IntroductionMVT-5873, a fully human IgG1 monoclonal antibody (mAb), targets sialyl Lewis A (sLea), an epitope on CA19-9. CA19-9 is expressed in pancreatic (PDAC) and other GI cancers, plays a role in tumor adhesion and metastasis, and is a marker of an aggressive tumor phenotype. MVT-5873 is active as a single agent and in combination with nab-paclitaxel (nab-P) and gemcitabine (gem) in murine xenografts. MethodsSingle agent: for each 28-day treatment cycle, MVT-5873 was given IV every second week (Group 1) or weekly (Group 2) at doses ranging from 1 to 3 mg/kg. Combination with nab-P and gem: for each 28-day treatment cycle MVT-5873 was administered IV weekly (1.0mg/kg or 0.125mg/kg) followed by IV infusion of 125 mg/m2 of nab-P and then 1000mg/m2 gem, on day 1, 8 and 15 (Group 3). Eligible patients had recurrent progressive (single agent) or newly diagnosed (combination), locally-advanced or metastatic PDAC or other CA19-9+ malignancy and ECOG PS ≤1. Dose escalation followed a standard 3+3 design with a 10 patient expansion at the maximally tolerated dose (MTD). Trial endpoints include safety, MTD, dose limiting toxicities (DLT), pharmacokinetics (PK) and efficacy. Exploratory endpoints include changes in serum CA19-9 levels.ResultsAs of 7-September-2017, data are available for single agent N=32 in Groups 1 (N=9) and 2 (N=23) at 1, 2, 2.5 and 3 mg/kg and combination Group 3 (N=6) at 1.0 and 0.125mg/kg. DLTs of transient grade 3 elevations in AST, ALT, and total bilirubin were encountered in the single agent groups at 2, 2.5 and 3mg/kg in both single agent groups and in the combination group at 1mg/kg. Single agent liver function laboratory abnormalities typically emerged and resolved within a week of dosing although they were more persistent in the combination treated patients. Other toxicities associated with all groups included low grade GI toxicity (abdominal pain/cramps/diarrhea/nausea) and infusion reactions. Infusion reactions were mitigated with pre-medications and an increase in the infusion time. Combination DLTs for MVT-5873 at 1mg/kg included AST, ALT, and bilirubin elevations as well as neutropenia and pneumonitis resulted in significant dose de-escalation. MVT-5873 dosed at 0.125 mg/kg in combination was generally well tolerated. Single agent activity included SD of >4 months in 5 of 32 of patients with an MTD established at 1 mg/kg. Combination activity at 0.125 mg/kg MVT-5873 with nab-P/gem included 2 PRs and 1 SD in 3 patients. Interestingly, sustained suppression below ULN of CA19-9 levels was observed in 3 of the 6 patients in the combination arm and >95% CA19-9 reduction at the 0.125mg/kg combination dose. Dose escalation in this arm is in progress, and updated safety, PK/PD, and efficacy data will be presented.ConclusionsSingle agent MVT-5873 appears safe and tolerable at biologically active doses. DLTs included reversible liver function abnormalities. Determination of the MTD in combination with first line nab-P/gem is underway and preliminary response data are encouraging. Overall, the safety profile, efficacy, and reductions in serum CA19-9 levels over time support further development of MVT-5873 in this indication both as a single agent and in combination.

Citation Format: Eileen Mary O'Reilly, Judy Sing-Zan Wang, Kenneth H. Yu, Maeve Aine Lowery, Anna M. Varghese, Johanna C. Bendell, Erkut Hasan Borazanci, Hayley Estrella, Kimberly Fowler, Mariella Hoskins, Stephanie Bussen, Teresa J. Melink, Christine M. Kearns, H Toni Jun, Paul W. Maffuid, John C. Gutheil, Todd Michael Bauer. Preliminary phase I data comparing HuMab-5B1 (MVT-5873), a monoclonal antibody targeting sLea, as a single agent and in combination with first line nab-paclitaxel and gemcitabine in patients with CA19-9 positive pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B25.