Solid Tumors
Conditions
Keywords
advanced/metastatic, solid tumors, Selumetinib
Brief summary
This is a multicenter, worldwide, open-label study of MK-8353 in combination with selumetinib in participants with histologically or cytologically confirmed diagnosis of advanced solid tumor. This study will evaluate the safety, tolerability, and exploratory efficacy of MK-8353 in combination with selumetinib.
Detailed description
As specified by Phase 1 protocol-flexible language, modifications to the dose or dosing regimen can be made to achieve the scientific goals of the trial objectives and/or ensure appropriate safety of the trial participants. The proposed doses may be adjusted based on evaluation of safety, tolerability, and pharmacokinetic data.
Interventions
DRUGMK-8353
Participants will receive MK-8353 orally twice daily (BID), escalated sequentially from 50 mg to 250 mg.
DRUGSelumetinib
Participants will receive selumetinib orally BID, escalated sequentially from 25 mg to 75 mg.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Groups of participants are assigned to receive interventions based on prior milestones being reached in the study, such as in some dose escalation and adaptive design studies.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a histologically- or cytologically-documented, locally-advanced or metastatic solid tumor by pathology report and have received, or been intolerant to, all treatment known to confer clinical benefit. * Provide an archival or newly obtained tumor tissue sample and blood samples for assessment of proto-oncogene rat sarcoma virus (RAS)/rapidly accelerated fibrosarcoma (RAF) mutation and for biomarker analysis. * Have at least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) on imaging studies (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) as assessed by the investigator/local radiology review. * Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. (Obtain within 7 days prior to first dose of study treatment.) * Have the ability to swallow and retain oral medication. * Demonstrate adequate organ function. * Male participants must agree to use an acceptable contraception during the treatment period and for at least 120 days after the last dose of study intervention and refrain from donating sperm during this period. * Female participants must not be pregnant, not breastfeeding, and either not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the study's contraceptive guidance during the treatment period and for at least 120 days, after the last dose of study intervention.
Exclusion criteria
* Have had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) prior to the first dose of study treatment, or has not recovered to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier (this includes participants with previous immunomodulatory therapy with residual immune-related AEs). * Have clinically active central nervous system metastases and/or carcinomatous meningitis. * Have an active infection requiring therapy. * Have known human immunodeficiency virus (HIV) and/or Hepatitis B or C infections, or known to be positive for Hepatitis B antigen (HBsAg)/ Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) or Hepatitis C Antibody or ribonucleic acid (RNA). * Have clinically significant cardiovascular disease as defined by study criteria. * Have a history of thromboembolic or cerebrovascular events within 6 months prior to treatment start, including transient ischemic attacks (TIAs), cerebrovascular accidents (CVAs), deep vein thrombosis, or pulmonary embolism. * Have neuromuscular disorders associated with an elevated creatine kinase (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy). * Have one or more study-defined ophthalmological findings/conditions. * Have a known history of Gilbert's Syndrome. * Have a history or current evidence of a gastrointestinal (GI) condition (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis) or impaired liver function or diseases that in the opinion of the investigator may significantly alter the absorption or metabolism of oral medications. * Have a known psychiatric or substance abuse disorder, or any other cognitive disorder that would interfere with the participant's ability to cooperate with the requirements of the study. * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 120 days after the last dose of study treatment. * Received prior therapy with a mitogen activated protein kinase (MEK) inhibitor (e.g., cobimetinib, trametinib), or an extracellular signal-regulated kinase (ERK) inhibitor (e.g., MK-8353, GCD-0994, ulixertinib), or a proto-oncogene BRAF inhibitor (e.g., dabrafenib, vemurafenib). * Is currently participating and receiving study treatment in a study of an investigational agent or has participated and received study treatment in a study of an investigational agent or has used an investigational device within 28 days of administration of selumetinib. * Have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to agents and/or excipients used in the study. * A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Dose Limiting Toxicities | Cycle 1 (3-week Cycle) (Up to 3 weeks) | A dose limiting toxicity (DLT) is defined as any hematologic or non-hematologic toxicity ≥Grade 3 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The occurrence of any of the designated toxicities during Cycle 1 (3-week cycle) were considered a DLT, if assessed by the investigator to be possibly, probably, or definitely related to study treatment administration. The number of participants experiencing DLTs was assessed. |
