Abstract: 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.

Abstract: Targeted modalities are playing a an increasing role in modern oncology. We have previously demonstrated that the unconjugated humanized anti-CD33 monoclonal antibody, HuM195 has activity in the setting of relapsed AML. Given these results, we designed a clinical trial investigating whether antibody therapy can be combined with other therapeutic approaches including dose intensive chemotherapy and drug/growth factor immunomodulation as the initial therapy for adults with AML and whether such patients can safely proceed to stem cell transplantation. Patients in this study were treated with MEC (mitoxantrone 8 mg/m2, etoposide 80 mg/m2, and cytarabine 1 gm/m2 daily for 6 days). HuM195 was administered for 4 days at a dose of 12 mg/m2 on days 6–9 and days 19–22. GM-CSF (250 ug/m2/day) was begun on day 8 and continued until neutrophil recovery. Patients who achieved CR and had a suitable related donor proceeded directly to allogeneic stem cell transplantation (SCT). Others received two additional cycles of high-dose cytarabine followed by autologous SCT augmented by combination cyclosporin and GM-CSF in an effort to induce an autologous graft versus leukemia (GvL) effect. Thirty patients have been treated to date (15 patients with de novo AML; 15 patients with secondary AML). The median age was 51 years (range 24–71). Nineteen of the 28 evaluable patients (68%) achieved CR with 14 of the 15 (93%) de novo AML patients achieving a CR. Three deaths from uncontrolled infection occurred during induction. In patients achieving CR, the median time to recover an ANC & gt; 500/mm3 was 23 days (range 20–36) and a platelet count & gt; 20,000/mm3 was 17 days (range 12–42). Four patients proceeded directly to allogeneic stem cell transplantation without any consolidation therapy and three remain free of disease with a median follow-up of 24 months. One patient is too early for evaluation. Five patients went on to autologous stem cell transplant (AuSCT) and two remain in remission after 13 and 24 months. Three patients relapsed after AuSCT. Two expired from refractory leukemia, and one was salvaged with allogeneic SCT. Among the AuSCT patients, the median time to recovery of the ANC & gt; 500/mm3 and platelet count & gt; 20k/mm3 was 7 days (range 1–9) and 7.5 days (range 5–22), respectively, comparable to patients who received standard induction regimens. There was no clinical evidence of graft verses host disease in the AuSCT patients. No evidence of veno-occlusive disease was observed after either autologous or allogeneic transplantation. Preliminary results suggest combined modality therapy is feasible and well-tolerated as initial therapy for AML. Patients are able to receive dose intensive consolidation therapy including transplantation safely after the use of an intensive induction with combined modality therapy incorporating HuM195. All patients who underwent an allograft after induction remain in remission with two year follow up. Further follow-up is needed to determine the effect on long term outcomes.

Abstract: Combination therapy with purine analogs, alkylators, and monoclonal antibodies has transformed the treatment paradigm in patients with CLL by dramatically enhancing both the quality and frequency of responses that can be achieved in these patients. However, combinations utilizing fludarabine as the purine analog have augmented myelosuppression and immunosuppression requiring careful attention to dosing and schedule in order to minimize these complications. Even with these precautions many patients are unable to complete the entire treatment program at full dose and for the planned number of cycles. Comparative experience with pentostatin indicates that it is less myelosuppressive than either fludarabine or cladribine. We previously reported our experience with pentostatin and cyclophosphamide. Subsequently, we have added rituximab to this active combination (PCR regimen) and treated a second cohort of 46 patients with previously treated CLL (32 patients) and other low grade lymphoid neoplasms (14 patients). The PCR regimen consists of pentostatin 4mg/m2, cyclophosphamide 600mg/m2, and rituximab 375mg/m2 all given on a single day with anti-emetics, hydration, and careful monitoring of renal function. The treatment was administered every 3 weeks for a total of 6 treatments. Rituximab was not given during the first cycle to reduce the frequency and severity of infusion reactions. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. The median age of the patients treated was 62 (range 44–80) and the median number of prior regimens was 2 (range 1–7). The overall frequency of response was 75% with 25% achieving a complete response, 3% a nodular response, and 47% a partial response. We have compared these results to the recently reported MD Anderson FCR regimen. In terms of pre-treatment characteristics the patient groups in both studies appear comparable with the exception of a higher proportion of high-risk patients treated with PCR (78%) compared to FCR (50%) (P=0.003). The response frequencies are virtually identical in both studies with responses seen 75% of PCR treated patients and 73% of FCR treated patients and CR achieved in 25% in both studies. In terms of toxicity, however, PCR compares favorably to FCR in the following categories: Grade 3/4 neutropenia PCR 53% vs FCR 81% (P=0.0007), thrombocytopenia PCR 16% vs FCR 34% (P=0.04), anemia PCR 9% vs FCR 24% (P=0.06), and grade 3/4 infections (including fever of unknown origin) PCR 28% vs FCR 47% (P=0.05). PCR also appeared to be better tolerated than FCR as indicated by the fraction of patients completing all planned cycles of chemotherapy at full dose 72% vs 38% (P=0.0004). An important caveat in these comparisons is that myeloid growth factor was routinely administered to patients on the PCR study but was not routinely administered to patients treated with FCR. In conclusion, PCR appears to be equivalent in activity to FCR but may be better tolerated and less toxic. These results indicate that a prospective randomized comparison is warranted.

