ALBERT

Description: [1]  Rising CO 2 concentration in the atmosphere, global climate change, and the sustainability of the Earth's biosphere are great societal concerns for the 21st century. Global climate change has, in part, resulted in a higher frequency of flooding events, which allow for greater exchange between soil/plant litter and aquatic carbon pools. Here we demonstrate that the summer 2011 flood in the Mississippi River basin, caused by extreme precipitation events, resulted in a “flushing” of terrestrially derived dissolved organic carbon (TDOC) to the northern Gulf of Mexico. Data from the lower Atchafalaya and Mississippi rivers showed that the DOC flux to the northern Gulf of Mexico during this flood was significantly higher than in previous years. We also show that consumption of radiocarbon-modern TDOC by bacteria in floodwaters in the lower Atchafalaya River and along the adjacent shelf contributed to northern Gulf shelf waters changing from a net sink to a net source of CO 2 to the atmosphere in June and August 2011. This work shows that enhanced flooding, which may or may not be caused by climate change, can result in rapid losses of stored carbon in soils to the atmosphere via processes in aquatic ecosystems.

Description: Background ARRY-520 is a novel KSP inhibitor with encouraging activity in patients (pts) with RRMM. In preclinical models, the activity of ARRY-520 is synergistic with BTZ, providing a rationale to combine these drugs in the clinic. Methods ARRAY-520-111 is a Phase 1 study to identify the maximum tolerated dose of ARRY-520, BTZ and dex. Eligible pts have RRMM with ≥ 2 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent. ARRY-520 is administered intravenously (IV) on Days 1, 2, 15 and 16 (Schedule 1) or on Days 1 and 15 (Schedule 2); BTZ is administered IV or subcutaneously (SC) on Days 1, 8 and 15; and 40 mg oral dex, if applicable, is taken on Days 1, 8 and 15 in a 28-day cycle. Results A total of 41 pts have been treated to date at various dose levels of ARRY-520 and BTZ. Patients had a median of 5 prior regimens (range 2-10). All pts received a prior PI, 39 pts received prior BTZ, and 25 pts received at least 2 prior PI- including regimens (range 1-6). In Schedule 1, the initial dose level of ARRY-520 (1.0 mg/m2/day) with BTZ (1.3 mg/m2/day) and dex was not tolerated, with dose-limiting toxicities (DLT) in 2/3 pts (pneumonia and pseudomonal sepsis). After a protocol amendment, dose escalation resumed at reduced doses of ARRY-520 (0.5 mg/m2/day) and BTZ (1.0 mg/m2/day) without dex. The addition of prophylactic filgrastim (G-CSF) enabled escalation to full dose ARRY-520 and BTZ (1.5 and 1.3 mg/m2/day, respectively). Only 1 DLT of pneumonia was observed during the further dose escalation, at 1.0 mg/m2/day ARRY-520 and 1.0 mg/m2/day BTZ. Dex has been added to the combination at 1.25 mg/m2/day ARRY-520 and 1.3 mg/m2/day BTZ and this dose level has been well tolerated. Enrollment is ongoing in the final planned dose level. In Schedule 2, the initial dose level of ARRY-520 (2.25 mg/m2/day) with BTZ (1.3 mg/m2/day) and dex was well tolerated and enrollment is ongoing at 3.0 mg/m2/day ARRY-520 and 1.3 mg/m2/day BTZ + dex, the maximum planned dose of both drugs. The most commonly reported adverse events (AEs) (in ≥ 15% of pts) include anemia, diarrhea, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, neutropenia, constipation, headache, fatigue, hyperuricemia, nausea, vomiting, and dizziness. All Grade 3 – 4 non-hematologic AEs have an incidence of 〈 10%. Based on the laboratory data, Grade 4 neutropenia was observed in 15% of patients, Grade 4 thrombocytopenia was observed in 10%. Apart from the one pt described above with the DLT of pseudomonal sepsis, no other febrile neutropenic events were reported. Neuropathy (Grade 2) was observed in 1 pt. Monopolar spindles have been observed in a post-dose biopsy for a pt treated at 1.0 mg/m2/day ARRY-520 + 1.3 mg/m2/day BTZ, indicating that pharmacodynamic activity of ARRY-520 is maintained in the presence of full dose BTZ. Preliminary signs of efficacy have been observed in this ongoing dose-escalation