ALBERT

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: Introduction: Patients with International Prognostic Scoring System (IPSS) intermediate (Int) and high risk (HR) MDS benefit from therapy with hypomethylating agents (HMAs). Treatment with the HMAs decitabine (DAC) and azacitidine (AZA) requires 5 or 7 daily parenteral doses respectively every month with some patients remaining on treatment for extended periods. An orally administered HMA would provide significant patient convenience, potentially enhance adherence to treatment, and may allow exploring extended treatment schedules with lower doses of DAC. Neither DAC nor AZA is readily bioavailable in oral form due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDAi, is orally bioavailable with a large safety margin in preclinical models. We report here the first Phase 1 results of a PK-guided FIH dose escalation trial of ASTX727 (the combination of oral DAC and E7727). Methods: Adult patients with Int or HR MDS or Chronic Myelomonocytic Leukemia (CMML) were enrolled in this dose-escalating trial with a 3+3 design. In addition to assessing the safety of the combination, the primary PK objective was to achieve a mean AUC of DAC following oral ASTX727 comparable to that achieved by IV DAC at the approved dose of 20 mg/m2. In the first cycle, each patient received an IV DAC dose of 20 mg/m2 on Day 1 as an internal comparator followed by oral ASTX727 on Days 2-5 escalated by cohort. Subsequent cycles were given with oral ASTX727 on Days 1-5 at the same dose of Cycle 1. Cycles were 28 days in length. Pharmacodynamics (PD) were evaluated by LINE-1 DNA methylation in peripheral blood. A data safety review committee evaluated safety, PK and PD on patients in each completed cohort and determined dosing for each component of ASTX727 at the next cohort. Only one component at a time was escalated in each cohort and oral doses were not adjusted for weight or body surface area. Responses were assessed using the International Working Group (IWG) criteria for response (Cheson et al, 2006). Results: The Phase 1 portion of the trial completed dosing of 4 cohorts with 6 subjects each (24 subjects). The median age was 71 years (range 59-85), 15/24 (63%) were male, and median time from diagnosis was 307 days (range 5-3024). Prior therapies were administered to 10 patients including five who had received prior HMA. In cohorts 1-3 ASTX727 was given as a fixed oral DAC dose of 20 mg with escalating doses of oral E7727 at 40, 60, and 100 mg respectively. In cohort 4, the oral DAC dose was escalated to 40 mg while E7727 was kept at 100 mg. The Day 1 AUC for IV DAC 20 mg/m2 over all 4 cohorts had a mean (SD) value of 193(82) ng*hr/mL. After oral ASTX727 on Days 2-5, the mean DAC AUC as % of IV DAC AUC was 17, 19, 32, and 98% on Day 2 and 31, 41, 58 and 148% on Day 5, in cohorts 1-4 respectively (Figure). DAC AUC variability after oral ASTX727 was acceptable (CV% 35-53 across 4 cohorts). DAC Cmax values after oral ASTX727 approached IV (87%) in Cohort 4 on Day 5. Mean % LINE-1 demethylation on cycle 1 Day 8±SE was 6.8%±2.7; 8.6%±2.7; 9.5%±3.3; and 15.3%±3.4 from baseline for cohorts 1-4 respectively. No Dose Limiting Toxicities (DLTs) or Grade ≥ 3 drug-related non-hematologic AEs were observed in any patient. The most common Grade ≥ 3 AEs regardless of relationship to the drug were thrombocytopenia (37.5%), anemia (33.3%), neutropenia (29.2%) and febrile neutropenia (16.7%). Twenty patients remain on therapy, and at least 5 so far have experienced objective clinical responses (including 1 Complete Response (CR), 1 marrow CR, 1 Partial Response and 2 Hematologic Improvement). Conclusions: ASTX727 (the combination of oral DAC and oral CDAi E7727 administered concomitantly) achieved the primary PK objective of reaching (at Day 2) or exceeding (at Day 5) IV DAC 20 mg/m2 AUC levels at the doses of 40 mg DAC and 100 mg E7727 with an excellent safety profile. Day 8 LINE-1 demethylation in Cohort 4 is consistent with that historically reported following DAC 20 mg/m2 IV for 5 days. Clinical responses have been observed. The trial will explore lower doses of oral DAC and will proceed to dose expansion followed by randomized phase 2 portion comparing IV DAC to oral ASTX727 in previously untreated Int or HR MDS and CMML patients. Figure 1. Mean DAC AUC after IV DAC 20 mg/m2 (D1) and oral ASTX727 (D2 and D5) for cohorts 1-4 Figure 1. Mean DAC AUC after IV DAC 20 mg/m2 (D1) and oral ASTX727 (D2 and D5) for cohorts 1-4 Disclosures Savona: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Astex Pharmaceuticals, Inc: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Michaelis:Incyte: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Wyeth: Membership on an entity's Board of Directors or advisory committees; Pfizer: Equity Ownership. Faderl:JW Pharma: Consultancy; Karyopharm: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Astellas: Research Funding; Celator: Research Funding; Ambit: Research Funding; Onyx: Speakers Bureau; BMS: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Oganesian:Astex Pharmaceuticals, Inc.: Employment. Dua:Astex Pharmaceuticals, Inc.: Employment. Nawabi:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment.