| Number of Participants Experiencing Adverse Events | ~90 days after last treatment dose (up to ~45 weeks) | An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants experiencing AEs was assessed. |
| Number of Participants Discontinuing Study Treatment Due to AEs | Up to ~33 weeks | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants discontinuing study treatment due to AEs was assessed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax for Selumetinib | Study Days 1 and 4 of Cycle 1 (3-week cycle) at pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose | Blood samples were collected to determine the Cmax which is the measure of the maximum amount of drug in the plasma after the dose is given. |
| Minimum Observed Plasma Concentration for MK-8353 | Study Days 1 and 4 of Cycles 1 and 2 (3-week cycles). For Cycle 1, pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose; and for Cycle 2 pre-dose, and at 1 and 4 hours post-dose | Blood samples were collected to determine the minimum observed plasma concentration (Cmin) which is the minimum amount of drug in the plasma after the dose is given. In cases where Cmin values were below the limit of quantification (BLOQ), arithmetic mean (percent coefficient of variation \[%CV\]) was reported instead of geometric mean (percent geometric coefficient of variation \[%GCV\]), since geometric mean (%GCV) was not calculable. In cases where all Cmin values were BLOQ, mean was not calculable and indicated as NA. |
| AUC0-12 for Selumetinib | Study Days 1 and 4 of Cycle 1 (3-week cycle) at pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose | Blood samples were collected to determine the AUC0-12. AUC is a measure of the amount of drug in the blood over time. |
| Area Under the Plasma Concentration-Time Curve for MK-8353 From Time 0 to 12 Hours | Study Days 1 and 4 of Cycle 1 (3-week cycle) at pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose | Blood samples were collected to determine the area under the curve from time 0 to 12 hours (AUC0-12). AUC is a measure of the amount of drug in the blood over time. |
| Cmin for Selumetinib | Study Days 1 and 4 of Cycles 1 and 2 (3-week cycles). For Cycle 1, pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose; and for Cycle 2 pre-dose, and at 1 and 4 hours post-dose | Blood samples were collected to determine the Cmin which is the minimum amount of drug in the plasma after the dose is given. In cases where Cmin values were BLOQ, arithmetic mean (%CV) was reported instead of geometric mean (%GCV), since geometric mean (%GCV) was not calculable. In cases where all Cmin values were BLOQ, mean was not calculable and indicated as NA. |
| Maximum Observed Plasma Concentration for MK-8353 | Study Days 1 and 4 of Cycle 1 (3-week cycle) at pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose | Blood samples were collected to determine the maximum observed plasma concentration (Cmax) which is the measure of the maximum amount of drug in the plasma after the dose is given. |
Countries
Canada, Switzerland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MK-8353 50 mg + Selumetinib 25 mg Participants received 50 mg twice daily (BID) of MK-8353 and 25 mg selumetinib orally with 4 days on and 3 days off until disease progression or discontinuation. | 3 |
| MK-8353 100 mg + Selumetinib 50 mg Participants received 100 mg BID of MK-8353 and 50 mg selumetinib orally with 4 days on and 3 days off until disease progression or discontinuation. | 12 |
| MK-8353 150 mg + Selumetinib 75 mg Participants received 150 mg BID of MK-8353 and 75 mg selumetinib orally with 4 days on and 3 days off until disease progression or discontinuation. | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 3 | 7 | 4 |
| Overall Study | Lost to Follow-up | 0 | 2 | 0 |
| Overall Study | Sponsor Decision | 0 | 2 | 8 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 3 |
Baseline characteristics
| Characteristic | MK-8353 50 mg + Selumetinib 25 mg | MK-8353 100 mg + Selumetinib 50 mg | MK-8353 150 mg + Selumetinib 75 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 57.0 Years STANDARD_DEVIATION 8.2 | 58.6 Years STANDARD_DEVIATION 13.3 | 60.2 Years STANDARD_DEVIATION 16.1 | 59.2 Years STANDARD_DEVIATION 14.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 12 Participants | 15 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 2 Participants | 11 Participants | 13 Participants | 26 Participants |
| Sex: Female, Male Female | 0 Participants | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 8 / 12 | 6 / 15 |
| other Total, other adverse events | 3 / 3 | 11 / 12 | 15 / 15 |
| serious Total, serious adverse events | 0 / 3 | 3 / 12 | 4 / 15 |
Outcome results
Primary
Number of Participants Discontinuing Study Treatment Due to AEs
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants discontinuing study treatment due to AEs was assessed.
