20 pts accrued and if ≥3 responses were observed the cohort expanded to 40 pts. Both PTCL and CTCL cohorts have completed the first stage. The primary endpoint is response according to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Pts are treated until progression, intolerance, or response adequate to allow stem cell transplantation (SCT). All pts receive antimicrobial prophylaxis (typically Bactrim). Results: As of July 26, 38 pts with PTCL and 22 with CTCL have received cerdulatinib. Pt characteristics: median (range) age: PTCL: 65 (34-84) years and CTCL: 63 (24-39) years; median prior systemic therapies: PTCL: 3 (1-10) and CTCL: 3 (1-12); 21% of PTCL pts and 5% of CTCL pts had prior SCT; refractory to last therapy: PTCL: 53% and CTCL: 50%. In the PTCL cohort: 26 pts are evaluable for response and 12 pts have yet to reach their first assessment. The ORR is 35% (9/26) and CR is 31% (8/26). Seven responding pts remain on drug for 3-12+ months, 1 proceeded to allogeneic SCT after achieving a CR, and 1 progressed at 15 months. Responses have been observed in pts with AITL, PTCL-NOS, and gamma-delta TCL. In the CTCL cohort: 10 pts are evaluable for response and 12 have yet to be evaluated. The ORR is 50% (5/10) and CR is 10% (1/10). All responders and 2 pts with stable disease remain on drug. Responses have been seen in pts with MF and Sezary Syndrome. Rapid improvements in pruritus appear to correlate with clinical response. Among all pts, the most common AEs of any grade were diarrhea (30%), lipase increase (20%), amylase increase (18%), nausea (13%), and neutropenia (12%). AEs ≥ Grade 3 occurring in ≥3 pts were lipase increase (n=9), neutropenia (n=6), and amylase increase (n=6). The amylase and lipase increases occurred without clinical pancreatitis and resolved with dose reduction or dose interruption. Conclusion: In ongoing 2 stage expansion cohorts, cerdulatinib has shown good tolerability and sufficient activity in both PTCL and CTCL to proceed to the second stage. Significant efficacy includes both complete and durable responses across a spectrum of PTCL and CTCL subtypes. Correlative studies are aimed at identifying predictors of response. This phase 2a study will inform the design of a pivotal trial in T-cell lymphoma. Disclosures Horwitz: Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Aileron Therapeutics: Consultancy, Research Funding; Portola: Consultancy; Trillium: Consultancy; Innate Pharma: Consultancy; Spectrum: Research Funding; Corvus: Consultancy. Feldman:Pharmacyclics: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Johnson and Johnson: Speakers Bureau; Portola: Research Funding; KITE: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau. Khodadoust:Innate Pharma: Research Funding. Kim:Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Merck: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Tetralogic: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Soligenix: Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; miRagen: Research Funding. Munoz:Gilead: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Kite: Consultancy, Honoraria, Speakers Bureau; Juno: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Alexion: Consultancy; Pfizer: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy. Phillips:Genentech: Consultancy; Gilead: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding. Smith:Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Incyte Corporation: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Genentech: Research Funding; Portola Pharmaceuticals: Research Funding; Acerta Pharma BV: Research Funding. Smith:Portola: Honoraria; BMS: Consultancy. Wilcox:Incyte, Corp: Research Funding. Steele:Portola Pharmaceuticals, Inc.: Employment. Pandey:Portola Pharmaceuticals, Inc.: Employment. Birrell:Portola Pharmaceuticals, Inc.: Employment. Leeds:Portola Pharmaceuticals, Inc.: Employment. Conley:Portola: Employment. Michelson:Portola Pharmaceuticals, Inc.: Employment. Coffey:Portola Pharmaceuticals, Inc.: Employment. Curnutte:Portola Pharmaceuticals, Inc.: Employment. Hamlin:Portola: Consultancy.