@article {SanbornA246, author = {Rachel Sanborn and Ralph Hauke and Nashat Gabrail and Mark O{\textquoteright}Hara and Nina Bhardwaj and Rodolfo Bordoni and Michael Gordon and Danny Khalil and Maen Abdelrahim and Thomas Marron and Thomas Hawthorne and Lawrence Thomas and Tracey Rawls and Mark Rogalski and Diego Alvarado and Laura Vitale and Tibor Keler and Michael Yellin}, title = {405 CDX1140{\textendash}01, a phase 1 dose-escalation/expansion study of CDX-1140 alone (Part 1) and in combination with CDX-301 (Part 2) or pembrolizumab (Part 3)}, volume = {8}, number = {Suppl 3}, pages = {A246--A246}, year = {2020}, doi = {10.1136/jitc-2020-SITC2020.0405}, publisher = {BMJ Specialist Journals}, abstract = {Background CDX-1140 is an agonist anti-CD40 mAb selected to optimize systemic exposure and hence tumor microenvironment (TME) ingress. CDX-1140 activity may be enhanced by combining with CDX-301 (recombinant Flt3L), a dendritic cell growth factor, or with pembrolizumab, an anti-PD-1 mAb.Methods Patients with advanced solid or hematologic (Part 1 only) tumors are enrolled. Part 1 dose-escalation results have been presented (SITC 2019). In Part 2, CDX-1140 dose-escalation (0.09{\textendash}1.5 mg/kg q4w) is in combination with CDX-301 (75 mcg/kg sc QD x 5 for 2 cycles). In Part 3, CDX-1140 dose-escalation (0.72{\textendash}1.5 mg/kg q3w) is in combination with pembrolizumab 200 mg q3w. Part 1 and 2 expansion cohorts are dosed at the CDX-1140 MTD, 1.5 mg/kg q4w. Part 3 expansion cohorts are planned. Peripheral blood and tumor biomarkers analysis are ongoing.Results 92 patients have been treated (Part 1 n=57, Part 2 n=31, Part 3 n=4). Part 1 expansion cohorts in SCCHN (n=7) and RCC (n=5) are fully enrolled. Part 2 dose-escalation completed to the highest CDX-1140 dose and a SCCHN expansion cohort is ongoing. Part 3 dose-escalation recently initiated. Safety data is available for 23 and 10 patients at the MTD in Part 1 and 2, respectively. In general, the safety profiles were similar, with arthralgia (52\% vs. 50\%), pyrexia (44\% vs 50\%), fatigue (30\% vs. 50\%), chills (39\% vs. 40\%), vomiting (30\% vs. 20\%), nausea (26\% vs 40\%), myalgia (22\% vs. 30\%), increased ALT (22\% vs. 20\%), and increased AST (22\% vs. 30\%) being the most common drug related AEs at the MTD in Part 1 and 2, respectively. Most AEs were low grade. Across all cohorts, cytokine release syndrome (CRS) (G2 n=4, G3 n=2) occurred in 6 (Part 1 n=2; Part 2 n=4) and pneumonitis (G3) occurred in 5 (Part 1 n=4; Part 2 n=1) patients. Immune activation in the TME consistent with CD40 agonism and increases serum inflammatory cytokines were observed. Evidence of anti-tumor activity/clinical benefit include SD (n=13), tumor cavitation (n=2) and a uPR in solid tumors. A patient with follicular lymphoma has an ongoing durable complete metabolic response.Conclusions The CDX-1140 MTD dose of 1.5 mg/kg, a dose level expected to provide good systemic exposure and TME penetration, is generally well tolerated alone and with CDX-301. Transaminitis and CRS have generally been low grade and infrequent. A cohort combining CDX-1140 with chemotherapy will be initiated in patients with previously untreated metastatic pancreatic adenocarcinoma.Trial Registration NCT03329950Ethics Approval The study was approved by the following: Providence St. Joseph Health IRB, approval number MOD2020001128; WIRB, approval number 1188814 (Hauke, Gabrail, Bordoni \& Gordon); University of Pennsylvania IRB, approval number UPCC 18917; Mount Sinai School of Medicine IRB, approval number 18-00202; Memorial Sloan Kettering Cancer Center IRB, approval number 18-225A; Houston Methodist IRB, approval number MOD00000836}, URL = {https://jitc.bmj.com/content/8/Suppl_3/A246}, eprint = {https://jitc.bmj.com/content/8/Suppl_3/A246.full.pdf}, journal = {Journal for ImmunoTherapy of Cancer} }