ALBERT

Description: Introduction: Ublituximab (UTX) is a novel chimeric mAb targeting a unique epitope on the CD20 antigen, glycoengineered to enhance affinity to FcγRIIIa receptors, thereby demonstrating significantly greater ADCC than rituximab. UTX monotherapy in patients (pts) with rituximab relapsed/refractory NHL and CLL has reported a 43% ORR (ASCO 2014). TGR-1202 is a next generation, once daily, oral PI3Kδ inhibitor which notably lacks the hepatotoxicity associated with other PI3Kδ inhibitors, and is active in pts with relapsed and refractory hematologic malignancies (EHA 2014). UTX and TGR-1202 have shown synergistic activity in-vitroin various lymphoid cell lines (Lugano 2013). This Phase 1 trial evaluates safety and efficacy of the combination of a glycoengineered anti-CD20 (UTX) and a PI3Kδ inhibitor (TGR-1202) in pts with heavily pre-treated relapsed or refractory CLL and NHL. Methods: Eligible pts have relapsed/refractory CLL or NHL with an ECOG PS ≤ 2. A 3+3 design evaluates cohorts of CLL and NHL pts independently with UTX dosed on Days 1, 8, 15 of Cycles 1 & 2 followed by maintenance therapy. UTX starts at 600 mg in Cohort 1 and increases to 900 mg for pts with CLL and is fixed at 900 mg for pts with NHL. TGR-1202 starts at 800 mg QD in Cohort 1 and is increased in subsequent cohorts. An amendment in July 2014 was introduced to include an improved micronized formulation of TGR-1202, starting at 400 mg once daily and increasing in subsequent cohorts. There are no limits on prior therapy, and patients with Richter’s Transformation or who are refractory to prior PI3Kδ inhibitors or BTK inhibitors are eligible. Primary endpoints: Safety and Dose Limiting Toxicities (DLT). Secondary endpoints: Efficacy (ORR, CR rate). Results: As of August 2014, 21 pts have been enrolled: 8 CLL/SLL, 7 DLBCL, 5 Follicular Lymphoma, and 1 patient with Richter’s Transformation. Median age is 64 years (range 35-82); 12 male/9 female. Median prior Tx = 3 (range 1-9); median ECOG PS = 1. All pts are evaluable for safety. Adverse events have been manageable with no safety concerns noted. Day 1 infusion related reactions (IRR) were the most common treatment related adverse event (48%), with all but one event Grade 1 or 2 in severity, followed by neutropenia (38%), diarrhea (29%), and nausea (29%). Notably, no events of TGR-1202 related hepatotoxicity have been reported to date. All IRR and neutropenia events have been manageable with dose delays. One neutropenia related dose delay in a CLL patient at UTX 600 mg + TGR 800 mg met the criteria for a DLT, necessitating enrollment of additional pts into this cohort. No other DLTs have been reported, including at higher dose levels. Fifteen pts were evaluable for efficacy with 6 pts too early for response assessment. Among evaluable pts, 80% displayed a reduction in tumor burden at first efficacy assessment, despite pts exhibiting a number of high-risk characteristics, including 3/5 CLL pts having 17p/11q deletion and a median of 6 prior lines of therapy amongst pts with FL. Objective responses are summarized below: Table TypePts (n)PRn (%)ORRn (%)PD(n)% pts ≥ SD for 12 wksMedian Prior Rx CLL/SLL54 (80%)4 (80%)-5 (100%)2 (1 – 3) Richter’s1---1 (100%)1 FL4---4 (100%)6 (3 – 8) DLBCL52 (40%)2 (40%)14 (80%)3 (1 – 6) Total156 (40%)6 (40%)114 (93%)3 (1 – 8) Amongst pts with CLL, 2/2 pts with normal cytogenetics achieved a PR including a patient with prior treatment with a BTK inhibitor, while 2/3 pts with presence of 17p/11q deletion achieved a PR, with the remaining patient having SD with a 44% nodal reduction at first assessment. Conclusions: Preliminary data suggests the combination of UTX + TGR-1202 is well tolerated with early signs of clinical activity in heavily pre-treated and high-risk patient subsets. Enrollment is ongoing with at least 30 patients anticipated. Disclosures Lunning: Onyx: Consultancy; Alexion: Consultancy; Gilead: Consultancy; Spectrum Pharmaceuticals: Consultancy. Schreeder:TG Therapeutics, Inc.: Research Funding. Pauli:TG Therapeutics, Inc.: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Vakkalanka:Rhizen: Employment, Equity Ownership. Viswanadha:Incozen: Employment. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.