study. To date, among the subset of 13 evaluable pts who received doses at ≥ 1.25 mg/m2/day ARRY-520 + 1.3 mg/m2/day BTZ, 4 (31%) partial responses (PR) and 1 minimal response (MR) have been observed. By contrast, in the 27 patients receiving lower doses of ARRY-520 and BTZ, only 1 MR has been reported. An additional 29 pts experienced stable disease (SD) on ARRY-520 + weekly BTZ without the use of steroids (dex), including 17 pts with disease refractory to BTZ. Conclusions ARRY-520 + BTZ with prophylactic G-CSF appears well tolerated with manageable non-hematologic AEs in this heavily pretreated pt population and has demonstrated preliminary evidence of activity, including PRs and SD in pts with disease refractory to BTZ. These data support further exploration of this novel KSP inhibitor in combination with BTZ in expansion cohorts. The authors would like to acknowledge the dedicated research staff and physicians at the participating centers of the Multiple Myeloma Research Consortium for their contribution to this study. Disclosures: Chari: Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Millenium Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: ARRY-520 is an investigational drug being combined with bortezomib in multiple myeloma. Zonder:Celgene Corporation: Consultancy; Onyx: Consultancy; Skyline Diagnostics: Consultancy. Jakubowiak:Millenuim: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Janssen Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Kaufman:Millenium: Consultancy; Merck: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy; Janssen: Consultancy.

Description: Background The availability of multiple immunomodulators (IMiDs) and proteasome inhibitors (PIs) has resulted in improved outcomes for patients (pts) with multiple myeloma (MM). Pts refractory to these 2 classes of drugs have a poor prognosis and new drugs with novel mechanisms of action are needed. ARRY-520, a potent, selective inhibitor of the novel drug target KSP, has shown single-agent activity in MM. The acute-phase protein AAG can bind ARRY-520, reducing free drug, possibly resulting in reduced treatment effect in pts with high AAG. Methods ARRAY-520-212 is a Phase 1/2 study. The Phase 2 portion was designed to evaluate the efficacy and safety of 1.5 mg/m2/day ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks with filgrastim support. 2 Cohorts have been enrolled: Cohort 1 investigated single-agent ARRY-520 in pts with relapsed or refractory MM with ≥ 2 prior lines of therapy, including both bortezomib (BTZ) and an IMiD. Cohort 2 (cohort2) investigated ARRY-520 with Low-dose dexamethasone (LoDex -40mg weekly) in pts with RRMM with ≥ 2 prior lines of therapy, refractory (progression on or within 60 days of last treatment) to last line of therapy, and refractory to BTZ, lenalidomide (Len) and dexamethasone (triple-refractory). Pts intolerant to Len or BTZ were not included in cohort2. Baseline plasma AAG levels were measured in both cohorts. Results Results are summarized in the attached table. In cohort 1, 32 pts have been treated, with a median age of 65 years and a median of 6 prior regimens. 41% of cohort 1 pts were refractory to BTZ and Len. 6/27 pts (22%) had high baseline AAG. In cohort 2, 50 pts have been treated to date, with a median age of 63 years and a median of 9 prior regimens. As described in the table, cohort 2 pts had more prior treatment regimens, were primarily triple refractory and had a short time to progression (TTP) on prior therapy. 13/44 (30%) of cohort 2 pts had high baseline AAG. ARRY-520 showed a similar safety profile in both Cohorts. The most commonly reported (≥ 10% of pts) treatment-emergent Grade 3/4 adverse events, regardless of attribution, were thrombocytopenia (44% cohort 1, 42% cohort 2), anemia (38% and 50%), neutropenia (38% and 38%), fatigue (16% and 8%), leukopenia (13 and 4%) and pneumonia (3% and 12%). The incidence of febrile neutropenia was low in both cohorts (3% and 6%). ARRY-520 has shown activity both alone and with LoDex (See table). To date, in both cohorts, pts with High AAG have had no objective responses as compared to pts