Patel, Krish

Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in immune cells including B lymphocytes. It forms the Myddosome complex with the MYD88 adaptor protein, with IRAK4 being essential for downstream signaling, maximal activation of NFkB with inflammatory and immune response and tumor promotion [Treon 2012; Rhyasen 2015]. CA-4948 is a novel small molecule, oral inhibitor of IRAK4, first-in-class and only suppressor of the TLR pathway currently tested in hematological malignancies. When combined with the BTK inhibitor ibrutinib that blocks parallel BCR signaling and NF-kB activating pathway, it has shown synergy in in-vivo B-cell NHL models, providing strong rationale for clinical evaluation [Booher 2018]. Recent preclinical studies demonstrated the role of IRAK4 activation as a driver of secondary, adaptive tumor resistance and survival mechanisms of hematological and solid tumor malignancies [Melgar 2019] that could be blocked by CA-4948 to delay or reverse resistance. Study Design and Methods: This is a multicenter, open-label trial of oral CA-4948 combined with ibrutinib in adult patients with relapsed or refractory hematologic malignancies. (NCT03328078). It has 2 parts: a dose escalation (Part A2), and expansion basket of 4 cohorts (Part B). Part A2: Is a truncated 3+3 design: CA-4948 starting is 200 mg BID with subsequent escalation to 300 mg BID. Both dose are safe and active against NHL as seen in the nearly completed monotherapy Part A1 of this trial Patients will receive CA-4948 with ibrutinib at the labeled dose for the respective NHL subtype (560 mg or 420 mg) until toxicity or progression. Primary objectives are safety/tolerance (MTD, RP2D); 2nd objectives are pharmacokinetics and preliminary efficacy; exploratory objectives include biomarker correlations (e.g., MYD88-L265P mut, IRAK4 pathway, NFκB inhibition). Part B basket has four cohorts: 1 -MZL, 2 - ABC-DLBCL, 3 - PCNSL, and 4 - NHL with adaptive ibrutinib resistance. Cohorts 1-3 must be BTK-inhibitor naïve. Cohort 4 includes ibrutinib treated NHLs after developing adaptive, secondary resistance. All will receive the combination of ibrutinib and CA-4948. Cohort 4 patients will be allowed a <3 weeks gap since prior ibrutinib therapy. Primary objectives include CR or ORR and DOR compared to (matched) historical controls (closely matched if possible). 2nd objectives include tolerance/safety, PFS, and pop-PK sampling for CA-4948. Exploratory objectives; response correlation with biomarkers including MYD88-L265P or other genetic mutations, gene expressions, cell of origin, IRAK4 signaling, and resistance. Treatment: CA-4948 at RP2D+ibrubinib at labelled doses; 21-day cycles to be repeated in the absence of toxicity or progression. Samples sizes, statistical considerations: Approx. 18 patients in Part A2. In Part B, a Simon 2-Step design will be applied to each cohort. Early stopping rule for futility after approx. 20 patients in Stage 1: full accrual with Stage 2 will add about 25 patients. Successful signal efficacy identification in a cohort may support further expansion or a subsequent controlled trial. The safety population will include all patients in the study who received any test dose. The efficacy population will have a valid baseline and post-baseline disease assessment. Safety assessments include TEAEs, safety labs, vitals, physical exams, PK, and ECGs; efficacy assessments: tumor imaging, para-protein determination, and histo/cyto-morphologic examinations. Part A2 inclusion: Histopathologically confirmed B-cell NHL as per the WHO 2016 classification. Eligible NHL subtypes: FL, MZL, MCL, DLBCL (including extranodal lymphomas of leg, testicle, or other sites, excluding mediastinal lymphoma), CLL/SLL, primary or secondary CNS lymphoma, and WM/LPL. Patients with FL, MCL, MZL, WM/LPL, or CLL/SLL should meet clinical treatment criteria. Part B inclusion: Cohorts 1-3 include patients with MZL, ABC-DLBCL, or PCNSL who are BTK-inhibitor naïve. Cohort 4 will include ibrutinib pre-treated MCL, MZL, CLL/SLL, WM/LPL, ABC-DLBCL, or PCNSL with adaptive resistance. Exclusions for both Parts A2 and B: Significant acute or chronic toxicity from prior anti-cancer therapy that has not resolved to Grade ≤ 1, as determined by NCI CTCAE v 4.03 within 7 days prior to start of study or serious co-morbidities. Disclosures Nowakowski: NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Kymera: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees. Leslie:TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: 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. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Lunning:Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Research Funding; Verastem: Consultancy, Honoraria; Acrotech: Consultancy; ADC Therapeutics: Consultancy; Legend: Consultancy; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Curis: Research Funding; Gilead: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Patel:Adaptive Biotechnologies: Consultancy; Kite: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Landsburg:Takeda: Research Funding; Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Fenske:Medical College of Wisconsin: Current Employment. Ramchandren:Merck, Seattle Genetics, Janssen, Genentech: Research Funding; Seattle Genetics, Sandoz-Novartis, Pharmacyclics, an AbbVie Company, Janssen, Bristol-Myers Squibb: Consultancy. Skarbnik:Alexion: Consultancy; Beigene: Speakers Bureau; Verastem: Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tun:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding.

Introduction CA-4948 is a novel oral small molecule inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 is part of the Myddosome signaling pathway, and is essential for signaling downstream of toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family in immune cells including B lymphocytes. . Dysregulated signaling in these pathways is frequently observed in Non-Hodgkin Lymphomas (NHL), particularly in ABC-subtype of Diffuse Large B-Cell Lymphoma (DLBCL) and Waldenström macroglobulinemia (WM)[1]. Furthermore, IRAK4 activation has recently been identified as a driver of an adaptive resistance mechanism of malignancies [2]. CA-4948 is the first clinical candidate targeting IRAK4 to be evaluated in cancer patients. Here we present Phase I results of CA-4948 in patients with relapsed/refractory hematologic malignancies. Method CA-4948-101 is a phase I trial dose escalation trial with a 3 + 3 design. Seven dosing cohorts were assessed including 50 and 100 mg daily (QD), and 50, 100, 200, 300, or 400 mg twice daily (BID) continuous oral monotherapy in 21-day cycles. Objectives included safety and tolerance (primary), pharmacokinetic (PK), pharmacodynamics (PD) and early efficacy (secondary), and biomarker correlations (exploratory). As of July 2020, 30 patients with relapsed or refractory, NHL have been enrolled, including DLBCL (n=14), FL (n=6), transformed HGBL (n=1), WM (n=3), LPL (n=2), MZL (n=2) and MCL (n=2). Median age is 68.5 (range 50 - 87; 5 female / 25 male). Median number of prior treatments is 4 (range 1 - 8, incl. 5 CAR-T-cell or ASCT treatments). Results CA-4948 has been generally well tolerated. Eight patients were exposed at the highest dose level of 400 mg BID: 2 of 5 DLT-evaluable patients had Grade 3 rhabdomyolysis (DLTs), without complications and reversible after treatment interruption and hydration / analgesic treatment - both subsequently continued treatment at lower doses of 200 or 300 mg BID, respectively. Six patients have tolerated 300 mg BID well without DLT. Most non-hematologic TEAEs were Grade 1 or 2 and manageable, including diarrhea, vomiting, fatigue, dyspnea, and myalgia. Hematologic TEAEs including neutropenia, anemia, thrombocytopenia was mild/moderate and without complications. There were only 4 Grade 3 combined episodes in 18 patients at dose levels ranging between 200 and 400 mg BID without complications (Table 1). Drug discontinuation occurred in only 3 cases for rash, fatigue, and asymptomatic amylase/lipase elevation at lower dose levels. No toxic deaths occurred. Favorable and predictable PK characteristics included rapid absorption with Tmax at 2-3 hours, T1/2 of 6 hours (supporting bid dosing), moderate accumulation, and dose-proportional increases in exposure. Dose proportional PD changes were shown for inflammatory cytokine reductions. Treatment duration ranged between 15 days and 19+ months with sustained disease control. Eight of 28 evaluable patients experienced overall tumor burden decreases of ≥20% from baseline - more at higher doses (Table 2). A WM patient with 6 prior lines of