Cancer, Advanced
Conditions
Keywords
Relapsed cancer
Brief summary
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.
Interventions
DRUGridaforolimus
4 enteric-coated tablets, each containing 10 mg ridaforolimus, orally (total daily dose: 40 mg)
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Terminal Half-life (t1/2) of Ridaforolimus: Cycle 1 (Cycle 1 is 19 Days) | Cycle 1: Predose on Day 1 and at various time points through to 24 hours postdose on Day 19; 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. |
| Lag Time (Tlag) of Ridaforolimus: Day 1 | Cycle 1 Day 1: Predose and at various time points up to 24 hours postdose on Day 1; Cycle 1 is 19 days | 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. |
| Area Under the Curve From 0 to Infinity (AUC0-∞) of Ridaforolimus: Cycle 1 (Cycle 1 is 19 Days) | Cycle 1: Predose on Day 1 and at various time points through to 24 hours postdose on Day 19; 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-∞. |
| Area Under the Curve From 0 to 24 Hours (AUC0-24hr) of Ridaforolimus: Day 1, Day 19 | 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 | 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. |
| Maximum Concentration (Cmax) of Ridaforolimus: Day 1, Day 19 | 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 | 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. |
| Concentration at 24 Hours (C24hr) of Ridaforolimus: Day 1, Day 19 | 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 | 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. |
| Time to Maximum Concentration (Tmax) of Ridaforolimus: Day 1, Day 19 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Clinical and Laboratory Adverse Events (AEs) | From first dose up to 30 days after last dose (Up to 26 weeks) | 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. |
Participant flow
Recruitment details
Fifteen (15) Chinese participants with treatment-refractory advanced or relapsed cancers were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Part 1 (19 Days) | Adverse Event | 1 |
| Part 2 | Adverse Event | 5 |
| Part 2 | Disease Progression | 8 |
| Part 2 | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Ridaforolimus 40 mg |
|---|---|
| Age, Continuous | 51.3 years STANDARD_DEVIATION 12.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 15 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment China | 15 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 15 |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 4 / 15 |
Outcome results
Primary
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.
Time frame: Cycle 1: Predose on Day 1 and at various time points through to 24 hours postdose on Day 19; Cycle 1 is 19 days
Population: The Pharmacokinetic Evaluable population consisted of all participants who complied with the protocol sufficiently to ensure that these data will likely exhibit the effects of treatment according to the underlying scientific model and who had blood samples with concentrations above the lower limit of quantitation.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ridaforolimus 40 mg | Apparent Terminal Half-life (t1/2) of Ridaforolimus: Cycle 1 (Cycle 1 is 19 Days) | 52.9 Hours |
Primary
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.
Time frame: 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
Population: The Pharmacokinetic Evaluable population consisted of all participants who complied with the protocol sufficiently to ensure that these data will likely exhibit the effects of treatment according to the underlying scientific model and who had blood samples with concentrations above the lower limit of quantitation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ridaforolimus 40 mg | Area Under the Curve From 0 to 24 Hours (AUC0-24hr) of Ridaforolimus: Day 1, Day 19 | Day 1 | 1846 ng*hr/mL |
| Ridaforolimus 40 mg | Area Under the Curve From 0 to 24 Hours (AUC0-24hr) of Ridaforolimus: Day 1, Day 19 | Day 19 | 2014 ng*hr/mL |
Primary
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-∞.
Time frame: Cycle 1: Predose on Day 1 and at various time points through to 24 hours postdose on Day 19; Cycle 1 is 19 days
Population: The Pharmacokinetic Evaluable population consisted of all participants who complied with the protocol sufficiently to ensure that these data will likely exhibit the effects of treatment according to the underlying scientific model and who had blood samples with concentrations above the lower limit of quantitation.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ridaforolimus 40 mg | Area Under the Curve From 0 to Infinity (AUC0-∞) of Ridaforolimus: Cycle 1 (Cycle 1 is 19 Days) | 3648 ng*hr/mL |
Primary
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.
Time frame: 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
Population: The Pharmacokinetic Evaluable population consisted of all participants who complied with the protocol sufficiently to ensure that these data will likely exhibit the effects of treatment according to the underlying scientific model and who had blood samples with concentrations above the lower limit of quantitation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ridaforolimus 40 mg | Concentration at 24 Hours (C24hr) of Ridaforolimus: Day 1, Day 19 | Day 1 | 34.8 ng/mL |
| Ridaforolimus 40 mg | Concentration at 24 Hours (C24hr) of Ridaforolimus: Day 1, Day 19 | Day 19 | 49.7 ng/mL |
Primary
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.
Time frame: Cycle 1 Day 1: Predose and at various time points up to 24 hours postdose on Day 1; Cycle 1 is 19 days
Population: The Pharmacokinetic Evaluable population consisted of all participants who complied with the protocol sufficiently to ensure that these data will likely exhibit the effects of treatment according to the underlying scientific model and who had blood samples with concentrations above the lower limit of quantitation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ridaforolimus 40 mg | Lag Time (Tlag) of Ridaforolimus: Day 1 | 2.00 Hours |
Primary
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.
Time frame: 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
Population: The Pharmacokinetic Evaluable population consisted of all participants who complied with the protocol sufficiently to ensure that these data will likely exhibit the effects of treatment according to the underlying scientific model and who had blood samples with concentrations above the lower limit of quantitation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Ridaforolimus 40 mg | Maximum Concentration (Cmax) of Ridaforolimus: Day 1, Day 19 | Day 1 | 210 ng/mL |
| Ridaforolimus 40 mg | Maximum Concentration (Cmax) of Ridaforolimus: Day 1, Day 19 | Day 19 | 167 ng/mL |
Primary
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.
Time frame: 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
Population: The Pharmacokinetic Evaluable population consisted of all participants who complied with the protocol sufficiently to ensure that these data will likely exhibit the effects of treatment according to the underlying scientific model and who had blood samples with concentrations above the lower limit of quantitation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ridaforolimus 40 mg | Time to Maximum Concentration (Tmax) of Ridaforolimus: Day 1, Day 19 | Day 1 | 4.03 Hours |
| Ridaforolimus 40 mg | Time to Maximum Concentration (Tmax) of Ridaforolimus: Day 1, Day 19 | Day 19 | 4.00 Hours |
Secondary
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.
Time frame: From first dose up to 30 days after last dose (Up to 26 weeks)
Population: The Safety Population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ridaforolimus 40 mg | Number of Participants Experiencing Clinical and Laboratory Adverse Events (AEs) | Clinical & Laboratory AEs | 15 Participants |
| Ridaforolimus 40 mg | Number of Participants Experiencing Clinical and Laboratory Adverse Events (AEs) | Drug-related AEs | 15 Participants |
| Ridaforolimus 40 mg | Number of Participants Experiencing Clinical and Laboratory Adverse Events (AEs) | Serious AEs (SAEs) | 4 Participants |