HGS-ETR1, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: Results of a phase 1 and PK study

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2515 Background: HGS-ETR1 (mapatumumab) is a fully-human monoclonal antibody agonistic to the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 1 (TRAIL-R1, DR4). Activation of TRAIL-R1 by HGS-ETR1 initiates a caspase cascade leading to apoptosis. HGS-ETR1 in combination with platinum or taxanes results in at least additive activity in preclinical models. Phase 1 and 2 trials have demonstrated that single agent HGS-ETR1 is well tolerated. Methods: This Phase 1 study assesses the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of HGS-ETR1 in combination with standard doses of paclitaxel and carboplatin. Patients received 3, 10 or 20 mg/kg HGS-ETR1 with paclitaxel (200 mg/m2) and carboplatin (AUC 6) every 21 days for up to 6 cycles in the absence of disease progression. Results: Enrollment is complete; 28 patients have received 106 cycles of HGS-ETR1, including 12 patients in each of the 10 mg/kg and 20 mg/kg cohorts. Fourteen of 28 pts received at least 3 cycles (median = 2.5, range 1–12). Dose-limiting toxicity has been neutropenic fever (attributed to chemotherapy) and hypersensitivity (attributed to HGS-ETR1). Other non-dose limiting adverse events at least possibly related to HGS-ETR1 include fatigue, myalgia, transaminitis, anorexia and arthralgia. Preliminary analyses reveal that carboplatin and paclitaxel PK are not affected by HGS-ETR1. Similarly, the PK profile of HGS-ETR1 is not affected by paclitaxel and carboplatin, with plasma HGS-ETR1 concentrations consistent with those observed in the Phase 1 single agent trials. Three patients with NSCLC and 1 with adenocarcinoma of an unknown primary have experienced a confirmed partial response. Conclusions: HGS-ETR1 can be safely administered with carboplatin and paclitaxel. Evaluation of HGS-ETR1 in combination with other chemotherapeutic regimens is warranted. [Table: see text]

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