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Trametinib

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The proposed treatment schedule of GSK1120212 is continuous daily dosing. At the initiation of dosing, a loading dose will be given prior to starting continuous dosing (maintenance dose).

Alterations to the dose and schedule will be based on emerging PK, PD, and tolerability data. The goal will be to define a regimen that is well tolerated and provides adequate PK and PD. This will be the recommended Phase II schedule.

A dose determined by Phase I to further evaulate the safety profile, PK, PD, and clinical activity of GSK1120212.

Starting dose based on GSK protocol MEK111054 and then dose escalation based on Dose Limiting Toxicities per protocol.

GSK1120212

Dose will be maximum tolerated dose based on Phase I results.

GSK Clinical Trials

MEK111759 is a dose-escalation, Phase I/II, open-label study to determine the recommended dose and regimen for the orally administered MEK inhibitor GSK1120212 in subjects with relapsed or refractory leukemias. The recommended dose and regimen will be selected based on the safety, pharmacokinetic, and pharmacodynamic profiles. This study will identify the maximum tolerated and recommended Phase II doses using a dose-escalation procedure. Dose escalations will continue based on predefined parameters until a maximum tolerated dose is established. In Phase II, the clinical efficacy of GSK1120212 in subjects with relapsed or refractory leukaemias (AML, MDS or CMML) will be determined.

Open-label Study to Evaluate the Safety, PK, and PD of MEK Inhibitor GSK1120212 in Subjects With Relapsed or Refractory Leukemias

An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor GSK1120212 in Subjects With Relapsed or Refractory Leukemias

An AE is any untoward medical occurrence in a participant (par.) or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.

Hematology and clinical chemistry data were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 3.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Hematology tests where the toxicity grade is defined by NCI-CTCAE includes hemoglobin, international normalized ratio (INR), lymphocytes, total neutrophils, platelet count, and partial thromboplastin time (PTT). Participants with missing baseline grades were assumed to have a baseline grade of 0. Only those participants (par.) with laboratory values for worst-case on-therapy (defined as the worst shift that occurred at any time during the treatment period) are presented.

Hematology and clinical chemistry data were summarized according to NCI-CTCAE grade, version 3.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Clinical chemistry tests where the toxicity grade is defined by NCI-CTCAE includes albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase (AST), total bilirubin, calcium, creatinine, glucose, bicarbonate, potassium, magnesium, sodium, and phosphorus. Participants with missing Baseline grades were assumed to have a Baseline grade of 0. Only those participants (par.) with laboratory values for worst-case on-therapy are presented.

Change from Baseline in heart rate is categorized as decrease to \<60 beats per minute (bpm), change to normal or no change, and increase to \>100 bpm. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants are counted twice if the participant heart rate value decreased to \<60 bpm and increased to \>100 bpm post-baseline. Only those participants (par.) with heart rate values for worst-case on-therapy are presented.

Change from Baseline in systolic blood pressure (SBP) is categorized as: Grade 0 (\<120 millimeters of mercury \[mmHg\]), Grade 1 (120-139 mmHg), Grade 2 (140-159 mmHg), and Grade 3/4 (\>=160 mmHg). Change from Baseline in diastolic blood pressure (DBP) is categorized as: Grade 0 (\<80 mmHg), Grade 1 (80-89 mmHg), Grade 2 (90-99 mmHg), and Grade 3/4 (\>=100 mmHg). An increase is defined as an increase in the CTCAE grade relative to the Baseline grade. Participants with missing Baseline values are assumed to have a Baseline value of grade 0. Only those participants (par.) with blood pressure values for worst-case on-therapy are presented.

Change from Baseline in temperature is categorized as a decrease to \<=35 degrees celsius (C), change to normal or no change, and increase to \>=38 degrees C. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants (par.) are counted twice if the participant temperature value decreased to \<=35 degrees C and increased to \>=38 degrees C post-Baseline. Only those participants with temperature values for worst-case on-therapy are presented.