with Low AAG. In the completed cohort 1, ARRY-520 showed a durable 16% overall response rate (ORR) with an 8.6 month (mo) duration of response. In pts with Low AAG a prolonged OS (median = 23 mo) was observed compared to pts with High AAG (OS = 4.5 mo). Follow-up in cohort 2 is ongoing and ARRY-520+LoDex has shown a 16% ORR to date in this very heavily pretreated population. Notably in cohort 2, 4 PR were observed in the 16 patients (25%) who were previously treated with either a novel PI (carfilzomib or MLN9708) and/or IMiD (pomalidomide). Conclusions ARRY-520 is a novel first-in class agent in MM. In this Phase 2 analysis, ARRY-520 showed a similar activity and safety profile both alone and in combination with LoDex. While transient non-cumulative neutropenia is observed, the incidence of febrile neutropenia was low. ARRY-520 showed clear activity both alone and in combination with LoDex. Activity in pts refractory to novel PI and IMiDs suggests a lack of cross-resistance with drugs with existing mechanisms of action. High levels of AAG are associated with a lack of tumor responses and shorter OS following treatment with ARRY-520, suggesting AAG may be a potential patient selection marker identifying pts unlikely to benefit from ARRY-520. Disclosures: Lonial: Millennium: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy; Celgene Corporation: Consultancy. Off Label Use: ARRY-520 (Investigational Drug). Shah:Array BioPharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: 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; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Zonder:Celgene Corporation: Consultancy; Onyx: Consultancy; Skyline Diagnostics: Consultancy. Kaufman:Onyx: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Millenium: Consultancy; Merck: Research Funding. Hilder:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Walker:Array BioPharma: Employment. Orlowski: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; Resverlogix: Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: 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; Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity’s Board of Directors or advisory committees.

Description: Background ARRY-520, a kinesin spindle protein (KSP) inhibitor, has demonstrated promising clinical activity, both as a single agent and combined with dexamethasone in patients (pts) with bortezomib- and lenalidomide-refractory MM with a single agent response rate (≥ MR) of 19-33%. The maximum tolerated dose (MTD) of ARRY-520 as a single agent was 1.5 mg/m2 administered on days 1 and 2 every 2 weeks with minimal non-hematologic toxicity. Carfilzomib, an irreversible proteasome inhibitor (PI), also has demonstrated single agent activity in RRMM and received accelerated approval by the Food & Drug Administration (FDA). Preclinical data demonstrate synergy between the combination of a PI and ARRY-520 and the minimal overlapping side effect profile support the hypothesis that the combination of carfilzomib and ARRY-520 could be an attractive regimen. Methods The primary objective was to determine the MTD and the safety/tolerability of carfilzomib and ARRY-520 in RRMM. Secondary objectives were to determine efficacy as measured by the overall response rate (ORR), time to progression, progression free survival and time to next therapy. Pts had to be ineligible for autologous stem cell transplant (ASCT), have disease refractory/intolerant to bortezomib, and have had prior lenalidomide exposure. ARRY-520 was administered intravenously (iv) on days 1, 2, 15 and 16; carfilzomib was administered intravenously on days 1, 2, 8, 9, 15 and 16 of a 28 day cycle. All pts received growth factor support in cycle 1. Dose-escalation used a standard 3+3 schema with dose-limiting toxicities (DLTs) assessed during cycle 1. Four dose levels were studied with ARRY-520 escalated from 0.75 to 1.5 mg/m2 with the approved fixed dose of carfilzomib 20/27 mg/m2. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results 20 pts were enrolled in the completed phase 1 dose escalation portion of the study. The median age was 61 (range 43-80), and pts had received a median of 4 lines of prior therapy (range 2-10). 