ALBERT

Description: Background: Spleen tyrosine kinase (Syk) is a mediator of B-cell receptor signaling in normal and transformed B-cells. Entospletinib is an orally bioavailable, selective inhibitor of Syk (Kd 7.6 nM, no other kinase 〈 100 nM). Methods: This Phase 2 trial is evaluating Entospletinib 800 mg BID in a 41 subject cohort with previously treated FL in a study of 165 subjects with lymphoid malignancies. Tumor imaging was planned at weeks 8, 16, 24 and then every 12. Tumor response was assessed per Cheson 2007 criteria. Results: For the subjects with FL included in this analysis, median age was 67 years (range 41 – 89), 49% were male. The median number of prior Rx regimens was 2 (range 1-8). Prior treatments (Rxs) included anti-CD20 antibodies (rituximab 100%, ofatumumab 5%), alkylating agents (95%; bendamustine 51%) and anthracyclines (51%). Baseline risk factors: Ann Arbor Stg III-IV (66%), Gr 3a FL (27%), FLIPI ≥3 (34%). At the time of this analysis, 41 subjects with follicular lymphoma were enrolled and 38 subjects have been treated through first response assessment (1 subject ongoing prior to first response assessment, 1subject discontinued due to AE and 1 subject withdrew consent). Entospletinib was generally well tolerated. The most common TEAEs (any Grade/≥Gr 3, independent of causality) were fatigue (46%/12%), nausea (42%/2%), diarrhea(27%/0%), decreased appetite (22%/0%), vomiting (22%/0%) and common laboratory abnormalities were increased AST (37%/17%), increased ALT (34%/20%), increased total bilirubin (27%/5%), anemia (34%/10%) and neutropenia (22%/10%). Reversible Grade 3 or 4 ALT/AST elevations occurred in 8 (19.5%) FL subjects. 3 subjects died while on study: 2 from progressive disease and 1 from acute renal failure investigator reported as unrelated to study drug. Investigator response assessments are available for 29 subjects, 16/29 (55%) subjects experienced reduced tumor bulk measured by SPD; 3 (10%) achieved a decrease of ≥ 50%. CR has not been observed at this early evaluation. 14/41 subjects continue on Rx. Median duration of Rx for all patients was 15 weeks. Among all patients who experienced reduction in tumor volume, median duration of Rx was 25 weeks (range 4-51). Conclusions: Entospletinib monotherapy given with this dose and schedule was generally well tolerated and demonstrated moderate activity in subjects with advanced relapsed FL, including those with poor prognostic features. Updated data with longer follow-up duration will be presented at the meeting. Disclosures Sharman: Gilead Sciences: Research Funding. Klein:Gilead Sciences: Research Funding. Boxer:Gilead Sciences: Research Funding. Kolibaba:Gilead Sciences: Research Funding. Hawkins:Gilead Sciences: Research Funding. Abella:Gilead Sciences: Employment, Equity Ownership. Wu:Gilead Sciences: Employment, Equity Ownership. Yasenchak:Gilead Sciences: Research Funding.

