Phase I study of MEDI0639 in patients with advanced solid tumors.

Abstract

3024 Background: MEDI0639 is an investigational monoclonal antibody that selectively binds to Delta-like ligand 4 (DLL4) and blocks its ability to bind to and activate signaling through the Notch receptors, potentially inhibiting tumor growth by multiple mechanisms. Methods: This study (NCT01577745) included patients (pts) with advanced solid tumors who had ECOG performance status 0–1 and adequate organ function. MEDI0639 10–200 mg was given every 21 days with a 3+3 dose-escalation design. Primary objective was to determine maximum tolerated dose (MTD) and safety. Other objectives included pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity (IG), and antitumor activity. Results: As of Jan 7, 2015, 20 pts were enrolled (median age 61y [range 40–83y]; median number of prior therapies: 5). The most common tumors were colorectal (n = 5), small cell lung cancer (n = 4), and melanoma (n = 4). No dose-limiting toxicities were identified through the 150 mg dose; the 200 mg dose is currently being evaluated. Of 20 safety-evaluable pts, the most common treatment-related adverse events (trAEs) were increased aspartate aminotransferase, increased brain natriuretic peptide (BNP), and fatigue (n = 3 each). Grade 3/4 trAEs were observed in 3 pts (acute myocardial infarction [AMI], atrial fibrillation [AF], ventricular dilatation [VD], and ventricular hypokinesia [VH] in 1 pt; lower abdominal pain in 1 pt, and hypertension in 1 pt), and 3 pts had serious trAEs (AMI, AF, VD, VH in 1 pt; diplopia in 1 pt; hemorrhagic diarrhea (HD), chest discomfort, and back pain in 1 pt). One pt discontinued due to a trAE (AMI). The trAEs of interest consistent with the mechanism of action included AMI (n = 1), hypertension (n = 2), increased BNP (n = 3), and HD (n = 1). No treatment-related deaths occurred. Of 19 efficacy evaluable pts, partial response was observed in 1 pt with melanoma; 7 pts had stable disease lasting ≥ 12 weeks. Preliminary PK was nonlinear at doses < 100 mg, and PD showed target engagement at the doses tested. IG has not been observed. Conclusions: MEDI0639 150 mg did not exceed the MTD. Enrollment at the 200 mg dose level is ongoing. The safety profile is consistent with the mechanism of action and appears to be manageable. Preliminary evidence of antitumor activity was observed. Clinical trial information: NCT01577745.