Abstract LB-290: Targeting MUC16 with the antibody-drug conjugate (ADC) DMUC5754A in patients with platinum-resistant ovarian cancer: A phase I study of safety and pharmacokinetics.
Authors: Liu Joyce , Moore Kathleen , Birrer Michael , Berlin Suzanne , Matulonis Ursula , Infante Jeffrey , Xi Jian , Kahn Robert , Wang Yulei , Wood Katie , Coleman Daniel , Maslyar Daniel , Humke Eric , Burris Howard 
Published: August 2014

Abstract
Background: MUC16 is a large transmembrane protein overexpressed by the majority of ovarian cancers (OC), compared with normal tissues. The role of MUC16 in the pathogenesis of ovarian cancer is unknown; however, MUC16 may facilitate the binding of ovarian tumor cells to mesothelial cells lining the peritoneal cavity, and may inhibit natural killer cell-mediated anti-tumor cytotoxic responses. Conjugation of a highly potent cytotoxic drug to a MUC16-specific monoclonal antibody represents a novel approach to treatment of MUC16-expressing tumors. DMUC5754A is an ADC containing the humanized IgG1 anti-MUC16 monoclonal antibody linked to the potent anti-mitotic agent MMAE and demonstrates anti-tumor activity in MUC16-expressing tumor xenograft models.
Methods: This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamic (PD) activity of DMUC5754A (0.3-3.2 mg/kg) given every 3 weeks (q3w) to patients with advanced recurrent platinum-resistant OC. A standard 3+3 design was used to determine the maximum-tolerated dose, followed by cohort expansion. Tumor tissue was assessed for expression of MUC16 and other relevant markers. Clinical activity was evaluated per RECIST.
Results: Forty-four patients (22 escalation, 22 expansion at 2.4 mg/kg), median age 62 (44-79), ECOG PS 0-1, received a median of 4 doses (range 1-20) of DMUC5754A. Two DLTs, 1 Grade 4 neutropenia and 1 Grade 4 uric acid increase, occurred at the maximally administered dose of 3.2 mg/kg. Grade ≥ 3 related adverse events (AE) occurring in ≥ 5% of patients included fatigue (4 at 2.4 mg/kg; 9% total) and neutropenia (1 at 3.2 mg/kg, 3 at 2.4 mg/kg; 9% total). The most common related AEs over all dose levels were fatigue (57%), nausea (34%), vomiting (27%), decreased appetite (25%), peripheral neuropathy (25%), and diarrhea (23%). Serious drug-related AEs (SAE) were small intestine obstruction (2 patients), hypocalcemia (1 patient), and neutropenia (1 patient). Total antibody and conjugated MMAE were not impacted by circulating CA125 and displayed dose-dependent PK with clearance decreasing as dose increased. Accumulation of total antibody, conjugated MMAE and free MMAE was not observed due to their short half-lives (≤5 days). Tumor MUC16 expression was evaluable in 42 patients, showing 20% IHC 0, 16% IHC 2+, and 64% IHC 3+. All confirmed responses (1 CR and 4 PRs) occurred in patients treated at 2.4 mg/kg and whose tumors were MUC16 IHC 2+ or 3+. Six additional patients had minor responses (3 at 2.4 mg/kg). Sixteen of the twenty-nine patients at 2.4 mg/kg were on study ≥ 105 days. Human epididymis protein 4 was a potential surrogate marker for serologic response measures in the presence of anti-MUC16/CA125-binding therapy.
Conclusions: DMUC5754A at 2.4 mg/kg q3w has an encouraging safety profile and evidence of anti-tumor activity in MUC16-expressing OC. Further studies are planned.
Citation Format: Joyce Liu, Kathleen Moore, Michael Birrer, Suzanne Berlin, Ursula Matulonis, Jeffrey Infante, Jian Xi, Robert Kahn, Yulei Wang, Katie Wood, Daniel Coleman, Daniel Maslyar, Eric Humke, Howard Burris. Targeting MUC16 with the antibody-drug conjugate (ADC) DMUC5754A in patients with platinum-resistant ovarian cancer: A phase I study of safety and pharmacokinetics. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-290. doi:10.1158/1538-7445.AM2013-LB-290