Precision Dosing of Tyrosine Kinase Inhibitors in CML Patients

Preliminary Evaluation of TKI Exposure-response Relationships in Real World Patients (RWPs) With Chronic Myelogenous Leukemia (CML)

The purpose of this prospective, single-institution observational study is to evaluate associations between the pharmacokinetic (PK) parameters for tyrosine kinase inhibitors (TKIs) used to treat chronic phase chronic myeloid leukemia (CML) and clinical outcomes for up to 12 months. The study aims to identify associations between TKI clearance and/or exposure with demographic and clinical patient characteristics, CML milestones, medication toxicities, medication adherence, and germline genetic variants.

Because this is an observational study, standard-of-care therapy will not be altered during the course of participation. Blood samples will be collected at each study visit (up to 6 visits) over the course of 12 months to evaluate TKI concentrations, and PK parameters. Blood will also be collected during the first visit to isolate DNA for next generation sequencing (NGS). Demographic information will be collected at baseline, while clinical and medication adherence information will be collected at baseline and then throughout the study.

There will be no direct benefit to you for your participation. Risks are minor, but could include bruising, vein irritation, lightheadedness/dizziness, and/or infection from blood draws, as well as potential loss of confidentiality.

Study Overview

• Status: Completed
• Conditions: Chronic Myeloid Leukemia; Chronic Myeloid Leukemia, Chronic Phase; CML, Chronic Phase; CML - Philadelphia Chromosome; CML (Chronic Myelogenous Leukemia
• Intervention / Treatment: Drug: Bosutinib; Drug: Dasatinib; Drug: Imatinib; Drug: Nilotinib

Detailed Description

This study is a prospective, single-institution observational study designed to evaluate associations between the pharmacokinetic (PK) parameters (e.g., clearance and exposure) for four tyrosine kinase inhibitors (TKIs) used to treat chronic phase CML with key clinical milestones in CML, as well as associations between TKI PK and medication-induced toxicities and medication adherence. The four TKIs to be evaluated in this study include bosutinib, dasatinib, imatinib, or nilotinib, while the key clinical milestones for CML include complete hematologic response (CHR) at one month, early molecular response (EMR) at 3 months and 6 months, and major molecular response (MMR) at 9 months and 12 months. A total of 150 subjects will be enrolled in the study. The enrolled study subjects will have been prescribed one of these four TKIs by a UNC medical oncologist or advanced practice provider for their diagnosed chronic phase CML. Research personnel will identify potential research subjects using data from the Carolina Data Warehouse, and pharmacy prescription claims data. Research personnel will contact patients regarding study participation in-person in clinic or over the telephone to receive informed consent.

For patients who are newly initiated on a TKI, assessment procedures will occur as close to monthly time points as possible (baseline, 1,3,6,9 12, 15, etc) with at least 30 days between draws for time points at and after 3 months. For the blood collection at 1 month, there will be a +/- 2 week window. Each patient will be enrolled in the study for a maximum of 6 different study visit days, for a total of 12 total months. If a participant changes treatment to a new TKI of interest, the participant may be followed for an additional 12 months. Active participation in the study is expected to last approximately one year for these subjects. Subjects may also be identified and enrolled after having already been initiated on TKI therapy, in which case, the duration since initiation of their TKI will be 12 total months and they will enter at the closes study time point. If enrolled subjects require a change of therapy, they will restart their participation under the new TKI at baseline and be followed for an additional 12 months. Subjects who complete the 12-month study duration and subsequently change therapy may continue participation under the new TKI and restart their participation at baseline.

All study visits will align with standard-of-care follow-up appointments such that no additional research only visits to the UNCMC are required of the subjects. Up to seventy-two hours prior to each visit, one member of the study personnel will telephone (or email, if unreachable by telephone) the subject to remind them to take their medication the days prior to their study visit, but not the day of their study visit prior to blood sample collections. Subjects will also be reminded to record the exact time and date of the two doses prior to their study visit date. Subjects may resume their normal TKI dosing regimen after completion of the study visit, at the discretion of the treating provider.

At each clinic visit, the subject will have two blood samples drawn, and will be required to complete a series of surveys (Appendices D, E). Each blood sampling will collect approximately 4mL of peripheral blood, for a total of approximately 8mL of blood per study visit. Each subject will also have an additional 4mL of blood collected once at their first study visit for DNA extraction. The first research blood sample will be collected at the beginning of the clinic visit alongside the routine blood draws and processed according to the procedures listed in Appendix C. Surveys will then be administered during the visit, and lab results and clinical data will be collected. Prior to discharge, a final research blood sample will be drawn. Phlebotomy will be performed by trained phlebotomists, nurses, or physicians in the UNCMC. Blood samples will be processed per protocol by the study personnel as trained by PI or co-investigators. A detailed summary of clinic visit procedures can be found in Appendices A and B.

For subjects enrolled on the same day as their first study visit, blood samples will be drawn at the end of the study visit. All subsequent study visits will take place as described above.

• Study Type: Observational
• Enrollment (Actual): 45

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • UNC Hospital

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

This prospective, single-institution observational study is designed to evaluate associations between the pharmacokinetic (PK) parameters (e.g., clearance and exposure) for four tyrosine kinase inhibitors (TKIs) used to treat chronic phase CML with key clinical milestones in CML, as well as associations between TKI PK and medication-induced toxicities and medication adherence. The four TKIs eligible for this study include bosutinib, dasatinib, imatinib, or nilotinib. A total of 150 subjects will be enrolled in the study. The enrolled study subjects will have been prescribed one of these four TKIs by their UNC medical oncologist or advanced practice provider for their diagnosed chronic phase CML.

Description

Inclusion Criteria:

1. Patients who have signed written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
2. Patients must be ≥ 18 years old.
3. Patients must have been diagnosed with chronic phase CML.
4. Patients who will start or have already started receiving oral chemotherapy with bosutinib, dasatinib, imatinib, or nilotinib for their diagnosis of CML.

Exclusion Criteria:

1. Patients who have cognitive impairments that could affect informed decision making.
2. Patients who are prescribed bosutinib, dasatinib, imatinib, or nilotinib in combination with other chemotheapy agents (e.g., hydroxyurea or omacetaxine).
3. Patients who have undetectable BCR-ABL transcripts.
4. Patients with a confirmed T315I point mutation in BCR-ABL and/or prescribed ponatinib.
5. Patients who are incarcerated.
6. Patients with accelerated or blast phase CML.
7. Patients diagnosed with, or currently undergoing treatment for a concurrent second primary malignancy.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Bosutinib; Subjects who have been prescribed or administered bosutinib (Bosulif) for treatment of chronic-phase CML for less than 12 months.	Drug: Bosutinib; Subjects will be enrolled into this group if they are receiving bosutinib per standard of care. This is an observational study and no interventions will be made.; Other Names: Bosulif
Dasatinib; Subjects who have been prescribed or administered dasatinib (Sprycel) for treatment of chronic-phase CML for less than 12 months.	Drug: Dasatinib; Subjects will be enrolled into this group if they are receiving dasatinib per standard of care. This is an observational study and no interventions will be made.; Other Names: Sprycel
Imatinib; Subjects who have been prescribed or administered imatinib (Gleevec) for treatment of chronic-phase CML for less than 12 months.	Drug: Imatinib; Subjects will be enrolled into this group if they are receiving imatinib per standard of care. This is an observational study and no interventions will be made.; Other Names: Gleevec
Nilotinib; Subjects who have been prescribed or administered nilotinib (Tasigna) for treatment of chronic-phase CML for less than 12 months.	Drug: Nilotinib; Subjects will be enrolled into this group if they are receiving nilotinib per standard of care. This is an observational study and no interventions will be made.; Other Names: Tasigna

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between TKI Exposure/Clearance and BCR-ABL transcript	TKI exposure/clearance will be evaluated by measuring levels of TKI in the blood during the 12 month study period. BCR-ABL transcripts at 12 months will be compared against the TKI levels.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Hematologic Response (CHR)	CHR at 1 month, defined as complete normalization of peripheral blood counts with leukocyte count < 10 x 1E9/L, platelet count < 450 x 1E9/L, no immature cells (such as myelocytes, promyelocytes, no blasts in peripheral blood, and no signs and symptoms of disease with disappearance of palpable splenomegaly.	1 month
Correlation between Early Molecular Response (EMR) and TKI Exposure/Clearance	Incidence of EMR at 3 and 6 months, defined as BCR-ABL transcript ≤ 10%, will be evaluated, and will be compared against TKI levels at 3 and 6 months.	3 months, 6 months
Correlation between Major Molecular response (MMR) and TKI Exposure/Clearance	Incidence of MMR at 9 and 12 months, defined as BCR-ABL transcript ≤ 0.1%, will be evaluated, and will be compared against TKI levels at 9 and 12 months.	9 months, 12 months
Correlation between Log10 change in BCR-ABL and TKI Exposure/Clearance	BCR-ABL transcripts will be obtained at each time point. The Log10 change in BCR-ABL transcripts will be evaluated, and will be compared against TKI levels at each time point.	Baseline and 1, 3, 6, 9, and 12 months
Medication Adherence	Subject adherence will be evaluated at each time point during standard-of-care study visits. The Wilson's 3-item Adherence Score (WAS) tool will be administered to each subject at each visit in survey form. The WAS tool provides a score from 0-100 (0, worst; 100, best) to evaluate adherence to medications in the last 30 days.	Baseline and 1, 3, 6, 9, and 12 months
Correlation between Medication-induced Toxicities and TKi Exposure/Clearance	Associate TKI exposure/clearance with subject-reported toxicity assessments. Medication-induced toxicity assessments will be conducted at each study visit using the validated MD Anderson Symptom Inventory for CML (MDASI-CML) tool. The MDASI-CML tool asks subjects to rate symptom severity in the last 24 hours on a 0-10 scale (0, not present; 10, as bad as one can imagine). The MDASI-CML also evaluates symptom interference with daily activities in the same manner.	Baseline and 1, 3, 6, 9, and 12 months

Collaborators and Investigators

• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Investigators: Principal Investigator: Daniel Crona, PharmD, PhD, University of North Carolina, Chapel Hill

Publications and helpful links

Helpful Links

• UNC Lineberger Comprehensive Cancer Center Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2019
• Primary Completion (Actual): June 15, 2022
• Study Completion (Actual): June 15, 2022

Study Registration Dates

• First Submitted: March 19, 2019
• First Submitted That Met QC Criteria: March 19, 2019
• First Posted (Actual): March 22, 2019

Study Record Updates

• Last Update Posted (Estimate): January 11, 2023
• Last Update Submitted That Met QC Criteria: January 9, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Observational; Nilotinib; Chronic Myeloid Leukemia; CML; Imatinib; Bosutinib; Dasatinib
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Chromosome Aberrations; Translocation, Genetic; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Philadelphia Chromosome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate; Dasatinib
• Other Study ID Numbers: LCCC1906; 18-2424 (Other Identifier: University of North Carolina IRB)

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