Clinical trial NCT03811834: A Study to Assess Absolute Bioavailability (ABA) of Mobocertinib (TAK-788) and to Characterize Mass Balance, Pharmacokinetics (PK), Metabolism, and Excretion of Carbon-14 ([14C])-Mobocertinib in Male Healthy Participants
Official title: A Phase 1 Study to Assess Absolute Bioavailability of TAK-788 and to Characterize Mass Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]-TAK-788 in Male Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2019-01-22
Enrollment: 7
Sex: MALE
Minimum age (years): 19
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: The purpose of this study is to determine:

Period 1 (ABA): ABA of mobocertinib following single microdose intravenous administration of 50 microgram (mcg) (approximately 2 microcurie \[mcCi\]) \[14 C\]-\]-mobocertinib and single oral administration of 160 milligram (mg) mobocertinib.

Period 2 (absorption, distribution, metabolism, and elimination \[ADME\]): the mass balance and metabolic profile of mobocertinib in plasma, urine, and feces, to characterize the PK of mobocertinib and its metabolites (AP32960 and AP32914) in plasma, whole blood, and urine, and total radioactivity concentration equivalents in plasma and whole blood following a single oral administration of 160 mg (approximately 100 mcCi) \[14C\]-mobocertinib solution.

Detailed description: The drug being tested in this study is called mobocertinib. The study will determine ABA of mobocertinib following single microdose of 50 mcg \[14C\]-mobocertinib and single oral administration of 160 mg mobocertinib and will assess the mass balance and metabolic profile of mobocertinib in plasma, urine, and feces following a single oral administration of 160 mg \[14C\]-mobocertinib solution, and will characterize the PK of mobocertinib and its metabolites in plasma, whole blood, and urine, and total radioactivity concentration equivalents in plasma and whole blood following a single dose of 160 mg \[14C\]-mobocertinib.

The study will enroll approximately 6 participants. The study is designed to consist of 2 periods: Period 1 (ABA study period) and Period 2 (ADME study period). In Period 1, all participants will receive single unlabeled oral 160 mg dose of mobocertinib as capsules. At 3.75 hours post oral dosing, participants will receive 15-minute intravenous infusion of a microdose of 50 mcg (approximately 2mcCi) \[14C\]-mobocertinib. In Period 2, participants will receive single dose of 160 mg (approximately 100 mcCi) \[14C\]-mobocertinib as an oral solution.

This single center trial will be conducted in the United States. The overall time to participate in this study is approximately 65 days including screening period. Participants will be contacted approximately 30 days after the last dose of study drug for a follow-up assessment.

Eligibility criteria: Inclusion Criteria:

1. Continuous non smoker who has not used nicotine containing products for at least 20 years prior to the first dosing and throughout the study, based on subject self-reporting.
2. Body mass index greater than or equal to (\>=)18 and less than (˂) 30.0 kilogram per square meter (kg/m\^2) at screening.

Exclusion Criteria:

1. Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study.
2. Has history or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing.
3. Has positive urine drug or alcohol results at screening or first check in.
4. Estimated creatinine clearance \< 80 milliliter per minute (mL/min) at screening.
5. Has tattoo(s) or scarring at or near the site of intravenous (IV) infusion or any other condition which may interfere with infusion site examination, in the opinion of the investigator.
6. Has infrequent bowel movements (less than approximately once per day) within 30 days prior to first dosing.
7. Has recent history of abnormal bowel movements, such as diarrhea, loose stools, or constipation, within 2 weeks of first dosing.
8. Has received radiolabeled substances or has been exposed to radiation sources within 12 months of first dosing or is likely to receive radiation exposure or radioisotopes within 12 months of first dosing such that participation in this study would increase their total exposure beyond the recommended levels considered safe (that is., weighted annual limit recommended by the Commission on Radiological Protection \[ICRP\] of 3000 millirem).
9. Donation of blood or significant blood loss within 56 days prior to the first dosing.
10. Plasma donation within 7 days prior to the first dosing.