Abstract: 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.

Abstract: Background: Though CD19 is expressed only rarely on multiple myeloma (MM) plasma cells (PC), rare CD19+ B cells can be identified in MM patients that are clonally related to the MM PC. These clonotypic B cells may exhibit properties of cancer stem cells (enhanced MM-propagating properties and drug resistance compared to MM PC) and thus be a potential therapeutic target in conjunction with therapies that target MM PC. CTL019 consists of autologous T cells transduced via lentiviral vector with an anti-CD19 scFv coupled to CD3-zeta and 4-1BB signaling domains and expanded ex vivo with anti-CD3/CD28-conjugated beads. To target both clonotypic B cells and MM PC, we conducted a pilot clinical trial of CTL019 administered after high-dose melphalan and autologous stem cell transplantation (ASCT) in relapsed/refractory MM patients who had previously undergone first-line ASCT with short progression-free survival (PFS). Methods: Subjects were required to be medically fit for ASCT and have progressed within 1 year of a prior ASCT performed as part of first-line therapy. Study therapy consisted of ASCT with melphalan 140-200 mg/m2 followed by 1-5x107 CTL019 cells 12-14 days later. The primary endpoint was safety and feasibility of CTL019 manufacturing and administration in this clinical setting. Secondary endpoints included assessments of CTL019 in vivo persistence and activity against normal B cells, plasma cell immunophenotype as a response biomarker, and PFS after ASCT + CTL019 in comparison to PFS after initial ASCT. Results: Twelve subjects enrolled, and 10 received study therapy; autologous T cells failed to expand ex vivo in one enrolled subject, and one enrolled subject elected to pursue off-study therapy. Median age was 61 (range 48-68). Median prior lines of therapy was 6 (range 2-10). Poor-prognosis features were present in 8/10 subjects (6/10 with poor-prognosis cytogenetics, 2/10 with BRAF V600E mutations, 1/10 with secondary plasma cell leukemia). Median PFS after first-line ASCT was 258 days (range 100-342). In pre-ASCT bone marrow (BM), the dominant MM PC population was CD19-negative by flow cytometry in 9/9 evaluable subjects, though 7/9 exhibited rare CD19+ subsets comprising 0.05-1.5% of MM PC. Melphalan dose was 140 (N=7) or 200 (N=3) mg/m2. All subjects infused received the maximum target dose of 5x107 CTL019 cells. Adverse events (AE) consisted mostly of expected ASCT toxicities. Grade ³3 AE that were at least possibly related to CTL019 included grade 3 autologous GVHD (N=1, resolved with corticosteroids) and oral mucositis (N=1). Grade 1 cytokine release syndrome occurred in 1 subject. There was no ASCT-related mortality. After infusion, CTL019 cells were detectable in peripheral blood (PB) of all subjects and persisted for median of 44 days (range 14-156). Presence of PB CTL019 cells was associated with absence of PB B cells. Notably, CTL019 cells were detected in BM in 9/10 subjects at day 42 and/or 100 post-ASCT. Median PFS after ASCT + CTL019 was 185 days (range 42-479); all subjects have progressed. The peak BM CTL019 frequency correlated significantly with favorable PFS (SpearmanÕs rho=0.77, P=0.009). There was no association between PFS and peak frequency of CTL019 or duration of CTL019 persistence in PB. In 3/10 subjects, PFS after ASCT + CTL019 met or exceeded PFS after first-line ASCT (Figure). For comparison, in a historical cohort of 18 patients who received first-line and salvage ASCT at our institution since 2008, no patients exhibited longer PFS after salvage ASCT. Conclusion: CTL019 manufacturing and administration post-ASCT is safe and feasible in patients with advanced MM. Correlation of PFS with CTL019 frequency in BM and prolonged PFS in 3 subjects is suggestive of clinical efficacy. A phase-two study of CTL019 using a 10-fold higher dose after first-line ASCT in high-risk MM patients is ongoing. Figure. Figure. Disclosures Garfall: Medimmune: Consultancy; Bioinvent: Research Funding; Novartis: Consultancy, Research Funding. Stadtmauer:Novartis: Consultancy; Takada: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Teva: Consultancy; Celgene: Consultancy. Maus:Novartis: Patents & Royalties: related to CTL019, Research Funding. Hwang:Novartis: Research Funding. Vogl:Takeda: Consultancy, Research Funding; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Constellation: Research Funding; Celgene: Consultancy; Acetylon: Research Funding; Karyopharm: Consultancy. Cohen:Bristol-Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy. Weiss:Novartis: Consultancy. Porter:Genentech: Employment; Novartis: Patents & Royalties, Research Funding. Frey:Novartis: Research Funding; Amgen: Consultancy. Milone:Novartis: Patents & Royalties, Research Funding. Mangan:Novartis: Speakers Bureau. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Patents & Royalties: Novartis, Research Funding. Ambrose:Novartis: Research Funding. Chen:Novartis: Research Funding. Kulikovskaya:Novartis: Research Funding. Levine:Novartis: Patents & Royalties, Research Funding; GE Healthcare Bio-Sciences: Consultancy. June:Johnson & Johnson: Honoraria; Tmunity Therapeutics: Equity Ownership; Novartis: Honoraria, Patents & Royalties, Research Funding; Immune Design: Consultancy, Equity Ownership; Celldex: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties, Research Funding; Pfizer: Honoraria.