Description: Introduction: Ublituximab (UTX) is a novel, chimeric monoclonal antibody (mAb) which targets a unique epitope on the CD20 antigen and has been glycoengineered to enhance affinity for all variants of FcγRIIIa receptors, demonstrating greater ADCC than rituximab and ofatumumab. In patients (pts) with rel/ref CLL, the combination of UTX with ibrutinib was well-tolerated and highly active demonstrating an 88% ORR (95% ORR in high-risk CLL) with responses attained rapidly (median time to iwCLL response of 8 weeks). Ibrutinib has demonstrated single agent activity in Mantle Cell Lymphoma (MCL), achieving a 68% ORR (21% CR) in a single arm trial in relapsed or refractory patients (Wang et al, NEJM 2013). Herein we report on the first combination of ibrutinib with a glycoengineered anti-CD20 mAb, UTX, in patients with Mantle Cell Lymphoma (MCL). Methods: Eligible patients had rel/ref MCL with an ECOG PS 〈 3. Prior ibrutinib treatment was permitted. UTX (900 mg) was administered on Days 1, 8, and 15 in Cycle 1 followed by Day 1 of Cycles 2 - 6. Ibrutinib was started on Day 1 and continued daily at 560 mg. Following Cycle 6, patients came off study but could remain on ibrutinib. Primary endpoints were safety and ORR with an emphasis on early activity with response assessments by CT scan scheduled prior to cycles 3 and 6 only (criteria per Cheson 2007). Results: 15 patients were enrolled: 13 M/2 F, median age 71 yr (range 55-80), ECOG 0/1: 9/6, median prior Tx = 3 (range 1-8), 53% with ≥ 2 prior anti-CD20 therapies, 40% prior bortezomib. Gr 3/4 AE's occurring in at least 5% of patients and at least possibly related to UTX and/or ibrutinib included: neutropenia (13%), fatigue (7%), rash (7%) and atrial fibrillation (7%). Ibrutinib was dose reduced due to an AE in 1 patient (rash) and discontinued in 1 patient due to atrial fibrillation. No UTX dose reductions occurred. All 15 pts are evaluable for response with best response to treatment as follows: 87% (13/15) ORR with 33% (5/15) Complete Response. Three of the CR's occurred at week 8. Of the two patients not achieving an objective response, one patient was stable at first scan and came off treatment prior to second efficacy assessment (ibrutinib related A-Fib) and one patient progressed at first assessment. Responses generally improved from first to second assessment with median tumor reduction of 64% by week 8 and 82% by week 20. Conclusions: Ublituximab, a glycoengineered anti-CD20 mAb, in combination with ibrutinib is both well-tolerated and highly active in pts with rel/ref MCL. Response rate, depth of response, and time to response compare favorably to historical data with ibrutinib alone. A randomized phase 3 trial with ibrutinib +/- ublituximab is currently ongoing in high-risk CLL pts and future studies using this combination in MCL are being evaluated. Disclosures Kolibaba: Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; GSK: Research Funding; Genentech: Research Funding; Cell Therapeutics: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Acerta: Research Funding. Burke:Gilead: Consultancy; Millenium/Takeda: Consultancy; Seattle Genetics, Inc.: Research Funding; Incyte: Consultancy; Janssen: Consultancy; TG Therapeutics: Other: Travel expenses. Farber:TG Therapeutics, Inc.: Research Funding. Fanning:Celgene and Millennium/Takeda: Speakers Bureau. Schreeder:TG Therapeutics, Inc: Research Funding. Boccia:Incyte Corporation: Honoraria. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Sharman:Roche: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding; Calistoga: Honoraria; Janssen: Research Funding; TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding.

Description: Key Points U2 exhibited low rates of immune-mediated toxicities associated with other PI3K-δ, including diarrhea, colitis, pneumonia, and hepatic toxicity. This combination had promising preliminary activity across a broad range of B-cell malignancies, including a 17% complete response rate.

