TY - JOUR
T1 - First-in-human trial of an anti-5T4 antibody-monomethylauristatin conjugate, PF-06263507, in patients with advanced solid tumors
AU - Shapiro, Geoffrey I.
AU - Vaishampayan, Ulka N.
AU - LoRusso, Patricia
AU - Barton, Jeremy
AU - Hua, Steven
AU - Reich, Steven D.
AU - Shazer, Ronald
AU - Taylor, Carrie T.
AU - Xuan, Dawei
AU - Borghaei, Hossein
N1 - Publisher Copyright:
© 2017, The Author(s).
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Antibodies, Monoclonal, Humanized/adverse effects
KW - Antigens, Neoplasm/adverse effects
KW - Antineoplastic Agents, Immunological/adverse effects
KW - Female
KW - Humans
KW - Immunoconjugates/adverse effects
KW - Keratitis/chemically induced
KW - Male
KW - Maximum Tolerated Dose
KW - Membrane Glycoproteins/antagonists & inhibitors
KW - Middle Aged
KW - Neoplasms/drug therapy
KW - Oligopeptides/adverse effects
KW - Photophobia/chemically induced
KW - Treatment Outcome
UR - http://www.scopus.com/inward/record.url?scp=85008712555&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000400859100008&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1007/s10637-016-0419-7
DO - 10.1007/s10637-016-0419-7
M3 - Article
C2 - 28070718
SN - 0167-6997
VL - 35
SP - 315
EP - 323
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 3
ER -