Time frame: Up to ~33 weeks
Population: The analysis population included all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-8353 50 mg + Selumetinib 25 mg | Number of Participants Discontinuing Study Treatment Due to AEs | 0 Participants |
| MK-8353 100 mg + Selumetinib 50 mg | Number of Participants Discontinuing Study Treatment Due to AEs | 3 Participants |
| MK-8353 150 mg + Selumetinib 75 mg | Number of Participants Discontinuing Study Treatment Due to AEs | 1 Participants |
Primary
Number of Participants Experiencing Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants experiencing AEs was assessed.
Time frame: ~90 days after last treatment dose (up to ~45 weeks)
Population: The analysis population included all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-8353 50 mg + Selumetinib 25 mg | Number of Participants Experiencing Adverse Events | 3 Participants |
| MK-8353 100 mg + Selumetinib 50 mg | Number of Participants Experiencing Adverse Events | 12 Participants |
| MK-8353 150 mg + Selumetinib 75 mg | Number of Participants Experiencing Adverse Events | 15 Participants |
Primary
Number of Participants Experiencing Dose Limiting Toxicities
A dose limiting toxicity (DLT) is defined as any hematologic or non-hematologic toxicity ≥Grade 3 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The occurrence of any of the designated toxicities during Cycle 1 (3-week cycle) were considered a DLT, if assessed by the investigator to be possibly, probably, or definitely related to study treatment administration. The number of participants experiencing DLTs was assessed.
Time frame: Cycle 1 (3-week Cycle) (Up to 3 weeks)
Population: The analysis population included all participants who received at least 1 dose of study treatment who met the criteria for DLT evaluability (finished Cycle 1 without a DLT or experienced a DLT in Cycle 1).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-8353 50 mg + Selumetinib 25 mg | Number of Participants Experiencing Dose Limiting Toxicities | 0 Participants |
| MK-8353 100 mg + Selumetinib 50 mg | Number of Participants Experiencing Dose Limiting Toxicities | 1 Participants |
| MK-8353 150 mg + Selumetinib 75 mg | Number of Participants Experiencing Dose Limiting Toxicities | 7 Participants |
Secondary
Area Under the Plasma Concentration-Time Curve for MK-8353 From Time 0 to 12 Hours
Blood samples were collected to determine the area under the curve from time 0 to 12 hours (AUC0-12). AUC is a measure of the amount of drug in the blood over time.
