Abstract 5443: A phase 1 evaluation of 64Cu-DOTA-patritumab to assess dosimetry, receptor occupancy, and safety in advanced solid tumors
Authors: Lockhart Albert C. , Liu Yongjian , Dehdashti Farrokh , Laforest Richard , Picus Joel , Wang-Gillam Andrea , Trull Lauren , Belanger Stefanie , Desai Madhuri , Mendell Jeanne , Mahmood Syed , Siegel Barry A. , Welch Michael J. 
Published: May 2015

Abstract
Background: Patritumab (P) is a HER3-specific human mAB that promotes receptor downregulation, inhibits ligand binding and tumor growth in xenografts models, and is safe in humans. The radioisotope 64Cu conjugated with P with a DOTA chelate, was confirmed by mass spectrometry and stable in serum for 24-hours. A microPET study in a mouse model (BxPC3) revealed significant tumor uptake of 64Cu-DOTA-patritumab (64Cu-DOTA-P) and uptake blockage (&gt;50%) with co-injection of unlabeled P. Clinically administering 64Cu-DOTA-P could identify serum concentrations needed for maximal receptor occupancy.
Methods: This Phase 1 study evaluated the safety, dosimetry (Cohort 1) and HER3 receptor occupancy (Cohort 2) of escalating doses of GMP generated intravenously administered 64Cu-DOTA-P in subjects with HER3+, solid tumors. Cohort 1 subjects received 64Cu-DOTA-P (8-15 mCi) on D1, then PET/CT scans at 3, 24, and 48 hours (± 3 hours). Sequential PET/CT scans and time integrated organ activity concentrations were used to compute organ residence times and radiation doses. Cohort 2 subjects received 64Cu-DOTA-P on D1 (tracer only) and D8 (tracer after 9.0 mg/kg of P), each followed by PET/CT scans at 24 hours (± 3 hours). Receptor occupancy was measured by: 1) tracer tumor “uptake” at D1 versus D8; and 2) D1 “uptake” versus tumoral HER3 expression with validated IHC (membrane H-Score). After dosimetry and receptor occupancy studies, subjects received P (18.0 mg/kg loading, then 9.0 mg/kg Q3 weeks) were followed for safety and had PK samples collected.
Results: Eleven subjects (mean age 61.7) were evaluated. In Cohort 1 (n=5), the mean tumor uptake (SUV ± SD) at 3, 24 and 48 hours was 5.6 (± 4.5), 3.2 (±1.7), and 2.9 (±1.1), respectively. The mean tumor uptake (Tumor-To-Muscle Uptake Ratio [T/M] ± SD) at 3, 24 and 48 hours was 3.0 (± 2.1), 2.1 (±1.2), and 1.6 (±0.5), respectively. The tracer localized primarily in the blood pool and liver, with modest uptake in tumors. The average effective dose was 0.16 ± 0.016 rem/mCi with largest tracer uptake in the liver (1.61 ± 0.30 rad/mCi). In Cohort 2 (n=6), the mean SUV uptake of 64Cu-DOTA-P after administration of unlabeled P was 3.4 (± 1.1) baseline and 4.1 (± 1.3) after 24 hours (p&gt;NS). T/Ms were 1.6 (± 0.6) and 2.8 (± 1.7), respectively. No correlation existed between SUV, T/M, and HER3 H-Score. After D1 injection, tracer signal was detected primarily in the liver. Following D8 co-injection with unlabeled P, tracer signal was higher in the circulation and unchanged in the tumor. Common AEs were diarrhea (27%); and dizziness, fatigue, headache, hypertension, and weight loss (18% each).
Conclusions: 64Cu -DOTA-P administration is safe and feasible in humans. This study was unable to determine HER3 receptor occupancy. Possible reasons include lower tumor HER3 expression versus xenografts, tracer liver accumulation, and target internalization. A modified design should be considered for future studies.
Citation Format: Albert C. Lockhart, Yongjian Liu, Farrokh Dehdashti, Richard Laforest, Joel Picus, Andrea Wang-Gillam, Lauren Trull, Stefanie Belanger, Madhuri Desai, Jeanne Mendell, Syed Mahmood, Barry A. Siegel, Michael J. Welch. A phase 1 evaluation of 64Cu-DOTA-patritumab to assess dosimetry, receptor occupancy, and safety in advanced solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5443. doi:10.1158/1538-7445.AM2014-5443