Description: Introduction: Ublituximab (UTX) is a novel anti-CD20 mAb that has been glycoengineered for enhanced ADCC. TGR-1202 is a novel once daily oral PI3Kδ inhibitor with clinical activity in B-cell lymphoma and a notably differentiated tolerability profile compared to similar agents. The combination of UTX + TGR-1202 showed strong synergistic activity in-vitro (Lugano 2013). Herein we report the results from the Phase 1 (dose-escalation) and updated results from the Phase Ib (dose-expansion) evaluating the safety and efficacy of the combination of UTX + TGR-1202 in patients (pts) with heavily pre-treated rel/ref NHL and CLL. Methods: A 3+3 design was utilized with rel/ref NHL and CLL pts accruing independently and no limit on the number or type of prior therapies. Patients refractory to prior PI3K or BTK inhibitors were eligible. UTX was administered D1, 8, 15 of Cyc 1 & 2, followed by D1 of Cyc 4, 6, 9 & 12. TGR-1202 was administered orally once-daily starting on D1 of Cyc 1. Primary endpoints: Safety and dose limiting toxicities (DLT). Secondary endpoints: Efficacy (ORR, CR rate). Results: 56 patients have been enrolled to date and are evaluable for safety: 16 CLL/SLL, 16 FL, 16 DLBCL, 5 MZL, 2 MCL and 1 Richter's transformation. Med age 64 yo (range 29-86); 37 M/19 F; median # prior treatment regimens = 3 (range 1-9). Day 1 infusion reactions (2% G 3/4), neutropenia (23% G 3/4), diarrhea (2% G 3/4), and nausea (0% G 3/4) were the most commonly reported adverse events considered at least possibly related to either study drug. One patient (CLL cohort 1) with baseline Gr 3 neutropenia at study entry worsened to Gr 4 resulting in a dose delay which necessitated enrollment of an additional 3 pts at that dose level. Dose escalation continued into all planned subsequent NHL and CLL cohorts (up to 1200 mg). No MTD was observed in the Phase I portion and subtype specific expansion cohorts (Phase Ib) with 800 and 1200 mg dose of micronized TGR-1202 followed. Activity was observed at all dose levels; however a possible dose-response relationship was observed with TGR-1202 at higher doses compared to the lower doses. Of the 37 evaluable pts treated at the higher doses of TGR-1202 (1200 mg original formulation or 〉 600 mg micronized), overall response was as follows: CLL/SLL (5/7); FL/MZL (10/15); DLBCL (5/12); MCL (0/2) and Richter's (1/1). No CLL pts progressed at the first efficacy assessment, despite 4/5 having high-risk cytogenetics. Two CLL pts with SD include a 17p del, ibrutinib refractory patient who eventually progressed on treatment and the other remains on study awaiting future assessments. Of interest, 7 of the DLBCL pts were GCB subtype of which 71% were rituximab refractory, with 3/7 achieving an objective response, 2 remaining in stable disease (4+ and 5+ mos each), and 2 having progressed to date (avg time on study 7 mos, range 2 - 16+ mos). Conclusions: The combination of UTX + TGR-1202 is active and well tolerated in pts with both indolent and aggressive rel/ref NHL and CLL. The Phase I portion is complete and enrollment remains open in expansion cohorts for CLL, FL/MZL and DLBCL pts evaluating TGR-1202 micronized doses at 800 to 1200 mg in combination with UTX. Given the favorable safety profile and clinical activity observed, Phase 3 programs are planned with UTX + TGR-1202. Disclosures Lunning: BMS: Consultancy; Juno: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy. Vose:Seattle Genetics, Inc.: Honoraria, Research Funding. Nastoupil:Genentech: Honoraria; Celgene: Honoraria; TG Therapeutics: Research Funding; AbbVie: Research Funding; Janssen: Research Funding. Burger:Pharmacyclics LLC, an AbbVie Company: Research Funding. Schreeder:TG Therapeutics, Inc: Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; Pharmacyclics/Jannsen: Speakers Bureau; Kite pharma: Other: attended advisory board meeting. Flowers:Seattle Genetics: Consultancy; Millennium/Takeda: Research Funding; OptumRx: Consultancy; Millennium/Takeda: Research Funding; Infinity Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Research Funding; AbbVie: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; Gilead Sciences: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Pharmacyclics: Research Funding; Spectrum: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; OptumRx: Consultancy; Spectrum: Research Funding; Onyx Pharmaceuticals: Research Funding; Gilead Sciences: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Celegene: Other: Unpaid consultant, Research Funding. Cutter:Clearview Cancer Center: Employment. Pauli:Clearview Cancer Institute: Employment; TG Therapeutics, Inc.: Consultancy, Research Funding. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership.

