ALBERT

Description: Background: A histologic finding of large cell transformation (LCT) in Mycosis fungoides (MF) is often associated with an aggressive clinical course and inferior prognosis (Arulogun et al. Blood 2008). In patients (pts) with advanced MF (stage IIB-IV), LCT has been established as an independent prognostic factor (Scarisbrick et al. JCO 2015). Although CD30 expression is observed more frequently in MF with LCT vs without LCT, a wide range of CD30 expression levels is observed in LCT lesions and the level of expression lacks prognostic value for MF (Vergier et al. Blood. 2000). The ALCANZA study (NCT01578499) demonstrated significantly better rates of objective response lasting ≥4 months (ORR4) (∆43.8%; p

Description: Introduction: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab (moga) compared to vorinostat (vori) in patients with mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least one prior course of systemic therapy (NCT01728805). Primary results have been reported (Kim et al. Lancet Oncol 2018) and were based on a data cutoff date of December 31, 2016. The primary endpoint was progression-free survival (PFS); patients in the moga treatment arm experienced significantly longer PFS compared to patients in the vori treatment arm (median 7.7 months vs 3.1 months; p

Description: Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation. Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006). Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented. Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. Disclosures Thomas: Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.

Description: Background Chemoimmunotherapy (CIT) is the standard of care to treat fit patients (pts) with CLL. These CIT regimens include the use of rituximab, an anti-CD20 monoclonal antibody (mAb), with standard chemotherapy such as fludarabine/cyclophosphamide (FC) or bendamustine (B). GA101 is a novel, glycoengineered, type II CD20 mAb designed to increase direct and antibody-dependent cellular cytotoxicity. Early phase 1/2 GA101 studies in pts with CLL demonstrated single-agent activity with treatment-related neutropenia. GALTON (NCT01300247) is a non-randomized, parallel group, phase 1b study of the safety and preliminary efficacy of GA101 plus FC or B in the initial therapy of pts with CLL. Methods Untreated CLL pts requiring therapy who had a performance status ≤2 were treated with GA101 1000 mg (100 mg IV d1, 900 mg d2, 1000 mg d8 and d15 of cycle 1; 1000 mg d1 in cycles 2–8) with either FC (25/250 mg/m2 IV on d2–4 of cycle 1, then d1–3 of cycles 2–6; G-FC) or B (70 mg/m2 IV on d2–3 of cycle 1, then d1–2 of cycles 2–6; G-B). Each cycle was 28 days. Pts received acetaminophen and an antihistamine before each infusion of GA101. Pts also received methylprednisolone or dexamethasone prior to the 1st and 2nd GA101 infusions. Each center chose to participate in either the G-FC or G-B arm, and physicians could reduce the dose of FC or B after the 1st cycle if there was concern about tolerance to chemotherapy. The primary endpoint was to evaluate safety and tolerability of GA101 with chemotherapy. Secondary endpoints included response rates per iwCLL criteria, including required CT scans to confirm response. Complete response (CR) required resolution of all disease, and single lymph nodes (LNs) needed to be ≤ 1.5 cm in long axis by CT. Partial response (PR) required a ≥ 50% decrease in lymphocyte count, ≥ 50% reduction in sum of product diameter (SPD) of LNs, ≥ 50% reduction of liver and/or spleen, and either neutrophil, platelet or hemoglobin recovery. Results We enrolled 41 pts (Table 1) with a median follow-up time of 11.9 months. The most common adverse events (AEs) (any grade) occurring in ≥ 9 pts in the G-FC arm were GA101 infusion–related reactions (IRRs) (91%), nausea (76%), fatigue (57%), constipation (48%), and neutropenia (43%); in the G-B arm, they were GA101 IRRs (90%), nausea (65%), neutropenia (55%), diarrhea (50%), and pyrexia (45%). The most common Grade (Gr) 3/4 AEs are in Table 1. In both cohorts, Gr 3/4 GA101 IRRs only occurred with the 1st dose. Fourteen pts experienced serious AEs (6 pts in G-FC, 8 pts in G-B), with events including febrile neutropenia (n=5 events); infections (n=4); IRRs (n=3); nausea, vomiting, pyrexia (n=2 each); and diarrhea, fatigue, tachycardia, tumor lysis syndrome, syncope, mental status changes, neutropenia, face swelling, and hypertension (n=1 each). Nine pts (7 in G-FC, 2 in G-B) had AEs leading to treatment discontinuation, including Gr 3/4 neutropenia (3 in G-FC [1 of 3 pts also had Gr 4 cellulitis], 2 in G-B), Gr 3 thrombocytopenia (2 in G-FC), Gr 4 pancytopenia (1 in G-FC), and Gr 4 AST/Gr 3 ALT elevation (1 in G-FC). The overall response rate was 62% (2 CR, 3 CRi, 8 PR) in the G-FC arm, and 90% (4 CR, 5 CRi, 9 PR) in the G-B arm, including 6 pts (4 in G-FC, 2 in G-B) not evaluable due to inadequate response evaluation. Four pts in the G-FC arm (0 in G-B) had stable disease during and after therapy. No pt progressed during the study. Conclusions GA101 plus chemotherapy can be administered safely to pts requiring initial therapy for CLL. IRRs were the most common AE, but typically occurred during the initial infusions of GA101 and were not dose-limiting. The AE rates observed in pts treated with G-FC or G-B did not appear to be greater than those in pts treated with standard CIT. Our data show GA101 plus FC or B has clinical activity in the initial therapy of pts with CLL, warranting further clinical study. Disclosures: Brown: Pharmacyclics, Genentech, Celgene, Emergent, Onyx, Sanofi Aventis, Vertex, Avila, Novartis: Consultancy; Genzyme, Celgene: Research Funding. Off Label Use: GA101 is a novel, glycoengineered, type II anti-CD20 monoclonal antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in chronic lymphocytic leukemia, Non-Hodgkin’s Lymphoma and other hematologic indications. O'Brien:CLL Global Research Foundation: Membership on an entity’s Board of Directors or advisory committees; Emergent, Genentech, Gilead Sciences, Infinity, MorphoSys, Pharmacyclics, Talon: Research Funding; Teva/Cephalon, Celgene, Emergent, Genentech, Gilead Sciences, Infinity, Pharmacyclics, Talon: Consultancy. Eradat:Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Lymp:Roche: Stock options, Stock options Other; Genentech: Employment. Hirata:Roche: Stock options, Stock options Other; Genentech: Employment. Kipps:Genentech: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Description: Abstract 3701 Background: Waldenstrom's macroglobulinemia (WM) is an indolent B-cell non-Hodgkin's lymphoma (B-NHL) characterized by production of a monoclonal IgM paraprotein and variable CD20 expression due to the downregulation of CD20 as B cells differentiate into plasma cells. Rituximab monotherapy (R) achieves an overall response rate (ORR) of 25–50% in therapy naïve and relapsed WM and is associated with IgM flares in 25–75% of patients (pts) that potentially lead to hyperviscosity due to a rapid rise in IgM. Ofatumumab (OFA) is a fully human monoclonal anti-CD20 antibody approved for the treatment of fludarabine and alemtuzumab-refractory chronic lymphocytic leukemia (CLL) and has demonstrated activity in indolent B-NHL. Since OFA is active in CLL, with its low CD20 expression, we initiated a phase II single-arm trial of OFA in pts with WM. We report primary endpoint data from this study. Methods: Pts (age ≥ 18 years) with WM requiring therapy by 2nd International Workshop on WM (IWWM) criteria were eligible. Cycle 1 (C1) of therapy consisted of OFA 300 mg week 1 and 1000 mg weeks 2–4 (Treatment Group A [TGA]) or OFA 300 mg week 1 and 2000 mg weeks 2–5 (TGB). Premedication included acetaminophen and antihistamine (all infusions) and glucocorticoid (infusions 1 and 2). Pts with grade 3–4 infusion-related adverse events (AEs) during weeks 1 and 2 also received glucocorticoid during weeks 3–5. Pts with stable disease (SD) or a minor response (MR) at week 16 of cycle 1 were eligible to receive a re-dosing cycle (C2) consisting of OFA 300 mg week 1 and 2000 mg weeks 2–5. The primary endpoint was ORR assessed by 3rd IWWM criteria. Toxicity was assessed according to NCI-CTCAE, v 3.0. Results: Thirty-seven pts were enrolled between March 2009 and February 2011. Median age was 63 years (range 43–85); 22 pts were male. Median IgM level was 3.11 g/dL (range 0.81–8.64); median hemoglobin (hgb) was 9.8 g/dL (range 5.3–13.2). Nine pts were treatment naïve; 28 pts had received a median of 3 prior therapies (range 1–5) including R (25 pts) and purine analog (14 pts). The first 15 pts were enrolled in TGA and the next 22 pts in TGB; pt characteristics were similar in both groups. Thirty-four pts completed C1; 1 pt withdrew after 1 dose and 2 pts received only 3 doses due to serious AEs (SAEs). Eleven pts achieved partial response (PR) and 7 achieved MR after C1 (ORR=49%; 95% CI [32%, 66%]). Twelve pts received C2, after which 4 pts improved their response (1 MR to PR, 1 SD to PR, 2 SD to MR) and 1 nonevaluable pt attained MR. After C1 and C2, the ORR was 59% (13 PR, 9 MR; 95% CI [42%, 75%]). Responses were seen in 67% (6/9) of therapy naïve pts, 57% (16/28) of relapsed pts, 52% (13/25) of pts who had prior R, 75% (9/12) of R-naïve pts, 64% (16/25) of pts with IgM 〈 4 g/dL and 50% (6/12) of pts with IgM ≥ 4 g/dL. ORR was 47% (7/15) in TGA and 68% (15/22) in TGB. ORR in TGA was negatively affected by prior R exposure and IgM ≥ 4 g/dL, whereas ORR in TGB was not affected by prior therapy, prior R or IgM level. Fifteen of 26 (58%) pts with hgb 〈 11.0 g/dL experienced ≥ 3.0 g/dL increase in hgb (range 3.0–7.1). Infusion-related events occurred with dose 1 in 30 (81%) pts and with dose 2 in 21 (57%) pts; all infusion events were grade 1–2 except 4 grade 3 events (1 rash, 1 chest pain, 1 chest discomfort, 1 back pain). Fifteen pts developed 22 infections including 8 upper respiratory tract, 4 urinary tract (UTI) and 4 sinus infections; all infections were grade 1–2 except 1 grade 3 UTI. One pt developed grade 3 febrile neutropenia. In total, there were 14 grade 3–4 AEs (all grade 3). Five pts developed 8 SAEs possibly related to OFA. One pt withdrew due to grade 3 hemolytic anemia. Two pts with baseline IgM of 6.63 and 4.75 g/dL required plasmapheresis for grade 3 renal insufficiency and hyperviscosity symptoms, respectively, with resolution of symptoms and were able to complete C1. Two pts developed IgM flare, defined as 〉 25% rise in IgM followed by subsequent MR or PR. Conclusions: OFA is clinically active in pts with WM, with an acceptable toxicity profile and a lower incidence (5%) of IgM flare. The ORR to OFA was 59% (TGA 47%, TGB 68%) including a 50% ORR (TGA 17%, TGB 83%) in pts with IgM ≥ 4.0 g/dL. Pts' anemia responded to OFA with 58% of pts with baseline hgb 〈 11.0 g/dL experiencing ≥ 3.0 g/dL increase in hgb. TGB achieved ORR 〉 60% in all pt groups regardless of prior therapy or baseline IgM level. A higher dose of OFA appeared to be more effective in pts previously exposed to R or with baseline IgM ≥ 4.0 g/dL. Further study of OFA in WM is warranted. Disclosures: Furman: Genentech: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Off Label Use: • Ofatumumab is an anti-CD20 monoclonal antibody approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia, and is currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma), as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Eradat:Millennium: Speakers Bureau; Genentech, A Roche Company: Speakers Bureau. DiRienzo:GlaxoSmithKline: Employment. Leonard:GlaxoSmithKline: Consultancy. Advani:GSK: Research Funding. Switzky:GlaxoSmithKline: Employment. Liao:GlaxoSmithKline: Employment. Shah:GSK: Employment. Lisby:Genmab A/S: Employment. Lin:GlaxoSmithKline: Employment.

