Pharmacokinetics of Ridaforolimus (MK-8669) in Chinese Participants (MK-8669-059)

A Study to Assess the Pharmacokinetics of Ridaforolimus in Chinese Patients

Part 1 of the study will assess the pharmacokinetics, safety, and tolerability of ridaforolimus (MK-8669) after administration of single and multiple 40 mg doses in Chinese participants with advanced cancer. Part 2 of the study is optional; participants can continue to receive the study treatment in a weekly regimen of daily oral doses of ridaforolimus 40 mg for five consecutive days followed by two days off-treatment.

Study Overview

• Status: Completed
• Conditions: Cancer, Advanced
• Intervention / Treatment: Drug: ridaforolimus

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Chinese descent with all 4 biological grandparents born in China and of Chinese descent.
• Histologically- or cytologically-confirmed metastatic or locally advanced solid tumor or lymphoma that has failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist.
• Performance status of ≤1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• Female participants must be post-menopausal.
• Male participants must agree to use a medically-acceptable method of contraception/barrier protection during the study and for 30 days after the last dose of study treatment.
• Participants must be healthy enough to receive the study treatments (that is, meet certain laboratory value parameters).
• Life expectancy of >3 months.

Exclusion criteria:

• Chemotherapy, radiotherapy, or biological therapy within 4 weeks (6 weeks for nitrosoureas, mitomycin C, and monoclonal antibodies) prior to first dose of study treatment (Part 1/Day 1) or has not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Any other concurrent anti-cancer therapy (except luteinizing hormone releasing hormone [LHRH] analogs for prostate cancer).
• Concurrent treatment with immunosuppressive agents, including corticosteroids, at doses greater than those used for replacement therapy.
• Clinically significant abnormality on electrocardiogram (ECG) performed at the screening visit and/or prior to administration of the initial dose of study treatment.
• New York Heart Association (NYHA) Class III or IV congestive heart failure or any other significant history of cardiac disease including: myocardial infarction within the last 6 months; ventricular arrhythmia or acute congestive heart failure within the last 3 months; uncontrolled angina; or uncontrolled hypertension.
• Current participation or participation in a study with an investigational compound or device within 30 days prior to the first dose of study treatment.
• Primary central nervous system tumor, active brain metastases or leptomeningeal carcinomatosis.
• Regular use (including use of any illicit drugs or had a recent history within the last year) of drugs, or alcohol abuse.
• Pregnant or breastfeeding, or expecting to conceive within the projected duration of the study.
• Human Immunodeficiency Virus (HIV)-positive.
• Newly diagnosed (within 3 months before the first dose of study drug) or poorly controlled Type 1 or 2 diabetes.
• Required treatment with medications that are inducers or inhibitors of cytochrome P450 (CYP3A).
• Active infection or use of intravenous (IV) antibiotics, antiviral, or antifungal agents within 2 weeks prior to the first dose of the study treatment.
• Use of or intention to use herbal teas or herbal remedies (including traditional Chinese medicine, St.John's Wort, shark cartilage, etc.) from 2 weeks prior to the first dose and throughout the study.
• Anticipation of need for immunologic therapy, radiation therapy, surgery, or chemotherapy during the study.
• Past high-dose chemotherapy with stem cell rescue.
• Blood transfusion within one week of study entry.
• Inability to swallow capsules and/or documented surgical or anatomical condition that will preclude swallowing and absorbing oral medications on an ongoing basis.
• Known hypersensitivity to the components of the study treatment or its analogs or antibiotics (e.g. clarithromycin, erythromycin, azithromycin).
• Intention to consume grapefruit or grapefruit juice for approximately 2 weeks prior to first dosing until the completion of the study.
• Inadequate recovery from any prior surgical procedure or any major surgical procedure within 4 weeks prior to the first dose of study treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Ridaforolimus 40 mg; In Part 1 (Days 1-19), participants received ridaforolimus (MK-8669) 40 mg via oral enteric-coated tablet on Day 1; followed by no study treatment on Days 2-7; followed by two weekly sequences (Days 8-19) consisting of 5 consecutive days of ridaforolimus 40 mg and 2 consecutive days off study treatment. Following Part 1, participants underwent at least a 2-day study treatment washout prior to starting Part 2. In Part 2, participants received a weekly treatment regimen consisting of 5 consecutive days (Days 1-5) of ridaforolimus 40 mg via oral enteric-coated tablet and 2 consecutive days (Days 6-7) off study treatment. This weekly treatment regimen was repeated every subsequent week for the remainder of participation in Part 2.

Drug: ridaforolimus; 4 enteric-coated tablets, each containing 10 mg ridaforolimus, orally (total daily dose: 40 mg); Other Names: AP23573; MK-8669; ridaforolimus was also known as deforolimus until May 2009