Time frame: Study Days 1 and 4 of Cycle 1 (3-week cycle) at pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose
Population: The analysis population included all participants who were compliant with the study procedures and had available MK-8353 AUC data from at least 1 treatment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8353 50 mg + Selumetinib 25 mg | Area Under the Plasma Concentration-Time Curve for MK-8353 From Time 0 to 12 Hours | MK-8353, Cycle 1, Day 1 | 14.3 hr*μmol/liter | Geometric Coefficient of Variation 62.7 |
| MK-8353 50 mg + Selumetinib 25 mg | Area Under the Plasma Concentration-Time Curve for MK-8353 From Time 0 to 12 Hours | MK-8353, Cycle 1, Day 4 | 16.7 hr*μmol/liter | Geometric Coefficient of Variation 365.7 |
| MK-8353 100 mg + Selumetinib 50 mg | Area Under the Plasma Concentration-Time Curve for MK-8353 From Time 0 to 12 Hours | MK-8353, Cycle 1, Day 1 | 9.66 hr*μmol/liter | Geometric Coefficient of Variation 50.7 |
| MK-8353 100 mg + Selumetinib 50 mg | Area Under the Plasma Concentration-Time Curve for MK-8353 From Time 0 to 12 Hours | MK-8353, Cycle 1, Day 4 | 19.0 hr*μmol/liter | Geometric Coefficient of Variation 36.9 |
| MK-8353 150 mg + Selumetinib 75 mg | Area Under the Plasma Concentration-Time Curve for MK-8353 From Time 0 to 12 Hours | MK-8353, Cycle 1, Day 1 | 13.7 hr*μmol/liter | Geometric Coefficient of Variation 32.8 |
| MK-8353 150 mg + Selumetinib 75 mg | Area Under the Plasma Concentration-Time Curve for MK-8353 From Time 0 to 12 Hours | MK-8353, Cycle 1, Day 4 | 20.9 hr*μmol/liter | Geometric Coefficient of Variation 60.6 |
Secondary
AUC0-12 for Selumetinib
Blood samples were collected to determine the AUC0-12. AUC is a measure of the amount of drug in the blood over time.
Time frame: Study Days 1 and 4 of Cycle 1 (3-week cycle) at pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose
Population: The analysis population included all participants who were compliant with the study procedures and had available selumetinib AUC data from at least 1 treatment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8353 50 mg + Selumetinib 25 mg | AUC0-12 for Selumetinib | Selumetinib, Cycle 1, Day 1 | 2.99 hr*μmol/liter | Geometric Coefficient of Variation 27.2 |
| MK-8353 50 mg + Selumetinib 25 mg | AUC0-12 for Selumetinib | Selumetinib, Cycle 1, Day 4 | 3.80 hr*μmol/liter | Geometric Coefficient of Variation 24.6 |
| MK-8353 100 mg + Selumetinib 50 mg | AUC0-12 for Selumetinib | Selumetinib, Cycle 1, Day 1 | 5.20 hr*μmol/liter | Geometric Coefficient of Variation 63.2 |
| MK-8353 100 mg + Selumetinib 50 mg | AUC0-12 for Selumetinib | Selumetinib, Cycle 1, Day 4 | 6.28 hr*μmol/liter | Geometric Coefficient of Variation 75.3 |
| MK-8353 150 mg + Selumetinib 75 mg | AUC0-12 for Selumetinib | Selumetinib, Cycle 1, Day 1 | 10.9 hr*μmol/liter | Geometric Coefficient of Variation 49.1 |
| MK-8353 150 mg + Selumetinib 75 mg | AUC0-12 for Selumetinib | Selumetinib, Cycle 1, Day 4 | 12.7 hr*μmol/liter | Geometric Coefficient of Variation 31.5 |
Secondary
Cmax for Selumetinib
Blood samples were collected to determine the Cmax which is the measure of the maximum amount of drug in the plasma after the dose is given.
Time frame: Study Days 1 and 4 of Cycle 1 (3-week cycle) at pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose
Population: The analysis population included all participants who were compliant with the study procedures and had available selumetinib Cmax data from at least 1 treatment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8353 50 mg + Selumetinib 25 mg | Cmax for Selumetinib | Selumetinib, Cycle 1,Day 1 | 1.01 μmol/liter | Geometric Coefficient of Variation 29.7 |
| MK-8353 50 mg + Selumetinib 25 mg | Cmax for Selumetinib | Selumetinib, Cycle 1, Day 4 | 1.04 μmol/liter | Geometric Coefficient of Variation 13.3 |
| MK-8353 100 mg + Selumetinib 50 mg | Cmax for Selumetinib | Selumetinib, Cycle 1,Day 1 | 1.96 μmol/liter | Geometric Coefficient of Variation 91.1 |
| MK-8353 100 mg + Selumetinib 50 mg | Cmax for Selumetinib | Selumetinib, Cycle 1, Day 4 | 1.44 μmol/liter | Geometric Coefficient of Variation 123.6 |
| MK-8353 150 mg + Selumetinib 75 mg | Cmax for Selumetinib | Selumetinib, Cycle 1,Day 1 | 3.37 μmol/liter | Geometric Coefficient of Variation 57.1 |
| MK-8353 150 mg + Selumetinib 75 mg | Cmax for Selumetinib | Selumetinib, Cycle 1, Day 4 | 2.37 μmol/liter | Geometric Coefficient of Variation 107.5 |
Secondary
Cmin for Selumetinib
Blood samples were collected to determine the Cmin which is the minimum amount of drug in the plasma after the dose is given. In cases where Cmin values were BLOQ, arithmetic mean (%CV) was reported instead of geometric mean (%GCV), since geometric mean (%GCV) was not calculable. In cases where all Cmin values were BLOQ, mean was not calculable and indicated as NA.