Description: 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.

Description: Background: Ricolinostat, an oral selective HDAC6 inhibitor, is well tolerated as monotherapy (Raje Blood 2012;120:4061) and demonstrates potent synergistic activity with lenalidomide (Len) and pomalidomide (Pom) in preclinical models (Quayle Blood 2013;122:1952). In an ongoing trial of ricolinostat in combination with Len and dexamethasone (Dex) in patients with relapsed or refractory multiple myeloma (MM), no dose limiting toxicities (DLTs) were observed at up to doses of 160 mg BID, with excellent activity and tolerability (Yee Blood 2014;124:4772). Pan-HDAC inhibitors vorinostat and panobinostat are active in MM in combination with bortezomib (Btz) and Len, but toxicities (thrombocytopenia, fatigue, and GI events) limit dosing exposure. This trial explores activity of ricolinostat in combination with Pom and Dex in a patient population comparable to that in MM-003 (San Miguel Lancet Oncol 2013;14:1055-66). At the time of achieving the primary endpoint of PFS in MM-003, the ORR was 16.6% at 18.1 weeks median follow-up (EMA Pom Celgene Assessment Report EMA/CHMP/427059/2013), and was 31% at 10 months in the same clinical trial (San Miguel Lancet Oncol 2013;14:1055-66). Methods: Phase 1b was a 3+3 design which explored ricolinostat 160 mg QD or BID combined with Pom (4 mg) for 21 days of a 28 day cycle with Dex (40 mg) on days 1, 8, 15 and 22. Patients had measurable disease, adequate BM reserve and hepatic function with CrCl ≥45 mL/min. Refractory was defined as PD on or within 60 days of last therapy. Patients with non-secretory MM, prior Pom or HDAC inhibitor therapy were excluded. Peripheral blood samples were obtained for PK/PD assessment of acetylated tubulin and histones. Patients with serum FLC only disease were excluded from Phase 2. The dose level of 160 mg dose was chosen based on prior experience in which PK plateau was reached at 160 mg of ricolinostat. A sample size of 66 was determined to be adequate to detect an ORR of 44% against a historical rate of 29%. Results: 7 patients were treated in phase 1b: 3 at 160 mg QD and 4 at 160 mg BID. No DLTs were observed; however, all 4 patients had grade 2 diarrhea in the 160 mg BID cohort and grade 3 fatigue and grade 3 or 4 neutropenia attributed to Pom were reported in patients in phase 1b. 1 patient remained on study for 12 cycles before PD; the other 6 Phase 1b patients were withdrawn for PD at 2-4 cycles. Following safety review committee (SRC) review, phase 2 opened at a dose of 160 mg BID, with a predetermined SRC review to occur after 6 patients had completed 1 cycle of therapy. 3 of the 6 patients had clinically relevant diarrhea requiring ricolinostat dose reduction to 160 mg QD in cycle 2 leading to SRC recommendation of QD dosing of ricolinostat. As of April 28, 2015 39 phase 2 patients were evaluable for safety and 28 evaluable for response. Median age was 68 and median number of prior regimens was 4 (2-9) in 3 (2-6) line of therapy. 37 patients were refractory to Len as defined in the entry criteria. Common toxicities were predominantly low grade and included fatigue (40%), diarrhea (38%), neutropenia (36%), anemia (31%), thrombocytopenia (26%), and constipation (21%). Important grade 3/4 related toxicities included neutropenia (5 patients, 13%) and diarrhea (3 patients, 8%). PK of ricolinostat was similar to that observed in combination with Btz and Len. There was no evidence of ricolinostat accumulation or drug-drug interaction with Pom. Median follow-up of 12 (4-32) weeks; ORR (≥PR) was 29% with 3 VGPR and clinical benefit rate (≥MR) was 50% with 68% SD or better for the 28 response evaluable patients. Updated safety and efficacy data will be presented as enrollment continues and data matures including for the 49 patients enrolled in phase 2 to date. Conclusion: These early data with a median follow-up of 12 weeks (compared to historical control of 16.6% ORR at 18.1 weeks for Pom/Dex alone in MM-003) in a rigorously defined patient population suggest that selective HDAC6 inhibition is associated with encouraging tolerability and promising clinical activity. Accrual is continuing in US, Canada, and Europe. Overall, ricolinostat is an active and safe