Primary outcomes:
measure: Period 1: Percent Absolute Oral Bioavailability (%F) for Mobocertinib
timeFrame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
measure: Period 2: Percentage of Total Radioactivity (Cum%Dose) Recovered in Urine Relative to the Administered Radioactive Dose
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2: Percentage of Total Radioactivity (Cum%Dose) Recovered in Feces Relative to the Administered Radioactive Dose
timeFrame: Day 1 pre-dose and at multiple time points (up to 432 hours) post-dose
measure: Period 2: Amount of Total Radioactivity Excreted in Urine (Ae[UR])
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2: Amount of Total Radioactivity Excreted in Feces (Ae[Fe])
timeFrame: Day 1 pre-dose and at multiple time points (up to 432 hours) post-dose
measure: Period 2: Percentage of Administered Radioactive Dose (%Dose) Excreted in Urine for Mobocertinib
timeFrame: Day 1: Pre-dose, 0-12 hours (hrs), 12-24 hrs, 24-48 hrs, 48-72 hrs, 72-96 hrs, 96-120 hrs, 120-144 hrs, 144-168 hrs, 168-192 hrs, 192-216 hrs, 216-240 hrs post-dose
measure: Period 2: Percentage of Administered Radioactive Dose (%Dose) Excreted in Feces for Mobocertinib
timeFrame: Day 1: at Pre-dose, 0-24 hours (hrs), 24-48 hrs, 48-72 hrs, 72-96 hrs, 96-120 hrs, 120-144 hrs, 144-168 hrs, 168-192 hrs, 192-216 hrs, 216-240 hrs; 240-264 hrs, 264-288 hrs, 288-312 hrs, 213-408 hrs and 408-432 hrs
measure: Period 2, Cmax: Maximum Observed Plasma and Whole Blood Concentration for Mobocertinib and Its Metabolites (AP32960 and AP32914)
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2, Tmax: Time to Reach the Maximum Plasma and Whole Blood Concentration (Cmax) for Mobocertinib and Its Metabolites (AP32960 and AP32914)
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2: t(1/2): Terminal Disposition Phase Half-life of Mobocertinib and Its Metabolites (AP32960 and AP32914) in Plasma and Whole Blood
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2, AUC∞: Area Under the Plasma and Whole Blood Concentration-time Curve From Time 0 to Infinity for Mobocertinib and Its Metabolites (AP32960 and AP32914)
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2, AUClast: Area Under the Plasma and Whole Blood Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Mobocertinib and Its Metabolites (AP32960 and AP32914)
timeFrame: Day 1 pre-dose at multiple time points (up to 240 hours) post-dose
measure: Period 2, AUCt: Area Under the Plasma and Whole Blood Concentration-time Curve From Time 0 to Time t for Mobocertinib and Its Metabolites (AP32960 and AP32914)
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2, Cmax: Maximum Observed Plasma Radioactivity Concentration Equivalents for [14C]-Mobocertinib
timeFrame: Day 1 pre-dose at multiple time points (up to 240 hours) post-dose
measure: Period 2, Cmax: Maximum Observed Whole Blood Radioactivity Concentration Equivalents for [14C]-Mobocertinib
timeFrame: Day 1 pre-dose at multiple time points (up to 240 hours) post-dose
measure: Period 2, Tmax: Time to Reach the Maximum Plasma and Whole Blood Radioactivity Concentration (Cmax) Equivalents for [14C]-Mobocertinib
timeFrame: Day 1 pre-dose at multiple time points (up to 240 hours) post-dose
measure: Period 2, t(1/2z): Terminal Disposition Phase Half-life of Plasma and Whole Blood Radioactivity Concentration Equivalents for [14C]-Mobocertinib
timeFrame: Day 1 pre-dose at multiple time points (up to 240 hours) post-dose
measure: Period 2, AUC∞: Area Under the Plasma Radioactivity Concentration Equivalents-time Curve From Time 0 to Infinity for [14C]-Mobocertinib
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2, AUC∞: Area Under the Whole Blood Radioactivity Concentration Equivalents-time Curve From Time 0 to Infinity for [14C]-Mobocertinib
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2, AUClast: Area Under the Plasma Radioactivity Concentration Equivalents -Time Curve From Time 0 to Last Quantifiable Concentration for [14C]-Mobocertinib
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2, AUClast: Area Under the Whole Blood Radioactivity Concentration Equivalents -Time Curve From Time 0 to Last Quantifiable Concentration for [14C]- Mobocertinib
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2, AUCt : Area Under the Plasma Radioactivity Concentration Equivalents-time Curve From Time 0 to Time t for [14C]-Mobocertinib
