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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.

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Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Mayer 446, Boston, MA, 02215, USA.
Karmanos Cancer Institute, Detroit, MI, USA.
Yale University, New Haven, CT, USA.
Pfizer Oncology, La Jolla, CA, USA.
Pfizer Oncology, La Jolla, CA, USA.
Pfizer Early Oncology Development and Clinical Research, 10777 Science Center Drive, CB-1, San Diego, CA, 92121, USA.
Fox Chase Cancer Center, Philadelphia, PA, USA.


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.


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

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