Safety, Tolerability and Pharmacokinetics Study of MK-7252 in Healthy Adult Participants (MK-7252-001)

Cancer Clinical Trial

Official title:

A Single Ascending Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-7252 in Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03326986
• Other study ID #: 7252-001
• Secondary ID: 2017-003407-22MK
• Status: Completed
• Phase: Phase 1
• Start date: November 10, 2017
• Est. completion date: December 17, 2018

Study information

• Verified date: December 2019
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the safety, tolerability and pharmacokinetics (PK) of MK-7252 in healthy adults. Participants receive ascending doses of MK-7252 over five treatment periods. Each treatment period is separated by a 7-day washout period.

Upon review of the interim safety and preliminary PK data of human exposure to date, Protocol Amendment 3 includes a third panel of participants, Panel C, to assess the PK of higher doses of MK-7252 and to assess the food effect of MK-7252.

Description:

Three panels (Panels A, B, and C) of 8 healthy participants (n=6 MK-7252, n=2 placebo) are enrolled. In Panels A and B, participants will alternately receive single rising doses of MK-7252 or placebo for 5 treatment periods. In Panel C, participants will receive single rising doses of MK-7252 or placebo for up to 5 treatment periods. All doses in Panels A and B will be administered in the fasted state during the 5 treatment periods. Doses in Panel C will be administered in a fasted state in treatment periods 1 through 4 and the treatment period 1 dose will be repeated in a fed state during treatment period 5. Panel A will begin first. At least 3 days will elapse before participants in Panel B will receive the next higher dose. For all panels, there will be at least 7 days washout between treatment periods for any given participant. Participants may only be enrolled in one panel of the study. The planned dose levels may be adjusted downward or replaced based on evaluation of safety, tolerability, pharmacokinetic and/or pharmacodynamic data observed after previous treatment periods. All participants in the treatment periods of all panels (with exception of 120 mg fasted/fed periods in Panel C) will be randomly assigned to either study drug or placebo; that is a participant could be assigned to receive study drug in one period and placebo in another. As per the protocol allocation plan, the same participants in Panel C will receive 120 mg MK-7252 in a fasted and fed state. In addition, during any of the treatment periods if a participant demonstrates change in any one of the protocol-defined parameters lasting ≥2 hours, dose escalation in that participant will be halted and the participant may be withdrawn from the study or re-challenged at same dose or at a lower or divided dose. Participants that meet criteria listed will be followed up until parameters no longer meet stopping rule criteria.

During the study, participants in Panel A were planned to receive placebo, 1 mg, 6 mg, 24 mg, 72 mg and 108 mg, all in a fasted state in 5 periods. Participants in Panel B were planned to receive placebo, 3 mg, 12 mg, 48 mg, 72 mg and 162 mg, all in a fasted state in 5 periods. All periods in Panels A and B were conducted. Participants in Panel C were planned to receive placebo fasted, placebo fed, 120 mg fasted, 240 mg fasted, 360 mg fasted, 540 mg fasted, and 120 mg fed in 5 periods. Periods 4 and 5 were not conducted and, as a result, the 240 mg fasted, 360 mg fasted, 540 mg fasted, 120 mg fed, and placebo fed doses were not administered. A 180 mg fasted dose was added during Period 3.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: December 17, 2018
• Est. primary completion date: December 17, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

• Male or female participants of non-childbearing potential (Note: If postmenopausal female: participant is without menses for at least 1 year and has a documented follicle stimulating hormone [FSH] level in the postmenopausal range at pre-trial [screening] - OR - If surgically sterile female: participant is status post hysterectomy, oophorectomy or tubal ligation.)

• Body Mass Index (BMI) between 18.5 and 32 kg/m^2, inclusive. BMI = weight (kg)/height (m)^2.

• While in semi-recumbent position, has a systolic blood pressure =140 mmHg and diastolic blood pressure =90 mm Hg and a respiratory rate =20 breaths/min at the pre-study (screening) visit and prior to randomization.

• Judged to be in good health based on medical history, physical examination, vital sign measurements and electrocardiogram (ECG) performed prior to randomization.

• Non-smoker and/or has not used nicotine or nicotine-containing products (e.g., nicotine patch) for at least approximately 3 months.

Exclusion Criteria:

• Mentally or legally incapacitated, has significant emotional problems at the time of pretrial (screening) visit or expected during the conduct of the study or has a history of clinically significant psychiatric disorder of the last 5 years.

• History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological (including stroke and chronic seizures) abnormalities or diseases.

• History of liver disease (chronic hepatitis, cirrhosis, etc.).

• History of cancer (malignancy). Exceptions include adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix and other malignancies which have been successfully treated =10 years prior to the pre-study (screening) visit.

• History of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e. systemic allergic reaction) to prescription or non-prescription drugs or food.

• Tests positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV).

• Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pre-study (screening) visit.

• Participated in another investigational study within 4 weeks (or 5 half-lives), whichever is greater, prior to the pre-study (screening) visit.

• QTc interval =470 msec (for males) and =480 msec (for females).

• Taken a Proton Pump Inhibitor (PPI) during the 5 days prior to start of study treatment.

• Unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug, throughout the study (including washout intervals between treatment periods), until the post-study visit.

• Consumes >3 glasses of alcoholic beverages (1 glass is approximately equivalent to:

beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day.

• Consumes excessive amounts, defined as >6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy-drinks, or other caffeinated beverages per day.

• Regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within approximately 1 year. Participants must have a negative result for urine drug screen test prior to randomization.

Related Conditions & MeSH terms

• Cancer
• Pharmacokinetics

Intervention

Drug:
• MK-7252
1 mg/mL or 20 mg/mL of powder for oral suspension administered with a water volume that brings the total ingested volume to approximately 240 mL
• Placebo
Placebo powder for oral suspension administered with a water volume that brings the total ingested volume to approximately 240 mL

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis Gent ( Site 0001)	Gent

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Who Experienced at Least One Adverse Event (AE)	An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have had a causal relationship with this treatment. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. Adverse events are reported by dose taken at time of event and not by panel or period. The adverse events for placebo are pooled over periods across panels. The number of participants who experienced at least one AE is presented.	Up to approximately 21 weeks
Primary	Number of Participants Who Discontinued Study Treatment Due to an AE	An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have had a causal relationship with this treatment. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. Discontinuations are reported by dose taken at time of event. The discontinuations for placebo are pooled over periods across panels. The number of participants who discontinued study treatment due to an AE is presented.	Up to approximately 19 weeks
Secondary	MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-8)	Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 AUC0-8 reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. Pharmacokinetic (PK) results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma AUC0-8 following a high-fat breakfast (fed state) was planned to be compared to the plasma AUC0-8 in the fasted stated in Panel C, the fed state dose was not administered.	Predose (Day 1) and 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose
Secondary	MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr)	Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 AUC0-24hr reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma AUC0-24hr following a high-fat breakfast (fed state) was planned to be compared to the plasma AUC0-24hr in the fasted stated in Panel C, the fed state dose was not administered.	Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, and 24 hours postdose
Secondary	MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr)	Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 AUC0-12hr reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma AUC0-12hr following a high-fat breakfast (fed state) was planned to be compared to the plasma AUC0-12hr in the fasted stated in Panel C, the fed state dose was not administered.	Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, and 12 hours postdose
Secondary	MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast)	Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 AUClast reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma AUClast following a high-fat breakfast (fed state) was planned to be compared to the plasma AUClast in the fasted stated in Panel C, the fed state dose was not administered.	Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose
Secondary	MK-7252 Maximal Plasma Concentration (Cmax)	Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 Cmax reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma Cmax following a high-fat breakfast (fed state) was planned to be compared to the plasma Cmax in the fasted stated in Panel C, the fed state dose was not administered.	Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose
Secondary	MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr)	Blood samples were obtained 12 hours postdose to calculate the plasma MK-7252 C12hr reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. For participants in a given dose that had C12hr values less than the lower limit of quantification (LLOQ), the C12hr value was imputed as half x LLOQ. The LLOQ was 2.74 nmol/L. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma C12hr following a high-fat breakfast (fed state) was planned to be compared to the plasma C12hr in the fasted stated in Panel C, the fed state dose was not administered.	12 hours postdose
Secondary	MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr)	Blood samples were obtained 24 hours postdose to calculate the plasma MK-7252 C24hr reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. For participants in a given dose that had C24hr values less than the lower limit of quantification (LLOQ), the C24hr value was imputed as half x LLOQ. The LLOQ was 2.74 nmol/L. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma C24hr following a high-fat breakfast (fed state) was planned to be compared to the plasma C24hr in the fasted stated in Panel C, the fed state dose was not administered.	24 hours postdose
Secondary	MK-7252 Time to Reach Maximal Concentration (Tmax)	Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 Tmax. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma Tmax following a high-fat breakfast (fed state) was planned to be compared to the plasma Tmax in the fasted stated in Panel C, the fed state dose was not administered.	Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose
Secondary	MK-7252 Apparent Terminal Half-life (t½)	Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 t½ reported as Geometric Mean with Percent Geometric Coefficient of Variation. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma t½ following a high-fat breakfast (fed state) was planned to be compared to the plasma t½ in the fasted stated in Panel C, the fed state dose was not administered.	Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose
Secondary	Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours	Assessment of the change from baseline in SBP was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 SBP measurements: baseline and 4 hours postdose. SBP results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in SBP and a negative number indicates a decrease in SBP.	Baseline (Predose Day 1) and 4 hours postdose
Secondary	Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours	Assessment of the change from baseline in SBP was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 SBP measurements: baseline and 24 hours postdose. SBP results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in SBP and a negative number indicates a decrease in SBP.	Baseline (Predose Day 1) and 24 hours postdose
Secondary	Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours	Assessment of the change from baseline in DBP was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 DBP measurements: baseline and 4 hours postdose. DBP results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in DBP and a negative number indicates a decrease in DBP.	Baseline (Predose Day 1) and 4 hours postdose
Secondary	Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours	Assessment of the change from baseline in DBP was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 DBP measurements: baseline and 24 hours postdose. DBP results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in DBP and a negative number indicates a decrease in DBP.	Baseline (Predose Day 1) and 24 hours postdose
Secondary	Change From Baseline in Heart Rate (HR) at 4 Hours	Assessment of the change from baseline in HR was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 HR measurements: baseline and 4 hours postdose. HR results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in HR and a negative number indicates a decrease in HR.	Baseline (Predose Day 1) and 4 hours postdose
Secondary	Change From Baseline in Heart Rate (HR) at 24 Hours	Assessment of the change from baseline in HR was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 HR measurements: baseline and 24 hours postdose. HR results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in HR and a negative number indicates a decrease in HR.	Baseline (Predose Day 1) and 24 hours postdose