oral agent which combines favorably with Pom and Dex in relapsed-and-refractory MM. Disclosures Raje: Novartis: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Eli Lilly: Research Funding; AstraZeneca: Research Funding; Millenium: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; Celgene Corporation: Consultancy; BMS: Consultancy. Bensinger:Sanofi: Research Funding; Acetylon Pharmaceuticals, Inc: Research Funding; BMS: Research Funding; Novartis: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Research Funding; Onyx: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Lonial:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Jagannath:BMS: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria; Janssen: Honoraria; MERCK: Honoraria; Celgene: Honoraria. Valent:Takeda/Millennium: Speakers Bureau; Celgene: Speakers Bureau. Harb:Idera Pharmaceuticals: Research Funding; Astex Pharmaceuticals, Inc.: Research Funding. Sandhu:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Bahlis:Johnson & Johnson: Research Funding; Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Reece:Merck: Research Funding; Lundbeck: Honoraria; Amgen: Honoraria; Onyx: Consultancy; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Millennium Takeda: Research Funding; Otsuka: Research Funding. Terpos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Takeda: Honoraria; Celgene: Honoraria, Other: Travel expenses; Novartis: Honoraria; Amgen: Honoraria, Other: Travel expenses, Research Funding. Tamang:Acetylon Pharmaceuticals, Inc.: Employment. Jones:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Wheeler:Acetylon Pharmaceuticals, INC: Employment. Markelewicz:Acetylon Pharmaceuticals, Inc: Employment. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

Description: Background: PNT2258 is a 24-base, single-stranded liposome-encapsulated DNA oligonucleotide that hybridizes to regions of the BCL2 gene, modulating its function. As previously reported, PNT2258 demonstrates antitumor activity in patients with advanced-stage NHL. The updated clinical data that are provided in this abstract (as of 07/25/14) now include anti-tumor activity in patients with DLBCL and Richter’s syndrome. Methods: All patients had CT-measureable, FDG-PET positive disease with progression prior to study entry, and had previously received rituximab and combination cytotoxic chemotherapy. Refractory tumor status or concomitant medical issues precluded the use of additional cytotoxic therapy in all patients included in the study. PNT2258 induction cycles were administered as a 3-hour IV infusion at 120 mg/m2 days 1-5 of each 21-day cycle for up to 8 cycles. Response evaluation occurred at the end of cycles 2, 6 and 8. Following induction, patients could receive maintenance dosing at 100 mg/m2days 1-2 of each 28-day cycle until PD. Results: Thirteen patients (median age 65; 8 males, 5 females; ECOG PS 0/1/2: 3/9/1) received all scheduled doses of PNT2258. Regardless of attribution, there were no cycle 1, grade 3/4 AEs. The most common grade 1/2 AEs in cycle 1 included chills, low-grade fever, transient nausea, and tumor or back pain (n=5 for each). There was no evidence of tumor lysis syndrome, febrile neutropenia or significant GI toxicity. Of 4 patients with DLBCL, including 1 with Richter’s syndrome and 1 with Burkitt-like histology, PFS was 9.2 months, range 5.5-12.3 months as of 7/25/14. Best response data (CR/PR/SD/PD) for the DLBCL group was 2/1/1/0. Additionally, in 5 FL patients, best response was 1/1/3/0. Five patients, including 3 DLBCL and 2 FL remain on study as of 7/25/14 receiving maintenance treatment with PNT2258. Conclusions: PNT2258 is well tolerated and can be administered over prolonged periods of time. Durable single agent activity was previously reported in patients with FL, and has now been observed in patients with aggressive DLBCL. Studies in DLBCL and Richter’s syndrome are being implemented and updated information will be provided at the time of the meeting. Clinical trial information: NCT01733238. Disclosures Gaylor: ProNAi Therapeutics: Employment. Rodrigueza:ProNAi Therapeutics: Employment. Woolliscroft:ProNAi Therapeutics: Employment. Sooch:ProNAi Therapeutics: Employment. Messmann:ProNAi Therapeutics: Employment.

