ALBERT

Description: Background: We have previously reported results from a Phase 2 trial in which both treatment naïve (TN) and relapsed/refractory (R/R) pts with stable disease (SD) or a clinical response (PR or CR/CRu) following 4 weekly doses of rituximab received mitumprotimut-T active immunotherapy (Koc et al, Blood2006; 108: #691). We report here 4-year follow up of conversion of pts into complete remission (CR/CRu) and an assessment of the DUR in this population. Treatment: Pts received rituximab (375mg/m2 iv weekly x 4) and those with ≥SD assessed at Week 11 received mitumprotimut-T, 1 mg sq every month (mo) x 6 starting on Week 12 along with Leukine (sargramostim, GM-CSF), 250 mcg, sq on Days 1–4. Pts continued to receive booster injections on a reduced schedule (every 2 mos x 6, then quarterly) until disease progression. Radiological scans were performed every 3 mos for the first 2 years then every 6 mos, and reviewed centrally. Objective response and progression were assessed using modified IWG criteria. Results: 89 pts (54 RR, 35 TN) had ≥SD following rituximab received mitumprotimut-T + Leukine. Two pts (RR) achieved a CR following rituximab and prior to receiving mitumprotimut-T. As shown in Fig. 1, an additional 16 pts (9 TN, 7 RR) converted to CR/CRu over the next 31 mos. At a median follow-up of 42 mos, only 6 (3 TN, 3 RR) of the 18 CR pts have relapsed (Fig. 2). Discussion: Long-term follow-up has shown a continuing conversion of pts into CR occurring as late as 31 mos. These data suggest clinical activity of mitumprotimut-T in these pts as determined by the increasing CR rate and the durability of this response. These data are of particular interest since a blinded interim analysis of best response in an ongoing controlled Phase 3 study of single agent rituximab vs. rituximab followed by mitumprotimut-T showed 47% of pts in this study to be in CR/CRu with 12–18 mos of follow-up (Freedman et al, Blood2006; 108: #2756). Figure Figure Figure Figure

Description: Background: Id/KLH vaccine (FavId) administered as a single agent has been associated with tumor regressions in patients with relapsed/refractory (RR) FL. B-cell depletion has been demonstrated to augment the T-cell immune response to subsequent vaccine administration in mice (Qin 1998 Nat Med 4:627). Objective: To evaluate the efficacy and safety of Id-KLH administered during the period of rituximab induced B-cell depletion. Eligibility: FL pts who were: treatment naïve (TN); RR following chemotherapy; or relapsed following rituximab. Treatment: Following rituximab (375mg/m2 i.v. weekly x 4) pts received Id-KLH (1 mg s.q. monthly x 6) starting on week 12. GM-CSF, 250 mcg, was administered s.q. at the Id-KLH injection site on days 1–4. Pts could continue Id-KLH until progression. Results: 103 pts received rituximab. Response to rituximab at month 3 was 35% (3-CR; 33-PR). Eleven (11) pts were PD following rituximab (11%). Id/KLH could not be made for 4 pts (4%). Eighty-eight (88) pts were begun on Id-KLH. Among the 45 RR pts, 32 (72%) have not progressed at a median follow-up of 12 months compared with 40% of historical control pts treated with rituximab alone (Witzig 2002 JCO 20:2453). Among the 43 TN pts, 82% have not progressed after a median follow-up of 9 months. RRI (SD to PR, PR to CR after month 3) was observed in 21 pts (12-SD to PR; 9-PR to CR). Robust T-cell responses to both Id and KLH were observed (3 of 3 pts tested). Anti-KLH antibody responses were generally not seen until B-cell recovery. The most frequent adverse event was an injection site reaction. A flu-like syndrome was also observed consistent with GM-CSF administration. Conclusion: Id/KLH vaccine (FavId), administered to pts with FL during a period of B-cell depletion induced by rituximab, can result in an anti-Id T-cell response, and appears to result in an RRI and an increased TTP compared to historical controls. A randomized, double-blind, placebo-controlled, Phase 3 trial of rituximab + FavId has been initiated.