Description: Introduction: Umbralisib (UMB) is a next generation, once daily, PI3Kδ/CK1ε inhibitor, active in patients with relapsed or refractory (rel/ref) hematologic malignancies that, in long-term follow-up, has demonstrated a uniquely differentiated safety profile from prior PI3Kδ inhibitors (Davids, 2018). Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen. Bendamustine (Benda) is an active chemotherapy agent in pts with lymphoma. The combination of UMB + UTX (U2) is tolerable and active in patients with rel/ref hematologic malignancies and registration directed trials for patients with CLL & NHL are ongoing. This Phase 1 trial evaluates the safety and efficacy of U2 + Benda in patients with advanced diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Methods: Eligible patients had rel/ref DLBCL or FL with an ECOG PS ≤ 2 w/o limit to number of prior therapies. ANC of ≥ 750 and Platelets ≥ 50,000 were required; no growth factor support was permitted in Cycle 1 (cohort escalation group only). Patients refractory to prior PI3Kδ, Benda, or anti-CD20's were eligible. UTX was dosed on Days 1, 8, 15 of Cycle 1, Day 1 of Cycle 2-6, followed by Cycle 9 & 12. UMB was started at 800 mg QD with a -1 dose reduction cohort at 600 mg if not tolerated in ≥ 2/6 patients. Benda was dosed at 90 mg/m2 on Days 1 & 2 of Cycles 1-6 only. Primary endpoints included safety and efficacy (Cheson 2007). Results: Thirty-nine patients were evaluable for safety: 26 DLBCL and 13 FL. Med age 67 yo (range 31-81); 23 M/16 F; median prior treatment regimens = 2 (range 1-6); 22 pts (56%) were refractory to prior treatment and 6 patients had progressed post-transplant; ECOG PS 0/1/2 (12/25/2). Initially 2/4 patients at 800 mg UMB experienced AE's in Cycle 1 that led to treatment interruption (rash, neutropenia) thus the 600 mg dose of TGR-1202 was explored. No additional Cycle 1 treatment delays were reported at the 600 mg dose level, which was later expanded and the 800 mg UMB dose was evaluated with the use of growth factor support in cycle 1 permitted. The most common AE's regardless of causality included diarrhea (54%; G3/4 15%), nausea (49%; G3/4 5%), vomiting (38%; G3/4 0%), neutropenia (33%; G3/4 33%) and pyrexia (31%; G3/4 0%). Thirty-eight patients (25 DLBCL/13 FL) were evaluable for efficacy (1 DLBCL patient came off study for G4 neutropenia prior to first assessment). ORR in the respective groups is shown in Table 1. The median time to response was 8 weeks. The median DOR was 9.6 months (95% CI: 2.5-NR) for patients with DLBCL, and was not reached (95% CI: 8.0-NR) for patients with FL, at a median duration of follow-up for responders of 11.5 months (range 2.9 - 30+ mos). Conclusions: The combination of U2 + bendamustine has exhibited manageable toxicity with significant activity in advanced DLBCL and FL patients, including an encouraging CR rate in advanced patients. Based upon the early activity of the triplet, a registration directed study is underway for patients with rel/ref DLBCL (UNITY-NHL). Disclosures Lunning: Gilead: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy; Bayer: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Genzyme: Consultancy; Kite: Consultancy; Juno: Consultancy; Genentech: Consultancy; Portola: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Verastem: Consultancy. Siddiqi:Juno Therapeutics: Other: Steering committee. Flowers:Abbvie: Research Funding; TG Therapeutics: Research Funding; Gilead: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Consultancy; Pharmacyclics: Research Funding; V Foundation: Research Funding; Abbvie: Consultancy, Research Funding; Bayer: Consultancy; Karyopharm: Consultancy; Burroughs Wellcome Fund: Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Gilead: Consultancy; Millennium/Takeda: Research Funding; OptumRx: Consultancy; Pharmacyclics/ Janssen: Consultancy; Spectrum: Consultancy; Janssen Pharmaceutical: Research Funding; Denovo Biopharma: Consultancy; Acerta: Research Funding. Cohen:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: 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; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy. Blumel:TG Therapeutics, Inc.: Consultancy. Cutter:TG Therapeutics, Inc.: Consultancy. Pauli:TG Therapeutics, Inc.: Consultancy. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics: Employment, Equity Ownership. Vose:Kite Pharma: Research Funding; Legend Pharmaceuticals: Honoraria; Roche: Honoraria; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria; Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Acerta Pharma: Research Funding; Epizyme: Honoraria; Celgene: Research Funding.

Description: Background:Despite the effectiveness of novel agents in treating CLL, single agent use requires prolonged administration which can lead to drug resistance, toxicity and considerable cost over time. Combinations may provide deeper prolonged remissions using defined treatment durations. Umbralisib (Umbra) is a novel, highly-specific PI3Kδ inhibitor and ublituximab (Ubli) is a chimeric monoclonal antibody targeting a unique epitope on CD20 and glycoengineered to enhance antibody dependent cellular toxicity. Combining these agents with the BCL2 inhibitor venetoclax (Ven) may prevent drug resistance (Choudhary, Cell Death Dis 2015), avoid tumor lysis syndrome (TLS) and achieve undetectable minimal residual disease (MRD). This phase 1/2 trial evaluates the safety and efficacy of Umbra + Ubli + Ven for 12 cycles followed by MRD evaluation in relapsed or refractory CLL patients (pts). Methods:Pts received three 28-day cycles of Umbra daily along with Ubli, administered weekly during cycle 1, then once during cycles 2 and 3, followed by Umbra + Ven for 9 additional cycles. During the phase 1 study, dose levels including Umbra 600mg and 800mg were tested with Ubli 900mg and Ven, increased in standard fashion to 400 mg during cycle 4. The primary endpoint for phase 1 was safety; the primary endpoint for phase 2 was complete remission (CR) rate by iwCLL criteria. MRD negativity (20% of pts) infusion reactions (62%), thrombocytopenia (57%), neutropenia (52%), anemia (52%), fatigue (52%), ALT or AST increase (43%), nausea (33%), diarrhea (29%) and headache (24%). Grade 1 creatinine increase, hypocalcemia and hyperkalemia were observed in 12 (57%), 6 (29%) and 5 (24%) of pts respectively. These AEs predominately occurred outside of venetoclax ramp up. Grade 3/4 AE's occurring in ≥ 2 pts included neutropenia (n=4, 19%), infusion reaction (n=2, 10%) and thromboembolism (n=2, 10%). No grade ≥ 3 PI3Kδ-associated toxicities were noted (0 events of pneumonitis, colitis or grade 3/4 transaminitis). No events of TLS were observed. One pt discontinued study treatment due to grade 3 rash. All pts were converted to low TLS risk after 3 cycles of Umbra + Ubli, except for 1 pt who remained medium risk after discontinuing Ubli secondary to a grade 3 infusion reaction, allowing outpatient venetoclax initiation in all pts. In evaluable pts, the overall response rate was 85% (11/13) after cycle 3, 100% (9/9) after cycle 7 and 100% (5/5) after cycle 12. Of the 5 pts who finished 12 cycles of therapy, a median reduction in nodal disease of 87% occurred resulting in 2 CRs and 3 PRs by iwCLL criteria. 4 pts have undetectable MRD (

Description: Introduction: Preclinical data suggest that PD-1 and PD-L1/PD-L2 mediate immune evasion in CLL. However, clinical data (Ding, BLOOD 2017) demonstrate that pembrolizumab monotherapy (pembro) is ineffective in relapsed/refractory (r/r) CLL patients (pts) (ORR 0%, med PFS 2.4 months). Additional data with an anti-PD1 demonstrated a 90% failure rate in Richter's Transformation (RT) with a med 2-month OS (Rogers, BJH 2018). Combinations may represent the future of anti-PD-1 therapy in CLL/RT, especially in RT pts rel/ref to ibrutinib, where median OS is ~3.5 mos. We hypothesized synergistic activity with PD-1 + PI3K blockade. Umbralisib (UMB), is a highly-specific PI3K-δ inhibitor with additional effects on casein kinase-1 epsilon (CK-1ε), which may have an inhibitory effect on Treg function (Deng et al, 2016). We tested the safety and activity of UMB in combination with the anti-CD20 mAb ublituximab (UTX) and pembro in r/r CLL and RT - the first reported combination of a PD-1 inhibitor + PI3K-δ inhibitor in this population. Methods: Ph I (3+3 design), multicenter study to assess the safety/efficacy of UMB + UTX + pembro in pts with r/r CLL and RT. Treatment for CLL pts involved three stages: Induction: UMB (800mg daily) and UTX (900mg 3 out of 4 wks) for the first two 28-day cycles. Consolidation: Pembro (dose level 1=100mg, dose level 2=200mg) was then initiated every 3 wks in combination with UMB and UTX (900mg week 2 of cycle 4 and 6) for cycles 3-6. Maintenance: Cycle 〉 6, UMB 800 mg daily until progressive disease (PD) or unacceptable AE. For RT pts, all study drugs are started in cycle 1 with the following schedule: UMB 800 mg daily; UTX 900 mg cycle 1 (D1, 8, 15), D1 cycles 2-4, cycle 7 and q3 cycles thereafter; and pembro D3 of cycle 1 and D2 of cycles 2-4. The primary endpoint is safety of the triple combination with efficacy as a secondary endpoint. Response assessments for CLL, based on the iwCLL 2008 criteria, were performed after cycles 2, 6 and 12. RT response assessments (Cheson 2007) were completed at the end of cycles 2, 4 and every 3 cycles until month 12. Peripheral blood and/or bone marrow biopsy, enriched for mononuclear cells, were obtained for correlative analyses at screening, month 2 and 6. Results: Fourteen pts have been treated to date: 9 with CLL (3 at 100 mg pembro / 6 at 200 mg pembro) and 5 with RT (4 at 100 mg pembro / 1 at 200 mg). Baseline demographics were as follows: male/female (9/5), med age 71 yrs (range 60-81), med prior therapies 2 (1-8), 79% were refractory to immediate prior therapy. 10 pts had prior ibrutinib of which 9 were ibrutinib refractory. 64% of pts had at least 1 high risk genetic feature (del17p, del11q, TP53 mut, NOTCH1 mut or complex karyotype). AE's (all causality) were manageable. Grade 3/4 AE's occurring in ≥ 3 pts included neutropenia (n=6, 43%), ALT/AST increase (n=3, 21%) and hypophosphatemia (n=3, 21%). One DLT occurred in a CLL pt at 200 mg dose level (ALT/AST elevation) which trigged expansion to 6 pts. No additional DLTs were reported, and no MTD was achieved. No increase in expected grade ≥ 3 PI3Kδ-associated toxicities were noted (1 pneumonitis event, no colitis events). ORR was 89% for CLL pts with ORR of 75% in BTK refractory CLL pts (3/4). Notably 2/4 BTK refractory CLL pts achieved a response to UMB + UTX (U2) induction alone prior to the addition of pembro. 4/5 RT pts were eligible for efficacy evaluation with 50% ORR (2/4, CR). The 2 RT CRs were durable and are ongoing (15+ mos and 7+ mos); both pts were ibrutinib refractory and had 7 (including SCT) and 8 prior lines respectively, and one had failed CAR-T. With a med follow up of 15 mos, 10/14 (71%) remain progression free (range 3 - 44 mos, Fig 1), including one CLL pt who completed consolidation and has been off therapy for 27+ mos. Sequential sampling for correlative studies demonstrated modest changes in Tregs numbers (Fig 2). Conclusion: The triplet combination of umbralisib + ublituximab + pembro was well-tolerated. Responses were durable in BTK refractory, high risk pts, including two CR's in RT pts. In contrast to pembro monotherapy, data suggest that CLL/RT pts who achieve ≥ PR with this checkpoint inhibitor-containing regimen can achieve durable responses. Correlative studies suggest that maintenance of Tregs may limit autoimmune sequelae. Enrollment is ongoing in both the CLL (BTK refractory only) and RT cohorts. Disclosures Mato: AbbVie: Consultancy, Research Funding; Portola: Research Funding; Regeneron: Research Funding; AstraZeneca: Consultancy; Johnson & Johnson: Consultancy; Celgene: Consultancy; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Acerta: Research Funding; Prime Oncology: Honoraria. Svoboda:Regeneron: Research Funding; KITE: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding. Schuster:Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding. Becker:GlycoMimetics: Research Funding. Brander:DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Dwivedy Nasta:Aileron: Research Funding; Pharmacyclics: Research Funding; Debiopharm: Research Funding; Incyte: Research Funding; Rafael/WF: Research Funding; Roche: Research Funding; Takeda/Millenium: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Other: DSMC. Landsburg:Takeda: Consultancy; Curis: Consultancy, Research Funding. Kennard:AbbVie, Gilead, Verastem: Consultancy. Zelenetz:Abbvie: Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy; Novartis/Sandoz: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding. Purdom:TG Therapeutics: Employment, Equity Ownership. Paskalis:TG Therapeutics: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics: Employment, Equity Ownership. Shadman:Gilead Sciences: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy; Beigene: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Genentech: Consultancy; Mustang Biopharma: Research Funding; Acerta Pharma: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding; Verastem: Consultancy.

Description: Introduction: Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen. TGR-1202 is a next generation, once daily, PI3Kδ inhibitor, active in patients (pts) with rel/ref hematologic malignancies that has demonstrated a notably differentiated safety profile, including in long-term follow up (Burris, 2016). Bendamustine (Benda) is an active chemotherapy agent in pts with lymphoma. The combination of UTX + TGR-1202 has been previously explored in patients with rel/ref hematologic malignancies and is both well tolerated and highly active. This Phase 1 trial evaluates the safety and efficacy of UTX + TGR-1202 + Benda in pts with advanced diffuse large B-cell lymphoma (DLBCL) and Follicular Lymphoma (FL). Methods: Eligible pts had rel/ref DLBCL or FL with an ECOG PS ≤ 2 w/o limit to number of prior therapies. ANC of ≥ 750 and Platelets ≥ 50,000 were required; no growth factor support was permitted in Cycle 1 (safety evaluation period). Pts refractory to prior PI3Kδ, Benda, or anti-CD20's were eligible. The study was designed to evaluate the safety and efficacy of the triplet combination. UTX was dosed on Days 1, 8 & 15 of Cycle 1, Day 1 of Cycle 2-6, followed by Cycle 9 & 12. TGR-1202 was started at 800 mg QD with a -1 dose reduction cohort at 600 mg if not tolerated in ≥ 2/6 pts. Benda was dosed at 90 mg/m2on Days 1 & 2 of Cycles 1-6 only. Efficacy was evaluated per Cheson 2007. Results: Thirteen pts were evaluable for safety: 9 diffuse large B-cell (DLBCL) and 4 follicular (FL). Med age 65 yo (range 51-81); 7 M/6 F; median prior treatment regimens = 3 (range 1-6); 8 pts (62%) were refractory to prior treatment; 10 pts (77%) were rituximab refractory; ECOG PS 0/1 (1/12). Two of four pts at 800 mg TGR-1202 experienced AE's in Cycle 1 (rash, neutropenia) that led to treatment interruption thus the 600 mg dose of TGR-1202 was explored. No additional Cycle 1 treatment delays were reported at the 600 mg dose level, which was later expanded (n=9). The most common AE's regardless of causality included diarrhea (46%), nausea (38%), decreased appetite and neutropenia (31% each). Grade 3/4 AE's (all causality) reported in 〉 10% of pts were neutropenia (31%), followed by anemia and hypokalemia (15% each). Two pts had dose reductions (both benda and TGR-1202 reduced). Eight pts (6 DLBCL/2 FL) were evaluable for efficacy (4 too early, 1 withdrew due to non-related AE): ORR was 100% (8/8) with all pts achieving a response at the first efficacy assessment (8 weeks), and 50% (4/8) achieving a complete response (CR), of which 3 were DLBCL and 1 FL. Median follow-up time on study is 3 mos for all pts (range 1 - 9+ mos). No pts have progressed on study to date. Conclusions: The combination of UTX, TGR-1202, and bendamustine has exhibited manageable toxicity with significant activity (100% ORR) including a 50% CR rate in pts with advanced DLBCL and FL. Enrollment continues at the 600 mg TGR-1202 dose level and the use of growth factor prophylaxis is now being explored at the TGR-1202 800 mg dose in consideration of the advanced patient population. Safety and efficacy data for all pts will be updated at the meeting. Based upon the early activity of the triplet, future registration directed studies are under consideration. Disclosures Lunning: Bristol-Myer-Squibb: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy; TG Therapeutics: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; Celgene: Consultancy. Blumel:TG Therapeutics, Inc.: Consultancy. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: Ublituximab (UTX) is a novel, chimeric monoclonal antibody (mAb) which targets a unique epitope on the CD20 antigen and has been glycoengineered to enhance affinity for all variants of FcγRIIIa receptors, demonstrating greater antibody-dependent cellular cytotoxicity (ADCC) activity than rituximab and ofatumumab, particularly against cells that express low CD20 levels. Two Phase I trials of single agent UTX in relapsed/refractory CLL reported significant response rates with rapid and sustained lymphocyte depletion and a manageable safety profile. Ibrutinib, a novel oral BTK inhibitor approved for patients with previously treated CLL and MCL, displays high single agent activity and has reported increased activity in combination with non-glycoengineered anti-CD20 mAbs. Herein we report safety and efficacy data on the first combination of ibrutinib with a glycoengineered anti-CD20 mAb, UTX, from an ongoing Phase 2 trial. Methods: Eligible patients have relapsed or refractory CLL/SLL or MCL with an ECOG PS ≤ 2. The study was designed to assess safety, tolerability, and early overall response rate, with an initial safety run-in period consisting of 6 patients followed by open enrollment. UTX (Cohorts of 600 and 900 mg for CLL and at 900 mg for MCL patients) is administered on Days 1, 8, and 15 in Cycle 1 followed by Day 1 of Cycles 2 - 6. Ibrutinib is started on Day 1 and continues daily at 420 mg and 560 mg for CLL and MCL patients respectively. Following Cycle 6, patients come off study but remain on ibrutinib. Primary endpoint for safety: Adverse Events and Dose Limiting Toxicities (DLT) during safety run-in. Phase II primary efficacy endpoint: ORR with an emphasis on early activity with response assessments by CT scan scheduled prior to cycles 3 and 6 only. Results: 40 patients (33 CLL/ 7 MCL) have been enrolled to date with enrollment continuing. 23 M/17 F, median age 72 yr (range 52-86), ECOG 0/1/2: 20/19/1, median prior Tx = 2 (range 1-6), 38% with ≥ 2 prior anti-CD20 therapies; prior purine analog = 43%; prior alkylating agent = 68%; and prior purine and alkylating agent = 43%. No DLTs were observed during the safety run-in. Gr 3/4 AE’s occurring in at least 5% of patients and at least possibly related to UTX and/or ibrutinib included: neutropenia, thrombocytopenia, diarrhea, rash, leukocytosis, and infusion related reaction. There were no Grade 3/4 adverse events reported in ≥ 10% of patients. Ibrutinib was dose reduced due to an AE in 2 patients (1 diarrhea, 1 rash) and discontinued in 2 patients due to ibrutinib related AE’s (diarrhea and rash). IRR’s were managed with infusion interruptions with no patient requiring an ublituximab dose reduction. As of July 2014, 24/40 patients are evaluable for response. Best response to treatment is as follows: TableTypePts (n)CR (n)PR (n)SD (n)ORR (%)CLL non 17p/11q10-9190%17p/11q817-100%Total CLL18116194%MCL632183% The one CLL patient who achieved stable disease had a 46% nodal reduction. UTX appears to control ibrutinib related lymphocytosis with more than half of the patients within normal range for ALC by first efficacy assessment. Conclusions: Data suggests ublituximab, a glycoengineered anti-CD20 mAb, in combination with ibrutinib is both well-tolerated and highly active in patients with relapsed or refractory CLL and MCL. ORR was 94% in patients with CLL (100% in patients with high risk CLL: 17p, 11q del with 1 CR), with responses attained rapidly (median TTR: 8 weeks). In MCL, 83% of patients achieved a response at first efficacy assessment, with 50% of patients achieving a CR by week 20. For most patients, responses improved by the second efficacy assessment. The addition of ublituximab appears to mitigate ibrutinib related lymphocytosis producing earlier clinical responses than historically seen with ibrutinib monotherapy. Efficacy and safety will be updated on all enrolled patients. Disclosures Sharman: TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Research Funding. Farber:Leukemia Lymphoma Society NJ Chapter: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Stock ownership Other. Schreeder:TG Therapeutics, Inc.: Research Funding. Kolibaba:TG Therapeutics: Research Funding; Gilead: Research Funding; Glaxo Smithkline: Research Funding. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Greenwald:TG Therapeutics: Research Funding.

Description: In order to develop long-lifespan batteries, it is of utmost importance to identify the relevant aging mechanisms and their relation to operating conditions. The capacity loss in a lithium-ion battery originates from (i) a loss of active electrode material and (ii) a loss of active lithium. The focus of this work is the capacity loss caused by lithium loss, which is irreversibly bound to the solid electrolyte interface (SEI) on the graphite surface. During operation, the particle surface suffers from dilation, which causes the SEI to break and then be rebuilt, continuously. The surface dilation is expected to correspond with the well-known graphite staging mechanism. Therefore, a high-power 2.6 Ah graphite/LiNiCoAlO2 cell (Sony US18650VTC5) is cycled at different, well-defined state-of-charge (SOC) ranges, covering the different graphite stages. An open circuit voltage model is applied to quantify the loss mechanisms (i) and (ii). The results show that the lithium loss is the dominant cause of capacity fade under the applied conditions. They experimentally prove the important influence of the graphite stages on the lifetime of a battery. Cycling the cell at SOCs slightly above graphite Stage II results in a high active lithium loss and hence in a high capacity fade.