PARTNER
Research type
Research Study
Full title
Personalizing docetaxel dosing in advanced prostate cancer
IRAS ID
284513
Contact name
Jim Millen
Contact email
Sponsor organisation
Physiomics plc
Duration of Study in the UK
1 years, 2 months, 20 days
Research summary
Research Summary: Patients with advanced prostate cancer are often treated with the chemotherapy drug docetaxel. The manufacturers of this drug suggest using the same amount of drug for everybody who needs it, however we know that because everyone is different, people end up with more or less of the drug circulating in their blood even after they have been given the same dose.
A software program (a “Dosing Tool”) has been developed to provide information to doctors on how docetaxel will affect individual patients. The program may help doctors to make smarter decisions about exactly how much drug to give to different people.
The purpose of the PARTNER study is to gather information from blood tests on patients being treated with docetaxel to help in the further development of the Dosing Tool. Some of these blood tests would have been taken anyway as part of patients’ routine treatment. Others are extra for this study. Apart from the additional blood tests everyone who enters the study is treated just as they would normally be if there weren’t taking part in the study at all.Using the information gathered from the study it is hoped that the Dosing Tool can eventually be approved for use across the UK and help ensure patients get the best possible outcomes when they are being treated with docetaxel for prostate cancer.
Summary of results:
In the UK, prostate cancer represents around 13% of all cases of cancer, with almost 50,000 new cases diagnosed each year. Net 5-year survival is greater than 85% when considering all cancer stages, but drops below 30% in stage IV (advanced disease).
Docetaxel is often used to treat patients with advanced (castrate resistant metastatic) disease. It is typically administered at a fixed starting dose of 75mg per meter square body surface area (BSA) of the patient, administered as an IV infusion over one hour. Docetaxel is administered in 3-weekly cycles until progression occurs or treatment has to be stopped due to toxicity or disease progression. Toxicity-related adverse events can lead the clinician to reduce the dose or terminate treatment. The most common side-effects of docetaxel are associated with hematologic toxicity (decrease of neutrophil (ANC) and other white blood cell populations) and include neutropenic fever and infections. Granulocyte Colony Stimulating Factor (G-CSF) may be administered with docetaxel to mitigate the risk of neutropenia.
For any given dose of docetaxel, there is a large inter-individual variability in the concentration of compound measured in the patient’s blood (exposure). Furthermore, patients show varying levels of sensitivity to the drug. This variability leads to a significant number of patients being under or over-dosed.
Physiomics (PYC) have developed a prototype precision dosing tool for docetaxel in prostate cancer. The tool aims to significantly improve patient outcomes at a low cost compared with novel pharmaceuticals, without disrupting the current clinical treatment pathway. The only information it requires which does not form part of current clinical practice is the results of three once-weekly standard blood tests during the first chemotherapy cycle. The tool is intended to provide decision support for clinicians, assisting them in adapting docetaxel dose for individual patients from the second treatment cycle onwards. After administration of the standard BSA-guided first dose, neutrophil and other leucocyte counts from weekly blood samples are collected. When entered in the tool, these measurements are used to estimate the patient’s individual exposure and hematologic sensitivity to docetaxel. Using mathematical models relating administered dose to concentration in blood (pharmacokinetics - PK) and concentration in blood to level of neutropenia (pharmacodynamics - PD), these data can then be used to predict the effect of a dose variation on patient-specific neutropenia and thus inform dose selection.
The PARTNER observational clinical study (NCT04823910) aimed to evaluate the tool against data collected on prostate cancer patients treated with docetaxel following standard of care. This study was performed at the Portsmouth Technologies Trials Unit (Portsmouth Hospitals NHS Trust).
Between September 2021 and August 2022, 31 patients were recruited who completed at least the first trial visit. Patients were of median age 71 years and median BSA 2.04 m2. The majority of patients (22/31) were administered the standard docetaxel regimen (75mg/BSA in 1 hour infusion). Four patients were administered a lower dose (60-71mg/BSA) and four patients were treated along a longer infusion time (up to 3.2 hours). All 31 clinical records reported the first administered dose of docetaxel (day 0) and the ANC counts at baseline (<= day 0), close-to-nadir (~day 7) and during recovery (~day 14) of the first cycle, and were thus usable for the purposes of the dosing tool evaluation. Out of these 31 patients, 17 did not receive G-CSF co-medication in either of the first two cycles, 10 received G-CSF in both, and 4 received G-CSF in one cycle but not the other (Figure 1). The only form of G-CSF administered was filgrastim. All 31 patients also provided blood samples for measurement of docetaxel concentration in blood at two time points on the day of first administration (day 0).
Measured docetaxel concentrations in blood were compared to the predictions of the PK model. The PK model was subsequently updated to correct for the observed over-estimation of blood concentration.
Weekly levels of absolute neutrophile count (ANC) and total non-neutrophile white blood cell counts (WBC) were used to evaluate two PD models. The first one, referred to as the ‘original framework’, represented simultaneous evolution of ANC and WBC under docetaxel treatment without G-CSF co-medication. Patient-specific model parameters were estimated using a custom fitting procedure. The second model, referred to as the ‘extended model’, represented the evolution of ANC under docetaxel plus G-CSF co-medication and was fitted with a standard procedure (known as non -linear mixed effect).
The original framework for patient-specific PK/PD modelling of docetaxel-induced myelosuppression (in the absence of G-CSF co-medication) presented high goodness of fit on ANC data from the first cycle, associated with low ANC prediction error for the second cycle.
The extended framework also presented high goodness of fit and low prediction error for patients not co-treated with G-CSF. These measures of model performance were however generally lower than those of the original framework. The extended model captured shortening of neutropenia due to G-CSF co-medication. It also captured general trend in lesser severity and earlier occurrence of peak neutropenia compared to docetaxel treatment alone. However, overall fits remained poorer than for docetaxel treatment alone.
All parties involved in this study wish to thank the study participants. This study confirmed the potential of the PK/PD models implemented by Physiomics in supporting clinicians for docetaxel dose adjustments in the absence of GCSF co-medication. A follow-up study implementing model refinements would provide a mean to predict duration and level of neutropenia during chemo + G-CSF treatment and thus infer the cost/benefice of longer G-CSF treatment.REC name
Yorkshire & The Humber - Bradford Leeds Research Ethics Committee
REC reference
20/YH/0341
Date of REC Opinion
10 Dec 2020
REC opinion
Further Information Favourable Opinion