BNT321, a novel monoclonal antibody targeting sialyl Lewis A: Phase 1 monotherapy and combination with mFOLFIRINOX in patients with advanced CA19-9 expressing cancers.
Authors: O'Reilly Eileen Mary , Bauer Todd Michael , Borazanci Erkut Hasan , Pelster Meredith , Varghese Anna M. , Park Wungki , Patel Manish R. , Jameson Gayle S. , Larsen Mary , Chin Kathryn , Melink Teresa J. , Gutheil John , Cosgrove Elizabeth O'Reilly , Balogh Kristen N. , Maiwald Tim , DeMario Mark , Celik Ilhan , Türeci Özlem , Sahin Ugur , Wang Judy S. 
Published: January 2024

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Background: BNT321 is a high affinity human monoclonal antibody targeting the sialyl Lewis A epitope of CA19-9. This Phase 1/1b dose escalation/expansion study investigated BNT321 as monotherapy and in combination with mFOLFIRINOX (mFFX) in patients (pts) with advanced CA19-9 expressing cancers. Methods: Eligible pts: progressive CA19-9 expressing solid tumors, liver transaminases ≤ 2 x ULN, bilirubin WNL, ECOG PS 0-1. BNT321 given on Qwk, Q2wk, and Q4wk schedules. Lead in dose (1 mg/kg given 1 wk prior to assigned dose) evaluated on Q2wk + Q4wk schedules. BNT321 + mFFX given Q2wk as 1L or 2L metastatic therapy (1L+2L met). Dexamethasone given as premedication. Endpoints: safety, MTD, RP2D, efficacy, PK, changes in serum CA19-9. Results: 82 pts received BNT321 monotherapy and 15 received BNT321 + mFFX. BNT321 monotherapy MTD was 2 mg/kg Q2wk and MTD with mFFX was 1 mg/kg. Schedule and lead in dose did not significantly alter MTD. Dose limiting toxicities (DLTs) for BNT321 monotherapy and with mFFX were elevations in hepatic AST and ALT with or without bilirubin elevations. These events generally occurred early (cycle 1), resolved with drug hold, and did not preclude subsequent reduced dose BNT321. Frequent related AEs (total %/ > grade 3 %) for BNT321 include increased ALT (39%/19%), AST (35%/12%), T bilirubin (27%/9%), fatigue (21%/0%), infusion related reaction (IRR) (17%/1%) and for BNT321 + mFFX fatigue (67%/0%), increased AST (40%/27%), ALT (33%/20%), diarrhea (33%/0%), nausea (20%/0%). At combination MTD (n=7): fatigue (71%/0%), diarrhea (29%/0%), IRR (29%/0%), nausea (28%/0%), increased AST (14%/14%), ALT (14%/14%). BNT321 demonstrated a T1/2 of 11.75 days + dose proportional Cmax and AUC with intra-patient variability. Enhanced clearance observed among pts with higher baseline (BL) serum CA19-9. For BNT321 monotherapy stable disease (RECIST 1.1) was best response, with time on study > 90 days and > 180 days in > 20% and 10% of pts, respectively. Correlation between time on study and post BL normalization of CA19-9 was observed. For BNT321 + mFFX (1L+2L met), PRs were observed in 3/11 (27%) response evaluable pts who had time on study 10.0-15.8 months. Conclusions: BNT321 and BNT321 + mFFX MTDs were 2 mg/kg and 1 kg/kg, respectively. DLTs were hepatic AST, ALT and T bilirubin elevations which were generally cycle 1 and did not preclude subsequent BNT321 at reduced dose. BNT321 monotherapy resulted in disease stabilization and prolonged time on study (> 90 days for > 20%) in pts with advanced line, metastatic PDAC and other CA19-9+ cancers. BNT321 significantly decreased CA19-9 in the majority of pts and PK was similar to other human monoclonal antibodies. BNT321 + mFFX (1L+2L met) demonstrated multicycle tolerability and a 27% PR rate with 10+ months duration on study. BNT321 + mFFX is being evaluated in resected PDAC in the adjuvant setting. Clinical trial information: NCT02672917 .