Eradat, Herbert

2517 Background: Approximately 50% to 60% of pts with r/r LBCL will either not achieve a complete response (CR) or will relapse with current treatments and require additional therapy. Autologous anti-CD19 chimeric antigen receptor T (CAR T) therapies have revolutionized the care of patients whose disease progresses following standard therapies, but patient-specific manufacturing processes and long wait times to treatment present challenges for their broad clinical use. Allogeneic (healthy-donor-derived), off-the-shelf, anti-CD19 (CAR T) treatment promises broader and more rapid access to one-dose treatment with curative intent. Initial phase 1 data for the anti-CD19 AlloCAR T cell product ALLO-501 (NCT03939026) and successor, ALLO-501A (NCT04416984), demonstrated a manageable safety profile with no dose-limiting toxicities (DLTs), and efficacy comparable to autologous CAR T therapy in pts with r/r LBCL who were autologous CAR T-naïve. This update provides additional follow up and a focus on participants who received the conditioning regimen and cells made with an optimized manufacturing process currently under study in the first potentially pivotal trial for an allogeneic CAR T product. Methods: In these two multicenter, single-arm, open-label, phase 1 trials, a cohort of autologous CAR T-naïve pts with r/r LBCL underwent 3-day lymphodepletion (LD) with FCA90, fludarabine (F, 30 mg/m2/day), cyclophosphamide (C, 300 mg/m2/day), and ALLO-647 (A [anti-CD 52 mAb] 30 mg/day; total dose: 90 mg) followed by a single dose of ALLO-501 or ALLO-501A produced by the Alloy manufacturing process. Results: As of Jan 26, 2023, 12 pts received the FCA90 LD regimen and CAR T therapy with 100% receiving product per specifications with a median time from enrollment to LD of 3 days. Median follow-up time (actual) was 7.1 months (range: 1.4, 36.0). No DLTs, severe (Gr3+) cytokine-release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) events occurred. An overall response rate and a CR rate of 66.7% and 58.3%, respectively, were observed. Median DOR was 23.1 months. Among 8 pts with the opportunity to be followed for 6 months, 5 (62.5%) had achieved CR and 4 (50.0%) sustained CR through 6 months. Analyses of vector copy number pharmacokinetics at Days 28 and 56 documented substantial and sustained expansion of CAR T cells. Conclusions: A one-time dose of allogeneic CAR T therapy following LD with FCA90 provided durable responses with a manageable safety profile in patients with r/r/ LBCL comparable to those treated with autologous CAR T cells. This treatment enables rapid access to off-the-shelf treatment with a median time from trial enrollment to treatment of 3 days. These findings support broader evaluation of ALLO-501A in the ongoing, first potentially pivotal phase 2 trial (ALPHA2) of off-the-shelf allogeneic CAR T cells. Clinical trial information: NCT03939026 .

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved in recent years. Targeted therapy with Bruton’s tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors has emerged as an effective chemotherapy-free option for patients with previously untreated or relapsed/refractory CLL/SLL. Undetectable minimal residual disease after the end of treatment is emerging as an important predictor of progression-free and overall survival for patients treated with fixed-duration BCL-2 inhibitor-based treatment. These NCCN Guidelines Insights discuss the updates to the NCCN Guidelines for CLL/SLL specific to the use of chemotherapy-free treatment options for patients with treatment-naïve and relapsed/refractory disease.

