Gabrilove, Janice

8032 Background: Btk supports activation, survival, and proliferation of malignant B cells in CLL and B-NHL. AVL-292 is an oral, potent (IC50 < 0.5nM), selective small molecule covalent inhibitor of Btk. Methods: Patients (pts) with previously treated CLL or B-NHL were administered AVL-292 in escalating cohorts of 125, 250, or 400 mg po QD using a 3+3 design in continuous 28 day cycles until progressive disease (PD) or toxicity. Key objectives were safety, DLT, MTD, PK, and Btk occupancy. Plasma AVL-292 levels were assessed by LC-MS-MS. Btk occupancy by AVL-292 was assessed by covalent probe assay in peripheral blood mononuclear cells. Results: 12 pts have enrolled (3 each at 125 and 250 mg and 6 at 400 mg: 5M/7F; median age 68 years, range 45-79; median 2.5 prior therapies, range 1-10) including 8 CLL (2 with 17p-, 2 with 11q22-, 2 with both 17p-/11q22-; 2 mutated IGHV, 5 unmutated IGHV, 1 missing) and 4 B-NHL (1 diffuse large B cell lymphoma (DLBCL); 1 follicular (FL); 2 marginal zone (MZL)). Median time on treatment is 65 days, range 28-158. Ten of 12 pts continue on treatment: 1 pt (DLBCL) discontinued for PD after 1 cycle and 1 pt (FL) for DLT (Gr 4 plts; 400 mg QD). No other DLTs or grade 4 adverse events (AEs) have occurred and MTD has not been reached. Most frequent AEs reported include transient diarrhea, rash/skin infection, URI, nausea, and fatigue. Gr 3 AEs include 1 atrial fibrillation (not drug related) and 1 ANC low (probably drug related). To date, 8 of 8 CLL patients have stable disease (SD) with median 28% decrease from baseline lymph node measurement (range 3-40% decrease). Six of 8 pts with CLL experienced increased ALC in cycle 1: median increase 89.5% (range 50-212%). Two of 4 NHL pts have SD (both MZL), 1 PD (DLBCL), and 1 not evaluable due to DLT (FL). Full Btk occupancy was achieved with dose levels ≥ 250 mg. Multiple dose PK exposure (AUClast) was linear with no accumulation from Day 1 to 15. Conclusions: AVL-292 was well tolerated from 125-400 mg po QD and early efficacy analysis in CLL and B-NHL shows 10/11 efficacy evaluable pts with SD. Full Btk occupancy was achieved with ≥ 250 mg QD and PK was predictable with no accumulation. Dose escalation is ongoing and MTD cohort expansion is planned.

Abstract Background Therapy-related myeloid neoplasm (tMN) includes t-myelodysplasia (tMDS) and t-acute myeloid leukemia (tAML) and are serious late effects of the treatment of cancer. Prognosis of tMN is poor, related to the increased frequency of adverse cytogenetics and other clinical features which predict poor response to conventional treatment. Over the last years, azacitidine (AZA) has become the standard of treatment for high risk MDS (Silverman, JCO 2002; Fenaux, Lancet Oncol 2009) and has shown efficacy in AML. AZA represents an interesting option for patients with tMN considering its safety profile and its efficacy in poor prognosis subgroups of apparently de novo MDS patients including those with monosomy 7. Most prospective trials of AZA have excluded patients with tMN. Most tMN data are retrospective or registry studies (Bally, Leuk Res 2013). This abstract presents the results of 47 t-MN patients prospectively enrolled as a specific cohort in the E1905 study. Methods E1905 study is a randomized phase 2 study from the North American Leukemia Intergroup (NCT00313586, Prebet , ASH 2010) testing 10 days of AZA (50mg/m2/d s.c.) vs. 10 days of AZA + the histone deacetylase inhibitor entinostat (4 mg/m2/d PO days 3 and day 10). 6 cycles of treatment were planned; responding patients could receive up to 24 cycles. MDS, CMML, and AML with myelodysplasia-related changes were included. Patients with tMN were subsequently accrued as a separate cohort after amendment of the protocol. Response was assessed using IWG 2000 criteria (Cheson et al, Blood 2000); the primary endpoint of the overall trial was achievement of a normal hemogram in 25% of treated patients in either treatment arm. Results A total of 47 patients were included. Median age was 70 years (39y-83y), 45% male, and 94% of patients had ECOG PS 0-1. 29 patients could be subclassified as t-MDS and 18 as t-AML. At inclusion, median peripheral blood counts were: neutrophils 1.0 G/l, Platelets 35 G/L, Hemoglobin 9.2 g/l, peripheral blood blasts 0%, marrow blasts 14.0%. 68% of patients were RBC transfusion dependent and 40% platelet transfusion dependent. As expected, the cytogenetic evaluation showed a high frequency of unfavorable risk cytogenetics (74%) as compared to normal or intermediate risk cytogenetics (26%). Baseline characteristics were not statistically different between the 2 arms. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4 and was significantly higher in patients treated with AZA monotherapy (6 cycles vs.3 cycles, p=0.008). 