Fruquintinib DDI Study With P-gp and BCRP Substrates

A Phase 1, Open-label, 2-part, 2-period Fixed-sequence Study to Evaluate the Effect of Fruquintinib on the Pharmacokinetics of Dabigatran Etexilate (A P-GP Substrate) and Rosuvastatin (A BCRP Substrate) in Healthy Subjects

Fruquintinib DDI Study with P-gp and BCRP Substrates

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Fruquintinib; Drug: Dabigatran Etexilate; Drug: Rosuvastatin

Detailed Description

A phase 1, open-label, 2-part, 2-period fixed-sequence study to evaluate the effect of Fruquintinib on the pharmacokinetics of Dabigatran Etexilate (A P-GP substrate) and Rosuvastatin (A BCRP substrate) in healthy subjects

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Austin, Texas, United States, 78744
      • Ppd Development

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The subject is male or female between the ages of 18 and 55 years old (inclusive) at the time of informed consent.
2. The subject has a body mass index (BMI) >18 and ≤29 kg/m2 at screening.
3. Female subjects must be of non-childbearing potential (eg, postmenopausal [defined as cessation of all menstrual periods for at least 1 year without an alternative medical cause, and confirmed by follicle-stimulating hormone (FSH) test ≥40 IU/L] or surgically sterile by hysterectomy, bilateral oophorectomy, or bilateral tubal ligation).

4. Male subjects with partners of childbearing potential must always use a condom and must agree in addition to use a highly effective form(s) of contraception, that results in a low failure rate (<1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 90 days after taking the last dose of study drug. Such methods include:

   1. Oral hormonal contraception (combined estrogen/progestogen, or progestogen-only) associated with inhibition of ovulation
   2. Intrauterine device (IUD)
   3. Intrauterine hormone-releasing system (IUS)
   4. Bilateral tubal ligation
   5. Vasectomy
   6. True sexual abstinence in line with the preferred and usual lifestyle of the subject.

   Highly effective contraception should always be combined with an additional barrier method (eg, diaphragm, with a spermicide).

5. The subject must provide written informed consent prior to any study-specific screening procedures.
6. The subject is willing and able to comply with all aspects of the protocol, as determined by the Investigator.

Exclusion Criteria:

1. Clinical laboratory test results from the coagulation panel (international normalized ratio [INR], prothrombin time, and activated partial thromboplastin time) must be within the normal laboratory reference ranges or deemed not clinically significant by the Investigator and Sponsor.
2. The subject has clinically significant renal laboratory findings, including estimated glomerular filtration rate <80 mL/min as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
3. The subject has a known history of any gastrointestinal surgery or any condition possibly affecting drug absorption (eg, cholecystectomy, gastrectomy, achlorhydria, peptic ulcer disease, history of stomach or intestinal surgery or resection). Appendectomy and hernia repair are allowed.
4. The subject had a clinically significant illness within 8 weeks or a clinically significant infection within 4 weeks prior to the first dose.
5. The subject has evidence of a clinically significant deviation from normal in the physical examination, vital signs, or clinical laboratory determinations at screening or at Day -1 check-in (baseline).
6. The subject has systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg.
7. The subject has a clinically significant ECG abnormality, including a marked baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTcF interval >480 msec), or had a family history of prolonged QTc syndrome or sudden death.
8. The subject has a history of smoking or use of nicotine-containing substances within the previous 2 months, as determined by medical history or subject's verbal report and confirmed by cotinine test at check in for each treatment period.
9. The subject has a history of drug or alcohol misuse within 6 months prior to screening or a positive urine drug test at screening or at check in for each treatment period.
10. The subject has been diagnosed with acquired immune deficiency syndrome (AIDS) or has performed tests that are positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).
11. The subject has participated in a clinical trial of other drug before screening, and the time since the last use of other study drug is less than 5 times the half-life or 4 weeks, whichever is longer, or the subject is currently enrolled in another clinical trial.
12. The subject has consumed grapefruit, starfruit, Seville oranges, or their products within 7 days prior to the first dose.
13. The subject has consumed herbal preparations/medications, including, but not limited to, kava, ephedra (ma huang), Ginkgo biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng, within 7 days prior to the first dose.
14. The subject has experienced a weight loss or gain of >10% within 4 weeks prior to the first dose as noted by medical history and weight at screening and check-in.