Abstract: 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.

Abstract: While international stage (ISS) and the presence of absence of cytogenetic abnormalities on FISH somewhat define the clinical risk of MM patients, additional biomarkers are necessary for more precise risk-based classification. Emerging studies have shown that circulating microRNAs (miRNAs) can be detected in patients with a variety of malignancies, including MM, and they could be non-invasive biomarkers. We measured serum miRNA levels of a large cohort of well-characterized previously untreated MM patients and correlated results with clinical outcome to test their prognostic impact. Methods and Patients To profile the expression of circulating microRNAs in the serum of MM patients, we performed NanoString-nCounter microRNA assays on samples obtained from a discovery cohort of 54 newly diagnosed MM patients enrolled on a randomized GIMEMA phase 3 study comparing Velcade-Melphalan-Prednisone-Thalidomide versus Velcade-Melphalan-Prednisone followed by maintenance with Velcade-Thalidomide. To further analyze the expression of the differentially expressed microRNAs, stem-loop-RT-PCR was performed on a validation cohort of 234 MM patients enrolled in the same trial. The prognostic significance of differentially expressed microRNAs were evaluated in relation to progression-free (PFS) and overall survival (OS) using univariate and multivariate Cox proportional hazards models. The utility of incorporating microRNA expression into a risk score with known risk factors – specifically ISS stage and the presence of del17, t(4;14) or t(14;16) by FISH – was also explored. Results Out of the 800 miRNAs evaluated, only 25 were detectable (≥100 counts) in at least 20% of the patients. The expression of these miRNAs were then measured in a validation set, but only 10 (miRs-92a, 21, 30a, 720, 451, 223, 126, 19b, 25 and miR-16) were validated to be differentially expressed. We found that levels of miR-16 and miR-25, used as continuous variables, had significant impact on OS duration: miR-16 (HR 0.87; p=0.019) and miR-25 (HR 0.81; p=0.0012) where low expression corresponded with worse survival. Based on these observations we generated a microRNA-based risk score which was significantly associated with OS duration (p=0.008). We then integrated this score with ISS stage and presence of high risk features by FISH, generating an integrated-microRNA risk score that was significantly associated with OS (p 〈 0.0001), and was better than a risk score that combined ISS and FISH (p=0.014), see figure. Conclusions Circulating miR-16 and miR-25 can risk stratify elderly, previously untreated, MM patients beyond ISS-stage and high risk genetic features. The opportunity to isolate circulating miRNAs allows us to sequentially sample cancer patients in a relatively non-invasive manner, opening new avenues of investigation for disease stratification and response to therapy. Disclosures: Bringhen: Onyx: Consultancy.