8 patients in the combination arm and 1 patient in the AZA monotherapy arm died of infection or hemorrhage before cycle 3. In an intent to treat analysis, overall response rates (CR, PR, or trilineage Hematologic improvement) were 11/24 (46%) in AZA monotherapy (95% CI 26 – 67%) and 4/23 (17%) in the combination arm (95% CI 5 – 39%, p=0.06 comparing the two arms). Median overall survival in the two arms were 12.8 months and 5.7 months (p=0.008). Conclusions In this group of very high risk patients with therapy-related myeloid neoplasms, the use of the novel 50 * 10 schedule of azacitidine monotherapy appears effective, with response rates comparable to those for patients with de novo MDS/AML treated on the same protocol (74 pts, 40% with unfavorable cytogenetics, ORR=32%, median OS=18 months). Because there are no prospective data examining the approved dose schedule of AZA (75 mg/m2/day * 7 days), it is not clear if this surprisingly high response rate derives from the current extended schedule of lower dose AZA, or would be true with standard dose AZA as well. This high response may enable many of these patients to proceed to allogeneic stem cell transplant. Entinostat combined with azacitidine at the dose and schedule applied in E1905 does not appear to be effective and tolerable as compared to azacitidine alone. Disclosures: Prebet: CELGENE: Honoraria. Off Label Use: Use of azacitidine in acute myeloid leukemia. Gore:CELGENE: Equity Ownership, Research Funding.

Abstract Abstract 4013 Background: In recent years, azacytidine (AZA) has become the standard of treatment for high risk myelodysplasia (MDS). The approved schedule of AZA uses a 75mg/m2/d s.c. regimen for 7 days based on the CALGB-9221 (Silverman, JCO 2002) and the AZA-001 studies (Fenaux, Lancet Oncol 2009). The clinical response rates after AZA have been extensively presented but there is only limited data on the rates of cytogenetic response (CyR). Based on the review of the literature, there are no specific cytogenetic data published on prospective trials. Methods: We based our analysis on a randomized phase 2 study from the US Leukemia Intergroup (E1905 study, NCT00313586) testing 10 days of AZA (50mg/m2/d s.c.) vs 10 days of AZA+ the histone deacetylase inhibitor entinostat (4 mg/m2/d PO days 3 and day 10). MDS, CMML, and AML with myelodysplasia-related changes were included. This analysis includes all patients with cytogenetic abnormalities (at baseline or acquired following treatment) with available cytogenetic follow-up (cycle 6). Of 150 patients, 70 demonstrated baseline cytogenetic abnormalities. To date, forty patients (27 MDS and 13 AML) were evaluable for both time points. Karyotypes were performed at local laboratories, and reviewed centrally (RPK and GH). Cytogenetic response was assessed using IWG 2000 (Cheson et al, Blood 2000) criteria. Results: The clinical response rate (CR+PR+ trilineage HI) according to IPSS cytogenetic risk stratification were of 20%, 33%, and 35% for favorable, intermediate and poor cytogenetic risk groups respectively (p=NS). Patients with Chr 7 abnormalities (i.e. -7 or -7q, n=18) had a response rate of 28% including 17% CR. Of patients with complete cytogenetic data, the rate of overall CyR was 52% (n=21): 22% (n=9) complete CyR, 30% (n=12) partial CyR. This represents a complete CyR of 13% and a partial CyR of 23% as a proportion of all treated patients with initial cytogenetic abnormalities (including those who did not receive six cycles of therapy). To date, confirmatory FISH analyses were available for 4 patients with CyR (2 CCyR and 2 PCyR). All four had complete clearance of their cytogenetic clone. Among the cytogenetic responders, 15 had MDS and 6 had AML (p=NS). CyR did not differ between the two treatment arms. CyR and clinical response were highly correlated (p<0.001): all patients with complete CyR and 7/10 partial CyR had a clinical CR. Only 3 patients (1 CCyR and 2 PCyR) had a CyR without associated clinical response. Among 8 patients with cytogenetic progression, 3 pts showed increased frequency of a known aberration and 5 showed new or additional aberration including 2 cases involving Chr7. 65 AZA-treated patients from AZA001 had comparable cytogenetic results available. Only 3 patients experienced complete CyR 4.6% with 33.8% partial CyR (n=22). In contrast, the reported rate of clinical response was similar in the two studies. Complete CyR were more frequent in the E1905 10 days AZA schedule compared to the 7 days AZA schedule (p=0.007). There was no difference in overall CyR between the two studies. Conclusions: Both the standard AZA schedule and the 10 day schedule administered on E1905 lead to high rates of cytogenetic response. The novel schedule explored in E1905 demonstrated a particularly high rate of complete CyR (22%) with complete clearance of abnormal clone by FISH in 4 tested patients. Further prospective comparison of different AZA schedules will be needed to confirm this higher rate of complete CyR and determine its clinical significance. Disclosures: Beach: Celgene: Employment. Gore:Celgene: Consultancy, Research Funding, stock options; Syndax: Consultancy.

