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Introduction: Liver disease is often marked by changes in hemostasis. Vitamin K is frequently administered to cirrhotic patients with an elevated INR to improve their coagulopathy, though strong evidence justifying this approach is lacking. Questions regarding the efficacy of vitamin K have been gathering based on an increased understanding of the rebalanced hemostasis of liver disease. This study evaluated the effect of vitamin K on the INR 24-72 hours after administration. Methods: This retrospective chart review used the VA Informatics and Computing Infrastructure (VINCI) database to identify 886 admissions for patients with liver disease who received vitamin K between January 1, 2001 and March 31, 2014. Patients were included if they had a coded diagnosis of cirrhosis, acute hepatitis, non-alcoholic steatohepatitis, hepatocellular carcinoma, or end stage liver disease. Charts for patients with one of those diagnoses who received vitamin K at the LSCDVAMC were included. All data was collected from the Computerized Patient Record System (CPRS). Medication route and dosing was determined from the pharmacy administration record. Patients were excluded if they received heparin, LMWH, FFP, or if they did not have an INR value before the administration of vitamin K or 24-72 hours after the dose was given. Results: A total 886 individual admissions were identified, 333 admissions met inclusion criteria for analysis. The mean INR on admission for the included encounters was 1.88 (95% CI 1.798 - 1.955) the lowest INR was 0.86 and the highest was 5.99. In the 333 admissions analyzed the mean decrease in the INR was 0.08 (95% CI 0.028 - 0.132). 180 encounters had a repeat INR during the hospitalization. The mean decrease in INR from admission to the second post-vitamin K INR was 0.123 (95% CI 0.058 - 0.187). Of the 333 included patient encounters 37 had a change in INR (increase or decrease) >0.4, of which in 11 the INR increased and in 24 the INR decreased (mean change in INR 0.313; 95% CI -0.139 to 0.765). The average INR of those 37 encounters was 2.83 (95% CI 2.497 - 3.171). There was no significant difference in albumin in encounters when the INR increased vs. decreased in response to vitamin K. There was a trend towards higher total bilirubin (TBILI) when the INR did not decrease in response to vitamin K. Mean TBILI was 5.9 in INR responders (95% CI 5.011 - 6.789) and was 6.66 (95% CI 5.219 - 8.101) in the encounters where the INR increased despite vitamin K. Conclusion: Vitamin K administration to improve the coagulopathy of patients with liver disease is common and often administered in response to an elevated INR. This is the largest retrospective review to date evaluating the effect of vitamin K on the INR of patients with liver disease. While a statistically significant decrease in INR of 0.08 was found, it is unclear if such a difference from vitamin K would be clinically significant. Moreover, only a very small portion of the patients included in this study (24/333) had an INR decrease of greater than 0.4. A limitation of our study is that patient centered outcomes, such as bleeding events, were not assessed. Future research should evaluate if there is a role for vitamin K in liver disease patients with a significantly elevated INR and low total bilirubin. Disclosures No relevant conflicts of interest to declare.

Background c-MET receptor tyrosine kinase (RTK) activity has been implicated in establishing the oncogenic phenotype across several human cancers with high levels of the activating c-MET ligand, hepatocyte growth factor (HGF). Malignant plasma cells secrete HGF-activator (HGFA), which converts HGF to its active form, and high HGF levels are correlated with a poor prognosis in multiple myeloma. Syndecan 1 (CD138) on malignant plasma cells binds HGF and potentiates interleukin-6-induced growth and migration. HGF stimulation of myeloma cells also activates autophosphorylation of c-MET and other critical downstream signaling pathways promoting oncogenesis. Finally, pre-clinical studies have shown that suppression of c-MET signaling with a number of small molecules, including ARQ 197, induced myeloma cell apoptosis. Tivantinib-mediated cytotoxic response was observed at concentrations of less than 5 µM, which are achievable in the clinic. These findings supported the hypothesis that suppression of the HGF/c-MET signaling axis could be a rational strategy against RRMM. Methods In this phase II study, the efficacy and safety of ARQ 197, a non-competitive and highly selective inhibitor of the c-MET RTK, was studied in patients with RRMM. Primary objectives were to determine the overall response rate (ORR) to single-agent tivantinib in patients who had received one to four prior lines of therapy, and to define the toxicities in this population. A Simon’s Minimax 2-stage design was used for the study. ARQ 197 was administered at a starting oral dose of 360 mg twice daily with meals for each day of every 4-week treatment cycle. This dose was selected from prior phase I investigations in solid tumors, and at this dose level, steady-state plasma levels of ARQ 197 were 7 µM. Treatment could continue providing that patients did not experience undue toxicities, or disease progression. Tivantinib is provided through the Cancer Therapy Evaluation Program (CTEP), and this study was supported by CTEP, as well as the MD Anderson Cancer Center SPORE in Multiple Myeloma. Results A total of 16 patients were enrolled and treated to date, including 9 men and 7 women, who had received a median of 1 prior line of therapy (range 1-3), including stem cell transplant