Time frame: Study Days 1 and 4 of Cycles 1 and 2 (3-week cycles). For Cycle 1, pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose; and for Cycle 2 pre-dose, and at 1 and 4 hours post-dose
Population: The analysis population included all participants who were compliant with the study procedures and had available selumetinib Cmin data from at least 1 treatment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8353 50 mg + Selumetinib 25 mg | Cmin for Selumetinib | Selumetinib, Cycle 1, Day 1 | NA μmol/liter | — |
| MK-8353 50 mg + Selumetinib 25 mg | Cmin for Selumetinib | Selumetinib, Cycle 1, Day 4 | 0.101 μmol/liter | Geometric Coefficient of Variation 35.1 |
| MK-8353 50 mg + Selumetinib 25 mg | Cmin for Selumetinib | Selumetinib, Cycle 2, Day 1 | NA μmol/liter | — |
| MK-8353 50 mg + Selumetinib 25 mg | Cmin for Selumetinib | Selumetinib, Cycle 2, Day 4 | 0.127 μmol/liter | Geometric Coefficient of Variation 74.6 |
| MK-8353 100 mg + Selumetinib 50 mg | Cmin for Selumetinib | Selumetinib, Cycle 2, Day 4 | 0.174 μmol/liter | Geometric Coefficient of Variation 80.3 |
| MK-8353 100 mg + Selumetinib 50 mg | Cmin for Selumetinib | Selumetinib, Cycle 1, Day 1 | NA μmol/liter | — |
| MK-8353 100 mg + Selumetinib 50 mg | Cmin for Selumetinib | Selumetinib, Cycle 2, Day 1 | 0.00202 μmol/liter | Geometric Coefficient of Variation 232.9 |
| MK-8353 100 mg + Selumetinib 50 mg | Cmin for Selumetinib | Selumetinib, Cycle 1, Day 4 | 0.265 μmol/liter | Geometric Coefficient of Variation 38.9 |
| MK-8353 150 mg + Selumetinib 75 mg | Cmin for Selumetinib | Selumetinib, Cycle 2, Day 4 | 0.257 μmol/liter | Geometric Coefficient of Variation 47.5 |
| MK-8353 150 mg + Selumetinib 75 mg | Cmin for Selumetinib | Selumetinib, Cycle 1, Day 4 | 0.456 μmol/liter | Geometric Coefficient of Variation 160.1 |
| MK-8353 150 mg + Selumetinib 75 mg | Cmin for Selumetinib | Selumetinib, Cycle 2, Day 1 | 0.00124 μmol/liter | Geometric Coefficient of Variation 215.7 |
| MK-8353 150 mg + Selumetinib 75 mg | Cmin for Selumetinib | Selumetinib, Cycle 1, Day 1 | NA μmol/liter | — |
Secondary
Maximum Observed Plasma Concentration for MK-8353
Blood samples were collected to determine the maximum observed plasma concentration (Cmax) which is the measure of the maximum amount of drug in the plasma after the dose is given.
Time frame: Study Days 1 and 4 of Cycle 1 (3-week cycle) at pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose
Population: The analysis population included all participants who were compliant with the study procedures and had available MK-8353 Cmax data from at least 1 treatment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8353 50 mg + Selumetinib 25 mg | Maximum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 1, Day 1 | 1.24 μmol/liter | Geometric Coefficient of Variation 138.4 |
| MK-8353 50 mg + Selumetinib 25 mg | Maximum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 1, Day 4 | 1.87 μmol/liter | Geometric Coefficient of Variation 149.4 |
| MK-8353 100 mg + Selumetinib 50 mg | Maximum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 1, Day 1 | 1.65 μmol/liter | Geometric Coefficient of Variation 60.9 |
| MK-8353 100 mg + Selumetinib 50 mg | Maximum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 1, Day 4 | 2.53 μmol/liter | Geometric Coefficient of Variation 51.5 |
| MK-8353 150 mg + Selumetinib 75 mg | Maximum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 1, Day 1 | 2.95 μmol/liter | Geometric Coefficient of Variation 62.3 |
| MK-8353 150 mg + Selumetinib 75 mg | Maximum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 1, Day 4 | 3.61 μmol/liter | Geometric Coefficient of Variation 80.9 |
Secondary
Minimum Observed Plasma Concentration for MK-8353
Blood samples were collected to determine the minimum observed plasma concentration (Cmin) which is the minimum amount of drug in the plasma after the dose is given. In cases where Cmin values were below the limit of quantification (BLOQ), arithmetic mean (percent coefficient of variation \[%CV\]) was reported instead of geometric mean (percent geometric coefficient of variation \[%GCV\]), since geometric mean (%GCV) was not calculable. In cases where all Cmin values were BLOQ, mean was not calculable and indicated as NA.
Time frame: Study Days 1 and 4 of Cycles 1 and 2 (3-week cycles). For Cycle 1, pre-dose and at 1, 2, 4, 6 hours, and between 8 and 12 hours post-dose; and for Cycle 2 pre-dose, and at 1 and 4 hours post-dose
Population: The analysis population included all participants who were compliant with the study procedures and had available MK-8353 Cmin data from at least 1 treatment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8353 50 mg + Selumetinib 25 mg | Minimum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 1, Day 1 | NA μmol/liter | — |
| MK-8353 50 mg + Selumetinib 25 mg | Minimum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 1 Day 4 | 0.695 μmol/liter | Geometric Coefficient of Variation 222.6 |
| MK-8353 50 mg + Selumetinib 25 mg | Minimum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 2 Day 1 | 0.0361 μmol/liter | Geometric Coefficient of Variation 173.2 |
| MK-8353 50 mg + Selumetinib 25 mg | Minimum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 2 Day 4 | 0.598 μmol/liter | Geometric Coefficient of Variation 172.6 |
| MK-8353 100 mg + Selumetinib 50 mg | Minimum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 2 Day 4 | 0.995 μmol/liter | Geometric Coefficient of Variation 90.7 |
| MK-8353 100 mg + Selumetinib 50 mg | Minimum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 1, Day 1 | NA μmol/liter | — |
| MK-8353 100 mg + Selumetinib 50 mg | Minimum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 2 Day 1 | 0.0313 μmol/liter | Geometric Coefficient of Variation 191 |
| MK-8353 100 mg + Selumetinib 50 mg | Minimum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 1 Day 4 | 1.10 μmol/liter | Geometric Coefficient of Variation 50.6 |
| MK-8353 150 mg + Selumetinib 75 mg | Minimum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 2 Day 4 | 1.47 μmol/liter | Geometric Coefficient of Variation 84.8 |
| MK-8353 150 mg + Selumetinib 75 mg | Minimum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 1 Day 4 | 1.47 μmol/liter | Geometric Coefficient of Variation 455.5 |
| MK-8353 150 mg + Selumetinib 75 mg | Minimum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 2 Day 1 | 0.0166 μmol/liter | Geometric Coefficient of Variation 189.7 |
| MK-8353 150 mg + Selumetinib 75 mg | Minimum Observed Plasma Concentration for MK-8353 | MK-8353, Cycle 1, Day 1 | NA μmol/liter | — |