1543TiP - Phase I/II Study to Assess the Safety, Pharmacokinetics (PK) and Efficacy of Lorvotuzumab Mertansine (LM, IMGN901) in Combination with Carboplatin/Etoposide in Patients with Solid Tumors Including Small-Cell Lung Cancer (SCLC)

Abstract

ABSTRACT Purpose SCLC expresses CD56 almost universally. LM is a CD56-targeting antibody-drug conjugate. This study was initiated to evaluate LM for the treatment of SCLC when used in combination with carboplatin (C) and etoposide (E). Its phase 1 portion was designed to establish the recommended phase 2 dose (RP2D) of LM with C and E. PK data with the combination also was obtained. Methods Patients (pts) with advanced solid tumors were accrued to a standard 3 + 3 dose-escalation study design. Successive cohorts received escalating doses of LM IV on days 1 and 8 in combination with C IV on day 1 and E IV on days 1-3 every 21 days. LM PK was measured by an ELISA-based method. C and E levels were measured using optimized LC-MS/MS assays. PK parameters were determined by noncompartmental analysis. Results 33 patients (13M, median age = 57.3) were treated in 5 cohorts (2 using C AUC6; 3 using C AUC5) at LM doses ranging from 60-112 mg/m2. The RP2D was defined as LM 112 mg/m2 with C AUC5 and E 100 mg/m2. PK samples were analyzed for Cycle 1, first dose. At the RP2D, LM exposure and maximum concentration were similar to those observed in single-agent trials, with the t1/2 of LM approaching 1 day (24.2 hours). PK findings for C/E were similar to published reports (Oguri, 1988; D'Incalci, 1982) with the observed AUC of C = 5.1 ± 0.7 min*mg/mL and E = 6921 ± 1231 min*µg/mL. The most common treatment-related adverse events (AEs) were anemia, thrombocytopenia, nausea, peripheral neuropathy, decreased lymphocytes and neutrophils, and fatigue. The majority of related grade 3/4 AEs were cytopenias which, while known to occur with C/E regimens, typically have not been associated with LM monotherapy. Among 13 pts with SCLC accrued to phase 1, 6 (46%; 4 previously treated) achieved PR after at least one response assessment. Conclusion The combination is well tolerated with no apparent drug-drug interactions. Preliminary signs of activity have been observed in this predominantly pre-treated population. The randomized phase 2 portion of the study in chemo-naive patients with SCLC has opened to accrual. Updated data will be presented. Disclosure R. Guild: Employee of ImmunoGen, Inc. R. Mastico: Employee of ImmunoGen, Inc. All other authors have declared no conflicts of interest.