Exploratory Drug Interaction Study Between SMIs and DOACs

Real-world Exploratory Evaluation of the Potential Drug-drug Interaction Between Anticancer Small Molecule Inhibitors and Direct Oral Anticoagulants in Patients With Solid Tumours and Exploration of the Role of Therapeutic Drug Monitoring

The main objective of this study is to investigate the effect of small molecule inhibitors (SMIs), used in targeted therapy for tumours, on direct oral anticoagulants (DOACs).

Study Overview

• Status: Completed
• Conditions: Solid Tumor; Cancer, Lung

Detailed Description

Patients who receive anticoagulant therapy in the form of a direct oral anticoagulant (DOAC) and simultaneously receive anti-cancer targeted therapy with a small molecule inhibitor (SMI), potentially have an increased risk on thromboembolic complications and bleeding events due to interfering drug-drug interactions. Some SMIs influence CYP3A4 and/or p-glycoprotein (p-gp) for which DOACs are substrates. In this study, the effect of theoretically relevant SMIs on the pharmacokinetics, efficacy and safety of DOACs in patients with solid tumours will be investigated. For this purpose, plasma concentration analyses will be performed.

• Study Type: Observational
• Enrollment (Actual): 37

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500HB
      • Radboud UMC
  • Limburg
    • Maastricht, Limburg, Netherlands, 6202AZ
      • Maastricht UMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with cancer who will be, or are already, treated with an SMI and a DOAC simultaneously, at the MUMC+ or Radboudumc can participate in this study.

Description

Inclusion Criteria:

• Diagnosed with a solid tumour
• 18 years of age or older
• Patients receive or start treatment with an SMI-DOAC combination, that may cause a clinically significant DDI at the level of CYP3A4 and/or P-gp, based on the SmPC
• Combined use of a DOAC-SMI combination is expected to be continued at the same dose for at least three weeks
• The DOAC is used for at least seven days and the SMI has already been used for at least 21 days at time of blood collection to ensure steady-state
• Patients receive a DOAC at maintenance dose

Exclusion Criteria:

• Unable to understand the information in the patient information letter
• Any concurrent medication beside the SMI and DOAC that is known to strongly inhibit or induce CYP3A4 or P-gp
• Patients who are pregnant or lactating

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Group 1; Patients in group 1 already receive a DOAC and will start treatement with an SMI. Blood samples will be drawn before start of the SMI and during concomittant use with the SMI.
Group 2; Patients in group 2 already use a potentially relevant DOAC-SMI combination or already use an SMI and start with a DOAC. In this group, blood samples are taken after the start of concomittant use of the DOAC-SMI combination.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DOAC trough concentration	DOAC trough concentration before and during concomitant use with an SMI	At least 7 days after start DOAC use and in combination with an SMI at steady-state (after at least 21 days)
DOAC peak concentration	DOAC peak concentration before and during concomitant use with an SMI	At least 7 days after start DOAC use and in combination with an SMI at steady-state (after at least 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thromboembolic and bleeding events during follow-up	Thromboembolic and bleeding events during follow-up	within 6 months after the last blood sampling
SMI trough concentration during concomitant use with a DOAC	SMI steady-state trough concentration during concomintant use with a DOAC	After the start of the DOAC use in combination with an SMI at steady-state (after at least 21 days)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thrombin generation before and during concomitant use of a DOAC and an SMI	Thrombin generation before and during concomitant use of a DOAC and an SMI	At least 7 days after start DOAC use and in combination with an SMI at steady-state (after at least 21 days)

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: Radboud University Medical Center
• Investigators: Principal Investigator: Robin van Geel, PharMD, PhD, Maastricht UMC

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2021
• Primary Completion (Actual): October 1, 2023
• Study Completion (Actual): February 29, 2024

Study Registration Dates

• First Submitted: January 27, 2023
• First Submitted That Met QC Criteria: February 7, 2023
• First Posted (Actual): February 17, 2023

Study Record Updates

• Last Update Posted (Actual): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Therapeutic drug monitoring; targeted therapy; direct oral anticoagulant; small molecule inhibitors
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms
• Other Study ID Numbers: NL78003.068.21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No