Description: Background: Cobomarsen (MRG-106) is an inhibitor of miR-155, a microRNA with a strong link to cutaneous T cell lymphoma (CTCL) pathogenesis. The goals of this first in human study are to evaluate the safety, tolerability, pharmacokinetics, and efficacy of cobomarsen in mycosis fungoides (MF) patients. Methods: This Phase 1 trial evaluated cobomarsen given via intralesional injection (75 mg/dose), subcutaneous (SC), IV rapid bolus injection, or 2-hour IV infusion (300, 600 or 900 mg/dose). Patients must have MF stage I-III with plaques and/or tumors and could remain on concurrent stable CTCL therapy. Patients received 6 doses, either subcutaneous or intravenous, in the first 26 days of the study followed by weekly or bi-monthly doses. Safety was monitored by physical exams, clinical lab tests, and reported adverse events (AEs). Efficacy was assessed by CAILS and by the modified Severity Weighted Assessment Tool (mSWAT). The effect of cobomarsen on quality of life was assessed by Skindex-29. Results: 38 subjects receiving IV or SC treatment (25 male/13 female, median age 59 years) have been on study for up to 22 months. As of the data cut off, no serious AEs have been attributed to cobomarsen. The most common AEs reported in greater than 15% of subjects were: fatigue, neutropenia, injection site pain, nausea, pruritus, and headache. Two AEs were deemed dose limiting toxicities (DLTs): Grade 3 worsening pruritus and Grade 3 tumor flare. The maximum tolerated dose (MTD) has not yet been reached. In the subcutaneous and IV cohorts, 29 out of 32 (91%) evaluable subjects had improvement in mSWAT score. Skin improvements were observed as early as the first assessment (Day 17). The best improvements were observed after more than 1 month of treatment. Eleven out of twenty-one (52%) patients receiving more than one month of dosing (6 doses) achieved greater than 50% reduction in mSWAT score. The mean duration of response (n=11) was 213 days, as of data cut off. Eight patients achieved a partial response meeting the criteria for ORR4, an objective response rate lasting at least four months in duration. The overall skin response in patients who received cobomarsen as monotherapy or cobomarsen with concurrent stable therapy were not significantly different. Improvement in quality of life (QOL), as measured by the Skindex-29 total score, correlated with reductions in mSWAT score during the treatment phase. Conclusions: These results demonstrate that cobomarsen is well-tolerated, has clinical activity, and has the potential to impact MF quality of life. These encouraging data support the continued investigation of cobomarsen in the CTCL population. The study is expanded to enroll patients with other hematologic malignancies in which miR-155 is elevated and relevant, including chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), and adult T cell lymphoma/leukemia (ATLL). Final safety and efficacy data on CTCL mycosis fungoides will be presented. Disclosures Foss: Seattle genetics: Consultancy; Miragen: Consultancy, Speakers Bureau; Spectrum: Consultancy; Mallinkrodt: Consultancy.

