Abstract CT009: Targeting MUC16 with the THIOMABTM-drug conjugate DMUC4064A in patients with platinum-resistant ovarian cancer: a Phase I escalation study
Authors: Joyce F. Liu, Kathleen N. Moore, Judy S. Wang, Manish Patel, Michael J. Birrer, Erika Hamilton, Lisa Barroilhet, William M. Flanagan, Yulei Wang, Amit Garg, Xuyang Lu, Anjali Vaze, Dilip Amin, Doug Leipold, S Renee Commerford, Eric W. Humke, Harold A. Burris
Journal: Cancer Research (2017)

Abstract Background: MUC16 is a transmembrane protein that is overexpressed by ovarian cancer. The role of MUC16 in the pathogenesis of ovarian cancer is unknown; however, MUC16 may facilitate binding of ovarian tumor cells to mesothelial cells lining the peritoneal cavity. Traditional antibody drug conjugates, with conjugation through inter-chain disulfides, are heterogeneous mixtures of drug antibody ratios (DAR) ranging from 0-8, resulting in complex pharmacokinetics (PK) and potentially unfavorable safety and efficacy. In contrast, THIOMABTM drug conjugates (TDCs) use novel technology that achieves site-directed drug conjugation yielding a homogeneous DAR. DMUC4064A is a cysteine-engineered TDC comprising a humanized anti-MUC16 IgG1 and 2 potent anti-mitotic monomethyl auristatin E (MMAE) molecules. Methods: The dose-escalation component of the Phase I study evaluated safety, tolerability, PK, pharmacodynamics, and early activity of DMUC4064A given Q3W to patients with platinum-resistant ovarian cancer. A standard 3+3 design was used to determine the maximum-tolerated dose. Archival tumor tissue was used to assess expression of MUC16 and other markers. Clinical activity was evaluated per RECIST v4.0 criteria. Results: Forty-four female patients, median age 63 (35-84), ECOG PS 0-1, received a median of 4 doses (range 1-12) of DMUC4064A at 1.0-5.6 mg/kg. At 5.6 mg/kg, one patient experienced three adverse events (AE) each qualifying as a DLT (colitis, hyperglycemia, and hypokalemia; all Grade 3). At 5.2 mg/kg, another patient experienced a DLT of Grade 5 septic shock. Grade ≥ 3 AE occurring in ≥ 5% of patients included hyponatremia (1 each at 1.8, 3.2, and 5.2 mg/kg; 2 at 2.4 mg/kg; 11% total), ascites (2 at 2.4 mg/kg and 1 at 3.2 mg/kg; 7% total) and hyperglycemia (3 at 5.6 mg/kg; 7% total), all unrelated except hyperglycemia. The most common (≥20%) related AEs for all dose levels were fatigue (34%), nausea (32%), diarrhea (23%) and abdominal pain (21%). Ocular toxicities (related, Grade ≥ 2) included keratitis (Grade 3, n=2), blurred vision (Grade 3, n=1; Grade 2, n=3), and dry eye (Grade 2, n=1). Total antibody and conjugated MMAE showed dose-dependent PK; neither were impacted by circulating CA125. Total antibody, conjugated and free MMAE accumulation was minimal. At doses ≥2.4 mg/kg, DMUC4064A had decreased clearance and achieved higher exposures versus MUC16 MMAE ADC. Confirmed responses (1 CR and 6 PRs) occurred at ≥ 3.2 mg/kg (n=30). Tumor MUC16 IHC scores were 2+/3+ in responders for whom data were available (n=5). Conclusions: These data are the first reported for an MMAE-containing TDC in a clinical trial (clinicaltrials.gov NCT02146313). DMUC4064A has an acceptable safety profile with improved stability compared to MUC16 MMAE ADC and shows evidence of anti-tumor activity, warranting further evaluation in ovarian cancer. Citation Format: Joyce F. Liu, Kathleen N. Moore, Judy S. Wang, Manish Patel, Michael J. Birrer, Erika Hamilton, Lisa Barroilhet, William M. Flanagan, Yulei Wang, Amit Garg, Xuyang Lu, Anjali Vaze, Dilip Amin, Doug Leipold, S Renee Commerford, Eric W. Humke, Harold A. Burris. Targeting MUC16 with the THIOMABTM-drug conjugate DMUC4064A in patients with platinum-resistant ovarian cancer: a Phase I escalation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT009. doi:10.1158/1538-7445.AM2017-CT009