Abstract Introduction: Bruton tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and certain B-cell neoplasms. However, resistance to BTKi develops primarily through mutations at the cysteine binding site (C481) or PLCγ2 mutations. MK-1026 (formerly ARQ-531) is a non-covalent, potent inhibitor of both wild type and C481- mutated BTK. In the phase 1/2 dose escalation and dose expansion study NCT03162536, the preliminary recommended phase 2 dose (RP2D) of MK-1026 was determined to be 65 mg once daily. The efficacy and safety of MK-1026 in participants with CLL/SLL and B-cell non-Hodgkin lymphoma (NHL) were also evaluated at a higher dose during the dose expansion phase. Methods: In this open-label, single-arm phase 2 study, 9 expansion cohorts were initiated following determination of preliminary MK-1026 RP2D. Approximately 10-25 eligible participants were enrolled into Cohort A (relapsed/refractory (r/r) CLL/SLL, with ≥2 prior therapies including covalent BTKi, with documented C481 mutation), Cohort B (r/r CLL/SLL progressed on/intolerant to a BTKi, with ≥2 prior therapies without C481 mutation), Cohort C (participants with Richter transformation [RT] with ≥1 prior therapy), Cohort D-H (participants with follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), high-grade B cell lymphoma (BCL) with known MYC, BCL-2 or BCL-6 translocations, and Waldenström macroglobulinemia (WM), respectively, who received ≥2 prior therapies), Cohort I (food effect cohort including participants with B-cell NHL, CLL/SLL, and WM). Treatment continued until unacceptable toxicity, clinical or radiological progression, participant/physician withdrawal. Primary endpoint was overall response rate (per iwCLL criteria, by investigator) for participants with CLL/SLL. Secondary endpoints included duration of response and safety and tolerability. The data cut-off date for this analysis was April 7, 2021. Results: Among 118 participants enrolled, 44 had B-cell NHL (including 6 with DLBCL, 11 with FL, 3 with high-grade BCL, 6 with MCL, 2 with MZL, 16 with RT), 68 CLL/SLL, and 4 WM. Of these, 94 (79.6%) were treated at the preliminary RP2D, including 51 (54.3%) participants with CLL/SLL. Participants with CLL/SLL had a median (range) number of prior therapies of 4 (1-18), 43 (84%) had prior BTKi therapy, 12 (23%) had del17p, 26 (51%) had IGHV unmutated status, and 32 (63%) had C481S BTK mutation. At data cut-off, median (range) follow-up was 4.56 months (0.1-26.7) for all treated participants. ORR was 57.9% (N = 22 of 38; 1 CR, 21 PR/PRL) per iwCLL criteria in the efficacy evaluable population of participants with CLL/SLL treated at preliminary RP2D. The median duration of response in these participants was not estimable [NE] (range, 8.3 months-NE). At data cut-off, the median duration of treatment exposure was 3.2 months (range, 0-35.9). Among all treated participants, 114 (97%) had a treatment-emergent adverse event (TEAE), with 78 (66%) having a drug-related TEAE, and 9 (8%) having a drug-related TEAE that led to discontinuation. Common TEAEs (≥ 20%) included fatigue (33%), constipation (31%), dysgeusia (28%), cough (25%), nausea (25%), pyrexia (25%), dizziness (23%), hypertension (23%), peripheral edema (22%), arthralgia (20%), and diarrhea (21%). Grade ≥3 TEAEs occurred in 80 (68%) participants. Grade 5 TEAEs occurred in 7 (6%) participants and included death following disease progression in 3 (3%), sepsis 1 (1%), dyspnea 1 (1%), and respiratory failure 2 (2%) participants. Common drug-related TEAEs (≥10%) included dysgeusia (15%), nausea (11%), fatigue (11%), and decreased neutrophil count (10%). Grade 3-4 drug-related TEAEs occurred in 31 (26%) participants. No drug-related TEAEs led to death. Conclusion: MK-1026 has promising antitumor activity with a manageable safety profile in participants with CLL/SLL exposed to multiple lines of therapy, including in those who had progression of disease on prior covalent BTKi. Further evaluation of MK-1026 in B-cell malignancies is ongoing. Disclosures Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Flinn: Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Awan: Verastem: Consultancy; Incyte: Consultancy; Dava Oncology: Consultancy; MEI Pharma: Consultancy; Beigene: Consultancy; Celgene: Consultancy; Johnson and Johnson: Consultancy; Karyopharm: Consultancy; Kite pharma: Consultancy; Gilead sciences: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; BMS: Consultancy; Merck: Consultancy; Cardinal Health: Consultancy; ADCT therapeutics: Consultancy; Abbvie: Consultancy; Astrazeneca: Consultancy; Genentech: Consultancy. Eradat: AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Speakers Bureau; Juno: Research Funding; Kite: Research Funding; Genentech: Research Funding. Brander: Pfizer: Consultancy, Other: Biosimilars outcomes research panel; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; ArQule: Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; BeiGene: Research Funding; DTRM: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; MEI Pharma: Research Funding; TG Therapeutics: Consultancy, Research Funding; Novartis: Research Funding; LOXO: Research Funding; Verastem: Consultancy; ArQule/Merck: Consultancy; Genentech: Consultancy, Research Funding; NCCN: Other: panel member; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Phillips: BMS: Consultancy, Research Funding; AstraZeneca: Consultancy; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; Bayer: Consultancy, Research Funding. Reddy: Merck & Co., Inc.: Current Employment. Farooqui: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Stephens: CSL Behring: Consultancy; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Arqule: Research Funding; Mingsight: Research Funding; JUNO: Research Funding; Novartis: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 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.

Abstract 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.