Description: Background Idelalisib (IDELA) is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues. Phase 1 trials demonstrated that IDELA is highly active as a single agent or in combination with rituximab (R) in heavily pretreated patients (pts) with CLL. Pts in these trials experienced reductions in disease-associated chemokines, improvement of organomegaly and cytopenias, profound reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (Brown 2013; Barrientos 2013). Patients with early progression and significant co-morbidities have limited treatment options; single-agent rituximab is an option in these pts (NCCN 2013; Zelenetz 2013). Methods This Phase 3 study evaluated the efficacy and safety of IDELA + R vs placebo + R in pts with previously treated CLL. Eligibility criteria included the need for treatment per IWCLL guidelines, measurable lymphadenopathy, and CLL progression 6), renal dysfunction, or cytopenias due to poor marrow reserve. All pts received R at 375 mg/m2 [1st dose] and then 500 mg/m2q2 wks x 4, followed by q4 wks x 3 [8 doses total]) and were randomized to Arm A (n=110; IDELA 150 mg BID continuously) or Arm B (n=110; placebo BID continuously). Primary endpoint was progression-free survival (PFS). Response and progression in both arms were assessed by an independent review committee using standard criteria (Hallek 2008; Cheson 2012). Results were reviewed by an external Data Monitoring Committee (DMC). Results Results are from a pre-specified interim analysis after ∼50% of the total number of 119 planned events of CLL progression or death from any cause. Data cutoff was 30 Aug 2013. Pt characteristics (n=220) included a median age of 71 yrs (78% ≥ 65 yrs); CIRS 〉 6 in 85%; median creatinine clearance of 63.6 mL/min; and presence of anemia (73%), thrombocytopenia (61%), neutropenia (34%). Median time since diagnosis was 8.5 yrs, median number of prior therapies was 3 (range: 1-12), 44% had del(17p)/TP53 mutation, and 84% had unmutated IGHV. PFS in the IDELA + R arm was superior to placebo +R (HR [95% CI] = 0.15 [0.08, 0.28]; p = 3.0 x 1011). Median PFS of pts treated with IDELA + R was not reached and for placebo + R was 5.5 mos. At 24 wks, the PFS rate for IDELA +R was 93% compared to 46% for placebo + R. PFS strongly favored IDELA + R in all subgroups, including those with del(17p)/TP53 or unmutated IGHV. Pts treated with IDELA + R and with ≥1 post-baseline assessment also had a superior overall response rate (ORR) relative to those in the control arm (81% vs. 13%; odds ratio 29.9; p = 3.0 x 1019) and a higher lymph node response (LNR) rate (93% vs. 4%; odds ratio 264.5; p = 1.3 x 10-30). Relative to the control group, pts treated with IDELA +R also had a significant improvement in overall survival (OS): HR (95% CI) = 0.28 (0.09, 0.86), p = 0.018. Adverse events (AEs) occurring in ≥20% of pts (any Gr/Gr ≥3) by arm were: pyrexia (IDELA + R 29%/3%; placebo + R 16%/1%), fatigue (IDELA + R 24%/3%; placebo + R 27%/2%), nausea (IDELA + R 24%/0%; placebo + R 22%/0%), chills (IDELA + R 22%/2%; placebo + R 16%/0%), infusion-related reactions (IDELA + R 16%/0%; placebo + R 28%/4%), and cough (IDELA + R 15%/0%; placebo + R 25%/2%). Other selected AEs (any Gr/Gr ≥3) included diarrhea (IDELA + R 19%/4%; placebo + R 14%/0%) and rash (IDELA + R 10%/2%; placebo + R 6%/0%). Select lab abnormalities (any Gr/Gr ≥3) included ALT elevation (IDELA + R 31%/6%; placebo + R 9%/1%), anemia (IDELA + R 26%/6%; placebo + R 30%/14%), neutropenia (IDELA + R 55%/34%; placebo + R 49%/22%), and thrombocytopenia (IDELA + R 17%/10%; placebo + R 26%/16%). The most common SAEs were pneumonia (6.4%), pyrexia (6.4%), and febrile neutropenia (4.5%) in IDELA + R, and pneumonia (8.4%), febrile neutropenia (5.6%), and dyspnea (3.7%) in placebo + R. AEs led to study drug discontinuation in 9 pts (8.2%) in IDELA + R and 11 pts (10.3%) in placebo + R. Based on a review of efficacy and safety, the DMC recommended stopping the study early. Conclusions IDELA + R demonstrated statistically significant improvement with acceptable safety over placebo + R in PFS, ORR, LNR and OS in heavily pretreated pts with relapsed CLL, including those with adverse genetic features. Disclosures: Furman: Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Consultancy, Research Funding. Coutre:Gilead Sciences: Research Funding. Cheson:Gilead Sciences: Research Funding. Pagel:Gilead Sciences: Research Funding. Hillmen:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kipps:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Ghia:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Eradat:Gilead Sciences: Research Funding. Ervin:Gilead Sciences: Research Funding. Lamanna:Gilead Sciences: Research Funding. Hallek:Gilead Sciences: Research Funding. Coiffier:Gilead Sciences: Research Funding. Pettitt:Gilead Sciences: Research Funding. Ma:Gilead Sciences: Research Funding. Stilgenbauer:Gilead Sciences: Honoraria, Research Funding. Aiello:Gilead Sciences: Employment. Johnson:Gilead Sciences: Employment, Equity Ownership. Miller:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Sciences: Employment. Jahn:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment, Equity Ownership. O'Brien:Gilead Sciences: Research Funding.