Description: Background: Adult patients undergoing remission-induction (RI) chemotherapy for newly diagnosed acute lymphoblastic leukaemia (ALL) are at high risk of invasive fungal disease (IFD), particularly invasive aspergillosis. The prevalence of IFD in this population has not been widely studied. There is currently no approved standard for antifungal prophylaxis and it is recommended by the European Working Group for Adult ALL that azole antifungal agents be avoided because of drug interactions with vincristine, a standard component of induction chemotherapy regimens. Methods: This was a double-blind, multicentre, placebo-controlled study in patients aged ≥18 years receiving RI chemotherapy for newly diagnosed ALL. Study subjects received either liposomal amphotericin B (L-AMB) 5mg/kg or placebo by IV infusion twice weekly in a 2:1 random allocation. The primary endpoint of the study was the proportion of subjects with proven or probable invasive fungal infection (IFI) assigned in a blinded review by an independent data review board (IDRB) using EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group) definitions (1). Subjects were closely monitored for signs and symptoms of IFI, including biweekly galactomannan and β-D-glucan assessments. Clinical, laboratory or radiographic findings suggestive of IFI prompted further investigation according to a specified protocol. Subjects with defined clinical and mycological criteria or a halo sign on chest CT had prophylaxis interrupted and pre-emptive antifungal therapy initiated while further diagnostic procedures were undertaken. Prophylaxis was stopped when subjects met protocol-specified criteria for proven or probable IFI and appropriate antifungal therapy started. Secondary objectives included safety and tolerability of prophylactic L-AMB and the impact of IFI prevention on the efficacy of RI chemotherapy. Results: A total of 355 subjects from 83 centres in 13 countries in Europe (including Turkey and Israel) and South America were randomised and received at least 1 dose of either L-AMB (n=237) or placebo (n=118). Sixteen subjects were excluded from the efficacy analysis, 1 due to misdiagnosis (AML) and 15 due to protocol-prohibited antifungal treatment. 7.9% (18/228) subjects in the L-AMB group and 11.7% (13/111) subjects in the placebo group were considered by the IDRB to have experienced a proven or probable IFI (p=0.24, RR 0.33 [CI -0.32 to 0.66]). Of these, 1 case (0.4%) in the L-AMB group and 3 cases (2.7%) in the placebo group were considered proven. In subjects who were neutropenic (absolute neutrophil count 5%) study drug-related adverse events (AEs) were hypokalaemia (10.5% [25/237] vs 3.4% [4/118] p=0.02) and increased creatinine (6.3% [15/237] vs. 0% [p=0.003]). Complete remission at the end of RI chemotherapy was achieved by 72.6% (172/237) subjects in the L-AMB group versus 78.8% (93/118) subjects in the placebo group (p=0.24). Conclusions: In this study, the largest of its kind to date, the rate of IFI among adult patients undergoing RI chemotherapy for newly diagnosed ALL was 11.7% in the placebo group. Study subjects who received L-AMB at 5mg/kg twice weekly for prophylaxis showed a reduction in IFIs relative to placebo (RR 0.33 [CI -0.32 to 0.66]), although this did not reach statistical significance (p=0.24). L-AMB prophylaxis was generally well tolerated. The incidence of IFI in patients with ALL receiving RI therapy indicates that antifungal prophylaxis is merited in this patient population. Further analysis is needed to determine which patients might benefit the most. clinicaltrials.gov number: NCT01259713 (1) De Pauw et al 2008 Clin Infect Dis 46: 1813–1821 Disclosures Cornely: Gilead Sciences: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Liposomal Amphotericin B (AmBisome®) is a broad spectrum antifungal agent indicated for the treatment of severe systemic and/or deep mycoses, empiric treatment of presumed fungal infections in febrile neutropenic patients and treatment of visceral leishmaniasis. In this study the efficacy, safety and tolerability of prophylactic liposomal amphotericin B (AmBisome®) was explored for the prevention of invasive fungal infections in subjects receiving remission-induction chemotherapy for Acute Lymphoblastic Leukaemia (the AmBiGuard trial).. Leguay:Gilead Sciences: Research Funding. Maertens:Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Castagnola:Gilead Sciences: Research Funding. Anagnostopoulos:Gilead Sciences: Research Funding. Allione:Gilead Sciences: Research Funding. Heussel:Gilead Sciences: Consultancy, Speakers Bureau. Donnelly:Astellas, Gilead, Merck, Pfizer: Consultancy, Honoraria, Research Funding. Agrawal:Gilead, Pfizer, Astellas, MSD, Bio-Rad: Honoraria, Research Funding. Garner:Gilead Sciences: Employment, Equity Ownership. Simcock:Gilead Sciences: Employment, Equity Ownership. Hawkins:Gilead Sciences: Employment, Equity Ownership. Goekbuget:Gilead Sciences: Consultancy, Honoraria.