in ten. The mean patient age was 66 (range 49-76), with ethnicity including 13 Caucasian Americans, 2 African Americans, and 1 Asian American. Patients have received a median of 3 cycles of therapy to date (1-11) with one patient continuing on study, and all were evaluable for toxicity, while 11 were evaluable for response based on having completed two treatment cycles. The most common adverse events (AEs) of any grade seen in at least 25% of patients and felt to be at least possibly drug related included fatigue or decreased neutrophils (94% each), pain (81%), myalgias (56%), diarrhea (38%), memory impairment, respiratory disorders, and rash (31% each), and hypertension (25%), and these were predominantly grade 1 or 2. Grade 3 or 4 AEs included neutropenia (31% and 25%, respectively), syncope, infection, pain (13% of each, all grade 3), and anal fissure, cough, fatigue, hypertension, and pulmonary embolism (6% each, all grade 3). Stable disease (SD) has been seen as the best response in 4/11 (36%) evaluable patients, which was maintained for up to 11 cycles, while the remaining patients showed evidence of disease progression. Conclusion Single-agent tivantinib has been well tolerated in patients with RRMM, and the ability to achieve stable disease in patients with previously progressing myeloma does support the possibility that targeting c-MET has some promise. Future studies with rationally designed combination regimens incorporating a c-MET inhibitor and other novel agents may better define the role of this class of drugs in our armamentarium against myeloma. Disclosures: Orlowski: Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Thomas:Millenium: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Shah:Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

Abstract 2976 Background: c-Met receptor tyrosine kinase (RTK) activity has been implicated in establishing the oncogenic phenotype across several human cancers with high levels of the activating c-Met ligand, hepatocyte growth factor (HGF). Malignant plasma cells secrete HGF-activator (HGFA), which converts HGF to its active form, and high HGF levels are correlated with a poor prognosis in multiple myeloma (MM). Syndecan 1 (CD138) on malignant plasma cells binds HGF and potentiates interleukin-6-induced growth and migration. HGF stimulation of myeloma cells also activates autophosphorylation of c-Met and other critical downstream signaling pathways promoting oncogenesis. Finally, pre-clinical studies have shown that suppression of c-Met signaling with a number of small molecules, including ARQ 197, induced myeloma cell apoptosis. Tevantinib-mediated cytotoxic response was observed at concentrations of less than 5 μM, which are achievable in the clinic. These findings supported the hypothesis that suppression of the HGF/c-Met signaling axis could be a rational strategy against relapsed multiple myeloma. Methods: In this phase II study, the efficacy and safety of ARQ 197, a non-competitive and highly selective inhibitor of the c-Met RTK, is being studied in patients with relapsed multiple myeloma. Primary objectives were to determine the overall response rate (ORR) to single-agent tivantinib in patients with relapsed multiple myeloma who had received one to four prior lines of therapy, and to define the toxicities in this population. ARQ 197 was administered at a starting oral dose of 360 mg twice daily with meals for each day of every 4-week treatment cycle. This dose was selected from prior phase I investigations in solid tumors, and at this dose level, steady-state plasma level sof ARQ-197 were 7 μM. Treatment could continue providing that patients did not experience undue toxicities, or disease progression. Tivantinib is provided through the Cancer Therapy Evaluation Program (CTEP), and this study is supported by CTEP, as well as the M. D. Anderson Cancer Center SPORE in Multiple Myeloma. Results: A total of 10 patients have been enrolled and treated to date, all of whom were evaluable for toxicity, with 8 evaluable for response based on having completed two treatment cycles. Patients had received from 1–3 prior lines of therapy for their disease, and 7/10 (70%) had presented with International Staging System stage I disease at diagnosis. All patients on study had an ECOG performance status of 1 or better, and received a median of 3.5 cycles of tivantinib (range 1–7). The most common adverse events (AEs) of any grade seen in at least 30% of patients included diarrhea (30%), dizziness (30%), dry eyes (30%), shortness of breath (30%), memory change (30%), myalgias (40%), fatigue (60%), and neutropenia (60%). Serious AEs (SAEs) occurred in 2 patients, including one patient with grade 3 syncope, and another with grade 4 neutropenia and a grade 3 anal fissure. Stable disease (SD) has been seen as the best response in 5/7 (71%) evaluable patients, which was maintained for up to 7 cycles, while the remaining patients showed evidence of disease progression. Conclusion: Enrollment is continuing to this first study of any c-Met inhibitor in patients with relapsed multiple myeloma to better define the role of single-agent tivantinib in this setting. To date, tivantinib has been tolerated well, and some evidence of activity has been seen, with stable disease in 63% of patients, all of whom were progressing at the time of enrollment. Updated toxicity and efficacy data will be presented at the time of the Annual Meeting. Correlative studies are also underway with the goal of identifying potential predictive biomarkers. Disclosures: Off Label Use: Tivantinib is being evaluated for patients with relapsed myeloma, but is not yet approved in this setting.

