TY - JOUR
T1 - A phase 1 study of LY3076226, a fibroblast growth factor receptor 3 (FGFR3) antibody–drug conjugate, in patients with advanced or metastatic cancer
AU - Kollmannsberger, Christian K.
AU - Britten, Carolyn D.
AU - Olszanski, Anthony J.
AU - Walker, Joan Andrews
AU - Zang, Wei
AU - Willard, Melinda D.
AU - Radtke, David B.
AU - Farrington, Daphne L.
AU - Bell-Mcguinn, Katherine
AU - Patnaik, Amita
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2021/12
Y1 - 2021/12
N2 - Background We report a Phase 1 study of LY3076226, an antibody–drug conjugate composed of human IgG1 monoclonal antibody against the human FGFR3 attached with a cleavable linker to the maytansine derivative DM4 in patients with advanced or metastatic cancer. Methods This study was comprised of two parts: (A) dose escalation in patients with advanced or metastatic cancer and (B) dose expansion in patients with urothelial carcinoma with locally determined FGFR3 alterations. The dose range of LY3076226 tested was 0.2–5.0 mg/kg as an intravenous infusion on Day 1 of each 21-day cycle. The primary objective was to determine a recommended phase 2 dose (RP2D). Results Twenty-five patients were enrolled (Part A: 22, Part B: 3) and received ≥ 1 dose of LY3076226. No dose-limiting toxicities were reported. LY3076226 was generally well tolerated; most of the toxicities were Grade 1 or 2. Two patients experienced treatment-related Grade 3 toxicity (embolism and decreased platelet count). Four patients experienced serious adverse events (not treatment-related), all in Part A. Dose-proportional exposure was observed, with an estimated half-life of 2–7 days. No responses were seen with LY3076226 treatment. Stable disease persisting for > 6 months was observed in 1 patient receiving 3.2 mg/kg of LY3076226. Conclusion The study demonstrates acceptable safety and tolerability of LY3076226 up to the 5.0 mg/kg dose. Recruitment was stopped due to pipeline prioritization. Dose escalation of LY3076226 beyond 5.0 mg/kg in patients with advanced tumors may be possible. The trial was registered on August 19, 2015 under identifier NCT02529553 with ClinicalTrials.gov.
AB - Background We report a Phase 1 study of LY3076226, an antibody–drug conjugate composed of human IgG1 monoclonal antibody against the human FGFR3 attached with a cleavable linker to the maytansine derivative DM4 in patients with advanced or metastatic cancer. Methods This study was comprised of two parts: (A) dose escalation in patients with advanced or metastatic cancer and (B) dose expansion in patients with urothelial carcinoma with locally determined FGFR3 alterations. The dose range of LY3076226 tested was 0.2–5.0 mg/kg as an intravenous infusion on Day 1 of each 21-day cycle. The primary objective was to determine a recommended phase 2 dose (RP2D). Results Twenty-five patients were enrolled (Part A: 22, Part B: 3) and received ≥ 1 dose of LY3076226. No dose-limiting toxicities were reported. LY3076226 was generally well tolerated; most of the toxicities were Grade 1 or 2. Two patients experienced treatment-related Grade 3 toxicity (embolism and decreased platelet count). Four patients experienced serious adverse events (not treatment-related), all in Part A. Dose-proportional exposure was observed, with an estimated half-life of 2–7 days. No responses were seen with LY3076226 treatment. Stable disease persisting for > 6 months was observed in 1 patient receiving 3.2 mg/kg of LY3076226. Conclusion The study demonstrates acceptable safety and tolerability of LY3076226 up to the 5.0 mg/kg dose. Recruitment was stopped due to pipeline prioritization. Dose escalation of LY3076226 beyond 5.0 mg/kg in patients with advanced tumors may be possible. The trial was registered on August 19, 2015 under identifier NCT02529553 with ClinicalTrials.gov.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Antibodies, Monoclonal, Humanized/administration & dosage
KW - Antineoplastic Agents/administration & dosage
KW - Area Under Curve
KW - Dose-Response Relationship, Drug
KW - Female
KW - Half-Life
KW - Humans
KW - Immunoconjugates/administration & dosage
KW - Male
KW - Maximum Tolerated Dose
KW - Maytansine/administration & dosage
KW - Metabolic Clearance Rate
KW - Middle Aged
KW - Neoplasms/drug therapy
KW - Receptor, Fibroblast Growth Factor, Type 3/antagonists & inhibitors
KW - Urologic Neoplasms/drug therapy
UR - http://www.scopus.com/inward/record.url?scp=85111831133&partnerID=8YFLogxK
U2 - 10.1007/s10637-021-01146-x
DO - 10.1007/s10637-021-01146-x
M3 - Article
C2 - 34264412
SN - 0167-6997
VL - 39
SP - 1613
EP - 1623
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 6
ER -