Description: Title Phase 2 Trial of GS-9973, a selective Syk inhibitor, has Activity in Subjects with Chronic Lymphocytic Leukemia (CLL) Introduction Spleen tyrosine kinase (Syk) is an essential mediator of B-cell receptor signaling in normal and transformed B-cells. GS-9973 is an orally bioavailable, small-molecule, selective inhibitor of Syk. The Kd of GS-9973 for Syk was 7.6 nM with no other kinase 〈 100 nM (Ambit scanMax at 10 mM). Methods and Subjects This Phase 2 trial enrolled subjects with CLL (1 cohort) or NHL (4 cohorts) of 40 subjects each. All subjects were treated with GS-9973 800 mg BID. Tumor imaging was conducted at weeks 8, 16, 24 and every 12 weeks thereafter. Response was evaluated according to standard criteria for CLL (Hallek 2008 and Cheson 2012). GS-9973 plasma levels were obtained throughout the study and concurrently obtained circulating CD5+CD19+ leukemic cells were assessed for changes in pSyk, pBLNK, pBTK and pAKT expression using a PhosFlow protocol. Chemokine/cytokine plasma levels were assessed using multiplexed bead suspension arrays. Results This study initiated in March 2013. At time of data lock, 56 subjects with CLL/SLL (32) or NHL(24) have been enrolled. 18 subjects with CLL/SLL and 16 subjects with NHL (10 iNHL, 3 DLBCL and 3 MCL) have completed ≥ 4 weeks of treatment and are included in the safety analysis. Median age was 71 (range 55 - 88), 65% were male. The median number of prior treatment regimens was 5 (range 1-14). All CLL/SLL subjects had received an anti-CD20 antibody, 89% had received an alkylating agent (56% had bendamustine) and 72% had received fludarabine. Investigator assessed week 8 efficacy analysis is available for 22/54 patients which included 13 CLL/SLL subjects, 7 of whom had 17p deletions and/or TP53 mutations. At the week 8 evaluation all subjects experienced reduced tumor bulk: 4 subjects achieved a decrease of 〉 50% in their measurable lymph node disease; 8 had 〈 50% decrease. One subject with a marked decrease in peripheral lymphadenopathy had unequivocal progression of non-measurable mediastinal disease and was considered to have disease progression. The waterfall plot is provided; the striped bars represent those CLL/SLL subjects with a 17p deletion and/or TP53 mutation. GS-9973 was generally well tolerated. 30 of 34 (88%) of subjects experienced an adverse event. All treatment emergent adverse events occurring in ≥ 10% of 34 subjects are listed in the table. Reversible Grade 3 or 4 transaminase elevations occurred in 4 subjects. Two of the 34 subjects who received at least 1 dose of GS-9973 died while on study: 1 from progressive disease, 1 from pneumonia that occurred after 7 days on study. The absolute lymphocyte count in CLL/SLL subjects increased a mean of 200%, by day 8 and then declined. Decreases in pSyk levels occurred in leukemic cells from 8 of 11 CLL/SLL subjects. The results of the disease-associated chemokines/cytokines assays are pending. Conclusions GS-9973 given on this dose and schedule was generally well tolerated. At the initial 8-week response assessment GS-9973 demonstrated activity in subjects with CLL/SLL, including those with poor prognostic features. Updated data on the larger cohort of CLL/SLL subjects will be presented. Disclosures: Sharman: Gilead Sciences: Research Funding. Hawkins:Gilead Sciences: Employment, Equity Ownership. Hu:Gilead Sciences: Employment, Equity Ownership. Reddy:Gilead Sciences: Employment, Equity Ownership. Jin:Gilead Sciences: Employment, Equity Ownership. Melchor-Khan:Gilead Sciences, Inc.: Employment, Equity Ownership.