First-in-human trial of an anti-5T4 antibody-monomethylauristatin conjugate, PF-06263507, in patients with advanced solid tumors

Geoffrey I. Shapiro, Ulka N. Vaishampayan, Patricia LoRusso, Jeremy Barton, Steven Hua, Steven D. Reich, Ronald Shazer, Carrie T. Taylor, Dawei Xuan, Hossein Borghaei

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Background The antibody-drug conjugate PF-06263507 targets the cell-surface, tumor-associated antigen 5T4 and consists of a humanized IgG1 conjugated to the microtubule-disrupting agent monomethylauristatin-F by a non-cleavable maleimidocaproyl linker. In this first-in-human, dose-finding trial (NCT01891669), we evaluated safety, pharmacokinetics, and preliminary antitumor activity of PF-06263507 in pretreated patients with advanced solid tumors, unselected for 5T4 expression. starting at 0.05 mg/kg, with 25, 56, and 95% dose increments, depending on observed dose-limiting toxicities (DLTs), applying a modified continual reassessment method. Results Twenty-six patients received PF-06263507 at 0.05 to 6.5 mg/kg. The first DLT, grade 3 photophobia, occurred at 4.34 mg/kg and two additional DLTs, grade 2 keratitis and grade 1 limbal stem cell deficiency (> 2-week dosing delay), at 6.5 mg/kg. The most common adverse events (AEs) were fatigue (38.5%), photophobia (26.9%), and decreased appetite, dry eye, nausea, and thrombocytopenia (23.1% each). No treatment-related grade 4–5 AEs were reported. Systemic exposure of PF-06263507 increased in a dose-related manner. At the maximum tolerated dose (MTD, 4.34 mg/kg), mean terminal half-life for PF-06263507 and unconjugated payload were ~6 and 3 days, respectively. Payload serum concentrations were substantially lower compared with PF-06263507. No objective responses were observed. Conclusions The MTD and recommended phase II dose were determined to be 4.34 mg/kg. Ocular toxicities accounted for the DLTs observed, as previously reported with monomethylauristatin-F payloads. Further studies are warranted to investigate clinical activity of this agent in patients with 5T4-expressing tumors. Trial registration ID: NCT01891669.

Original languageEnglish
Pages (from-to)315-323
Number of pages9
JournalInvestigational New Drugs
Volume35
Issue number3
DOIs
StatePublished - Jun 1 2017

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized/adverse effects
  • Antigens, Neoplasm/adverse effects
  • Antineoplastic Agents, Immunological/adverse effects
  • Female
  • Humans
  • Immunoconjugates/adverse effects
  • Keratitis/chemically induced
  • Male
  • Maximum Tolerated Dose
  • Membrane Glycoproteins/antagonists & inhibitors
  • Middle Aged
  • Neoplasms/drug therapy
  • Oligopeptides/adverse effects
  • Photophobia/chemically induced
  • Treatment Outcome

Fingerprint

Dive into the research topics of 'First-in-human trial of an anti-5T4 antibody-monomethylauristatin conjugate, PF-06263507, in patients with advanced solid tumors'. Together they form a unique fingerprint.

Cite this