Appropriate Dosing to Optimise Personalised Cancer Treatments

Study Overview
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Brief Summary
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This is a pilot study to assess feasibility of dried blood spot (DBS) samples for pharmacokinetic measurements of targeted anti-cancer drugs in oncology patients such as patients with BRAF-mutant melanoma receiving targeted treatment with BRAF and MEK inhibitors.

Detailed Description
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In the pharmacology laboratory, we have developed a method for measuring drug concentrations in animals using dried blood spots (DBS). DBS is a simple method that could be easily carried out by patients at home, using either filter paper-based DBS cards (e.g. Whatman 903, FTA DMPK-C) or small sponges (www.neoteryx.com). The routine use of DBS to clinically test blood was first used in the 1960s as a safe and simple method of testing for inherited metabolic disorders in new born babies. However, in recent years there has been increasing use of DBS to test blood for other things, including for drugs as a way to monitor the drug level in the blood. This method has great potential application in testing blood for drug levels in cancer patients. We wish to establish if this DBS technique is feasible in real-life practice for cancer patients on targeted anti-cancer therapies as should this be the case this innovation could herald a new era in personalised treatment of advanced human cancers allowing doctors to more safely use combinations of targeted therapies. These combinations of targeted therapies have been shown to inhibit development of drug resistance and are increasingly being used in clinical practice. However, targeted therapies often fail (especially combinations of targeted therapies) because of unacceptable toxicities making them intolerable for the patient. With an easy and acceptable method for monitoring the drug level in blood, as could be provided by DBS, the right amount of drug could be given to each individual patient and this 'personalised' drug dosing as standard of care might result in much greater success with combinations of anti-cancer drugs. This drug monitoring is especially important for targeted anti-cancer therapies because many of these (such as Dabrafenib, used for many cases of advanced melanoma) have profound affects on the liver enzymes that metabolise (get rid of) most medications. Dabrafenib is a potent inducer of P450 liver enzymes and this induction means that other drugs metabolised by the same liver pathway (the great majority of drugs are metabolised by the same pathways) will have significantly reduced blood levels if the patient is on Dabrafenib. So it is especially important to be able to monitor blood levels of both Dabrafenib and of other co-medications that the patient may be taking. The DBS sampling method would allow this and would provide a safe, convenient and cheap test that could be conducted in the patient's home and posted back to the laboratory.

Official Title
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Appropriate Dosing to Optimise Personalised Cancer Treatments

Conditions
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Melanoma Stage III, Melanoma Stage IV, Ovarian Cancer, Renal Cancer Stage III, Renal Cancer Stage IV, Lung Cancer, Non-small Cell

Intervention / Treatment
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* Diagnostic Test: Dried blood Spot (DBS)
* Diagnostic Test: Venous blood sampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants Age 18 years and over Confirmed diagnosis of stage 4 or stage 3 unresectable cancers; BRAF+ melanoma, c-KIT+ melanoma, advanced renal cell carcinoma, non-small cell lung carcinoma and ovarian carcinoma. Able to perform study assessments Individuals who are participating in the follow-up phase of another interventional trial/study, or who are enrolled in an observational study, will be co-enrolled where the CIs of each study agree that it is appropriate Exclusion Criteria: Inability to give informed consent World Health Organisation (WHO) performance status 3-4 Known allergy or intolerance to Dabrafenib +/- Trametinib, Prazopanib, Erlotinib, Gefitinib, Imatinib, Osimertinib or Olaparib Unstable co-morbidities; cardiovascular disease e.g. severe congestive cardiac failure, end stage renal failure, hepatic impairment, vasculopathy, inflammatory arthritis or interstitial lung disease/ pneumonitis which, in the opinion of the CI, would make the patient unsuitable to be enrolled in the study Language barrier preventing adequate understanding of the study and a lack of suitable translator service to overcome this barrier Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Stage 1 Participants<br>Blood test Day 1 DBS and venous blood Blood test Day 2 DBS (+/- and venous blood) Blood test Day 15 DBS only Blood test Day 16 DBS only | Diagnostic Test: Dried blood Spot (DBS)<br>* Dried Blood Spot filter paper and sponges<br>* Other names: DBS home collection kits;Diagnostic Test: Venous blood sampling<br>* Venous blood<br>* Other names: Phlebotomy;|
| Stage 2 Participants<br>Non-drug naive participants: Blood test Day 1 DBS Blood test Day 2 DBS Blood test Day 15 DBS Blood test Day 16 DBS Drug naive participants: Blood test Day 1 DBS Blood test Day 2 DBS Blood test Day 3, 4, or 5 DBS Blood test Day 4, 5 or 6 DBS Blood test Day 15 DBS Blood test Day 16 DBS | Diagnostic Test: Dried blood Spot (DBS)<br>* Dried Blood Spot filter paper and sponges<br>* Other names: DBS home collection kits;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The accuracy of DBS for measuring drug levels in venous blood following standard doses of targeted therapies for metastatic cancers such as BRAF mutant melanoma | Concentration of targeted anti-cancer drug in venous blood at timed intervals following oral dosing in standard clinical care pathway measured in venous blood and by DBS | Pre-dose,1 hour, 2 hours, 8 hours (if on a once daily drug regime) or pre-second dose (if on a twice daily drug regime) and 24 hours post-dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The ability of oncology patients receiving targeted cancer treatments to collect multiple DBS samples over a 24-hour period | Successful collection of DBS samples both under supervision in hospital and when at home | Pre-dose,1 hour, 2 hours, 8 hours (if on a once daily drug regime) or pre-second dose (if on a twice daily drug regime) and 24 hours post-dosing | 
| The safety and acceptability of DBS collections at timed intervals before and after taking anti-cancer targeted drugs | Number of Adverse Events per participant and measures of patient acceptability for collection of DBS | After each 24-hour period of DBS sampling and during telephone consultations in weeks 1 and 4 | 
| The stability of the drug levels stored in DBS, taken by the patient at home and posted to the laboratory | Demonstration that the drug concentrations measured in fresh and DBS samples stored for several days is the same. | Measurement of repeat samples at the timepoints chosen at 1, 2 and 3-days post-collection to ensure stability. | 
| Examine inter-patient variability in Pharmacokinetics (PK) | Changes in drug levels of co-medications over time following standard clinical dosing with targeted cancer treatments such as dabrafenib +/- trametinib | Measurement of co-medication drug levels at repeat time intervals (Pre-dose,1-hour, 2-hours, 8-hours (once-daily drug regime) or pre-second dose (twice-daily drug regime) and 24-hours post-dosing both before and after starting targeted Dabrafenib | 
| Drug tolerability collected from examination of clinical pathway for participating patients | Collection of drug tolerability data from examination of clinical pathway for participating patients | Before recruitment and after commencing relevant medication |