Description: AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin receptor. We report pooled data on acute use of immunoglobulin (IVIG or Anti D) in both splenectomized and nonsplenectomized patients from 2 randomized, double blind, placebo-controlled Phase 3 studies designed to evaluate the efficacy and safety of AMG 531 in adult patients with chronic ITP. Patients were randomized to receive either AMG 531 or placebo at a 2:1 ratio, and concomitant medications were continued. Of the 125 patients enrolled, 63 were splenectomized (placebo, 21; AMG 531, 42), and 62 were nonsplenectomized (placebo, 21; AMG 531, 41) with a median age of 52 years (range 21 to 88) and a mean baseline platelet count of 16.5x109/L. Immunoglobulin was allowed as rescue medication when medically necessary at the discretion of the physician. For both trial arms, we calculated the percentage of patients requiring immunoglobulin intervention in each month of treatment, and the age and sex-adjusted 24-week cumulative probability of immunoglobulin use. No difference was observed between splenectomized and nonsplenectomized patients; therefore pooled results are shown. Fisher’s exact tests and Log-Rank tests were used to compare the between-arm differences. We also performed subgroup analyses of immunoglobulin use in overall responders (defined as either platelet count ≥50x109/L for ≥6 weeks during the last 8 weeks of the 24-week treatment period in the absence of rescue medications at any point in the study, or ≥4 weekly platelet counts ≥50x109/L in the absence of rescue medications in the previous 8 weeks), and placebo patients. In the 24-week study period, there were 19 immunoglobulin administrations among 83 AMG 531 patients, and 68 immunoglobulin administrations among 42 placebo patients. The cumulative probability of incurring immunoglobulin use in 24 weeks was 0.51 (SE: 0.08) for the placebo arm and 0.13 (SE: 0.04) for the AMG 531 arm (see Figure), with a hazard ratio of 5.31 (95% CI: 2.55–11.06, p

Description: Introduction: Acute painful episodes, frequently called sickle cell-related pain crises (SCPC), are a substantial cause of morbidity in sickle cell disease (SCD). Although hydroxyurea (HU) is known to decrease the frequency of SCPC in sickle cell anemia, many patients continue to experience acute painful episodes despite such therapy. P-selectin is an adhesion molecule expressed on activated vascular endothelial cells and platelets. It is a key molecule in the initiation of leukocyte rolling on the vessel wall that leads to firm attachment and extravasation to underlying tissues during inflammation. Upregulation of P-selectin on endothelial cells and platelets also contributes to the cell-cell interactions involved in the pathogenesis of SCPC. The SUSTAIN study evaluated the safety of SelG1, a first-in-class humanized anti-P-selectin antibody, and its effect on the frequency of SCPC in SCD patients. Methods: We conducted a randomized, double-blind, placebo-controlled, multinational study. Patients were randomized to receive placebo, 2.5 mg/kg or 5.0 mg/kg SelG1; patients received their initial dose, a dose 14 days later, and then every 4 weeks through week 50 for a total of 14 doses. The primary efficacy endpoint was the annual rate of SCPC in the 5.0 mg/kg SelG1 group vs. placebo. A hierarchical testing procedure was employed (α = 0.05 for high dose vs. placebo, and if significant, low