A phase 1b study to assess the safety of lexatumumab, a human monoclonal antibody that activates TRAIL-R2, in combination with gemcitabine, pemetrexed, doxorubicin or FOLFIRI.

Abstract

B72 Background: Lexatumumab (HGS-ETR2) is a fully-human agonistic monoclonal antibody that targets and activates the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 2 (TRAIL-R2). TRAIL-R2 is a member of the Tumor Necrosis Factor Receptor (TNFR) superfamily that, when activated, induces apoptosis via the extrinsic pathway. Lexatumumab shows promising anti-tumor activity in preclinical models, particularly in combination with chemotherapeutic agents. Single-agent lexatumumab was well-tolerated in Phase 1 trials. This is the first study of the safety of a TRAIL-R2 agonist in combination with chemotherapy.
 Methods: Patients for whom gemcitabine, pemetrexed, doxorubicin or FOLFIRI was considered an appropriate treatment received one of the full-dose chemotherapy regimens plus lexatumumab every 2 weeks (for gemcitabine and FOLFIRI) or 3 weeks (for pemetrexed and doxorubicin). Four to 6 patients were treated with 5 mg/kg lexatumumab in each chemotherapy cohort prior to dose escalation to 10 mg/kg.
 Results: 41 patients with a wide range of cancer types received 190 courses of lexatumumab over the 2 dose levels. The majority (33/41) received at least 2 courses (range 1 to 24). Lexatumumab was well tolerated. Severe adverse events considered at least possibly related to lexatumumab included neutropenia, fatigue, anemia, increase in blood amylase levels, stomatitis and dehydration. Tumor shrinkage was observed, and 3 patients had confirmed partial responses (2 colorectal cancer patients in the FOLFIRI arm and 1 small cell lung cancer patient in the doxorubicin arm). None of the chemotherapeutic regimens affected lexatumumab disposition, nor did lexatumumab affect the pharmacokinetics of gemcitabine, doxorubicin or irinotecan.
 Conclusions: Lexatumumab can be safely administered in combination with a wide range of chemotherapeutic agents. Evaluation of the efficacy of lexatumumab in combination with chemotherapy in Phase 2 trials is warranted.