This is a dose-escalation, Phase I/II, open-label, three-part study. Part 1 is designed to determine the recommended dose and schedule for the orally administered MEK inhibitor trametinib, given together with the CDK4/6 inhibitor palbociclib in subjects with solid tumors. Multiple dose levels of each inhibitor will be tested to determine the recommended dose and schedule. Part 2 will evaluate the effect of the combination on tumor biomarkers safety, and anti-cancer activity in subjects with cutaneous melanoma that do not have a change at BRAFV600. Approximately 100-200 subjects will be enrolled. All subjects will receive trametinib and/or palbociclib until disease progression, death, consent withdrawal or unacceptable adverse event (AE). Data was only collected and analyzed for the Phase I component of the study, the Phase II component of the study was terminated without data collection
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
28
Trametinib is available as a 0.5 mg yellow oval tablet or as a 2.0 mg pink round tablet.
Palbociclib is available as a 75 mg (size 2 sunset yellow) or 100 mg (size 1 sunset yellow/caramel) or 125 mg (size 0 caramel) capsule.
GSK Investigational Site
Boston, Massachusetts, United States
GSK Investigational Site
Nashville, Tennessee, United States
GSK Investigational Site
Houston, Texas, United States
Part 1: Change from baseline in vital signs
Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
Time frame: Up to 36 months
Part 1: Change from baseline in physical examination findings
A complete physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities
Time frame: Up to 36 months
Part 1: Change from baseline in 12-lead electrocardiograms (ECG) assessment
Time frame: Up to 36 months
Part 1: Change from baseline in echocardiogram (ECHO) or Multi Gated Acquisition (MUGA) scans assessment
An ECHO (preferred) or a MUGA scan will be performed at baseline to assess cardiac ejection fraction and cardiac valve morphology for the purpose of study eligibility
Time frame: Up to 36 months
Part 1: Change from baseline in chemistry and hematology laboratory values
Time frame: Up to 36 months
Part 1: Number of subjects with adverse events (AEs)
All subjects (approximately 50)
Time frame: From the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment
Part 1: Composite of pharmacokinetic (PK) parameters following trametinib and palbociclib administration
PK parameters will include: maximum observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve (AUC\[0-t\]), oral clearance (CL/F), minimum observed concentration (Cmin). Blood samples of approximately 2 mL for trametinib and 2 mL for palbociclib (4 mL total) will be collected for PK analysis at each timepoint shown for all subjects (approximately 50)
Time frame: Cycle 1 Day 15 (pre-dose, and 1, 2, 4, 6, 8, and 10 hours post dose) and Cycle 2 Day 15 (pre-dose)
Part 1: Number of subjects with anti-cancer activity
Disease progression and response evaluations will be determined according to the definitions established in the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) for all subjects (approximately 50 in Part 1)
Time frame: Up to 36 months
Part 2: Change from baseline in tumor biomarkers
Change from baseline in biomarkers like pERK, total Rb, Ki67, FoxM1, p16, and CCDN1 will be calculated. These markers will be evaluated in formalin-fixed, paraffin-embedded tissue via immunohistochemistry (IHC)
Time frame: Screening and Cycle 1 Day 15 (pre-dose)
Part 1: GSK1120212 and PD-0332991 PK parameters following repeat-dose administration of trametinib and palbociclib
The following PK parameters will be calculated: Area under the concentration-time curve over the dosing interval (AUC\[0-tau\]), minimum observed concentration (Cmin), pre-dose (trough) concentration at the end of the dosing interval (Ctau), maximum observed concentration (Cmax), time of occurrence of Cmax (tmax), and terminal phase half-life (t1/2) (if data permits)
Time frame: Cycle 1 Day 15 (pre-dose, and 1, 2, 4, 6, 8, and 10 hours post dose) and Cycle 2 Day 15 (pre-dose)
Part 1 and Part 2: Number of subjects with response rate
Subjects whose disease responds (either complete response \[CR\] or partial response \[PR\]), using RECIST Version 1.1 (up to approximately 100 subjects)
Time frame: Up to 36 months for part 1 and 24 months for part 2
Part 1 and Part 2 : Number of subjects with Duration of response (DOR)
up to approximately 100 subjects
Time frame: Up to 36 months for part 1 and 24 months for part 2
Part 1 and Part 2: Number of subjects with Progression-free survival (PFS)
up to approximately 100 subjects
Time frame: Up to 36 months for part 1 and 24 months for part 2
Part 2 : Change from baseline in vital signs
Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate
Time frame: Up to 24 months
Part 2: Change from baseline in physical examination findings
A complete physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities
Time frame: Up to 24 months
Part 2: Change from baseline in 12-lead electrocardiograms (ECG) assessment
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Time frame: Up to 24 months
Part 2: Change from baseline in echocardiogram (ECHO) or Multi Gated Acquisition (MUGA) scans assessment
An ECHO (preferred) or a MUGA scan will be performed at baseline to assess cardiac ejection fraction and cardiac valve morphology for the purpose of study eligibility
Time frame: Up to 24 months
Part 2 : Change from baseline in chemistry and hematology laboratory values
Time frame: Up to 24 months
Part 2 : Number of subjects with adverse events (AEs)
up to 40 subjects
Time frame: From the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment
Part 2: Composite of pharmacokinetic (PK) parameters following trametinib and palbociclib administration
PK parameters will include: Cmax, tmax, AUC(0-t), CL/F, Cmin. Blood samples of approximately 2 mL for trametinib and 2 mL for palbociclib (4 mL total) will be collected for PK analysis (up to 40 subjects)
Time frame: Cycle 1 Day 15