dose vs. placebo). An SCPC was defined as acute sickle cell-related pain that resulted in a visit to a medical facility and required a parenteral or oral narcotic or parenteral NSAID. Acute chest syndrome (ACS), priapism, hepatic and splenic sequestration were also included in this definition. A blinded, independent committee adjudicated all SCPC events. Key inclusion criteria included patients 16 to 65 years of age; diagnosis of SCD (HbSS, HbSC, HbSβ0 thalassemia or HbSβ+ thalassemia); and history of 2 to 10 SCPC in the previous 12 months. Patients receiving HU or erythropoietin were included if prescribed for the preceding 6 months and dose was stable for at least 3 months. The randomization was stratified by historical SCPC in the prior year (2-4 or 5-10) and concomitant HU use (yes or no). Secondary endpoints included annual rate of days hospitalized, times to first and second SCPC and annual rate of uncomplicated SCPC (defined as typical SCPC other than ACS, priapism and hepatic or splenic sequestration) and ACS. Results: 198 SCD patients were randomized for the 1-year study. The Intent-To-Treat (ITT) population included all randomized patients; 67, 66 and 65 patients in the 5.0 mg/kg, 2.5 mg/kg and placebo groups, respectively. Demographic parameters were evenly distributed in the treatment groups. The primary endpoint, the annual rate of SCPC in the ITT population at 5.0 mg/kg vs. placebo, was reduced 47% (medians of 1.6 vs. 3.0, p = 0.010, Table 1). The SelG1 drug effect was dose-dependent as the annual rate of SCPC at 2.5 mg/kg vs. placebo was reduced 33% (medians of 2.0 vs. 3.0, p = 0.180). Time to first SCPC at 5.0 mg/kg vs. placebo was increased 2.9-fold (medians of 4.1 vs. 1.4 months, p = 0.001, Fig. 1) and time to second SCPC was increased 2.0-fold (medians of 10.3 vs. 5.1 months, p = 0.022, Fig. 2). The annual rate of uncomplicated SCPC at 5.0 mg/kg vs. placebo was reduced by 62% (medians of 1.1 vs. 2.9, p = 0.015). ACS events were rare in this study. The annual rate of days hospitalized at 5.0 mg/kg vs. placebo showed a non-significant, 42% reduction (medians of 4.0 vs. 6.9, p = 0.450). Adverse events that occurred in 5% or more of patients in an active dose group and were elevated over placebo by at least 2-fold were arthralgia, pruritus, vomiting, chest pain, diarrhea, road traffic accident, fatigue, myalgia, musculoskeletal chest pain, abdominal pain, influenza and oropharyngeal pain. There were no apparent increases in infections with SelG1 treatment. Five deaths occurred during the study, 2 at 5.0 mg/kg, 1 at 2.5 mg/kg and 2 in placebo; no deaths were deemed related to study drug. Conclusions: The P-selectin inhibitor SelG1 significantly reduced SCPC and appeared to be safe and well tolerated. Significant improvements were also achieved for several secondary endpoints including increases in times to first and second SCPC. Chronic inhibition of P-selectin with once a month IV dosing of SelG1 represents a novel and potentially new disease-modifying, prophylactic treatment option for patients with SCD. clinicaltrials.gov: NCT01895361 Disclosures Kutlar: Novartis Pharmaceuticals: Research Funding. Kanter:Novartis: Consultancy. Rollins:Selexys Pharmaceuticals: Equity Ownership, Other: Previous Employment. Stocker:Selexys Pharmaceuticals: Equity Ownership, Other: Previous Employment. Rother:Selexys Pharmaceuticals: Equity Ownership, Other: Previous Employment.

