Appropriate Dosing to Optimise Personalised Cancer Treatments

Ovarian Cancer Clinical Trial

— ADOPT  

Official title:

Appropriate Dosing to Optimise Personalised Cancer Treatments

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04154163
• Other study ID #: 2-032-19
• Status: Completed
• Start date: January 10, 2020
• Est. completion date: March 5, 2021

Study information

• Verified date: February 2022
• Source: University of Dundee
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: March 5, 2021
• Est. primary completion date: March 5, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Carcinoma, Renal Cell
• Kidney Neoplasms
• Lung Cancer, Non-small Cell
• Melanoma
• Melanoma Stage III
• Melanoma Stage IV
• Ovarian Cancer
• Renal Cancer Stage III
• Renal Cancer Stage IV

Intervention

Diagnostic Test:
• Dried blood Spot (DBS)
Dried Blood Spot filter paper and sponges
• Venous blood sampling
Venous blood

Locations

Country	Name	City	State
United Kingdom	NHS Tayside and University of Dundee	Dundee	Scotland

Sponsors (1)

Lead Sponsor	Collaborator
University of Dundee

Country where clinical trial is conducted

United Kingdom, 

References & Publications (5)

de Wit D, den Hartigh J, Gelderblom H, Qian Y, den Hollander M, Verheul H, Guchelaar HJ, van Erp NP. Dried blood spot analysis for therapeutic drug monitoring of pazopanib. J Clin Pharmacol. 2015 Dec;55(12):1344-50. doi: 10.1002/jcph.558. Epub 2015 Jul 14. — View Citation

Friedl B, Kurlbaum M, Kroiss M, Fassnacht M, Scherf-Clavel O. A method for the minimally invasive drug monitoring of mitotane by means of volumetric absorptive microsampling for a home-based therapeutic drug monitoring. Anal Bioanal Chem. 2019 Jul;411(17):3951-3962. doi: 10.1007/s00216-019-01868-1. Epub 2019 May 16. — View Citation

Nijenhuis CM, Huitema AD, Marchetti S, Blank C, Haanen JB, van Thienen JV, Rosing H, Schellens JH, Beijnen JH. The Use of Dried Blood Spots for Pharmacokinetic Monitoring of Vemurafenib Treatment in Melanoma Patients. J Clin Pharmacol. 2016 Oct;56(10):1307-12. doi: 10.1002/jcph.728. Epub 2016 Apr 8. — View Citation

Ouellet D, Gibiansky E, Leonowens C, O'Hagan A, Haney P, Switzky J, Goodman VL. Population pharmacokinetics of dabrafenib, a BRAF inhibitor: effect of dose, time, covariates, and relationship with its metabolites. J Clin Pharmacol. 2014 Jun;54(6):696-706. doi: 10.1002/jcph.263. Epub 2014 Jan 17. — View Citation

Robijns K, Koster RA, Touw DJ. Therapeutic drug monitoring by dried blood spot: progress to date and future directions. Clin Pharmacokinet. 2014 Nov;53(11):1053. doi: 10.1007/s40262-014-0197-3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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.
Secondary	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
Secondary	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