A Study to Evaluate Pharmacokinetics (PK) and Safety of Oral Mobocertinib in Participants With Moderate or Severe Hepatic Impairment (HI) and Normal Hepatic Function

Phase 1 Pharmacokinetics and Safety Study of Oral Mobocertinib in Subjects With Moderate or Severe Hepatic Impairment and Normal Hepatic Function

The purpose of this study is to characterize the single-dose plasma PK of mobocertinib and its active metabolites (AP32960 and AP32914) in participants with moderate and/or severe HI compared to matched-healthy participants with normal hepatic function.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers; Hepatic Impairment
• Intervention / Treatment: Drug: Mobocertinib

Detailed Description

29-Apr-2020 Enrollment of new participants into this study was paused due to the COVID-19 situation. The duration of this pause was dependent on the leveling and control of the COVID-19 pandemic.

The drug being tested in this study is called mobocertinib. The study will assess the PK of single dose mobocertinib and its active metabolites (AP32960 and AP32914) in participants with moderate and/or severe HI compared to matched-healthy participants with normal hepatic function.

The study will enroll approximately 24 participants. Participants will be assigned to 1 of the following 3 treatment groups in a staggered manner based on their degree of hepatic impairment which will be determined based on Child-Pugh Score as follow:

• Moderate HI (Child-Pugh B): Mobocertinib 40 mg
• Severe HI (Child-Pugh C): Mobocertinib 40 mg
• Normal Hepatic Function: Mobocertinib 40 mg

Healthy participants with normal hepatic function will be recruited to match both moderate and severe HI by age (mean plus or minus [+-] 10 years), gender (+-2 participants per gender), and body mass index (BMI, mean +-10 percent [%]).

All participants will be asked to take single dose of mobocertinib on Day 1. The dose level for severe HI may be modified based on the previous results of approximately 3 moderate HI and healthy participants who completed up to Day 10 study procedures.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is approximately 51 days. Participants will be contacted by telephone 30 days after the last dose of study drug for a follow-up assessment.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Hialeah, Florida, United States, 33014
      • Clinical Pharmacology of Miami
    • Orlando, Florida, United States, 32809
      • Orlando Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Inclusion Criteria for Healthy Participants

1. Continuous non-smoker or moderate smoker (less than or equal to (<=) 10 cigarettes/day or the equivalent) before screening. Participant must agree to consume no more than 5 cigarettes or equivalent/day from the 7 days prior to mobocertinib dosing and throughout the period of PK sample collection.
2. Body mass index (BMI) greater than or equal to (>=) 18.0 and <=39.0 kilogram per square meter (kg/m^2), at screening. Participants will be matched to hepatic impaired participants by BMI (mean plus minus [+-] 10%) at screening. At least 50% of the participants will be required to be of BMI >=18.0 and <=35.0 kg/m^2, at screening.
3. Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs or electrocardiograms (ECGs), as deemed by the Investigator or designee. Has liver function tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin within the upper limit of normal at screening and at check-in.
4. Creatinine clearance (estimated glomerular filtration rate [eGFR]) >=60 milliliter per minute per 1.73 square meter (mL/min/1.73 m^2) at screening.

Inclusion Criteria for Moderate or Severe HI Participants

1. Continuous non-smoker or moderate smoker (<=10 cigarettes/day or the equivalent) before screening. Participant must agree to consume no more than 5 cigarettes or equivalent/day from the 7 days prior to mobocertinib dosing and throughout the period of pharmacokinetic(s) (PK) sample collection.
2. BMI >=18.0 and <=39.0 kg/m^2, at screening. At least 50% of the participants will be required to be of BMI >=18.0 and <=35.0 kg/m^2, at screening.
3. Aside from HI, be sufficiently healthy for study participation based upon medical history, physical examination, vital signs, ECGs, and screening clinical laboratory profiles, as deemed by the Investigator or designee.
4. Creatinine clearance (eGFR) >=60 mL/min/1.73 m^2 at screening.

5. Chronic HI for at least 3 months before screening, and the HI must be stable, that is, no significant changes in hepatic function in the 30 days preceding screening (or since the last visit if within 6 months before screening) and treatment with stable doses of medication. Has a score on the Child-Pugh Class at screening as follows:

   • Moderate HI arm, Child-Pugh Class B: >=7 and <=9.
   • Severe HI arm, Child-Pugh Class C: >=10 and <=15.