treatment, sustained PR underwent intra-patient dose escalation and had a dose/response relationship and very good treatment tolerance (Figure 1). The median duration at doses of 200 or 300 mg bid was >6 months (range 1-19+; including 3 cases of 11, 14, and 19+ mo.). Downstream pharmacodynamic markers of IRAK4 and molecular characteristics including cell-of-origin will be presented. Conclusion CA-4948 demonstrates good safety profile, desirable pharmacokinetic properties, and preliminary clinical activity. Enrollment is ongoing to support the anticipated RP2D of 300 mg bid. These encouraging results provide clinical validation of IRAK4 as a viable, novel therapeutic target in B-cell malignancies will lead to clinical combinations with synergistic drugs including BTK or BCL2 inhibitors [3] in patients with advanced hematological malignancies. Clinical trial: NCT03328078. References: 1. Treon, S. P. et al., 2012. N Engl J Med, 367: 826-33 2. Melgar, K. et al., 2019. Sci Transl Med, 11: eaaw8828 3. Booher R, Grayson D., 2019. Waldenstrom Roadmap Symposium, www.Curis.com Disclosures Nowakowski: Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; Kymera: Consultancy; Seattle Genetics: Consultancy. Leslie:TG Therapeutics: 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; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Younes:Curis: Consultancy; Daiichi Sankyo: Consultancy; HCM: Consultancy; Epizyme: Consultancy; Takeda: Consultancy; Novartis: Consultancy; BioPath: Consultancy; BMS: Consultancy; Janssen: Consultancy; AstraZeneca: Current Employment. Lunning:Gilead: Consultancy, Honoraria; Curis: Research Funding; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Legend: Consultancy; ADC Therapeutics: Consultancy; Acrotech: Consultancy; Verastem: Consultancy, Honoraria; TG Therapeutics: Research Funding. Patel:Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Genentech: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Landsburg:Takeda: Research Funding; Seattle Genetics: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding. Tun:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding.

7520 Background: We report results of a phase 2, open-label study of durvalumab (durva) in combination with R-CHOP or R2-CHOP (R-CHOP + lenalidomide) in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL). Methods: Subjects (≥18 y; ECOG 0–2) with previously untreated, high/high-intermediate risk DLBCL (IPI ≥3/NCCN-IPI ≥4) were stratified to durva + R-CHOP (Arm A, GCB DLBCL) or R2-CHOP for 6–8 cycles (Arm B, ABC DLBCL) based on cell of origin identified by gene expression followed by durva consolidation up to month 12 from start of induction. After FDA placed clinical holds on trials including combination therapy with checkpoint inhibitors and immunomodulatory agents, the study was revised to include both ABC and GCB in Arm A (durva + R-CHOP). The primary endpoint was complete response rate (CRR) at end of induction; secondary endpoints were rate of subjects continuing to consolidation, safety, and response in biological. Results: A total of 46 subjects were treated (safety; A/B, n=43/3); median age, 62/66 y; male, 61%/67%; ECOG 2, 19%/33%; Ann Arbor stage IV, 79%/33%; bulky disease: 49%/67%; double/triple-hit lymphoma, 30%/33%. As of Aug 2, 2018, 30/3 (A/B) had completed induction therapy, and 19 subjects (A) were ongoing. CRR (95% confidence interval) at end of induction was (A) 54% (37%-71%) and (B) 67% (9%-99%); 68%/67% (A/B) continued to consolidation therapy and were progression free at month 12. Safety profile was as expected for the components of the combination regimen with no new safety signal identified. Frequent treatment-emergent adverse events (TEAEs; ≥25%; A+B) included fatigue (61%), neutropenia (52%), peripheral sensory neuropathy (50%), nausea (46%), diarrhea (28%); constipation, decreased appetite, insomnia, pyrexia (24% each); and alopecia, dizziness, dyspnea, headache, stomatitis (22% each). Grade 3/4 TEAEs occurred in 84%/100% of subjects (A/B), and 3 subjects (2/1) died with no death related to study treatment. Follow-up for efficacy and safety is ongoing. Conclusions: Durva + R-CHOP combination therapy is safe and demonstrates encouraging response rates in subjects with high-risk DLBCL including double-hit lymphoma. Clinical trial information: NCT03003520.

e19055 Background: IRAK4 is a signaling modulator of Toll-like receptors (TLRs) and members of the IL-1R family. TLR/IL-1R activity is frequently dysregulated in NHL, including DLBCL and Waldenström macroglobulinemia (WM). CA-4948, an oral inhibitor of IRAK4, has demonstrated anti-tumor activity in preclinical models. Methods: Dose finding cohorts (3+3 design) will test QD or BID dosing schedule in pts with R/R NHL. Dose expansion will occur in 2 cohorts of R/R NHL with or without MYD88 mutation at the RP2D or MTD. Key eligibility criteria: age ≥ 18 years, ECOG ≤1, and adequate organ function. Objectives: safety, MTD and RP2D (primary); PK and anti-tumor activity (secondary); exploratory biomarkers and PD effects. Plasma cytokine levels are being evaluated post ex-vivo TLR stimulation in whole blood. Results: 13 pts have been treated (6 at 50 mg QD; 3 at 100 mg QD; 4 at 50 mg BID). Tumor types included DLBCL (7), FL (5), WM (1). The most frequent treatment-emergent AEs (≥10% of pts) were fatigue (23%), conjunctivitis, constipation, neutrophil count decrease, white blood cell count decrease (each 15%). One pt treated at 100 mg QD experienced Gr 3 rash which resolved following oral steroid treatment; dose reduction to 50 mg QD was tolerated without flare up. One SAE of disease progression occurred. 9 pts completed the DLT evaluation period thru Cycle 2 including 2 ongoing in Cycle 4 and 6. Preliminary PK showed that CA-4948 is rapidly absorbed with maximum plasma concentration observed 1.0 to 4.0 hrs post administration. T1/2 in plasma was about 6 hrs. Minimal to no accumulation was observed following multiple doses. Plasma exposures were dose proportional. Preliminary PD data showed, similar to murine studies, on target reduction of NF-kB-associated factors such as IL-6 post-treatment from pts with complete sample sets (N = 8). Conclusions: Current dose/schedule is well tolerated with preliminary PK and PD effects at the initial dose level. MTD has not been reached. Clinical trial information: NCT03328078.

Introduction and Purpose IRAK4 kinase activity is essential for signaling downstream of toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family in a variety of myeloid and lymphoid cell types. Dysregulated signaling in these pathways is frequently observed in NHL, particularly in ABC-subtype of Diffuse Large B-Cell Lymphoma (DLBCL) and Waldenström macroglobulinemia (WM). A phase 1 trial in patients with NHL is being conducted to determine safety, pharmacokinetics, and preliminary efficacy of CA-4948 as monotherapy. Patients and Methods At the 18-Jul-2019 data cut-off date, 22 patients have been treated with single-agent CA-4948. Five dose-escalation cohorts from 50 mg QD to 200 mg BID have been tested and cleared; a cohort of patients treated at 400 mg BID dose is currently being evaluated. Patients were diagnosed with relapsed or refractory NHL, including DLBCL (n=13), FL (n=5), HGBL with MYC and BCL2 and/or BCL6 rearrangement (n=1), WM (n=1), LPL (n=1) and MCL (n=1), had a performance status of 0 or 1 (ECOG) at baseline, and were treated in 21-day cycles until progression of disease or unacceptable toxicity, lost to follow-up or death. 5 patients had prior autologous bone marrow transplants. Results CA-4948 has been generally well tolerated. Grade 3/4 treatment-related adverse events included amylase/lipase increased, diarrhea, neutrophil count decreased, rash, rhabdomyolysis. Pharmacokinetics has shown favorable characteristics with dose-proportional increases in exposure. Five patients have been on treatment through the end of Cycle 4, including one patient in Cycle 10 on study for over 7 months. Five patients experienced overall tumor burden decreases of ≥20% from baseline, including at least 2 of 4 patients treated at 200 mg BID. Downstream pharmacodynamic markers of IRAK4 activity are being evaluated. Molecular characteristics including cell-of-origin will be presented. Conclusion CA-4948 demonstrates preliminary clinical activity. Enrollment is on-going and the MTD has not been reached. These encouraging results warrant further clinical testing in patients with advanced hematological malignancies. Clinical trial: NCT03328078. Disclosures Younes: Roche: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; AstraZeneca: Research Funding; Syndax: Research Funding; Abbvie: Honoraria; Epizyme: Consultancy, Honoraria. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Tun:Mundi-pharma: Research Funding; DTRM Biopharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Lunning:Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Curis: Research Funding; Juno Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; TG Therapeutics: Consultancy, Research Funding; Spectrum: Consultancy; VANIUM: Consultancy; Verastem: Consultancy; DAVA: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Kite: Consultancy; Gilead Sciences, Inc.: Consultancy; Seattle Genetics: Consultancy; Portola: Consultancy; OncLive: Consultancy; Novartis: Consultancy. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Martell:Curis, Inc.: Employment. Patel:AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau; Sunesis: Consultancy.

Introduction: XmAb13676 is a humanized bispecific antibody that binds both CD20 and CD3 in order to recruit cytotoxic T cells to kill CD20 expressing malignant cells. Interim results of an ongoing first-in-human, dose-escalation study (XmAb13676-01; NCT02924402) in subjects with relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are reported here. Methods: The study is a first-in-human, multi-center, open-label, phase 1, dose-escalation study in subjects with R/R NHL and R/R CLL with a standard 3 + 3 design. The primary objectives are to determine safety, tolerability, and the maximum tolerated dose (MTD) or recommended dose of XmAb13676. Secondary objectives include preliminary anti-tumor activity and PK/PD of XmAb13676. This study is designed in two parts: Part A, escalating dose cohorts that establish an initial priming dose as part of repeated weekly infusions at a fixed dose in a 28-day cycle; and Part B, with a dosing schedule consisting of a priming dose on C1D1 , established in Part A, followed by escalated dose(s) on subsequent weeks. Cytokine Release Syndrome (CRS) prophylaxis with dexamethasone was mandated prior to each administration of XmAb13676. Treatment was continued for 2 cycles or longer if there was evidence of therapeutic benefit. Results: At data cut-off, 44 subjects have been treated, 36 with NHL and 8 with CLL. NHL: Subjects with R/R NHL had a median age of 61.5 years (range 32-89), a median of 3.5 prior therapies (range 1-9) and had been diagnosed a median of 24.6 months (range 6.3-181.2) prior to treatment in the study. Treatment-emergent adverse events (TEAEs) related to treatment occurring in ˃ 3 subjects are shown in Table 1A. Nine treatment-related serious adverse events (SAE) occurred in 6 subjects. The most common treatment-related SAE was CRS, which occurred in 4 (11.1%) subjects with 1 of the events being Grade 4 and the other events being ≤ Grade 2. Treatment responses were assessed by the Lugano criteria or International Working Group criteria for Waldenström Macroglobulinemia (WM). There have been 7 objective responses: 2 complete responses (CR; DLBCL), 1 Very Good PR (VGPR; WM), and 4 partial responses (PR; 1FL, 3 DLBCL) at doses of 20-125 µg/kg. In the efficacy-evaluable population, at doses of 80-125 µg/kg, objective responses were observed in 6/18 patients. A priming dose of 45 µg/kg has been chosen for Part B. An MTD has not been reached and dose escalation is ongoing in Part B in NHL. CLL: Subjects with R/R CLL had a median age of 76 years (range 62-81), a median of 4.5 prior therapies (range 2-6) and had been diagnosed a median of 76.1 months (range 17.5-328.9) prior to treatment in the study. Treatment-related TEAEs occurring in ˃ 1 subject are shown in Table 1B. Three treatment-related serious adverse events (SAE) occurred in 2 subjects. The treatment related SAEs were CRS (Grade 3), hepatocellular injury (Grade 3), and jaundice cholestatic (Grade 2), each of which occurred in 1 (12.5%) subject. There has been 1 CR reported (Richter transformation) in 5 subjects at 20 µg/kg, the highest dose administered thus far. The treatment response was assessed by the Lugano criteria. An MTD has not been reached and dose escalation is ongoing in Part A in CLL. Conclusions: XmAb13676 demonstrated evidence of clinical activity in heavily pretreated subjects with R/R NHL and R/R CLL treated at doses between 20 and 125 µg/kg. CRS was generally manageable with premedication. The study is ongoing with further optimization of dose and schedule. Disclosures Patel: AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau; Sunesis: Consultancy. Chanan-Khan:AbbVie: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding. Salles:Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria. Cartron:Gilead: Honoraria; Jansen: Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Thomas:Celgene: Research Funding; Amgen: Research Funding; Xencor: Research Funding; BMS: Research Funding. Wierda:KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; GSK/Novartis: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Juno Therapeutics: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Pharmacyclics LLC: Research Funding; Xencor: Research Funding; Janssen: Research Funding. Liebowitz:Xencor: Employment, Equity Ownership. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Ribrag:MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel, accommodations, and expenses ; Nanostring: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; Incyte: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding. Saville:Xencor: Employment, Equity Ownership. Johnson:Xencor: Employment, Equity Ownership. Ly:Xencor: Employment, Equity Ownership. Phillips:Pharmacyclics: Consultancy, Research Funding; Bayer: Consultancy; Abbvie: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: IRAK4 kinase activity is required for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in a variety of myeloid and lymphoid cell types. Recruitment of IRAK4 to these receptors and its subsequent activation is facilitated by the MYD88 adaptor protein. The MYD88-L265P activating mutation is prevalent in DLBCL (~30% in ABC subtype) and WM (>90%). MYD88- L265P leads to constitutive activation of NF-κB signaling that is associated with worse prognosis. In MCL, dysregulation of B-cell receptor (BCR) and TLR pathway components correlate with constitutive NF-κB signaling. CA-4948 is a small molecule inhibitor of IRAK4 kinase that modulates the TLR and IL-1R signaling cascades. CA-4948 is being developed as a novel agent for the treatment of hematologic cancers with dysregulated IRAK4 signaling and is currently in a Ph1 trial for R/R NHL (clinicaltrials.gov NCT03328078). In preclinical studies, CA-4948 demonstrates pharmacodynamic and antitumor activity in in vitro and in vivo models with MYD88 alterations, and was previously shown to have a synergistic anti-tumor activity when combined with venetoclax in vivo. To further guide CA-4948's clinical development in NHL, we report here nonclinical studies exploring a twice-daily dosing