Optimizing Oral Targeted Anticancer Therapies Study for Patients With Solid Cancer: Protocol for a Randomized Controlled Medication Adherence Program Along With Systematic Collection and Modeling of Pharmacokinetic and Pharmacodynamic Data (Preprint)

Abstract

BACKGROUND The strengthening or substitution of intravenous cytotoxic chemotherapy cycles by oral targeted anticancer therapies, such as protein kinase inhibitors (PKIs), has provided impressive clinical benefits and autonomy as well as a better quality of life for cancer patients. Despite these advances, adverse event management at home and medication adherence remain a challenge. In addition, PKI plasma concentrations vary significantly among cancer patients receiving the same dosage, which could explain part of the observed variability in the therapeutic response. OBJECTIVE The aim of the Optimizing oral targeted anticancer therapies (OpTAT) study is to optimize and individualize targeted anticancer treatments to improve patient care and self-monitoring through an interprofessional medication adherence program (IMAP) combined with monitoring PKI plasma concentrations. METHODS The OpTAT study has two parts: 1) a 1:1 randomized medication adherence program, where the intervention consists of regular motivational interviewing sessions between the patient and the pharmacist, along with the delivery of PKI in electronic monitors (EM); and 2) a systematic collection of blood samples and clinical and biological data for combined pharmacokinetic and pharmacodynamic analysis. Based on the EM data, the implementation will be described using a generalized estimating equation (GEE) models. The persistence of the use of PKI will be represented with a Kaplan-Meier survival curve. Longitudinal adherence is defined as the product of persistence and implementation. The PKI pharmacokinetics will be studied using a population approach. The relationship between drug exposure and efficacy outcomes will be explored using Cox regression analysis of progression-free survival. The relationship between drug exposure and toxicity will be analyzed by a pharmacokinetic-pharmacodynamic model and by logistic regression analysis. Receiver operating characteristic (ROC) analyses will be applied to evaluate the best exposure threshold associated with clinical benefits. RESULTS The first patient was included in May 2015. Since then, 259 patients have participated in at least one part of the study: 247 patients gave at least one blood sample, and 130 participated in the adherence study. Data collection is in process, and the final data analysis is planned to be performed in 2022. CONCLUSIONS The OpTAT study will inform us about the effectiveness of the IMAP program in patients with solid cancers treated with PKIs. It will also shed light on PKI pharmacokinetic-pharmacodynamic properties, with the aim of learning how to adapt the PKI dosage at the individual patient level to increase PKI clinical suitability. The IMAP program will enable interprofessional teams to learn about patients’ needs and to consider their concerns about their PKI self-management, considering the patient as an active partner. CLINICALTRIAL Clinicaltrials.gov NCT04484064