Dataset Information

Healthy volunteers in first-in-human oncology drug development for small molecules.

ABSTRACT: This review provides tools to consider the inclusion of healthy volunteers (HVs) in first-in-human (FIH) oncology clinical trials with small molecules, including targeted and immunomodulatory agents, a strategy that was not envisioned with classic chemotherapy. To enable an FIH oncology trial in HVs compared to cancer patients (CPs), a robust nonclinical package must be generated, which includes toxicokinetic and pharmacokinetic studies, as well as more extensive safety pharmacology, toxicology and genotoxicity studies. This strategy could provide an early clinical characterization of the pharmacokinetic parameters and clinical safety profile in the absence of comorbidities and concomitant medication. It also avoids the ethical issue of administrating subtherapeutic doses to CPs, and could potentially help to accelerate the timelines of clinical drug development for patient care. That being said, stakeholders involved in these studies need to proceed with caution, fully understand the regulatory guidance and thoroughly evaluate the benefits and risks. This paper serves to address the regulatory guidance and other considerations needed when using healthy volunteers in early oncology trials.

SUBMITTER: de Las Heras B

PROVIDER: S-EPMC10234445 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Healthy volunteers in first-in-human oncology drug development for small molecules.

de Las Heras Begoña B Bouyoucef-Cherchalli Dalila D Reeve Lesley L Reichl Andreas A Mandarino Debra D Flach Stephen S Vidal Laura L van Brummelen Emilie M J EMJ Steeghs Neeltje N

British journal of clinical pharmacology 20211019 4

This review provides tools to consider the inclusion of healthy volunteers (HVs) in first-in-human (FIH) oncology clinical trials with small molecules, including targeted and immunomodulatory agents, a strategy that was not envisioned with classic chemotherapy. To enable an FIH oncology trial in HVs compared to cancer patients (CPs), a robust nonclinical package must be generated, which includes toxicokinetic and pharmacokinetic studies, as well as more extensive safety pharmacology, toxicology ...[more]

PMID: 34558113

Similar Datasets

Project description:Backgroundα-Synuclein is a major component of pathologic inclusions that characterize Parkinson's disease. PRX002 is an antibody that targets α-synuclein, and its murine parent antibody 9E4 has been shown in preclinical studies to reduce α-synuclein pathology and to protect against cognitive and motor deteriorations and progressive neurodegeneration in human α-synuclein transgenic mice.MethodsThis first-in-human, randomized, double-blind, placebo-controlled, phase 1 study assessed the impact of PRX002 administered to 40 healthy participants in 5 ascending-dose cohorts (n = 8/cohort) in which participants were randomly assigned to receive a single intravenous infusion of study drug (0.3, 1, 3, 10, or 30 mg/kg; n = 6/cohort) or placebo (n = 2/cohort).ResultsPRX002 demonstrated favorable safety, tolerability, and pharmacokinetic profiles at all doses tested, with no immunogenicity. No serious adverse events, discontinuations as a result of adverse events, or dose-limiting toxicities were reported. Serum PRX002 exposure was dose proportional; the average terminal half-life across all doses was 18.2 days. A significant dose-dependent reduction in free serum α-synuclein (unbound to PRX002) was apparent within 1 hour after PRX002 administration, whereas total α-synuclein (free plus bound) increased dose-dependently, presumably because of the expected change in kinetics following antibody binding.ConclusionsThis study demonstrates that serum α-synuclein can be safely modulated in a dose-dependent manner after single intravenous infusions of an anti-α-synuclein antibody. These findings support continued development of PRX002, including further characterization of its safety, tolerability, pharmacokinetics, and pharmacodynamic effects in the central nervous system in patients with Parkinson's disease. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Dataset Information

Healthy volunteers in first-in-human oncology drug development for small molecules.

Publications

Healthy volunteers in first-in-human oncology drug development for small molecules.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets