Abstract P5-20-07: A phase Ib dose-finding study of subcutaneous pertuzumab in combination with subcutaneous trastuzumab in healthy male volunteers and female patients with early breast cancer
Authors: Kirschbrown WP , Wynne C , Kagedal M , Wada R , Li H , Nijem I , Badovinac Crnjevic T , Heeson S , Eng-Wong J , Garg A 
Published: February 2018

Abstract
Background:
A fixed-dose combination (FDC) of subcutaneous (SC) pertuzumab (F. Hoffmann-La Roche Ltd, Basel, Switzerland) + SC trastuzumab (F. Hoffmann-La Roche Ltd) is being developed to reduce the treatment burden on patients while improving treatment facility efficiency. This phase Ib dose-finding study (NCT02738970) aimed to identify the SC pertuzumab dose that is comparable to the intravenous (IV) dose, based on serum trough concentrations (Ctrough) and area under the concentration–time curve (AUC) when administered with or without SC trastuzumab.
Methods:
This two-part study consisted of SC pertuzumab dose determination in healthy male volunteers (HMVs) (Part 1) and a subsequent SC pertuzumab dose confirmation in patients with early breast cancer (EBC) (Part 2). Part 1 of the study was comprised of 48 HMVs who received various SC pertuzumab doses (400–1200 mg) or the standard IV dose (420 mg), administered alone or co-mixed with SC trastuzumab 600 mg. Non-compartmental and statistical methods were used to test the pharmacokinetic (PK) interaction between SC pertuzumab and SC trastuzumab when administered with recombinant human hyaluronidase, a permeation enhancer. Two population PK (popPK) models were built to estimate PK parameters and PK variability. Model 1 used IV/SC PK data from Part 1 of the current study only. Model 2 used Part 1 SC PK data and PK parameters from the published IV pertuzumab popPK model (Garg A, et al. Cancer Chemother Pharmacol 2014; 74: 819–829). Each popPK model was used to simulate 400 phase III clinical trials. Per simulated trial, the geometric mean ratio (GMR) of Cycle 8 Ctrough at steady state and AUC at steady state for SC/IV were calculated. The percentage of trials with the 5th percentile confidence interval of the GMR above 0.8 was tabulated.
Results:
In Part 1 of the study, there was no impact on pertuzumab or trastuzumab PK from co-mixing SC trastuzumab with SC pertuzumab. The absolute bioavailability of SC pertuzumab in HMVs was approximately 70–80%, with a median time to reach maximum concentrations of 4–5 days. Clinical trial simulations indicated that an SC pertuzumab dose of 600 mg will achieve the target Ctrough and AUC SC/IV GMRs &gt; 99% of the time. Results were consistent between the models. Safety data supported the selection of an SC pertuzumab maintenance dose of 600 mg. The 600 mg SC pertuzumab dose determined in HMVs was confirmed in Part 2 of the study in patients with EBC.
Conclusions:
These data support the development of an SC pertuzumab + SC trastuzumab FDC product.
Citation Format: Kirschbrown WP, Wynne C, Kagedal M, Wada R, Li H, Nijem I, Badovinac Crnjevic T, Heeson S, Eng-Wong J, Garg A. A phase Ib dose-finding study of subcutaneous pertuzumab in combination with subcutaneous trastuzumab in healthy male volunteers and female patients with early breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-07.