In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. CT036-CT036
Abstract:
Background: MUC16 is a transmembrane protein that is overexpressed by ovarian cancer. DMUC4064A is a cysteine-engineered THIOMABTM drug conjugate (TDC), comprising a humanized anti-MUC16 IgG1 and 2 potent anti-mitotic monomethyl auristatin E (MMAE) molecules. THIOMABTM technology allows site-directed drug conjugation yielding a homogeneous drug-antibody ratio. Phase 1 dose escalation results (AACR 2017 abstract CT009) indicated DMUC4064A was well-tolerated with anti-tumor activity in patients with platinum resistant ovarian cancer (PROC) at doses ≥ 3.2 mg/kg. The results from a subsequently enrolled expansion cohort at 5.2 mg/kg are reported here. Methods: The dose expansion stage of the Phase I study evaluated safety, tolerability, PK, pharmacodynamic, and early activity of DMUC4064A at 5.2 mg/kg IV Q3W in PROC. Tumor tissue was used to assess expression of MUC16. Clinical activity was evaluated per RECIST criteria. Results: Twenty female patients, median age 62 (51-75 y, ECOG PS 0-1), received a median of 7 doses (range 1-15) of DMUC4064A. Total antibody and antibody-conjugated MMAE (acMMAE) concentrations were bi-phasic, while unconjugated MMAE concentrations were & gt; 150-fold lower than acMMAE concentrations. Accumulation was minimal for all three analytes. The most common (≥ 25%) related AEs were blurred vision (65%), fatigue (40%), nausea (40%), peripheral neuropathy (35%), keratitis (30%), diarrhea (25%), and dry eyes (25%). Related ocular AEs occurred in 15 (75%) patients, 13 (65%) of whom experienced at least one G2 or G3 event. G3 ocular AEs included keratitis (n=2), blurred vision (n=1) and cataracts (n=1). Among patients with related G2 or G3 ocular events, 77% transiently experienced best corrected visual acuity of ≥ 20/40. Re-wetting drops (87%), dose reductions (60%) and/or steroid drops (40%) were the most commonly implemented treatments. No patients discontinued study due to ocular AEs and all but one of the patients who were dose reduced for ocular AEs recovered to G1 or G2 with manageable ocular AEs and tolerated subsequent redosing with DMUC4064A. Related G2 peripheral neuropathy was reported in 5 patients, presenting in 3 patients at cycles 2-5 and in 2 patients after 6 cycles. Four patients discontinued due to G2 peripheral neuropathy. The overall confirmed response rate at 5.2 mg/kg was 45% (1 CR and 8 PRs) with 4 responses exceeding 75% reduction in measurable tumor burden. Tumor MUC16 IHC scores were 2+/3+ in responders for whom data were available (n=8/9). Median PFS was 5.8 months and median duration of response was 4.4 months. Conclusions: Treatment with DMUC4064A (clinicaltrials.gov NCT02146313) at 5.2 mg/kg has an acceptable safety profile in PROC, a patient population with few treatment options. The ocular toxicities with DMUC4064A appear manageable and the overall and depth of response demonstrate promising anti-tumor activity. Citation Format: Kathleen Moore, Erica P. Hamilton, Howard A. Burris, Lisa M. Barroilhet, Martin Gutierrez, Judy S. Wang, Manish R. Patel, Michael J. Birrer, W. Mike Flanagan, Yulei Wang, Amit Garg, Xuyang Lu, Anjali Vaze, Dilip Amin, Douglas Leipold, S. Renee Commerford, Eric W. Humke, Joyce F. Liu. Targeting MUC16 with the THIOMABTM-drug conjugate DMUC4064A in patients with platinum-resistant ovarian cancer: A phase I expansion study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT036.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2018-CT036
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
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2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
