PMID- 28070718 OWN - NLM STAT- MEDLINE DCOM- 20180321 LR - 20231104 IS - 1573-0646 (Electronic) IS - 0167-6997 (Print) IS - 0167-6997 (Linking) VI - 35 IP - 3 DP - 2017 Jun TI - First-in-human trial of an anti-5T4 antibody-monomethylauristatin conjugate, PF-06263507, in patients with advanced solid tumors. PG - 315-323 LID - 10.1007/s10637-016-0419-7 [doi] 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. FAU - Shapiro, Geoffrey I AU - Shapiro GI AD - 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. FAU - Vaishampayan, Ulka N AU - Vaishampayan UN AD - Karmanos Cancer Institute, Detroit, MI, USA. FAU - LoRusso, Patricia AU - LoRusso P AD - Yale University, New Haven, CT, USA. FAU - Barton, Jeremy AU - Barton J AD - Pfizer Oncology, La Jolla, CA, USA. FAU - Hua, Steven AU - Hua S AD - Pfizer Oncology, La Jolla, CA, USA. FAU - Reich, Steven D AU - Reich SD AD - Pfizer Oncology, La Jolla, CA, USA. FAU - Shazer, Ronald AU - Shazer R AD - Pfizer Oncology, La Jolla, CA, USA. FAU - Taylor, Carrie T AU - Taylor CT AD - Pfizer Oncology, La Jolla, CA, USA. Carrie.Taylor@pfizer.com. AD - Pfizer Early Oncology Development and Clinical Research, 10777 Science Center Drive, CB-1, San Diego, CA, 92121, USA. Carrie.Taylor@pfizer.com. FAU - Xuan, Dawei AU - Xuan D AD - Pfizer Oncology, La Jolla, CA, USA. FAU - Borghaei, Hossein AU - Borghaei H AD - Fox Chase Cancer Center, Philadelphia, PA, USA. LA - eng SI - ClinicalTrials.gov/NCT01891669 GR - UL1 TR001863/TR/NCATS NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study DEP - 20170109 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antigens, Neoplasm) RN - 0 (Antineoplastic Agents, Immunological) RN - 0 (Immunoconjugates) RN - 0 (Membrane Glycoproteins) RN - 0 (Oligopeptides) RN - 0 (monomethylauristatin F) RN - 0 (trophoblastic glycoprotein 5T4, human) RN - V7U0JSO7FH (PF-06263507) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - *Antibodies, Monoclonal, Humanized/adverse effects/pharmacokinetics/therapeutic use MH - *Antigens, Neoplasm/adverse effects/therapeutic use MH - Antineoplastic Agents, Immunological/adverse effects/pharmacokinetics/therapeutic use MH - Female MH - Humans MH - *Immunoconjugates/adverse effects/pharmacokinetics/therapeutic use MH - Keratitis/chemically induced MH - Male MH - Maximum Tolerated Dose MH - Membrane Glycoproteins/*antagonists & inhibitors MH - Middle Aged MH - Neoplasms/*drug therapy/metabolism MH - *Oligopeptides/adverse effects/pharmacokinetics/therapeutic use MH - Photophobia/chemically induced MH - Treatment Outcome PMC - PMC5418317 OTO - NOTNLM OT - 5T4 OT - Antibody-drug conjugate OT - Immunoconjugate OT - Monomethylauristatin conjugate OT - PF-06263507 OT - Solid tumors COIS- CONFLICT OF INTEREST: G. I. Shapiro received research funding from Pfizer. U. N. Vaishampayan has nothing to disclose related to this study. P. LoRusso received an advisory board honorarium from Pfizer. H. Borghaei received research funding from Takeda (Millennium), Merck, and Celgene; and consulting honoraria from BMS, Lilly, Genentech, Pfizer, Celgene, Boehringer-Ingelheim, Trovogene, and EMD-Serono. J. Barton, S. Hua S, R. Shazer R, C. T. Taylor, and D. Xuan were employees of Pfizer during the conduct of this study. S. D. Reich is a contractor for Pfizer. RESEARCH INVOLVING HUMAN PARTICIPANTS: All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. INFORMED CONSENT: Informed consent was obtained from all individual participants included in the study. EDAT- 2017/01/11 06:00 MHDA- 2018/03/22 06:00 PMCR- 2017/01/09 CRDT- 2017/01/11 06:00 PHST- 2016/11/16 00:00 [received] PHST- 2016/12/22 00:00 [accepted] PHST- 2017/01/11 06:00 [pubmed] PHST- 2018/03/22 06:00 [medline] PHST- 2017/01/11 06:00 [entrez] PHST- 2017/01/09 00:00 [pmc-release] AID - 10.1007/s10637-016-0419-7 [pii] AID - 419 [pii] AID - 10.1007/s10637-016-0419-7 [doi] PST - ppublish SO - Invest New Drugs. 2017 Jun;35(3):315-323. doi: 10.1007/s10637-016-0419-7. Epub 2017 Jan 9.