Description: Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin Lymphoma (NHL) accounting for approximately 30-40% of NHL cases. Approximately 40% of all newly diagnosed DLBCL patients are either refractory or relapsed following initial response to therapy and represent a population with high unmet need for new therapeutic strategies to achieve or regain disease remission. Because of the near ubiquity and persistence of CD20 expression in B-cell malignancies, there is strong rationale to develop compounds with novel mechanisms of action targeting CD20. However, CD20's non-internalizing nature has, to date, leveraged only cytotoxic mechanisms such as antibody-dependent cellular cytotoxicity to which resistance can arise and has impeded the development of agents that internalize a cytotoxic payload. MT-3724 is a novel engineered toxin body designed to overcome this limitation by combining the specific target selectivity of a single chain variable fragment with the lethality of a genetically fused Shiga-like toxin A subunit that facilitates both internalization and cell killing by inactivating ribosomal protein synthesis. MT-3724 has been shown to specifically bind and kill CD20+ malignant human B-cells in vitro (IC50

Description: Background: In the pivotal phase 3 FIRST trial, continuous lenalidomide plus low-dose dexamethasone (Rd) improved progression-free survival (PFS), overall survival (OS), and response compared with fixed-duration treatment (Tx) with either Rd or the combination of melphalan-prednisone-thalidomide (MPT) in transplant-ineligible NDMM pts (Facon, Blood 2013). Here we examine if pts achieving complete remission (CR) or at least very good partial response (≥ VGPR) equally benefit from continuous Rd. Methods: Pts were randomized to continuous Rd until progressive disease (PD; N= 535); Rd for 18 cycles (72 weeks) (Rd18; N = 541); or MPT for 12 cycles (72 weeks) (N = 547). The primary endpoint was PFS (continuous Rd vs. MPT). The secondary endpoints included OS, response rate (assessed using IMWG criteria), time to response, duration of response (DOR), time to Tx failure, time to next antimyeloma Tx, health-related quality of life, and safety. With a data cutoff of May 24, 2013, the median follow-up was 37.0 months (mos). Results: In pts who achieved ≥ VGPR, median PFS was significantly longer (NR) with continuous Rd compared with Rd18 (31.0 mos; HR = 0.46; P 〈 0.01) or MPT (34.7 mos; HR = 0.55; P 〈 001). Even greater benefit of continuous Rd was observed compared with Rd18 or MPT in pts who achieved CR, where the median PFS with continuous Rd was NR vs. 45.2 mos with Rd18 (HR = 0.29; P 〈 0.01) and 44.6 mos with MPT (HR = 0.28; P 〈 0.01) (Table 1). In the intent-to-treat population, duration of response (DOR) was 35 mos with continuous Rd, which was significantly longer of almost a year vs. Rd18 (22.1 mos; HR = 0.60; P 〈 0.01) or MPT (22.3; HR = 0.63; P 〈 0.01). Importantly, the DOR was significantly longer with continuous Rd vs. Rd18 or MPT across all response categories, including pts with CR. Median duration of CR was NR vs. 43.6 mos in pts receiving continuous Rd vs. Rd18 (HR = 0.29; P 〈 0.01); ≥ VGPR, NR vs. 29.9 mos (HR = 0.46; P 〈 0.01); and ≥ PR, 35 mos vs. 22.1 mos (HR = 0.60; P 〈 0.01). In pts who achieved CR, 88% were disease-free after 36 mos with continuous Rd vs. 55% Rd18 and 54% MPT. In terms of OS, only interim data on continuous Rd vs. Rd18 or MPT on depth of response in the subgroups is presented in table 1. Conclusions: The DOR was significantly longer (12-18 mos) as was PFS in pts treated with continuous Rd vs. Rd18 or MPT regardless of the depth of response. The benefits of continuous Rd were more pronounced in pts who achieved a greater depth of response (≥ VGPR). These data suggest that continuing Tx after best response may further help in controlling the disease and delaying