Safety, tolerability and preliminary efficacy of CAN04, a first in class monoclonal antibody against IL1RAP, in combination with nab-paclitaxel and gemcitabine (NG) in subjects with pancreatic cancer.
Authors: Awada Ahmad , Ochsenreither Sebastian , Eefsen Rikke Loevendahl , Arnold Dirk , Yachnin Jeffrey , Pfeiffer Per , Jungels Christiane , Greil Richard , Poulsen Laurids , Van Cutsem Eric , Thorsson Lars , Svedman Christer , Garcia-Ribas Ignacio , Collignon Joelle 
Published: June 2021

e16228

Background: Interleukin-1 Receptor Accessory Protein (IL1RAP) is expressed on cancer and stromal cells in many solid tumors. CAN04 is a fully humanized IgG1 targeting IL1RAP blocking IL-1α and β signaling and triggering ADCC. As monotherapy, CAN04 has been administered without reaching MTD up to 15mg/kg. We report initial data from CAN04 in combination with NG in pts with pancreatic cancer (PDAC). Methods: Primary objective was to determine safety and tolerability of CAN04 in combination with standard NG as first line treatment in pts with locally advanced/metastatic PDAC. Secondary objectives included establishing preliminary efficacy. Tumor responses were evaluated according to RECIST/iRECIST. Results: 36 patients (pts) received at least 1 dose of CAN04: median age 62 yrs (46-87), 47% women, 94% stage IV, 8% had received prior adjuvant therapy; 59% ECOG 0, 41% ECOG 1. Dosing was initiated at 5mg/kg, escalated to 7.5mg/kg (n = 8) which was considered above MTD due to hematological toxicity, followed by expansion at 5mg/kg. Infusion related reactions (IRRs) were seen primarily with CAN04 priming dose of 0.5 mg/kg (25% G1, 25% G2, 3% G3). G3 or higher AEs (all/related) were dominated by hematological toxicity and reported in 89%/72% of pts (see table). SAEs were reported in 67% pts (44% G3/G4), in 33% considered related (19% G3/G4). 33% of pts discontinued due to AEs: 4 deterioration of general condition, 2 IRR, 2 bilirubin elevation, 1 bile duct obstruction, 1 hemolytic uremic syndrome, 1 pancreatitis, 1 asthenia, 1 decreased appetite, 1 pneumonitis. There were 3 on treatment deaths: disease progression, gastrointestinal obstruction and cholangitis. For the mITT efficacy analysis (n = 31), 5 pts were excluded: 3 discontinued before receiving NG (2 consent withdrawals after IRRs, tumor related physical deterioration) and 2 did not complete Cycle 1 due to cholangitis and GI obstruction respectively. 12 pts (39%) had confirmed or unconfirmed PR as best response, 8 (26%) more showed SD and 9 (29%) had PD. Six pts underwent PD confirmation: 3 pts had prolonged immune unconfirmed PD (iUPD) by iRECIST and > 50% decreases in CA19-9 and were on treatment for 4.5 (ongoing), 6 and 8 months, respectively. Clinical benefit rate (PR+SD+prolonged iUPD): 74%. At the time of this analysis, 12 pts (38%) are ongoing. Median duration of response is currently 7.5 months (1.8-13.8 months). Conclusions: The clinical benefit rate of CAN04 in combination with NG is encouraging (74%). The G3/G4 neutropenia and febrile neutropenia rate is higher than expected for NG alone. Expansion cohorts at lower CAN04 doses have been initiated. Clinical trial information: NCT03267316. [Table: see text]