Phase I Open-Label Study Evaluating the Safety, Pharmacokinetics, and Preliminary Efficacy of Dilpacimab in Patients with Advanced Solid Tumors

Michael S Gordon, John Nemunaitis, Minal Barve, Zev A Wainberg, Erika P Hamilton, Ramesh K Ramanathan, George W Sledge Jr, Huibin Yue, Susan E Morgan-Lappe, Martha Blaney, Sreeneeranj Kasichayanula, Monica Motwani, Lan Wang, Louie Naumovski, John H Strickler, Michael S Gordon, John Nemunaitis, Minal Barve, Zev A Wainberg, Erika P Hamilton, Ramesh K Ramanathan, George W Sledge Jr, Huibin Yue, Susan E Morgan-Lappe, Martha Blaney, Sreeneeranj Kasichayanula, Monica Motwani, Lan Wang, Louie Naumovski, John H Strickler

Abstract

Dilpacimab (formerly ABT-165), a novel dual-variable domain immunoglobulin, targets both delta-like ligand 4 (DLL4) and VEGF pathways. Here, we present safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy data from a phase I study (trial registration ID: NCT01946074) of dilpacimab in patients with advanced solid tumors. Eligible patients (≥18 years) received dilpacimab intravenously on days 1 and 15 in 28-day cycles at escalating dose levels (range, 1.25-7.5 mg/kg) until progressive disease or unacceptable toxicity. As of August 2018, 55 patients with solid tumors were enrolled in the dilpacimab monotherapy dose-escalation and dose-expansion cohorts. The most common treatment-related adverse events (TRAE) included hypertension (60.0%), headache (30.9%), and fatigue (21.8%). A TRAE of special interest was gastrointestinal perforation, occurring in 2 patients (3.6%; 1 with ovarian and 1 with prostate cancer) and resulting in 1 death. The PK of dilpacimab showed a half-life ranging from 4.9 to 9.5 days, and biomarker analysis demonstrated that the drug bound to both VEGF and DLL4 targets. The recommended phase II dose for dilpacimab monotherapy was established as 3.75 mg/kg, primarily on the basis of tolerability through multiple cycles. A partial response was achieved in 10.9% of patients (including 4 of 16 patients with ovarian cancer). The remaining patients had either stable disease (52.7%), progressive disease (23.6%), or were deemed unevaluable (12.7%). These results demonstrate that dilpacimab monotherapy has an acceptable safety profile, with clinical activity observed in patients with advanced solid tumors.

©2021 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
A, Best percentage change in tumor lesion for dilpacimab at all dose levels (n = 47). B, Patients with ovarian cancer treated with dilpacimab at all dose levels (n = 16). C, Change in tumor lesion over time for patients with ovarian cancer treated with dilpacimab at all dose levels (n = 16). aPatients without prior bevacizumab treatment.
Figure 2.
Figure 2.
Effect of dilpacimab administration on levels of free VEGF (A) and total sDLL4 (B). C, cycle. D, day.

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