PD, especially in pts achieving CR. Longer follow-up may be needed to determine the impact of response quality on OS in pts receiving continuous Tx. Abstract 3458. Table 1. PFS, DOR, and OS in pts with NDMM CR (n = 209) ≥ VGPR (n = 618) ≥ PR (n = 1140) ≤ SD (n = 483) ITT pts (N = 1623) Median PFS (mos) Rd NR NR 37.7 3.7 27.4 Rd18 45.2 31.0 24.0 4.6 21.3 MPT 44.6 34.7 26.3 4.9 21.8 PFS, HR (95% CI); P-value Rd vs. MPT 0.28 (0.13–0.61); P 〈 0.01 0.55 (0.40–0.76); P 〈 0.01 0.67 (0.55–0.82); P 〈 0.01 1.60 (1.22–2.11); P 〈 0.01 0.68 (0.56–0.83); P 〈 0.01 Rd vs. Rd18 0.29 (0.15–0.58); P 〈 0.01 0.46 (0.34–0.60); P 〈 0.01 0.60 (0.49–0.72); P 〈 0.01 1.10 (0.82–1.48); P = 0.53 0.68 (0.55–0.83); P 〈 0.01 Median DOR (mos) Rd NR NR 35.0 – 35.0 Rd18 43.6 29.9 22.1 – 22.1 MPT 41.9 31.8 22.3 – 22.3 DOR, HR (95% CI); P-value Rd vs. MPT 0.27 (0.13–0.59); P 〈 0.01 0.54 (0.39–0.74); P 〈 0.01 0.63 (0.51–0.76); P 〈 0.01 – 0.63 (0.51–0.76); P 〈 0.01 Rd vs. Rd18 0.29 (0.15–0.59); P 〈 0.01 0.46 (0.35–0.61); P 〈 0.01 0.60 (0.50–0.72); P 〈 0.01 – 0.60 (0.50–0.72); P 〈 0.01 Median OS (mos) Rd NR NR 55.1 33.2 55.1 Rd18 NR NR NR 26.8 53.6 MPT NR NR NR 31.6 48.2 OS, HR (95% CI); P-value Rd vs. MPT 0.59 (0.23–1.49); P = 0.26 0.77 (0.50–1.180; P = 0.23 0.85 (0.64–1.11); P = 0.23 0.98 (0.72–1.33); P = 0.89 0.78 (0.64–0.96); P 〈 0.02 Rd vs. Rd18 0.84 (0.34–2.07); P = 0.71 0.82 (0.56–1.22); P = 0.33 0.90 (0.69–1.17); P = 0.45 0.97 (0.70–1.35); P = 0.85 0.90 (0.73–1.10); P =0.31 CI, confidence interval; ITT, intent-to-treat. Disclosures Bahlis: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Stoppa:Celgene, Janssen: Honoraria. Decaux:Celgene and Janssen-Cilag : Consultancy, Honoraria. Marit:Celgene, Janssen: Congress expenses Other. Demuynck:Janssen-Cilag: Honoraria. Ervin-Haynes:Celgene: Employment. Leupin:Celgene: Employment. Marek:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Background: Rituximab is a chimeric monoclonal antibody targeting CD 20+ B lymphocytes (Rastetter et al, 2004). Combination of rituximab with conventional chemotherapeutic agents has become the mainstay of treatment for B-cell Non-Hodgkin’s Lymphomas. The role of rituximab in treatment of immune mediated disorders is currently under investigation. Earlier studies have reported significant responses to rituximab in chronic idiopathic thrombocytopenic purpura patients, who are refractory to steroids and in some cases to splenectomy. (Cooper et al, 2004). Methods: We retrospectively reviewed charts of 15 patients who received rituximab treatment for chronic ITP. All patients had clinical features consistent with chronic ITP and no other etiology was discovered to cause thrombocytopenia; diagnosis of ITP was confirmed by bone marrow examination in 8 patients. Previous treatments for patients in our series included: prednisone (80%), splenectomy (53%), Rho D immune globulin (40%), IV immunoglobulin (33%), danazole (27%), and vincristine (20%). Rituximab dose was 325mg/m2 for all patients, although the number of treatments varied between patients (Table 1). Complete or partial responses to therapy were defined as follows: Platelet count ≥ 150x10(9)/L at 12 weeks following first infusion was a complete response (CR). Platelet count 50–149x10(9)/L at 12 weeks following first infusion was a partial response (PR). Platelet count 〈 50x10(9)/L was defined as no response (NR). Response at the 12 week interval was not possible in 2 patients; therefore response was defined at the 8 week interval (Table 1). Results: Patient demographics consist of 5:10 male to female ratio with mean age=49.7, median age= 46 and age range=19–83. 10 patients attained a complete response, 3 patients attained a partial response, and 2 patients failed to show any response to treatment. It was possible to follow 12 patients in our series for a sustained duration of rituximab response; 9 patients (75%) showed a response of 〉6 months in this group. The most significant factor associated with response to rituximab was age, independent of all other variables when logistic regression analysis was utilized (p=0.003, α=0.05, df=1). Additionally, bivariate analysis was significant for age and number of days lapsed (following first infusion) until platelets increase ≥ 100x10(9)/L and was independent of baseline platelet count (p=0.047, α=0.05, df=1). Conclusion: Rituximab has shown significant activity in our series of ITP patients, with an overall response rate of 93%. Our results indicate a direct relationship between younger age and response. The availability of this agent provides another treatment option for chronic ITP, short of splenectomy. Guidelines for ITP may need further modification in view of the promising results with rituximab therapy. Clinical and hematologic characteristics of ITP patients. Age Gender Duration ITP, months No. Rituximab treatments Baseline Plts x10 9 /L Plts, wk 12 Response Duration of response, wks *=platelet count at 8 week timepoint 83 F 122 8 38 50 PR 104 54 F 33 1 10 603 CR 150 31 F 6 2 78 290 CR 25 20 F 6 4 67 264 CR 26 46 F 42 4 22 194 CR 148 26 F 21 4 24 371 CR 33 25 M 18 4 51 297 CR 81 40 F 9 4 72 169 CR 16 19 F 6 4 45 328 CR 13 46 M 109 4 76 150 CR 21 75 M 108 8 57 93 PR 31 75 F 4 3 30 72* PR 8 78 F 21 8 42 25 NR -- 72 M 25 2 74 479 CR 110 55 M 31 2 16 36* NR --

Description: Background: Studies of Id/KLH immunotherapy in treatment naïve (TN) fNHL pts following first remission from chemotherapy have demonstrated a prolonged duration of remission. We expanded this approach in a PhII trial to include TN and relapsed/refractory (R/R) pts with stable disease (SD) or PR or CR/CRu following 4 wkly doses of rituximab. We report here long term follow up of RRI, defined as the % of pts who converted from SD to PR or PR to CR/CRu following initiation of Id/KLH treatment, and analysis of disease progression. Treatment: Pts received rituximab (375mg/m2 i.v. wkly x 4 during wk1–4) and those with stable or responsive disease received Id/KLH (1 mg s.q. mo x 6) starting on wk 12 along with GM-CSF (250 mcg, s.q.) on days 1–4. Pts continued to receive booster injections on a reduced schedule until disease progression. Radiological scans, performed every 3 mos, were reviewed centrally. Disease progression and response were assessed using modified Cheson criteria. This data analysis was performed 32 mo from end of enrollment. Results: 103 pts were enrolled and received rituximab; 89 pts had ≥SD and received Id/KLH + GM-CSF of whom, 54 were R/R, and 35 were TN. The overall response rate (ORR) was 47% (42/89) at mo 3. After the initiation of Id/KLH dosing, ORR improved to 63% (56/89). In RRI pts, median time to best response was 9.1 mos from start of rituximab treatment (5.2 – 29.6 mos). 12 of 39 PR pts (31%) converted to CR/Cru. 14 of 43 SD pts (33%) converted to PR. Pt Groups # of Pts % Prog Free Median TTP Est by K-M (mo) Pts w/RRI 26 69% 37.9 TN rituximab responders 23 70% Not Reached (NR) Rituximab responders (All) 42 60% NR Non Responders (All) 47 36% 14.9 All Pts 89 47% 18.2 TN Pts (All) 35 66% NR Relapsed Pts (All) 54 37% 16.8 Conclusion: RRI following FavId is seen in nearly one third of pts. The magnitude of this improvement, the number of conversions to CR/CRu and median time to best response (9 mo and as late as 29.6 mo) suggests this is likely to be a FavId effect rather than late response to rituximab. Responders and TN pts show more durable responses compared to previously published data for rituximab therapy. FavId may also confer a benefit for nonresponders and R/R pts relative to rituximab alone. To confirm benefit of FavId following rituximab induction, a placebo controlled PhIII study was initiated; it completed enrollment in Jan 06. RRI data from this study is expected to be available in Nov 06.