ALBERT

Description: Introduction: Treatment for relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) remains an unmet medical need despite the recent approval of chimeric antigen receptor T-cell (CAR-T) therapeutic constructs. Many patients will be "too sick to CAR-T" or may have logistical/financial challenges that will not allow this treatment. As a result, non-chemotherapy agents with activity in rel/ref DLBCL require further development to help fill this need. Umbralisib (UMB) is dual PI3K delta/CK-1ε inhibitor that has single agent activity in rel/ref DLBCL with an ORR of 31% [Burris et al. 2018]. Ibrutinib (IBR) is a Bruton Tyrosine kinase (BTK) inhibitor with activity seen in the activated B-cell (ABC) subtype of DLBCL with an ORR of 37% in this subtype [Wilson et al. 2015]. Pre-clinical data (not shown) demonstrated synergistic activity of UMB-IBR against cell lines of both germinal center B-cell (GCB) and non-GCB subtypes of DLBCL. We report results of phase IIa study of the combination of UMB-IBR in rel/ref DLBCL. Methods: Eligible patients (pts) had relapsed or refractory DLBCL, ANC ≥1000 cells/mm3, platelets ≥100 K/mm3, and adequate organ function. The Hans algorithm defined cell of origin. UMB was dosed at 800 mg daily in AM and IBR 560 mg daily in PM. Treatment stratification was performed on a 1:1:1 design to Cohort A (UMB), B (IBR), or C (UMB+IBR) by consent to optional biopsies, which included optional pre-treatment and day 8 biopsies to assess pre-specified correlative flow cytometric analysis of the B-cell receptor (BCR) pathway. In cohorts A/B the combination was initiated at day 8. A cycle was 28 days. Pts received UMB-IBR for up to 1-year of therapy in the absence of progression disease (PD) or excess toxicity. The primary endpoint was monitoring for cumulative toxicity events (CTEs) occurring during cycles 1-4. A CTE was defined as grade (G) 4 neutropenia or thrombocytopenia, G3 neutropenia or thrombocytopenia last longer than 7 days, G3 non-hematologic toxicity, or any G adverse event which led to a drug hold 〉 7 days. Consecutive stopping rules for CTEs and efficacy were employed. Secondary endpoints included overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, progression-free survival (PFS), time to response (TTR), and duration of response (DOR). Results: Thirteen pts with rel/ref DLBCL were enrolled. Median age was 71 years (range 27-81) and 9 were male. Median number of prior therapies was 2 [range 1-7] with 8% having undergone prior autologous transplantation. Sixty-two percent were refractory to last therapy. DLBCL subtypes were GCB in 7 and non-GCB in 6 pts. The first 3 pts were enrolled to Cohort C regardless of optional biopsy consent. Cohorts A (n=1) and B (n=1) included pts that consented to optional biopsies. Cohort C (n=11) included the first 3 pts enrolled into the study and those thereafter that did not consent to optional biopsies. Two CTEs were seen: G3 rash and G3 Clostridium difficile (C. diff) diarrhea. No CTEs occurred during cycle 1. Notable serious or recurrent adverse events (SAEs or AEs) of interest occurring across all cycles regardless of attribution included elevated AST/ALT 0% G 3-4 (all G 31%), nausea 15% G 3-4 (all G 54%), and diarrhea 15% G 3-4 (all G 31%). The ORR of the UBR-IBR regimen was 23% with 2 PRs (both GCB) and 1 CR (non-GCB). The pt in CR remains on treatment at 7 months and recovered from a CTE during cycle 4 (C. diff). The median PFS was 3 months [95 % CI 0.85, 3.8]. No patient was taken off study for toxicity and there were no dose reductions necessary. Conclusion: In this phase IIa study of rel/ref DLBCL, the non-chemotherapy regimen of UMB-IBR was well tolerated with only 2 CTEs and limited AEs. The evaluation of CTEs was limited by the rapid PD in many pts seen prior to 4 cycles of therapy. The ORR of the UMB-IBR was modest (23%) and of limited durability in this difficult to treat patient population. Based on limited activity and difficulty in obtaining biopsies for correlative analyses, this study was terminated prematurely. Disclosures Lunning: Portola: Consultancy; Spectrum: Consultancy; Genzyme: Consultancy; Genentech: Consultancy; Juno: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Kite: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Gilead: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Blumel:TG Therapeutics, Inc.: Consultancy. Vose:Epizyme: Honoraria; Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Roche: Honoraria; Acerta Pharma: Research Funding; Abbvie: Honoraria; Kite Pharma: Research Funding; Legend Pharmaceuticals: Honoraria; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding.

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: 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.