Description: Abstract 1795 Background: Waldenstrom's macroglobulinemia (WM) is an indolent B-cell lymphoma characterized by a heterogeneous population of lymphocytes, plasmacytoid lymphocytes and plasma cells with variable CD20 expression. Rituximab (R) achieves an overall response rate (ORR) of 25–50% in relapsed/refractory WM and is associated with IgM flares, manifested by a rapid rise in IgM, potentially leading to complications of hyperviscosity. Ofatumumab (OFA) is a fully human monoclonal antibody that targets an epitope encompassing both the large and small extracellular loops of CD20 and effectively induces complement-dependent cytotoxicity of B-lymphoma cells. OFA is approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia (CLL) and has demonstrated clinical activity in non-Hodgkin's lymphoma. Given the efficacy of OFA in CLL, with its decreased CD20 antigen density, similar to WM where CD20 is down-regulated with differentiation of cells into plasma cells, a Phase II, open-label, single-arm trial of OFA in patients (pts) with WM was initiated to examine the safety and efficacy of OFA in this population. We report data from a planned interim analysis, which was performed to examine IgM flare, toxicity and response data. Methods: Pts (age ≥18 years) with WM requiring therapy by 2nd International Workshop on WM criteria were eligible. Pts received OFA 300 mg week 1 and 1000 mg weeks 2–4. Premedication included acetaminophen and antihistamine (all infusions) and glucocorticoid (infusions 1 and 2). Pts who experienced grade 3–4 infusion-related adverse events (AEs) during weeks 1 and 2 also received glucocorticoid during weeks 3 and 4. The primary endpoint was ORR assessed by 3rd International Workshop on WM criteria, and toxicity was assessed according to NCI-CTCAE, v3.0. Results: Fifteen pts were enrolled between March 2009 and January 2010. Median age was 59 years (range 43–85), and 9 pts were male. Pts had a median IgM level of 3.70 g/dL (range 1.21–6.62) and median hemoglobin (hgb) of 9.8 g/dL (range 5.3–11.7). Three pts were previously untreated; 12 pts had received a median of 3 therapies (range 2–5), including 11 pts who had received R, and 7 pts who had received a purine analog. Fourteen pts completed all 4 infusions of OFA. One pt withdrew from study after infusion 3 due to a drug-related serious AE (SAE). One pt had cryoglobulinemia, which interfered with IgM assessment. Of the 14 pts with evaluable IgM levels, 3 achieved partial response (PR), and 3 achieved minor response (ORR=43%) 8 weeks to 5 months after start of OFA therapy. One of 3 previously untreated pts and 5 of 12 relapsed pts responded. Four of 11 pts who had received prior R and 2 of 4 R-naïve pts responded. Five of 9 pts with IgM 4 g/dL responded. Four pts with a median hgb of 8.0 g/dL (range 5.3–9.2) experienced ≥2.8 g/dL increase in hgb, including 3 pts who had 〉5 g/dL increase; median time to reach hgb ≥11.0 was 4 weeks. Infusion-related events occurred with dose 1 (300 mg) in 12 pts and with dose 2 (1000 mg) in 7 pts; all infusion events were grade 1–2 except 2 grade 3 events (rash, serum sickness). Nine pts developed 11 infections: 7 URI, 2 UTI, 1 sinusitis, 1 oral candidiasis (all grade 2). One pt developed grade 3 febrile neutropenia. Two pts developed SAEs possibly related to OFA. One pt developed grade 3 Coombs-negative hemolytic anemia after infusion 3 resulting in study withdrawal, and 1 pt with a baseline IgM level of 6.62 g/dL developed grade 3 renal insufficiency due to a rapid rise in IgM and cast nephropathy 6 weeks after starting OFA. One additional pt, with a baseline IgM level of 4.69 g/dL, developed a rapid rise in IgM and hyperviscosity symptoms. Both pts with a rapid rise in IgM underwent plasmapheresis with resolution of symptoms. No other OFA-related hematologic toxicity was observed. Conclusions: OFA has