title: 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.affiliation: 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.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.affiliation: Karmanos Cancer Institute, Detroit, MI, USA.
authors.forename: Ulka N
authors.initials: UN
authors.lastname: Vaishampayan
authors.affiliation: Yale University, New Haven, CT, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Barton
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Hua
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Reich
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Shazer
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA. Carrie.Taylor@pfizer.com.|Pfizer Early Oncology Development and Clinical Research, 10777 Science Center Drive, CB-1, San Diego, CA, 92121, USA. Carrie.Taylor@pfizer.com.
authors.forename: Carrie T
authors.initials: CT
authors.lastname: Taylor
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: Dawei
authors.initials: D
authors.lastname: Xuan
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Hossein
authors.initials: H
authors.lastname: Borghaei
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000009:adverse effects / Q000627:therapeutic use; D000074322:Antineoplastic Agents, Immunological / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D007634:Keratitis / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009842:Oligopeptides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D020795:Photophobia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D000074322:Antineoplastic Agents, Immunological; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D009842:Oligopeptides; C513576:monomethylauristatin F; C063709:trophoblastic glycoprotein 5T4, human; C000626590:PF-06263507
keywords: 5T4; Antibody-drug conjugate; Immunoconjugate; Monomethylauristatin conjugate; PF-06263507; Solid tumors