Abstract Introduction CC-292, an oral, highly selective, small-molecule irreversible-inhibitor of Btk is under investigation for the treatment of CLL and other B-cell malignancies. This phase 1 trial investigated the safety, dose limiting toxicities (DLT), and clinical activity of CC-292 monotherapy in subjects with relapsed or refractory (R/R) CLL or non-Hodgkin's lymphoma. This interim analysis focused on the safety and clinical activity in subjects with CLL and small cell lymphocytic leukemia (SLL). Methods Eligible subjects with R/R (≥ 1 prior therapy) CLL/SLL were treated with monotherapy CC-292 in a dose-escalation study with doses ranging from 125 mg to 1000 mg QD and BID dose levels of 375 mg and 500 mg. As a maximum tolerated dose was not established, CLL patients have been enrolled in an early dose expansion cohort of 750 mg QD and preliminary recommended phase 2 dose expansion cohort at 500 mg BID. All subjects received continuous dosing in 28-day cycles until progressive disease or intolerable toxicity. Clinical activity was investigator assessed per the 2008 iwCLL criteria. Results 83 subjects with R/R CLL/SLL have been enrolled as of June 30, 2013. Baseline characteristics include median age of 67 years (34-89), 52% Rai stage 3/4 disease, median 3 prior therapies (1-12), and 34% refractory to last treatment. Poor-risk factors were present in 67% of subjects, including del11q (22%), del17p (24%), and unmutated IgVH (54%). 67% of subjects remain on study. Subjects have received a median of 6 treatment cycles (0.2-21.6). The most frequent grade 3/4 adverse events (AEs) included neutropenia (21%), thrombocytopenia (15%), pneumonia (10%), and anemia (8%). Rates of febrile neutropenia were low (4%). The most common treatment-emergent AEs (≥ 10% of subjects) were diarrhea (59.7%), fatigue (37.5%), neutropenia (26.4%), thrombocytopenia (26.4%), nausea (26.4%), pyrexia (22.2%), headache (19.4%), cough (19.4%), upper respiratory infection (16.7%), peripheral edema (15.3%), abdominal pain (15.3%), dizziness (13.9%), muscle spasms (13.9%), contusion (13.9%), anemia (12.5%), pneumonia (12.5%), sinusitis (12.5%), and urinary tract infection (11.1%). One CLL patient at the 500 mg BID dose level has experienced a drug-related adverse event of grade 4 thrombocytopenia during Cycle 1 that was assessed as a DLT. The number of patients discontinuing study treatment due to AEs was low (2.4%). Results are summarized for efficacy-evaluable patients treated at the 4 dose levels where at least a partial response (PR) was achieved (750 mg, 1000 mg, 375 mg bid and 500 mg bid) (n = 55). During cycle 1, 89% experienced a ≥ 25% increase in absolute lymphocyte count (ALC), which usually resolved with continued treatment. The table below details the best responses achieved to date. In subjects with del11q, del17p, unmutated IgVH, and no high-risk genomic factors, the PR rate was 42% (5/12), 25% (3/12), 44% (7/16), and 47% (7/15), respectively. Importantly, nodal responses were induced in the majority of subjects receiving BID dosing (375 mg: 67%; 500 mg: 62%) with an overall PR rate of 40%. When achieved, nodal responses were typically observed by cycle 2 and were sustained with continued treatment. Although the sample size is small, subjects treated at 375 mg or 500 mg BID showed continued lymph node size reduction over time from cycle 2 (mean reduction of 42% and 45%, respectively) to cycle 7 (mean reduction of 60% and 71%, respectively). Conclusion CC-292 is well tolerated as an oral daily therapy. Single-agent therapy with CC-292 is sufficient to achieve high nodal and partial response rates in relapsed/refractory CLL subjects, including those with high-risk genomic features. These results support continued development of CC-292 for the treatment of patients with CLL/SLL. Disclosures: Brown: Pharmacyclics: Consultancy; Genentech: Consultancy; Celgene: Consultancy, Research Funding; Emergent: Consultancy; Onyx: Consultancy; Sanofi Aventis: Consultancy; Vertex: Consultancy; Novartis: Consultancy; Genzyme: Research Funding. Off Label Use: The abstract shows scientific information on CC292 which is an investigational product developed by Celgene. This investigational product is not approved by any health authority for any indication. Harb:Celgene: Research Funding. Hill:Celgene: Honoraria, Research Funding. Sharman:Celgene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Cylene Pharmaceuticals: Consultancy, Research Funding; Avila Pharmaceuticals: Consultancy, Research Funding. Barr:Celgene: Consultancy. Foran:Celgene: Research Funding. Burger:Pharmalytics: Research Funding; Gilead: Research Funding. Mahadevan:Novartis: Speakers Bureau; Millennium: Speakers Bureau. Ma:Genentech: Consultancy; Abbvie: Consultancy. Barnett:Celgene: Employment, Equity Ownership. Marine:Celgene: Employment, Equity Ownership. Nava-Parada:Celgene: Employment, Equity Ownership. Azaryan:Celgene: Employment, Equity Ownership. Mei:Celgene: Employment, Equity Ownership. Kipps:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

AbstractTherapy‐related myeloid neoplasms (tMN) are serious late effects of the treatment of cancer with poor response to conventional treatment. Azacitidine (AZA) has been used to treat patients with tMN but current data are retrospective. We present here 47 tMN patients prospectively enrolled as a specific cohort in the E1905 study. TheE1905 study was a randomized phase 2 study (NCT00313586) testing 10 d of AZA (50 mg/m2/d) +/− the histone deacetylase inhibitor entinostat (4 mg/m2/d PO day‐3 and day‐10). A total of 47 patients [29 therapy‐related myelosyspastic syndrome (t‐MDS) and 18 therapy‐related acute myeloid leukaemia (t‐AML)] were recruited to the study. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4, significantly higher in patients treated with AZA (6 cycles vs. 3 cycles, P = 0·008). Haematological normalization rates were 46% in monotherapy and 17% in the combination arm. Median overall survivals were 13 and 6 months, respectively. The novel 50 * 10 schedule of azacitidine appears effective, with response rates, when given as single agent, comparable to those for patients with de novo MDS/AML treated on the same protocol. However, the combination of AZA and entinostat was associated with increased toxicity and could not be recommended for treatment of tMN.

SummaryReliable clinical or molecular predictors of benefit from azacitidine therapy in patients with myelodysplastic syndromes (MDS) are not defined. Doubling of platelet count at start of second cycle of azacitidine therapy compared to baseline was associated with achieving response and survival advantage in a Dutch cohort. To validate this observation, we analysed a larger cohort of North American patients, whose data was collected in a prospective clinical trial with a longer median follow‐up. We found a significant association between platelet count doubling after first cycle of azacitidine therapy and probability of achieving objective response. Among patients with MDS or oligoblastic acute myeloid leukaemia (<30% bone marrow blasts, n = 102), there was a statistically significant reduction in risk of death for patients who achieved platelet count doubling (n = 23, median OS, 21·0 months) compared to those who did not (n = 79, median OS, 16·7 months, adjusted hazard ratio (no/yes)=1·88, 95% confidence interval, 1·03–3·40, P = 0·04). Nonetheless, the addition of this platelet count doubling variable did not improve the survival prediction provided by the revised International Prognostic Scoring System or the French Prognostic Scoring System. Identification of reliable and consistent predictors for clinical benefit for azacitidine therapy remains an unmet medical need and a top research priority.