an acceptable toxicity profile, although a rapid rise in IgM requiring plasmapheresis was observed in 2 pts with high baseline IgM levels. OFA shows clinical activity in pts with WM, including those who relapse after R therapy, with rapid improvement in hgb and slower reduction of IgM levels. Based on the acceptable safety profile in this study and the dose of OFA approved for refractory CLL, the study was amended to increase the OFA dose to 2000 mg and allow a 2nd cycle of therapy for pts who do not attain PR after cycle 1. Accrual to the amended study is ongoing. Disclosures: Furman: GlaxoSmithKline: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Cephalon, Inc.: Speakers Bureau; Celegene: Consultancy; Calistoga: Consultancy. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Switzky:GlaxoSmithKline: Employment, Research Funding; Genmab: Employment, Research Funding. Leonard:GlaxoSmithKline: Consultancy. Liao:GSK: Employment. Shah:GlaxoSmithKline: Employment; Genmab: Research Funding. Brownell-Buttich:GlaxoSmithKline: Employment. Lisby:Genmab A/S: Employment. Lin:GlaxoSmithKline: Consultancy, Employment.

Description: Abstract 2951 Introduction: Everolimus (RAD001) is an inhibitor of MTORC1, a component of the Akt-MTOR pathway which regulates growth and survival of lymphoplasmacytic cells in Waldenstrom's Macroglobulinemia (WM). Everolimus also exhibits activity in WM patients with relapsed/refractory disease (Ghobrial et al, JCO 2010; 28 :1408–14). We therefore initiated this multicenter, prospective study to delineate the efficacy and tolerability of Everolimus as primary therapy in WM. Patients and Methods: WM patients with symptomatic disease, adequate organ function, who were not previously treated, and who did not have symptomatic hyperviscosity were eligible for this study. Intended therapy consisted of 10 mg of oral Everolimus administered daily, with sequential dose de-escalation to 7.5 mg daily, 5 mg daily, and 5 mg every other day permitted for toxicity. Patients were treated until progression or unacceptable toxicity. Patients were encouraged to use 5 mL of an oral dexamethasone solution (0.5 mg/5mL) to swish and spit up to 4 times daily for prevention of oral ulcerations associated with Everolimus. Study participants were assessed monthly for the first 3 months, and thereafter every 3 months which included a physical examination, complete blood counts, chemistries, and serum IgM monitoring. Bone marrow biopsies and aspirations were performed at baseline, at months 6 and 12, and as required for response assessment. Results: Thirty-three patients were enrolled on this prospective, multicenter study and are evaluable for response. Median baseline characteristics for all patients are as follows: Age 62 (range 41–80 years); Hematocrit 31.3% (range 24.5–45.7%); Hemoglobin 10.8 (range 7.8–15.7 g/dL); serum IgM 4, 440 (range 959–10, 256 mg/dL), with 23 (69.7%) patients demonstrating an IgM level ≥3, 000 mg/dL; serum M-protein 2.60 g/dL (range 0.31–5.31 g/dL), B2M 3.0 mg/L (1.6–6.7 mg/L). The median baseline bone marrow disease burden was 70% (range 7.5–95%), and 21 patients (63.6%) demonstrated adenopathy or splenomegaly by CT scans at baseline. At best response, serum IgM levels declined from 4, 440 to 1, 925 (p

Description: Purpose: Everolimus inhibits mTOR, a component of PI3K/AKT pro-survival signaling triggered by MYD88 and CXCR4 activating mutations in Waldenstrom's Macroglobulinemia (WM). Experimental design: We evaluated everolimus in a prospective, multicenter study of 33 symptomatic, previously untreated WM patients. Intended therapy consisted of everolimus (10 mg/day) until progression or unacceptable toxicity. Dose de-escalation was permitted. The study was registered at www.clinicaltrials.gov(NCT01470196). Results: At best response, median serum IgM levels declined from 4,440 to 1,360 mg/dL (p