Abstract A069: A phase I trial of emavusertib (CA-4948) in combination with gemcitabine and nab-paclitaxel in metastatic or unresectable pancreatic ductal adenocarcinoma (PDAC)

Abstract 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 preclincal 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 and the RP2D of emavusertib in combination with G/nP. Emavusertib is given at escalating doses of DL0 (150mg p.o. bid), DL1 (200mg bid) and DL2 (250mg bid) with G (1000mg/m2 i.v.) and nP (125mg/m2 i.v.) on days 1 and 8 of every 21 day cycle. DL3 (emavusertib 200mg bid) and DL4 (emavusertib 250mg bid) are given 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 18 patients in dose escalation (DL0 N=4, DL1 N = 6, DL2 N=3, DL3 N= 5) with a median number of 2 cycles (range 1-20). To date there have been only two G4 treatment-related adverse events (TRAE) (pancytopenia and sepsis [n=1 each], both events occurred concurrently in the same patient at DL0). G3 TRAE includes neutropenia in 10/18 patients (56%), G3 anemia in 3/18 patients (17%) and G3 CPK increase in 1/18 (6%) patients. 13 patients are evaluable for response. Among these, partial response was seen in 3/13 patients (23%), stable disease in 3/13 patients (23%) and progressive disease in 7/13 patients (54%) as their best response. There have been no complete responses. Objective response is 23% (3/13 patients) and disease control rate is 46% (6/13 patients). Conclusions: At this early stage of the study, emavusertib in combination with G and nP as second line therapy for metastatic or unresectable PDAC has a manageable toxicity profile and shows encouraging preliminary results. Escalation to DL4 is ongoing which will be followed by dose expansion at RP2D. Citation Format: Patrick Grierson, Farshid Dayyani, Robert Lentz, Mary Mulcahy, Ana De Jesus-Acosta, Jibran Ahmed, Gulam Manji, Shafia Rahman, Susanna Ulahannan, Janie Zhang, Monica Patel, Mina Abdianina, Kian-Huat Lim. A phase I trial of emavusertib (CA-4948) in combination with gemcitabine and nab-paclitaxel in metastatic or unresectable pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A069.