Exclusion Criteria:

1. Positive results for COVID-19 at screening or check in.
2. Seated blood pressure is less than 90/40 millimeters of Mercury (mmHg) or greater than 150/95 mmHg at screening.
3. Seated heart rate is lower than 40 beats per minute (bpm) or higher than 99 bpm at screening.
4. Healthy participants: QTcF interval is >=450 msec in males or >=470 msec in females; Moderate or Severe HI participants: QTcF interval is greater than (>) 500 msec OR has ECG findings deemed abnormal with clinical significance by the Investigator or designee at screening.
5. Unable to refrain from or anticipates the use of any medication or substance (including prescription or over-the-counter, vitamin supplements, natural or herbal supplements) for the prohibited time period.
6. Been on a diet incompatible with the on-study diet, in the opinion of the Investigator or designee, within the 30 days prior to dosing and throughout the study.
7. Donation of blood or had significant blood loss within 56 days prior to dosing.
8. Plasma donation within 7 days prior to dosing.
9. Healthy participants: Positive result at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV); Moderate or Severe HI participants: Positive result at screening for HIV, HBsAg positive participants are allowed to enroll if hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is below 1000 copies/milliliter (mL) in the plasma. Participants who are positive for hepatitis C virus antibodies (HCVAb) can be enrolled but must not have detectable HCV ribonucleic acid (RNA) in the plasma.

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Moderate HI (Child-Pugh B): Mobocertinib 40 mg; Mobocertinib 40 milligram (mg), capsule, orally, a single dose on Day 1.	Drug: Mobocertinib; Mobocertinib capsule.; Other Names: AP32788; TAK-788
Experimental: Severe HI (Child-Pugh C): Mobocertinib 40 mg; Mobocertinib 40 mg, capsule, orally, a single dose on Day 1.	Drug: Mobocertinib; Mobocertinib capsule.; Other Names: AP32788; TAK-788
Experimental: Normal Hepatic Function: Mobocertinib 40 mg; Mobocertinib 40 mg, capsule, orally, a single dose on Day 1.	Drug: Mobocertinib; Mobocertinib capsule.; Other Names: AP32788; TAK-788

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CL/F: Apparent Clearance After Extravascular Administration for Mobocertinib		Day 1 pre-dose and at multiple time points (up to 216 hours) post-dose
CLu/F: Apparent Clearance for Unbound Drug After Extravascular Administration for Mobocertinib		Day 1 pre-dose and at multiple time points (up to 216 hours) post-dose
Vz/F: Apparent Volume of Distribution During the Terminal Disposition Phase After Extravascular Administration for Mobocertinib		Day 1 pre-dose and at multiple time points (up to 216 hours) post-dose
Vz,u/F: Apparent Volume of Distribution for Unbound Drug During the Terminal Disposition Phase After Extravascular Administration for Mobocertinib		Day 1 pre-dose and at multiple time points (up to 216 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for Mobocertinib and Its Active Metabolites (AP32960 and AP32914)		Day 1 pre-dose and at multiple time points (up to 216 hours) post-dose
Cmax,u: Maximum Observed Unbound Plasma Concentration for Mobocertinib and Its Active Metabolites (AP32960 and AP32914)		Day 1 pre-dose and at multiple time points (up to 216 hours) post-dose
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Mobocertinib and Its Active Metabolites (AP32960 and AP32914)		Day 1 pre-dose and at multiple time points (up to 216 hours) post-dose
AUC∞,u: Area Under the Unbound Plasma Concentration-time Curve From Time 0 to Infinity for Mobocertinib and Its Active Metabolites (AP32960 and AP32914)		Day 1 pre-dose and at multiple time points (up to 216 hours) post-dose
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Mobocertinib and Its Active Metabolites (AP32960 and AP32914)		Day 1 pre-dose and at multiple time points (up to 216 hours) post-dose
AUClast,u: Area Under the Unbound Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Mobocertinib and Its Active Metabolites (AP32960 and AP32914)		Day 1 pre-dose and at multiple time points (up to 216 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Mobocertinib and Its Active Metabolites (AP32960 and AP32914)		Day 1 pre-dose and at multiple time points (up to 216 hours) post-dose
t1/2z: Terminal Disposition Phase Half-life for Mobocertinib and Its Active Metabolites (AP32960 and AP32914)		Day 1 pre-dose and at multiple time points (up to 216 hours) post-dose
λz: Terminal Elimination Rate Constant for Mobocertinib and Its Active Metabolites (AP32960 and AP32914)	Terminal elimination rate constant (λz) is a mathematical estimate calculated using log-linear regression of the terminal portions of a plasma concentration against time curve.	Day 1 pre-dose and at multiple time points (up to 216 hours) post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Protein Binding of Mobocertinib and Its Active Metabolites (AP32960 and AP32914)		Day 1 at multiple time points (up to 24 hours) post-dose
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.	Baseline up to 30 days after last dose of study drug (up to Day 32)

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.
• Investigators: Study Director: Medical Director, Takeda

Study record dates

Study Major Dates

• Study Start (Actual): October 9, 2020
• Primary Completion (Actual): February 5, 2022
• Study Completion (Actual): February 26, 2022

Study Registration Dates

• First Submitted: August 13, 2019
• First Submitted That Met QC Criteria: August 13, 2019
• First Posted (Actual): August 14, 2019

Study Record Updates

• Last Update Posted (Estimated): November 3, 2023
• Last Update Submitted That Met QC Criteria: January 12, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases
• Other Study ID Numbers: TAK-788-1008; U1111-1236-7377 (Registry Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

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