Kostić, Ana

Abstract Introduction: REGN1979 is a hinge-stabilized CD20xCD3bispecific full-length antibody (Ab) based on an IgG4isotype modified to reduce Fc binding. It is designed to bind T cells (via CD3) and CD20-expressing cells. Cross-linking results in specific, local T cell activation and engagement ofcytolytic functions, independent of T cell receptor mediated recognition. This mechanism of action (MOA) is distinct from approved anti-CD20 Abs, and may provide additional therapeutic benefit. This report describes safety and clinical outcomes in 25 patients (pts) treated with REGN1979. Methods: The study uses a 3+3 design to assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and activity of REGN1979 inpts with NHL and CLL, in separate dose escalation cohorts. REGN1979 is administered IV over 1-4 hours, weekly (QW) for 4 doses followed by every 4 weeks (Q4W) for 5 doses. Each dose level (DL) consists of an initial starting dose followed by a higher (step-up) dose.Pts with either progressive disease (PD) after initial response or suboptimal initial response could be retreated. Results: As of clinical cut-off, 25pts had been enrolled and treated with REGN1979 at flat doses ranging from 0.03 - 3.0 mg: 20pts with NHLand 5pts with CLL. NHL subtypes included DLBCL (n=12), FL (n=6), and MCL (n=2). Allpts hada medianof3 (range 1-7) prior regimens, and received a median of 5 (range 2-9) doses of REGN1979. Sixpts remained on initial treatment, 3pts completed treatment, and 16pts discontinued treatment (14 for PD; 2 subject decision). Of 4pts who entered retreatment, 2pts remained ongoing. The most common treatment-related treatment-emergent AEs (TR-TEAEs) were pyrexia (56%), infusionrelated reaction (IRR) (40%), chills (36%), cytokine release syndrome (CRS) (28%), fatigue (24%), tachycardia (24%), hypomagnesaemia (20%) and hypotension (20%). Grade >= 3 TR-TEAEs occurred in 8 pts(32%): IRR (12%), CRS (8%), hypotension (8%), and pyrexia, tachycardia, dyspnea, anemia, hypoxia, hypertension, tachypnea, transaminases increased, and tumor pain each in 1 pt(4%). All were grade 3 with the exception of 1 ptwith grade 4 hypotension. There were no protocol-defined DLTs, nor grade 5 TEAE. No ptsdiscontinued REGN1979 due to TR-TEAE. IRR and CRS events were most commonly reported with the first administration of both initial and step-up dose with incidence and severity decreasing with increasing exposure. Tenptsreported at least one TR-SAE: CRS (24%), IRR (20%), and increased AST and tumor pain, each in 1pt(4%). Threeptswith aggressive lymphoma who discontinued REGN1979 due to PD died of their disease within 30 days of their last dose. Notably, modifications to pre-medication(s) and drug administration instructions have improved tolerability (fewer and less severe IRR/CRS). No clinically significant CNS TEAEs have been observed. CT-based (Cheson, 2007) anti-tumor activity was observed in 11 ptswith NHL: PR [n=4,median duration of 50d];SD [n=7, median duration of >196d]. The overall response rate (ORR) in NHL ptsacross DLs was 20%. In 2 highest dose levels, ORR was 27% (Fig 1). Of the 14pts evaluated by PET, 4pts had a partial metabolic response, withmedian duration of 244d perLugano Criteria. Twopts with CLL attained SD as best overall response. PK: REGN1979 concentrations in serum increased with increasing DL and were variable across pts. Variability was less at higher DLs and also decreased over time during therapy. At DLs tested, REGN1979 concentrations did not notably increase over time during treatment. PD/Cytokines: At the lowest dose tested, 0.03 mg, transient B-cell depletion was observed inpts with measurable circulating B cells.Samples from 12pts were available for cytokine analysis. Interim analysis indicates REGN1979 induces cytokine release as expected based on MOA. An increase in IL-6, IL-10 and to lesser extent IFN-γ was observed. The magnitude of cytokine response generally correlated with symptomatic IRR/CRS. Conclusion: REGN1979 demonstrated an acceptable safety profile at flat doses of 0.03 - 3.0 mg (< 1% of rituximab dose) inpts with NHL and CLL. Most TEAEs were associated with IRR/CRS, and were managed with supportive therapy and modification to REGN1979 administration. No clinically significant neurological toxicity was observed. Preliminary antitumor activity demonstrates increased activity at higher doses. Dose escalation and treatment schedule optimization continue. Disclosures Brown: Acetylon, Gilead: Research Funding; Celgene, Roche/Genentech, Gilead, Infinity, Janssen, Pharmacyclics, ProNai, Sun BioPharma: Consultancy. Arnason:Gilead: Consultancy. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Chavez:Janssen: Speakers Bureau. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Topp:Amgen: Consultancy, Honoraria, Other: travel, Speakers Bureau; Roche: Honoraria, Other: travel; Boehringer: Consultancy, Other: Travel, Research Funding; Jazz: Consultancy; Pfizer: Consultancy, Other: Travel. Adriaens:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Ufkin:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Kostic:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Paccaly:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Gao:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership. Trail:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership. Lowy:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership. Brownstein:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership.

Abstract Background Denintuzumab mafodotin (SGN-CD19A) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. CD19 is a B cell-specific marker that is expressed in nearly all patients (pts) with B-lineage acute leukemia or lymphoma. Methods A phase 1 dose-escalation study is ongoing to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of denintuzumab mafodotin in pts with relapsed or refractory (R/R) B-ALL, B-cell lymphoma (B-LBL), or Burkitt leukemia/lymphoma (NCT 01786096). Eligible pts are ≥1 year of age and are R/R to ≥1 prior systemic regimen; patients with Philadelphia chromosome-positive (Ph+) disease must have failed a 2nd-generation TKI. A modified continual reassessment method was used for dose allocation and maximum tolerated dose (MTD) estimation. The study evaluated 2 dosing schedules: first weekly (Days 1 and 8 of 21-day cycles) and then once every 3 weeks (q3wk). This report presents data from the adult subset of pts in the study (≥18 years). Results To date, 71 adult pts with R/R B-ALL (n=59), B-LBL (n=6) or Burkitt leukemia/lymphoma (n=6) have been treated; median age is 45 years (range 18−77). Pts received a median of 2 prior therapies (range 1−8); 20 pts (28%) had prior allogeneic stem cell transplant. On the weekly schedule (0.3−3 mg/kg), 40 pts received a median of 2 cycles (range 1−27); 2 pts remain on treatment. On the q3wk schedule (4−6 mg/kg), 31 pts received a median of 3 cycles (range 1−6); 4 pts remain on treatment. An MTD was identified at 5 mg/kg q3wk and was not reached with weekly dosing. Best clinical responses to date for pts with B-ALL are summarized below: Table 1.Response category per Cheson 2003Efficacy-evaluable adult pts with B-ALLweekly dosing, N=32 n (%)q3wk dosing, N=23 n (%)Complete remission (CR)6 (19)3 (13)CR with incomplete platelet recovery (CRp)−3 (13)CR with incomplete blood recovery (CRi)−2 (9)Partial remission (PR)1 (3)−Resistant disease with clinical benefit15 (47)12 (52)Resistant disease without clinical benefit2 (6)-Progression8 (25)3 (13)CRc (CR+CRi+CRp), % (95% CI)19% (95% CI 7, 36)35% (95% CI 16, 57) In the q3wk schedule, the CRc rate was similar at 4, 5, and 6 mg/kg. The median duration of response across schedules is currently 27 weeks (95% CI 7, −). Of 12 pts with CRc and available minimal residual disease (MRD) assessment, 7 were MRD negative. 3 patients with MRD-negative CRs have been in remission for >1 year, 2 of whom have been on continuous treatment for 19 and 22 months. In the subset of pts with Ph+ B-ALL, 4 of 8 pts achieved CR and 1 pt a PR. In 6 pts with Burkitt leukemia/lymphoma, 1 achieved a CR. In 6 pts with B-LBL, objective responses were 1 CR and 2 PR. The adverse event (AE) profiles were similar across both dosing schedules; the most frequently reported AEs were pyrexia (54%), nausea (52%), fatigue (51%), headache (44%), chills (38%), vomiting (37%), blurred vision (35%), and anemia (34%). Ocular symptoms and corneal exam findings consistent with superficial microcystic keratopathy were observed in 40 pts (56%); symptoms were less severe than the associated corneal exam findings. Keratopathy was managed with topical steroids and dose modifications, and improved/resolved within a median of ~3 wks (range 1-17) in pts with sufficient follow-up. ADC exposures increased with dose, and in leukemia patients, target-mediated disposition was observed that diminished with higher doses in the q3wk schedule. Post treatment, flow cytometry data demonstrate that unbound CD19 on peripheral blasts inversely correlates with ADC concentration in circulation, and is present in the majority of evaluable patients at the end of the q3wk cycle. Conclusions Denintuzumab mafodotin is generally well tolerated and demonstrates activity in heavily pretreated adult pts with B-ALL and B-lineage highly aggressive lymphomas, including durable MRD-negative responses. The results of this trial indicate that the q3wk schedule, with a CRc rate of 35% in B-ALL, warrants further clinical investigation. Based on the encouraging responses observed to date in Ph+ B-ALL (CRs in 4 of 8 pts), an expansion cohort of these pts is currently enrolling on the q3wk schedule. Disclosures Fathi: Exelexis: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding. Off Label Use: SGN-CD19A is an investigational agent being studied in patients with B-cell malignancies. SGN-CD19A is not approved for use.. Borate:Seattle Genetics: Research Funding; Genoptix: Consultancy; Alexion: Speakers Bureau; Gilead: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau. DeAngelo:Agios: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Ariad: Consultancy; Novartis: Consultancy. O'Brien:Seattle Genetics, Inc.: Research Funding. Trippett:OSI Pharmaceuticals: Research Funding; Seattle Genetics, Inc.: Research Funding. Shah:NCCN: Consultancy; SWOG: Consultancy; Seattle Genetics: Research Funding; Acetylon Pharmaceuticals, INC: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Speakers Bureau; Bayer: Honoraria; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; DeBartolo Institute for Personlaized Medicine: Research Funding; Rosetta Genomics: Research Funding; Plexus Communications: Honoraria; Spectrum: Speakers Bureau. Hale:Seattle Genetics, Inc.: Research Funding; Hyundai: Research Funding; V Foundation: Research Funding. Silverman:Seattle Genetics, Inc.: Research Funding. Pauly:Seattle Genetics, Inc.: Research Funding. Kim:Bayer: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Eli Lilly: Consultancy. Kostic:Seattle Genetics, Inc.: Employment, Equity Ownership. Huang:Seattle Genetics, Inc.: Employment, Equity Ownership. Pan:Seattle Genetics, Inc.: Employment, Equity Ownership. Chen:Genentech: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau.