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

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.

• Authors: Geoffrey I Shapiro, Ulka N Vaishampayan, Patricia LoRusso, Jeremy Barton, Steven Hua, Steven D Reich, Ronald Shazer, Carrie T Taylor, Dawei Xuan, Hossein Borghaei
• Journal: Investigational new drugs (Invest New Drugs) Vol. 35 Issue 3 Pg. 315-323 (06 2017) ISSN: 1573-0646 [Electronic] United States
• PMID: 28070718 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antigens, Neoplasm
• Antineoplastic Agents, Immunological
• Immunoconjugates
• Membrane Glycoproteins
• Oligopeptides
• monomethylauristatin F
• trophoblastic glycoprotein 5T4, human
• PF-06263507

Topics

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