Nitric oxide- and cyclic nucleotide-linked pathways have been proposed to regulate fetal hemoglobin expression in sickle cell disease (SCD), and phosphodiesterase-5 (PDE5) inhibition and arginine supplementation can enhance these pathways. In an open-label gender-biased study (due to earlier concerns about sildenafil-induced priapism), we examined HbF and markers of disease activity in 12 patients with SCD (HbSS,) who had confirmed hematologic stability on hydroxyurea therapy and who had been treated with three months of thrice daily L-arginine supplementation (0.1–0.2 g/Kg, n=6, 4 male) or sildenafil (PDE5 inhibitor, 25–100 mg, n=6, all female). An additional 12 patients received study drug but did not have stable lead-in HbF levels; their data, where available, is included in analyses of amino acid levels, tricuspid regurgitant (TR) jet measurements, and 6-minute walk (6MW) distance. 25 mg of sildenafil increased cGMP by an average of 2 pM/ml at 2 hours (n=5). Statistics between groups are 2-way repeated measures ANOVA, while within groups are 1-way RMA, from data collected every 2 weeks. L-arginine increased serum arginine and ornithine concentrations while sildenafil did not. Percent change in HbF (%) and F-cells (%) from baseline rose with sildenafil, but did not change with L-arginine. Reticulocytes (K/μL) and arginase, markers of hemolysis, dropped with sildenafil, but LDH(IU/L) and MCHC rose with both treatments, although only modestly. TR jet velocity and 6-MW distance improved markedly in patients treated with sildenafil, whose parameters had suggested somewhat more severe disease at the start of therapy. We conclude that HbF and F-cell levels are modestly increased in patients on HU who also receive sidlenafil, consistent with prior studies suggesting that HU in part operates via NO-cGMP signaling pathways. Sildenafil, but not L-Arginine, improves physiologic, and some hematologic, parameters in SCD. These clinical data, while limited by small numbers, support earlier genetic data from other investigators that implicate members of the PDE family in the modulation of HbF in SCD. Measurement L-Arg, baseline L-Arg, week 12 Sildenafil, baseline Sildenafil, week 12 Arginine [mM], 47±16 96±58 35.0±15.6 28.6±11.3 p

We investigated the kinetics of hematologic change in patients with sickle cell disease (SCD, HbSS, n=6) or SC disease (HbSC, n=1) who had been newly started on hydroxyurea (HU), with the intention of identifying early correlates to fetal hemoglobin (HbF) responsiveness. We found that HbF increased in all patients on HU, and that the half-maximal degree of HbF response could be estimated by 2 months, in patients’ whose MCVs had risen ≥ 10% above baseline. All 7 patients were treated with HU and followed closely for 6 months or more, until hematologic stability. Hematologic stability was apparent by ≥ 5 months. White blood cell count (WBC), absolute neutrophil count (ANC), reticulocyte (retic) count, % HbF, and mean corpuscular volume (MCV) were examined at bi-weekly intervals. Baseline values (1 or 2 values averaged) were compared with mean values obtained during weeks 2 to 8 (3 or 4 values averaged). As expected, by 2 months WBC and ANC had fallen 30 +/− 8% and 26 +/− 8%, respectively. Change in total hemoglobin (5.8 +/−6.7%), total platelet count (less 11 +/− 10.8%), and LDH (5.3 +/− 8.7%) was not consistent during this two month interval. By eight weeks after initiation of HU, retic counts had dropped in all six SS patients, from 15 to 52% less than baseline while MCV rose 9–21% above baseline; in general, rise in MCV preceded the rise in HbF. Overall, by the time of hematologic stability, all patients had increased their percent HbF, at between 3–8.5-fold relative to baseline; baseline percent HbF of total hemoglobin (Hgb) ranged from 0.7 to 8.3% and, after stabilization, from 5.2% to 24.9%. Maximal percentage of Hgb that was accounted for by HbF at stabilization was arbitrarily set at 100; at 8 weeks, all patients had achieved ≥ 42% of their maximal HbF level, mean 55 +/− 9.4% of maximum HbF. Two additional patients in whom extensive lab data were available, but who were suspected to be non-compliant or sub-therapeutically treated, had a >10% rise in MCV that was temporally associated with an inflection upward for HbF. Patient 8 had mean bi-weekly MCVs of 94, 91, 93, and, after a family conference, 102 (p=.003); Concurrent HbF was 7, 6, 6 and then 10 (p=.046). Patient 9 had mean bi-weekly MCVs on low-dose HU of 97, 96, and, after dose adjustment, 109(p=.003); HbF was 2%, 3%, and then 5 (p=.0094). We speculate that, in many patients, an increase in MCV above baseline of ≥ 10% is a marker of adequate HU dosing, and that HbF levels at that time approximate half-maximal response. A larger series will be necessary to confirm this relationship; a predictive model, correlating MCV and HbF responsiveness, could be used to determine sufficiency of, and compliance to, HU therapy, and to early identify patients who are at high-risk from SCD (e.g. with pulmonary hypertension) whose HbF responsiveness may not be adequate from HU alone. Figure Figure