First-in-human phase 1 dose-escalation study of AV-203, a monoclonal antibody against ERBB3, in patients with metastatic or advanced solid tumors.

Abstract

11113 Background: AV-203 is an IgG1k humanized monoclonal antibody with high affinity and specificity for the anti-v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3) receptor. Based on promising preclinical activity and resistance prevention data, a phase 1 study was conducted (NCT01603979). Methods: A phase 1 study using a 3+3 dose-escalation design evaluated the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK) and pharmacodynamics of AV-203. AV-203 was given IV at 2, 5, 9, 14 or 20 mg/kg once every 2 wks (1 cycle = 28 days, 2 doses per cycle). Included patients (pts) had advanced solid tumors and progressed on standard therapies or had no proven treatment options. Results: AV-203 was administered to 22 pts (15M/7F; median age 68 y, range 31-82; ECOG PS 0/1: 8/13). Enrolled tumor types included colorectal (4), non–small-cell lung (NSCLC; 4), squamous cell carcinoma of the head and neck (2) and other solid tumors (12). There was a single dose-limiting toxicity of inability to tolerate the study drug (serious Grade 3 diarrhea and multiple concurrent adverse events [AEs]) at 2 mg/kg in an 80-y-old pt. The maximum administered dose of 20 mg/kg was well tolerated. All grade AEs observed in ≥25% of pts were: diarrhea (68%); decreased appetite (41%); hypokalemia, dry skin and hypomagnesemia (36% each); headache, dehydration, dizziness and dyspnea (27% each). Grade 3 and 4 AEs of anemia, diarrhea and hypokalemia occurred in ≥2 pts. The most common treatment-related AEs were diarrhea (59%), dry skin and decreased appetite (32% each), hypomagnesemia (27%) and pruritus (23%). No deaths were attributed to AV-203. Preliminary data show approximately dose proportional PK and no detection of anti-drug antibodies. Median time on treatment for all pts was 43 days (range: 1-491), with 15 pts discontinuing due to progressive disease during this time. There was one confirmed partial response (PR; 6 cycles) in a pt with squamous NSCLC which expressed high levels of neuregulin 1. Conclusions: AV-203 was well tolerated in the dose range tested; RP2D is 20 mg/kg IV every 2 wks. The PR in a pt with squamous cell NSCLC warrants further testing of AV-203 in this indication. Clinical trial information: NCT01603979.