16/20 pts were lenalidomide refractory/intolerant; 20/20 pts were bortezomib refractory/intolerant; and 18/20 pts had prior ASCT. Two pts in cohort 2 were not DLT evaluable due to non-compliance with study-related therapy in cycle 1 and replaced for assessment of DLT. No DLTs were observed in 3 patients dosed in cohort 1, with ARRY-520 at 0.75 mg/m2. In cohort 2, 1/6 patients encountered a DLT with influenza pneumonia and non-neutropenic fever. In cohort 3, 5 patients were enrolled, ARRY-520 was dose escalated to 1.25 mg/m2, 2 patients were unevaluable for assessment of DLT, and no DLTs were encountered in the remaining 3 patients. The final planned cohort 4 was full dose ARRY-520 at 1.5 mg/m2 and carfilzomib 20/27 mg/m2, where 1/6 patients encountered a DLT of non-neutropenic fever and pneumonia. Therefore, the MTD of ARRY-520 with carfilzomib 20/27 mg/m2 was established at 1.5 mg/m2. Among 19/20 patients evaluable for efficacy, for an ORR (≥ MR) was 58%: including nCR (n=1), uPR/PR (n=6), MR (n=4), uSD/SD (n=4) and PD (n=4). Among 20 pts enrolled to date, 10 patients remain on study, 6 discontinued due to progressive disease, 1 pt was lost to follow-up, 1 patient died with febrile neutropenia in cycle 4 related to treatment, and 2 pts withdrew consent after 1 cycle of therapy. Treatment emergent SAEs included 5 pts with 6 incidences of pneumonia (influenza; n=1), 1 patient each with G3 bacteremia, G2 lethargy, G3 febrile neutropenia(FN) and G5 FN. Conclusions MTD has been established at the maximum planned dose level 4, with carfilzomib 20/27mg/m2 and ARRY-520 at 1.5 mg/m2. ARRY-520 can be safely combined carfilzomib in patients with RRMM and the combination is well tolerated with limited hematologic toxicity with growth factor support. The combination is very active in a heavily pretreated patient population with an ORR (≥MR) of 58%. Enrollment in a dose expansion at dose level 4 is underway. In addition a second dose escalation of ARRY-520 and increasing doses of carfilzomib in a 30 minute infusion is also enrolling. Disclosures: Shah: Array biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Millennium: Research Funding; Novartis: Honoraria, Research Funding. Off Label Use: ARRY-520 in relapsed/refractory myeloma. Thomas:Celgene: Research Funding; Novartis: Research Funding; Millenium: 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. Hilder:Array BioPharma: Employment. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: 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: 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.

Description: Mood disorders and schizophrenia are common and complex disorders with consistent evidence of genetic and environmental influences on predisposition. It is generally believed that the consequences of disease, gene expression, and allelic heterogeneity may be partly the explanation for the variability observed in treatment response. Correspondingly, while effective treatments are available for some patients, approximately half of the patients fail to respond to current neuropsychiatric treatments. A number of peripheral gene expression studies have been conducted to understand these brain-based disorders and mechanisms of treatment response with the aim of identifying suitable biomarkers and perhaps subgroups of patients based upon molecular fingerprint. In this review, we summarize the results from blood-derived gene expression studies implemented with the aim of discovering biomarkers for treatment response and classification of disorders. We include data from a biomarker study conducted in first-episode subjects with schizophrenia, where the results provide insight into possible individual biological differences that predict antipsychotic response. It is concluded that, while peripheral studies of expression are generating valuable results in pathways involving immune regulation and response, larger studies are required which hopefully will lead to robust biomarkers for treatment response and perhaps underlying variations relevant to these complex disorders.