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

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 patients with cancer. Despite these advances, adverse event management at home and medication adherence remain challenging. In addition, PKI plasma concentrations vary significantly among patients with cancer receiving the same dosage, which could explain part of the observed variability in the therapeutic response. Objective The aim of this 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 measurement PKI plasma concentrations. Methods The OpTAT study has two parts: (1) a 1:1 randomized medication adherence program, in which the intervention consists of regular motivational interviewing sessions between the patient and the pharmacist, along with the delivery of PKIs in electronic monitors, and (2) a systematic collection of blood samples and clinical and biological data for combined pharmacokinetic and pharmacodynamic analysis. On the basis of the electronic monitor data, medication adherence will be compared between groups following the three operational definitions: implementation of treatment during the persistent period, persistence with treatment and longitudinal adherence. The implementation will be described using generalized estimating equation models. The persistence of PKI use will be represented using a Kaplan-Meier survival curve. Longitudinal adherence is defined as the product of persistence and implementation. 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 using a pharmacokinetic-pharmacodynamic model and by logistic regression analysis. Receiver operating characteristic analyses will be applied to evaluate the best exposure threshold associated with clinical benefits. Results The first patient was included in May 2015. As of June 2021, 262 patients had participated in at least one part of the study: 250 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 and 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. Trial Registration ClinicalTrials.gov NCT04484064; https://clinicaltrials.gov/ct2/show/NCT04484064. International Registered Report Identifier (IRRID) DERR1-10.2196/30090

Population Pharmacokinetics of Palbociclib and Its Correlation with Clinical Efficacy and Safety in Patients with Advanced Breast Cancer

“…Palbociclib samples were collected as part of the OpTAT (Optimizing oral Targeted Anticancer Therapies, ClinicalTrials.gov: NCT04484064) study implemented at the University Hospital of Lausanne (CHUV, Lausanne, Switzerland) and at the Center of Primary Care and Public Health (Unisanté, Lausanne, Switzerland) and approved by the Human Research Ethics Committee of the Canton de Vaud (Lausanne, Switzerland) [ 14 ]. All included patients were ≥ 18 years old, diagnosed with an advanced stage breast cancer, and provided written informed consent.…”

“…For all patients, palbociclib dosing history was collected at each blood sampling and was retrieved from patient’s medical records. Moreover, information was reconciled with data collected in the randomized controlled medication adherence study [ 14 , 15 ] in a subset of patients.…”

Palbociclib Adherence and Persistence in Patients with Hormone Receptor Positive/Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) Metastatic Breast Cancer

“…Our results represent one of the first efforts to provide current data on variations in palbociclib treatment patterns in the real-world practice setting and point to factors needed to aid identification of patient subgroups at risk for early discontinuation and non-adherence and to understand drivers of low adherence. An understanding of these factors is required to design programs such as the medication adherence monitoring and counseling programs 32 used in the Optimizing Oral Targeted Anticancer Therapies studies 33 to mitigate barriers to adequate adherence and persistence, and to improve patient outcomes. 34 …”

Estimation of adherence to medication treatment in presence of censoring

“…We showed on this data that adherence pattern was significantly worse among men. Several clinical trials have been conducted in the past to assess the impact of an intervention on medication intake 15,16 and others are planned for the future 17,18 . The method we have proposed will allow evaluation (estimate and test) of the effect of the intervention on the adherence trends, by introducing the intervention variable into the (weighted corrected) longitudinal adherence model.…”