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lag Time (Tlag) of Ridaforolimus: Day 1	Tlag is the time taken for ridaforolimus to appear in systemic circulation following oral administration. The median and full range (minimum, maximum) for Tlag after a single dose of ridafolorlimus are presented.	Cycle 1 Day 1: Predose and at various time points up to 24 hours postdose on Day 1; Cycle 1 is 19 days
Area Under the Curve From 0 to Infinity (AUC0-∞) of Ridaforolimus: Cycle 1 (Cycle 1 is 19 Days)	AUC0-∞ represents the total exposure to ridaforolimus and its average blood concentration multiplied by the total amount of time (extrapolated to infinity) that ridaforolimus was in the body. The (geometric) mean was calculated based on the back-transformed least-squares mean and the 95% confidence interval was determined from a linear mixed-effect model, containing a fixed effect for day and a random effect for participant, performed on natural log-transformed values. The geometric mean and back-transformed 95% confidence interval are presented for AUC0-∞.	Cycle 1: Predose on Day 1 and at various time points through to 24 hours postdose on Day 19; Cycle 1 is 19 days
Area Under the Curve From 0 to 24 Hours (AUC0-24hr) of Ridaforolimus: Day 1, Day 19	AUC0-24hr represents the total exposure to ridaforolimus and its average blood concentration multiplied by the total amount of time (extrapolated to 24 hours) that ridaforolimus was in the body. The (geometric) mean was calculated based on the back-transformed least-squares mean and the 95% confidence interval was determined from a linear mixed-effect model, containing a fixed effect for day and a random effect for participant, performed on natural log-transformed values. The geometric means and back-transformed 95% confidence intervals after a single dose of ridaforolimus and after multiple doses of ridaforolimus are presented for AUC0-24hr.	Cycle 1 Day 1: Predose and at various time points up to 24 hours postdose on Day 1; Cycle 1 Day 19: Predose and at various time points up to 24 hours postdose on Day 19; Cycle 1 is 19 days
Maximum Concentration (Cmax) of Ridaforolimus: Day 1, Day 19	Cmax is the peak blood plasma concentration following a dose of ridaforolimus. The (geometric) mean was calculated based on the back-transformed least-squares mean and the 95% confidence interval was determined from a linear mixed-effect model, containing a fixed effect for day and a random effect for participant, performed on natural log-transformed values. The geometric means and back-transformed 95% confidence intervals after a single dose of ridaforolimus and after multiple doses of ridaforolimus are presented for Cmax.	Cycle 1 Day 1: Predose and at various time points up to 24 hours postdose on Day 1; Cycle 1 Day 19: Predose and at various time points up to 24 hours postdose on Day 19; Cycle 1 is 19 days
Concentration at 24 Hours (C24hr) of Ridaforolimus: Day 1, Day 19	C24hr is the concentration of ridaforolimus in the blood 24 hours after a dose of ridaforolimus. The (geometric) mean was calculated based on the back-transformed least-squares mean and the 95% confidence interval was determined from a linear mixed-effect model, containing a fixed effect for day and a random effect for participant, performed on natural log-transformed values. The geometric means and back-transformed 95% confidence intervals after a single dose of ridaforolimus and after multiple doses of ridaforolimus are presented for C24hr.	Cycle 1 Day 1: Predose and at various time points up to 24 hours postdose on Day 1; Cycle 1 Day 19: Predose and at various time points up to 24 hours postdose on Day 19; Cycle 1 is 19 days
Time to Maximum Concentration (Tmax) of Ridaforolimus: Day 1, Day 19	Tmax is the time at which the Cmax of ridaforolimus is reached. The medians and ranges (minimum, maximum) for Tmax after a single dose of ridaforolimus and after multiple doses of ridaforolimus are presented.	Cycle 1 Day 1: Predose and at various time points up to 24 hours postdose on Day 1; Cycle 1 Day 19: Predose and at various time points up to 24 hours postdose on Day 19; Cycle 1 is 19 days
Apparent Terminal Half-life (t1/2) of Ridaforolimus: Cycle 1 (Cycle 1 is 19 Days)	t½ is the time that it takes for the concentration of ridaforolimus in the body to decrease by half. The (harmonic) means and 95% confidence intervals for t1/2 after a single dose of ridaforolimus and after multiple doses of ridaforolimus are presented.	Cycle 1: Predose on Day 1 and at various time points through to 24 hours postdose on Day 19; Cycle 1 is 19 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Clinical and Laboratory Adverse Events (AEs)	A laboratory AE (LAE) is defined as any unfavorable & unintended change in the chemistry of the body temporally associated with the use of study product, whether or not considered related to the use of the product. A clinical AE (CAE) is defined similarly but also includes changes in structure or function of the body. Serious AEs (SAEs) are those that result in one or more of the pre-specified outcome(s) that meet the criteria of seriousness, including death, life-threatening, significant disability, or hospitalization, etc. Drug-relatedness was determined by the investigator based on clinical judgement.	From first dose up to 30 days after last dose (Up to 26 weeks)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Liu L, Zhang W, Li W, Lv F, Xia Z, Zhang S, Liu W, Zandvliet AS, Waajen S, Zhang LX, Yan L, Li J. A phase I study of ridaforolimus in adult Chinese patients with advanced solid tumors. J Hematol Oncol. 2013 Jul 8;6:48. doi: 10.1186/1756-8722-6-48.

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2011
• Primary Completion (Actual): October 20, 2011
• Study Completion (Actual): April 5, 2012

Study Registration Dates

• First Submitted: June 22, 2011
• First Submitted That Met QC Criteria: June 22, 2011
• First Posted (Estimate): June 27, 2011

Study Record Updates

• Last Update Posted (Actual): April 19, 2019
• Last Update Submitted That Met QC Criteria: January 24, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Relapsed cancer
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: 8669-059; MK-8669-059 (Other Identifier: Merck Protocol Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf