Title: Utilising Therapeutic Drug Monitoring (TDM) approaches to optimise the treatment of neonates and other hard to treat patient groups in the setting of childhood cancer
Funder: Department of Health and Social Care

Abstract: Background: In childhood cancer there are patient subpopulations who are particularly challenging to treat and represent a significant dilemma in terms of prescribing appropriate drug dosages. These patient groups include pre-term infants and neonates, children without functioning kidneys (anephric patients), patients receiving high dose chemotherapy, obese patients and those undergoing uncommon procedures such as chemoembolisation. Patients may also have renal or hepatic toxicity from previous treatment, making the administration of additional chemotherapy particularly difficult. It is accepted that these patient groups require dosing adjustments, due to differences in exposure relating to how drugs are broken down and eliminated from the body, but there is commonly little scientific rationale to support dosing decisions made. There is currently inconsistency in dose reductions applied to many anticancer drugs, between tumour types and clinical trials, for each of these patient populations. Therapeutic drug monitoring (TDM) involves the real-time measurement of drug levels in the blood, commonly after administration of a test dose. Based on a combination of drug exposure data for the individual patient, and tolerability of the initial dose, informed decisions can be made about the patient s continued treatment. Aims: (1) to define the pharmacokinetics of widely used anticancer drugs in neonates and other hard to treat patient populations; (2) to investigate factors associated with pharmacokinetic variability and compare drug exposures with paediatric patient populations receiving standard treatment; (3) to utilise TDM approaches alongside clinical response/toxicity data to ensure that neonates and other challenging patient populations are not exposed to either sub-therapeutic or potentially toxic drug exposures; (4) to establish a national registry providing clinicians with access to data on a comprehensive library of chemotherapeutics in defined patient groups; (5) to publish the pharmacokinetic data generated and design evidence-based dosing regimens and national treatment guidelines. Plan of Investigation: The proposed TDM approach to treatment will be developed through the Experimental Cancer Medicine Centre Paediatric Network, funded by CRUK, the NIHR and the health departments of Scotland, Wales and Northern Ireland. Within the defined funding period, the research project will recruit an estimated 75-100 patients within defined hard to treat patient categories. Timing of blood sample collections will be based on the known pharmacokinetic profile of the particular chemotherapeutic agent, using data generated in-house or from published studies in paediatrics. Sample analysis will be carried out in real-time, with results commonly generated within a 24 hour period, to determine the individual patient drug exposure on the first course of treatment. Plasma drug concentrations will be quantified using validated assays according to the principles of Good Clinical Laboratory Practice (GCLP) and a report on the sample analysis (including details of pharmacokinetic parameters obtained for the individual patient alongside reference ranges from previously published paediatric patient populations) made available to the treating clinician. These results will be used alongside toxicity and response data following the first course of treatment, to inform dosing decisions on subsequent courses. Analysis of data from multiple patients within defined populations will allow generation of drug disposition data with the potential to appropriately assess the pharmacological basis for currently used dosing regimens and propose more rationally designed dosing approaches. All relevant clinical information and pharmacokinetic data generated will be entered onto a patient registry. Summary: Development of this approach to treatment will not only positively impact on patients studied during the lifetime of the study, but will lead to the publication of reference data and treatment guidelines to support evidence-based treatment of similar clinical cases worldwide. The proposed project will therefore result in a legacy of benefit for the future treatment of some of the most challenging paediatric cancer patient populations.

Lay abstract: It is particularly difficult to treat some groups of children diagnosed with cancer, including very young infants in the first weeks of life and children with poor kidney function. It can be especially difficult to know how much chemotherapy (anti-cancer drug) to give to these children. Doctors often have to make difficult decisions about the most appropriate dose of drug, without enough scientific information to help them decide. This can mean that patients might not get enough drug or might get too much, and this can be harmful in terms of causing long-term health problems or higher death rates due to under or overdosing. Our research group is a national centre for carrying out cancer drug trials in children. From our studies we have been able to work out how to best manage the treatment of patients for the chemotherapy drug carboplatin, which is commonly used in children. This involves measuring drug levels in individual children and modifying the dose of drug they are given based on the measurement obtained. Our work has influenced national guidelines on chemotherapy for childhood cancer patients. We now want to establish a national research programme to conduct similar work for a wide range of chemotherapy drugs. The work will help us understand how drugs are metabolised (broken down and used) in children of all ages and provide information on how much drug individual patients should be given to ensure they receive the appropriate dose that is effective without leading to excessive toxicity. The findings of the research programme will be made available through a registry designed to provide information for doctors treating children with cancer about what dose of drugs to prescribe. This will therefore positively impact not only on the patients who participate, but also on those being treated in the future.

Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;REPRODUCTIVE HEALTH AND CHILDBIRTH