schedule in DLBCL xenograft models. We also investigated the use of an ex-vivo whole-blood TLR-stimulation assay as a surrogate PD response biomarker. Additionally, we tested the efficacy of CA-4948 alone or in combination with the BTK inhibitor ibrutinib in DLBCL and MCL tumor models. Furthermore, preliminary PK and PD data from the first-in-human Ph1 trial are presented. Methods: Mice bearing DLBCL PDX tumors were orally administered CA-4948 twice-daily (BID) with 37.5 or 75 mg/kg doses and once-daily (QD) with 75 or 150 mg/kg doses. The ex-vivo whole blood assay involved TLR-stimulation of blood isolated at various time-points after CA-4948 administration. For the drug combination studies, mice bearing subcutaneous tumors of a MYD88-L265P DLBCL cell line or six MCL cell lines were treated. Results: (1) CA-4948 exhibited dose-dependent tumor growth inhibition in two DLBCL PDX xenograft tumor models with BID dosing showing equal or enhanced efficacy as compared to the equivalent total daily QD dose. The BID schedule was well tolerated with only a slight body weight loss as compared to the equivalent total QD dose schedule. (2) Overall, in mouse, the ex-vivo blood assay showed a time and exposure dependent relationship with the level of cytokine production after TLR-stimulation. A similar CA-4948 dose-dependent inhibition of TLR-stimulated cytokine production was observed in healthy human whole blood samples in which CA-4948 was spiked into the blood sample. Based on these findings, CA-4948 exposure levels capable of inhibiting TLR-stimulation are anticipated to be readily achievable in clinical studies. This was also supported by preliminary clinical PD data showing post treatment, on-target, reduced release of NF-κB-associated cytokines in 2 of 4 patients treated so far. (3) In xenograft efficacy studies using MCL models, single agent CA-4948 and ibrutinib exhibited anti-tumor activity and showed an additive effect when combined in the majority of the models known to have BCR-driven constitutive canonical NF-kB signaling (REC-1, MINO, and JeKo-1). Interestingly, neither CA-4948, ibrutinib, nor the combination had anti-tumor activity in Z-138 and GRANTA-591 xenograft models, consistent with these cell lines having activated NF-κB through the alternative NIK signaling pathway. (4) The human QD PK data (n=4) demonstrated that CA-4948: was rapidly absorbed, Tmax 1-3 hr, and t1/2 of 3.6 -6.8 hr. The bioavailability and exposure, as assessed by Cmax and AUC, is within the expected range compared to non-clinical PK and did not show any evidence of accumulation after QD dosing for 15 consecutive days. Conclusion: These results provide a rationale for CA-4948 BID dosing and incorporating the use of an ex-vivo whole-blood TLR-stimulation assay as a surrogate PD response biomarker, the former of which will be evaluated in the current Ph1 dose escalation soon and the latter of which is currently being implemented in the Ph1 trial for patients with advanced NHL. The murine xenograft results further support exploration of CA-4948 as monotherapy and in combination with canonical and alternative NF-κB pathway-targeted agents in DLBCL and MCL. Disclosures Booher: Curis, Inc: Employment, Equity Ownership. Patel:Juno Therapeutics: Consultancy; Pharmacyclics/Janssen: Speakers Bureau; Genentech: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Sunesis Pharmaceuticals: Consultancy. Lunning:Celgene: Consultancy; AbbVie: Consultancy; Astra-Zeneca: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Genzyme: Consultancy; Genentech: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Juno: Consultancy; Kite: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Samson:Curis, Inc: Employment, Equity Ownership. Atoyan:Curis, Inc: Employment, Equity Ownership. Ma:Curis, Inc: Employment, Equity Ownership. Xu:Curis, Inc: Employment, Equity Ownership. Dellarocca:Curis, Inc: Employment, Equity Ownership. Modafferi:Curis, Inc: Employment, Equity Ownership. Borek:Curis, Inc: Employment, Equity Ownership. Zhang:Curis, Inc: Employment, Equity Ownership. Parker:Curis, Inc: Employment, Equity Ownership. Whitney:Curis, Inc: Employment, Equity Ownership. Wang:Curis, Inc: Employment, Equity Ownership. Tuck:Curis, Inc: Employment, Equity Ownership. Younes:Merck: Honoraria; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; Abbvie: Honoraria; Seattle Genetics: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Incyte: Honoraria; Bayer: Honoraria; BMS: Honoraria, Research Funding; J&J: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Astra Zeneca: Research Funding; Curis: Research Funding.