15. The subject has received blood or blood products within 4 weeks, or donated blood or blood products within 8 weeks prior to the first dose or donated double red cell within 16 weeks prior to first dose.

    Clinical Study Protocol 2021-013-00US3 Fruquintinib Original Protocol HUTCHMED Limited Page 32 CONFIDENTIAL

16. The subject has used any over-the-counter (OTC) medications or prescription drugs that can affect gastric acid (proton pump inhibitors [PPIs], H2 blockers or locally acting antacids) or that inhibit CYP3A, P-gp, or BCRP in particular, within 2 weeks prior to the first dose.
17. Subject has used CYP3A inducers (including St John's wort) within 30 days before the first dose.
18. The subject is allergic to any of the study drugs (or its excipients) to be given in this study.
19. Female participant is pregnant, lactating, or breastfeeding.
20. Male subject who plans to donate sperm or father a child within 3 months after receiving the study drug.
21. The subject has any condition that would make him or her, in the opinion of the Investigator or Sponsor, unsuitable for the study, or who, in the opinion of the Investigator, is not likely to complete the study for any reason.

One repeat of laboratory assessments may be performed at screening and check in at the discretion of the Investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A; On Day 1, a single oral dose of dabigatran etexilate 150 mg will be given under fasted conditions and serial PK samples will be collected as indicated on the schedule of events. On Day 5, subjects will receive a single oral dose of fruquintinib 5 mg at approximately 1 hour prior to administration of a single oral dose of dabigatran etexilate 150 mg under fasted conditions and serial PK samples will be collected	Drug: Fruquintinib; Fruquintinib will be administered as a single oral 5mg dose on the morning of day 5; Other Names: HMPL-013; Drug: Dabigatran Etexilate; Dabigatran Etexilate will be administered as a single oral dose 150mg on the morning of day 1 and morning of day 5
Experimental: Part B; On Day 1, a single oral dose of rosuvastatin 10 mg will be given under fasted conditions and serial PK samples will be collected as indicated on the schedule of events. On Day 5, subjects will receive a single oral dose of rosuvastatin 10 mg with fruquintinib 5 mg under fasted conditions and serial PK samples will be collected	Drug: Fruquintinib; Fruquintinib will be administered as a single oral 5mg dose on the morning of day 5; Other Names: HMPL-013; Drug: Rosuvastatin; Rosuvastatin will be administered as a single oral dose 10mg on the morning of day 1 and the morning of day 5

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK parameter for dabigatran and rosuvastatin: AUC0-t:	area under the plasma concentration-time curve from time 0 to time of the last measurable concentration	Day 1 to Day 13
PK parameter for dabigatran and rosuvastatin: AUC0-inf:	area under the plasma concentration-time curve from time 0 to infinity (if data permit)	Day 1 to Day 13
PK parameter for dabigatran and rosuvastatin: Cmax:	maximum observed plasma concentration	Day 1 to Day 13

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of AEs/SAEs	Any untoward medical occurrence associated with the use of study drug	Day 1 to Day 13
PK parameter of fruquintinib and metabolite M11: AUC0-t:	area under the plasma concentration-time curve from time 0 to time of the last measurable concentration	Day 1 Day 13
PK parameters of fruquintinib and metabolite M11: AUC0-inf:	area under the plasma concentration-time curve from time 0 to infinity (if data permit)	Day 1 to Day 13
PK parameters of fruquintinib and metabolite M11: Cmax:	maximum observed plasma concentration	Day 1 to Day 13

Collaborators and Investigators

• Sponsor: Hutchmed

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2022
• Primary Completion (Actual): April 22, 2022
• Study Completion (Actual): April 22, 2022

Study Registration Dates

• First Submitted: April 21, 2022
• First Submitted That Met QC Criteria: May 5, 2022
• First Posted (Actual): May 10, 2022

Study Record Updates

• Last Update Posted (Actual): October 6, 2022
• Last Update Submitted That Met QC Criteria: October 5, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Protease Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Dabigatran; Rosuvastatin Calcium
• Other Study ID Numbers: 2021-013-00US3

Drug and device information, study documents

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