Quizartinib for Heart Rate Effects

Overseen By Daiichi Sankyo Contact for Clinical Trial Information

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Daiichi Sankyo

Disqualifiers: Pregnancy, Breastfeeding, Abnormal ECG, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: 3 days

70 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is quizartinib generally safe for humans?

Quizartinib has been tested in humans and is generally considered tolerable, but it can cause QT prolongation (a heart rhythm issue) as a dose-limiting side effect. In clinical trials, some patients experienced mild to moderate side effects, and careful management is needed to avoid drug interactions that could increase the risk of heart-related issues. ^{1 2 3 4 5}

How does the drug quizartinib differ from other treatments for heart rate effects?

Quizartinib is unique because it is primarily a tyrosine kinase inhibitor targeting the FLT3 receptor, used mainly for acute myeloid leukemia (AML). Its potential effects on heart rate are being studied, particularly its known side effect of QT prolongation, which is a measure of delayed heart repolarization that can lead to arrhythmias. ^{1 2 6 7 8}

What is the purpose of this trial?

This study will evaluate the impact of rapid acceleration in the heart rate on the QT prolongation of quizartinib.

Research Team

Global Clinical Leader

Principal Investigator

Daiichi Sankyo

Eligibility Criteria

This trial is for healthy individuals who can safely undergo procedures to rapidly increase their heart rate. Specific eligibility details are not provided, but typically participants should have no significant medical conditions.

Inclusion Criteria

I am a male and have been surgically sterilized, practice abstinence, or agree to use contraception.

Vital signs at Screening within specified ranges: heart rate 50-100 bpm, systolic BP 90-145 mmHg, diastolic BP 50-95 mmHg

Liver function test results (ALT, AST, TBil) must be equal to or below the upper limit of normal

Exclusion Criteria

I don't have any serious health or mental conditions that could affect my safety or the study's results.

I haven't had a serious illness in the last 4 weeks.

Pregnant or breastfeeding females

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a single oral dose of 90 mg of quizartinib or placebo on Day 1, and the alternate treatment on Day 2

3 days

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of treatment emergent adverse events

16 days

Treatment Details

Interventions

• Quizartinib

Trial Overview The study is testing the effects of a drug called Quizartinib on the electrical activity of the heart when the heart rate is quickly increased. Some people will get Quizartinib and others a placebo (no active ingredient) to compare results.

Participant Groups

Group I: Healthy Participants Experimental Treatment 2 Interventions

All participants will receive either an oral dose of 90 mg of quizartinib or placebo on Day 1. On Day 2, all participants will receive the treatment that was not given on Day 1.

Who Is Running the Clinical Trial?

Daiichi Sankyo

Lead Sponsor

Trials

443

Recruited

493,000+

Hiroyuki Okuzawa

Daiichi Sankyo

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

Yuki Abe

Daiichi Sankyo

Chief Medical Officer since 2023

MD

Findings from Research

Quizartinib, a second-generation FLT3 inhibitor, effectively inhibits both mutant and wild-type FLT3 at low concentrations and has shown promising activity and tolerability in phase I and II trials for acute myeloid leukemia, with QT prolongation as a notable side effect.

The drug also inhibits the transport function of ABCG2 and ABCB1 proteins, which may enhance the effectiveness of certain chemotherapy drugs while also raising concerns about potential drug interactions, particularly with medications like ciprofloxacin that can affect heart rhythm.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The FLT3 inhibitor quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions. Bhullar, J., Natarajan, K., Shukla, S., et al.[2021]

Quizartinib, a targeted therapy for acute myeloid leukaemia (AML), shows promise in treating patients with relapsed/refractory FLT3-ITD mutation-positive AML, but careful monitoring of genetic mutations is essential as patients may develop new mutations during treatment.

Patients may experience side effects such as QTc prolongation, which can be managed by dose adjustments, and careful selection of concomitant medications is crucial to avoid drug interactions, especially when preparing for procedures like hematopoietic stem cell transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical Considerations for Treatment of Relapsed/Refractory FLT3-ITD Acute Myeloid Leukaemia with Quizartinib: Illustrative Case Reports. Martínez-Cuadrón, D., Rodríguez-Macías, G., Rodríguez-Veiga, R., et al.[2020]

In a study involving 64 healthy subjects, quizartinib showed similar absorption profiles whether taken after fasting or with a high-fat meal, indicating it can be administered without food restrictions.

Food intake delayed the time it took for quizartinib to reach its maximum concentration in the blood by 2 hours, but all reported adverse events were mild to moderate, with no serious safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Food on the Pharmacokinetics of Quizartinib. Li, J., Holmes, M., Kankam, M., et al.[2021]

In a study involving 93 healthy subjects, quizartinib showed a significant increase in plasma concentration when coadministered with the strong CYP3A inhibitor ketoconazole, indicating that dose adjustments may be necessary to avoid potential toxicity.

The study found that quizartinib had a low incidence of related adverse events (5.4%), with no serious adverse events or deaths reported, suggesting it is generally safe when administered alone or with moderate CYP3A inhibitors like fluconazole.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of CYP3A inhibitors on the pharmacokinetics of quizartinib, a potent and selective FLT3 inhibitor, and its active metabolite. Li, J., Kankam, M., Trone, D., et al.[2021]

In a study of 226 patients with relapsed/refractory acute myeloid leukemia, higher concentrations of quizartinib and its active metabolite AC886 were associated with a significant increase in the QT interval, with a predicted mean increase of 21.1 ms at the highest dose of 60 mg/day.

Patient factors such as age, sex, and concurrent use of QT-prolonging drugs did not significantly influence the QTcF increase, highlighting the importance of monitoring quizartinib levels, especially in patients taking strong CYP3A inhibitors, which necessitates dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concentration-QTc analysis of quizartinib in patients with relapsed/refractory acute myeloid leukemia. Kang, D., Ludwig, E., Jaworowicz, D., et al.[2021]

In a phase 1 study involving 48 healthy subjects, futibatinib, an FGFR inhibitor, did not prolong the heart's QTcF interval at either therapeutic (20 mg) or supratherapeutic (80 mg) doses, indicating a favorable cardiac safety profile.

The study demonstrated that futibatinib's effects on QTcF were minimal (less than 10 milliseconds), with no significant impact on heart rate or other ECG parameters, and no serious adverse events were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Futibatinib on Cardiac Repolarization: Results of a Randomized, Controlled, Double-Blind, QT/QTc, Phase 1 Study in Healthy Subjects. Yamamiya, I., Lester, R., Sonnichsen, D., et al.[2023]

In a study of 60 patients with advanced solid tumors, daily administration of 500 mg fedratinib did not cause clinically significant changes in QTc prolongation or other ECG parameters, indicating it is safe in this regard.

The analysis showed that fedratinib had a shallow and statistically insignificant effect on QTc intervals, with no patients experiencing clinically relevant ECG effects, aligning with its known safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the Potential for QTc Prolongation With Repeated Oral Doses of Fedratinib in Patients With Advanced Solid Tumors. Ogasawara, K., Xu, C., Yin, J., et al.[2022]

Quizartinib is an effective treatment for patients with FLT3-ITD acute myeloid leukemia (AML), as it inhibits the FLT3 gene activity, leading to tumor cell death, and has shown promise in clinical trials for relapsed or refractory cases.

The drug has received breakthrough therapy designation from the FDA, highlighting its potential, but further studies are necessary to assess its safety, efficacy in combination with other treatments, and to address its side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quizartinib (AC220): a promising option for acute myeloid leukemia. Zhou, F., Ge, Z., Chen, B.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

The FLT3 inhibitor quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions. [2021]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Practical Considerations for Treatment of Relapsed/Refractory FLT3-ITD Acute Myeloid Leukaemia with Quizartinib: Illustrative Case Reports. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Effect of Food on the Pharmacokinetics of Quizartinib. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Effects of CYP3A inhibitors on the pharmacokinetics of quizartinib, a potent and selective FLT3 inhibitor, and its active metabolite. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Concentration-QTc analysis of quizartinib in patients with relapsed/refractory acute myeloid leukemia. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Effect of Futibatinib on Cardiac Repolarization: Results of a Randomized, Controlled, Double-Blind, QT/QTc, Phase 1 Study in Healthy Subjects. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Evaluation of the Potential for QTc Prolongation With Repeated Oral Doses of Fedratinib in Patients With Advanced Solid Tumors. [2022]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Quizartinib (AC220): a promising option for acute myeloid leukemia. [2020]