A phase I trial of emavusertib (CA-4948) in combination with gemcitabine and nab-paclitaxel in metastatic or unresectable pancreatic ductal adenocarcinoma (PDAC).

Abstract

e16410 Background: Interleukin-1 Receptor Associated Kinase -4 (IRAK4) drives pro-survival NF-kB signaling in PDAC. In preclinical animal models, the oral IRAK4 inhibitor, emavusertib (CA-4948), augments the efficacy of cytotoxic chemotherapy by suppressing cell intrinsic survival mechanisms and prolongs survival when combined with gemcitabine (G)/ nab-paclitaxel (nP) as well as reduces desmoplasia in preclinical models. Methods: This is a multi-institution, Phase I, dose escalation/expansion clinical trial of emavusertib in combination with G/nP as second-line therapy for metastatic or unresectable PDAC (NCI 10522, NCT05685602). The primary objectives of this study are to determine the dose-limiting toxicities (DLTs) and the RP2D of emavusertib in combination with G/nP. Emavusertib is given continuously at escalating doses of DL0 (150 mg p.o. BID), DL1 (200mg BID), and DL2 (250mg BID) with G (1000mg/m 2 i.v.) and nP (125mg/m 2 i.v.) on Days 1 and 8 of every 21-day cycle. DL3 (emavusertib 200mg BID) and DL4 (emavusertib 250mg BID) are given continuously with G/nP on Days 1, 8, and 15 of every 28-day cycle. Dose escalation is according to the BOIN design to determine the MTD of emavusertib in combination with G/nP. Toxicities are graded according to CTCAE v5.0. Response was evaluated according to RECIST v1.1 criteria. Results: We have treated 21 patients in dose escalation (DL0 N = 4, DL1 N = 6, DL2 N = 3, DL3 N = 6, DL4 = 2) with a median number of 3 cycles (range 1-20). To date, there has been one G4 treatment-related adverse event (TRAE) (pancytopenia) at DL0. G3 TRAE includes neutropenia in 10/21 patients (48%), G3 anemia in 4/21 patients (19%), and G3 CPK increase in 1/21 (5%) patients. DLTs occurred at DL1 (G3 CPK increase) and DL3 (G3 diarrhea) while DLTs are currently being assessed in DL4. Fifteen (15) patients are evaluable for response with partial response observed in 3/15 patients (20%), stable disease in 6/15 patients (40%), and progressive disease in 6/15 patients (40%) as their best response, with no complete responses. Objective response rate (ORR) is 20% (3/15 patients), and disease control rate (DCR) is 60% (9/15 patients). Conclusions: At this early stage of the study, emavusertib in combination with G/nP as second-line therapy for metastatic or unresectable PDAC has a manageable toxicity profile and shows encouraging preliminary results with an ORR of 20% and DCR of 60%, compared to historical ORR of 13-17% and DCR of 46-58% for G/nP, respectively. Escalation to DL4 is ongoing, which will be followed by dose expansion at RP2D. Clinical trial information: NCT05685602 .