Safety and pharmacokinetics of docetaxel in combination with pegvorhyaluronidase alfa in patients with non-small cell lung cancer

Thomas Heineman, Megan Baumgart, Charvi Nanavati, Nash Gabrail, Scott A Van Wart, Donald E Mager, Daniel C Maneval, Anas M Fathallah, Rose E Sekulovich, Thomas Heineman, Megan Baumgart, Charvi Nanavati, Nash Gabrail, Scott A Van Wart, Donald E Mager, Daniel C Maneval, Anas M Fathallah, Rose E Sekulovich

Abstract

This open-label, phase Ib study (NCT02346370) assessed the effect of pegvorhyaluronidase alfa (PVHA; PEGPH20) on the plasma pharmacokinetics (PKs) and safety of docetaxel in 15 patients with stage IIIB/IV non-small cell lung cancer (NSCLC). The docetaxel PK profile from this study was consistent with simulations from a published docetaxel population PK model, and did not demonstrate an effect of PVHA on docetaxel PK. A maximum a posteriori Bayesian fit of the literature PK model to the docetaxel PK appeared unbiased. Adverse events (AEs) were generally consistent with previous reports for docetaxel monotherapy in NSCLC, except for higher incidence of musculoskeletal events, including myalgias, with PVHA plus docetaxel. The most common AEs were fatigue (87%), muscle spasms (60%), and myalgia (53%). Four patients experienced thromboembolic events (27%), three leading to treatment discontinuation. PVHA appeared to demonstrate an acceptable safety profile when given with docetaxel without significantly changing the plasma PK of docetaxel in patients with stage IIIB/IV NSCLC.

Conflict of interest statement

T.H., D.C.M., R.E.S., C.N., and A.M.F. are former employees of Halozyme Therapeutics, Inc., and T.H., D.C.M., and R.E.S. hold shares in the company. D.E.M. and S.A.V.W. are employees of Enhanced Pharmacodynamics, LLC. All other authors declared no competing interests for this work.

© 2021 Halozyme Therapeutics Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1
FIGURE 1
Visual predictive check for the plasma docetaxel concentration–time data at 0–3 h (a) and 0–36 h (b) post dose. Docetaxel was administered at the standard dose of 75 mg/m2 infused i.v. Circles represent the observed docetaxel concentrations; the line and shaded region represent the median and 90% prediction interval for the simulated docetaxel data using the prior population pharmacokinetic model and the same dosing histories and demographic characteristics as the patients in the current study
FIGURE 2
FIGURE 2
Goodness‐of‐fit plots for the MAP‐Bayesian fit of the prior population PK model for docetaxel to the observed plasma docetaxel concentration–time data from patients with non‐small cell lung cancer (a, b), and conditional population‐weighted residuals versus time since last docetaxel dose (c) and docetaxel dose (d). IPRED, individual predicted; MAP, maximum a posteriori; OBS, observed; PK, pharmacokinetic; PRED, predicted

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