A phase 1 study of PF-05082566 (anti-4-1BB) in patients with advanced cancer.

Abstract

3007 Background: 4-1BB agonists markedly enhance cytotoxic T-cell responses, resulting in anti-tumor activity in several models. PF-05082566 is a fully humanized IgG2 agonist monoclonal antibody targeting 4-1BB.This portion of the first-in-human phase I study assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of PF-0508256 monotherapy in patients with advanced cancer. Methods: An open-label, dose escalation study was conducted in patients with advanced malignancies for which no curative therapy was available. Cohorts of 3-6 patients were enrolled initially using a 3+3 design (0.006 to 0.3 mg/kg), then a Time-To-Event CRM design for higher doses (0.6 to 5 mg/kg). Patients received PF-05082566 via intravenous infusion every 4 weeks (one cycle) with an 8 week period for assessment of dose-limiting toxicity (DLT). Radiographic assessments were conducted every 8 weeks, using RECIST 1.1. Results: 27 patients have been treated with PF-05082566 up to the 0.3 mg/kg dose level, including colorectal cancer (n=11), Merkel cell carcinoma (n=6), pancreatic adenocarcinoma (n=2), and one each of nasopharyngeal cancer, ampullary cancer, squamous cell lung cancer, carcinoma of unknown primary, melanoma, sarcoma, follicular lymphoma, and lymphocytic lymphoma (SLL). 25 patients completed the DLT assessment period and 7 patients remain on therapy. All discontinuations from treatment were due to disease progression. Median number of cycles ranged from 2 (at 0.006 mg/kg) to 7 (at 0.24 mg/kg). There was no apparent relationship between increasing doses and the frequency or severity of treatment emergent adverse events, which were mostly Grade 1. One patient treated at 0.06 mg/kg had Grade 3 elevation in alkaline phosphatase. No additional significant elevations in liver enzymes and no DLTs have occurred to date. Preliminary PK data suggests a linear increase in drug exposure with increasing dose, and a half life of ~10 days. A best overall response of stable disease was observed in 22% (6/27) patients. Conclusions: PF-05082566 was well tolerated, with evidence of disease stabilization in multiple patients. Enrollment continues at higher dose levels to obtain additional safety, PK, PD, and efficacy data. Clinical trial information: NCT01307267.