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Invest New Drugs. 2017 Jun;35(3):315-323. doi: 10.1007/s10637-016-0419-7. Epub 2017 Jan 9.

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

Author information

1
Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Mayer 446, Boston, MA, 02215, USA. geoffrey_shapiro@dfci.harvard.edu.
2
Karmanos Cancer Institute, Detroit, MI, USA.
3
Yale University, New Haven, CT, USA.
4
Pfizer Oncology, La Jolla, CA, USA.
5
Pfizer Oncology, La Jolla, CA, USA. Carrie.Taylor@pfizer.com.
6
Pfizer Early Oncology Development and Clinical Research, 10777 Science Center Drive, CB-1, San Diego, CA, 92121, USA. Carrie.Taylor@pfizer.com.
7
Fox Chase Cancer Center, Philadelphia, PA, USA.

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.

KEYWORDS:

5T4; Antibody-drug conjugate; Immunoconjugate; Monomethylauristatin conjugate; PF-06263507; Solid tumors

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