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2, AUCt : Area Under the Whole Blood Radioactivity Concentration Equivalents-time Curve From Time 0 to Time t for [14C]-Mobocertinib
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2, Aet1-t2: Amount of Unchanged Drug Excreted in the Urine in Each Collection Interval From t1 to t2 for Mobocertinib and Its Metabolites (AP32960 and AP32914)
timeFrame: Day 1: at Pre-dose, 0-12 hours (hrs), 12-24 hrs, 24-48 hrs, 48-72 hrs, 72-96 hrs, 96-120 hrs, 120-144 hrs, 144-168 hrs, 168-192 hrs, 192-216 hrs and 216-240 hrs post dose
measure: Period 2, CLR: Renal Clearance for Mobocertinib and Its Metabolites (AP32960 and AP32914)
timeFrame: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose
measure: Period 2, Percentage Change of [14C]-Radioactivity in Whole Blood Relative to Plasma Over the Time for [14C]-Mobocertinib, (Whole Blood : Plasma Partitioning Ratio)
timeFrame: At 0.5 hours (hrs), 1 hr, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, 8 hrs, 12 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 96 hrs, 120 hrs, 144 hrs, 168 hrs, 192 hrs, 216 hrs and 240 hrs post-dose
Secondary outcomes:
measure: Period 1, Ceoi: Plasma Concentration at the End of Infusion for [14C]-Mobocertinib, and Its Metabolites ([14C]-AP32960 and [14C]-AP32914)
timeFrame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
measure: Period 1, Cmax: Maximum Observed Plasma Concentration for Mobocertinib and Its Metabolites (AP32960 and AP32914) After Oral Administration
timeFrame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
measure: Period 1, Cmax: Maximum Observed Plasma Concentration for [14C]-Mobocertinib and Its Metabolites ([14C]-AP32960 and [14C]-AP32914) After Intravenous Administration
timeFrame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
measure: Period 1, Time to Reach the Maximum Plasma Concentration (Cmax) for Mobocertinib and Its Metabolites (AP32960 and AP32914) After Oral, and [14C]-Mobocertinib and Its Metabolites ([14C]-AP32960 and [14C]-AP32914) After Intravenous Administration
timeFrame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
measure: Period 1, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Mobocertinib and Its Metabolites (AP32960 and AP32914) After Oral Administration
timeFrame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
measure: Period 1, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for [14C]-Mobocertinib and Its Metabolites ( [14C]-AP32960 and [14C]-AP32914) After Intravenous Administration
timeFrame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
measure: Period 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Last Quantifiable Concentration for Mobocertinib and Its Metabolites (AP32960 and AP32914) After Oral Administration
timeFrame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
measure: Period 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Last Quantifiable Concentration for [14C]-Mobocertinib and Its Metabolites ([14C]-AP32960 and [14C]-AP32914) After Intravenous Administration
timeFrame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
measure: Period 1, AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t for [14C]-Mobocertinib and Its Metabolites ([14C]-AP32960 and [14C]-AP32914) After Intravenous Administration
timeFrame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
measure: Period 1, t(1/2):Terminal Disposition Phase Half-Life of Mobocertinib and Its Metabolites (AP32960 and AP32914) in Plasma After Oral, and [14C]-Mobocertinib and Its Metabolites ( [14C]-AP32960 and [14C]-AP32914) in Plasma After Intravenous Administration
timeFrame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
measure: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
timeFrame: Baseline up to 30 days after last dose of study drug in Period 2 (Day 41)
measure: Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiogram (ECG) Findings
timeFrame: Baseline up to 30 days after last dose of study drug in Period 2 (Day 41)
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: Baseline up to 30 days after last dose of study drug in Period 2 (Day 41)
measure: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values
timeFrame: Baseline up to 30 days after last dose of study drug in Period 2 (Day 41)
Other outcomes:
Locations:
city: Lincoln
country: United States
facility: Celerion
state: Nebraska
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References: