A phase I study of the safety and pharmacokinetics of DNIB0600A, an anti-NaPi2b antibody-drug-conjugate (ADC), in patients (pts) with non− small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (OC).

Abstract

2507 Background: NaPi2b (SLC34A2) is a multi-transmembrane, sodium-dependent phosphate transporter expressed in non-squamous NSCLC and non-mucinous OC. DNIB0600A is an ADC consisting of a humanized IgG1 anti-NaPi2b monoclonal antibody and anti-mitotic agent, MMAE, that shows anti-proliferative activity in xenograft models. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamics of DNIB0600A (0.2-2.8 mg/kg) given every 3 weeks (q3w) to pts with NSCLC or OC. A traditional 3+3 design was used for dose escalation followed by expansion by disease at the recommended Phase 2 dose (RP2D). Tumor NaPi2b expression was evaluated in archival tissue. Anti-tumor activity was evaluated per RECIST 1.1. Results: As of 10 Dec 2012, 30 dose escalation pts have enrolled (16 NSCLC; 14 OC), median age 61 (range 45-78), PS 0-1, median number of prior regimens 5 (1-12), received a median of 3 (1-17) doses of DNIB0600A. No DLTs occurred at the maximum assessed dose of 2.8 mg/kg; enrollment in the expansion cohort at 2.4 mg/kg is ongoing. The most common related AEs regardless of Grade were fatigue (43%), decreased appetite (37%), nausea (30%), constipation, dysgeusia, vomiting, and peripheral neuropathy (each 17%), and diarrhea (13%). One pt at 1.8 mg/kg experienced a DLT (Grade 3 dyspnea), however, no additional DLTs occurred through the maximally administered dose of 2.8 mg/kg. Expansion at 2.4 mg/kg was selected based on totality of safety data. No accumulation of total antibody, free MMAE, or conjugated MMAE was observed. Exposure of each analyte was dose proportional. Approximately 70% of NSCLCs and 85% of OC expressed high levels (IHC 2+/3+) of NaPi2b. Of the 18 pts treated at dose levels 1.8-2.8 mg/kg (10 NSCLC; 8 OC) 3 pts had a confirmed partial response (PR) with response durations of 8.8+ (OC), 4.4+ (NSCLC), and 1.4+ (OC) months, censored at data cutoff, and 1 additional pt had an unconfirmed PR (OC). Dose expansion data will be presented. Conclusions: DNIB0600A administered q3w has an encouraging safety profile and evidence of anti-tumor activity in both NSCLC and OC. Further studies are planned. Clinical trial information: NCT01375842.