Description: Background Aberrant BCL2 control mechanisms are a defining characteristic of a variety of cancers including follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). PNT2258 is a 24-base, single-stranded, chemically unmodified phosphodiester DNA oligonucleotide encapsulated in a specialized liposome (SMARTICLES®) that has demonstrated antitumor activity against human cell lines and xenograft models that include NHL, prostate cancer and melanoma. The oligonucleotide sequence is designed to hybridize with genomic sequences that reside within 5'-untranscribed regulatory regions of the BCL2 gene to block transcription of BCL2 through a mechanism called DNA interference (DNAi). In a previously conducted phase I study, PNT2258 was safe and well tolerated at doses from 1 through 150 mg/m2 and PNT2258 showed evidence of BCL2-targeted effects on a variety of biomarkers. Methods This study is a multi-center, single-agent, pilot Phase II investigation of PNT2258 administered at a dose of 120 mg/m2 as a 3-hour IV infusion on days 1-5 of a 21-day cycle. Objectives included characterization of anti-tumor activity and safety data in patients (pts) with relapsed or refractory lymphoma undergoing treatment with PNT2258 for six cycles or until progressive disease or unacceptable toxicity. Adult pts with measureable disease that was FDG-PET positive at baseline were eligible. Additional criteria included ECOG PS ≤2, adequate bone marrow, renal and hepatic function, and prior treatment that included rituximab and cytotoxic chemotherapy. Standard CTCAE and Cheson criteria were used for evaluation. Patients were scanned with CT/PET at baseline, after 2 cycles and at study end. Details are at ClinicalTrials.gov under study number NCT01733238. Results To date, 10 pts (median age, 61 [range 40 - 74]) have been treated with PNT2258. Median number of prior therapies was 4 (2 - 8) and 100% of pts had baseline adenopathy 〉5 cm with the majority 〉10 cm. Antitumor activity was observed in 4 of 4 patients with FL, including 1 complete response, 1 partial response (with 80% reduction in tumor size from 20 cm to 4 cm), and 2 patients with stable disease (SD); both with tumor shrinkage at interim (i.e., end-of-cycle 2) scan. One patient each with mantle cell lymphoma (MCL) and bulky chronic lymphocytic leukemia (CLL) has exhibited SD at interim scan. Two pts exhibited progressive disease (1 each MCL and CLL). Seven of ten pts continue treatment and updated results will be presented. Toxicity occurring in ≥2 pts included grade 1 chills (n=2), diarrhea (n=2), grade 2 nausea (n=3), tumor pain (n=2) and hypotension (n=2). The single grade 3 toxicity occurring in ≥2 pts was nausea (n=2) and no grade 4 toxicity was noted. Additionally, tumor lysis syndrome has not been observed. Conclusions PNT2258 is a first-in-class DNAi consisting of a native, single-stranded, chemically unmodified DNA oligonucleotide delivered to a nuclear genomic target via a protective lipid nanoparticle, and the first to target the regulatory upstream region of the BCL2 gene. PNT2258 is well tolerated with an acceptable safety profile and shows significant single agent anti-tumor activity in pts with heavily treated relapsed NHL, particularly in pts with FL. Additional studies are planned. Disclosures: Gaylor: ProNAi Therapeutics, Inc.: Employment. Woolliscroft:ProNAi Therapeutics, Inc.: Employment. Rodrigueza:ProNAi Therapeutics, Inc.: Employment, Equity Ownership. Sooch:ProNAi Therapeutics, Inc.: Employment, Equity Ownership. Messmann:ProNAi Therapeutics, Inc.: Employment. Al-Katib:ProNAi Therapeutics, Inc.: Research Funding.