Overall response rate (ORR=CR+CRp+Marrow CR+MLFS+PR) was calculated from the investigator's assessment of response recorded within the first eight weeks of treatment. CR includes complete remission. Complete remission is a state in which the participant must be free of all symptoms related to leukemia and have an absolute neutrophil count \>=1 x 10\^9/L, platelet count \>=100 x 10\^9/L, and normal marrow differential (\<=5% blasts). PR includes partial remission. Partial remission is a state in which the participant has a CR with 6 to 25% abnormal cells in the marrow or 50% decrease in bone marrow blasts. CRp is as per CR but platelet count \<100 x 10\^9/L. MLFS is a state in which the participant has a normal marrow differential (\<5% blasts), neutrophil, and platelet counts are not considered.

Area under the concentration-time (AUC) curve from time zero (pre-dose) to 24 hours (AUC\[0-24\]) for Cycle 1 Day 1 (C1D1), from time zero to the last time of a quantifiable concentration (AUC\[0-t\]) for C1D1 and Cylce 1 Day 15 (C1D15) and AUC curve over the dosing interval AUC\[0-tau\] for C1D15 were measured. Blood samples for PK analysis were taken on Day 1 and Day 15 (within 30 minutes \[min\] before study drug administration) and at 0.5 hour (h), 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 24 h post-dose. All other PK sampling were done pre-dose (i.e., within 30 min before study drug administration).

Cmax is defined as the maximum observed concentration of GSK1120212 and was measured for C1D1 and C1D15. Cmin is defined as the minimal observed concentration of GSK1120212 and was measured for C1D15. Blood samples for PK analysis were taken on Day 1 and Day 15 (within 30 min before study drug administration) and at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 24 h post-dose. All other PK sampling were done pre-dose (i.e., within 30 min before study drug administration).

t1/2 is defined as terminal phase half-life, which is the time required for the amount of the drug in the body to decrease by half and was measured for C1D1. t1/2eff. is defined as the effective half-life and was measured for C1D15. Blood samples for PK analysis were taken on Day 1 and Day 15 (within 30 min before study drug administration) and at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 24 h post-dose. All other PK sampling were done pre-dose (i.e., within 30 min before study drug administration).

Tmax is defined as the time to reach the observed maximum concentration and was measured for C1D1 and C1D15. Blood samples for PK analysis were taken on Day 1 and Day 15 (within 30 min before study drug administration) and at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 24 h post-dose. All other PK sampling were done pre-dose (i.e., within 30 min before study drug administration).

AR is the ratio of the Day 15 AUC0-tau (0 hour to last dose interval) and Day 1 AUC0-tau (AUCtau C1D15/AUCtau C1D1). Blood samples for PK analysis were taken on Day 1 and Day 15 (within 30 min before study drug administration) and at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 24 h post-dose. All other PK sampling were done pre-dose (i.e., within 30 min before study drug administration).

Ctau is the pre-dose (trough) concentration at the end of the dosing interval and was measured for Cycle 1 Day 15 (C1D15), Cycle 2 Day 1(C2D1), Cylce 3 Day 1 (C3D1), Cycle 4 Day 1 (C4D1), Cycle 5 Day 1 (C5D1), Cycle 6 Day 1 (C6D1), Cycle 7 Day 1 (C7D1), Cycle 8 Day 1 (C8D1), Cycle 9 Day 1 (C9D1), Cycle 10 Day 1 (C10D1), Cycle 11 Day 1 (C11D1) and Cycle 12 Day 1 (C12D1). Blood samples for PK analysis were collected pre-dose (i.e., no later than 15 min prior to dosing).

Overall survival is defined as the time from the start of study treatment (GSK1120212) until death due to any cause. For the analysis of overall survival, the last date of known contact was used for those participants who had not died at the time of analysis; such participants were considered censored.

GlaxoSmithKline

SAEs and non-serious AEs were collected in members of the All treated Population, comprised of all participants (par.) who received at least one dose of study medication. One Phase 2 par. was incorrectly dosed (received \<2 mg \[0.5 mg\]); thus, 6 par. receiving GSK1120212 \<2 mg OD were analyzed. .

Participants with relapsed or refractory leukemias received either GSK1120212 3 mg LD followed by 1 mg OD (3/1 mg LD/OD), or 1 mg OD as a continuous dose.

GSK1120212 <2 mg OD

Participants with relapsed or refractory leukemias received GSK1120212 2 mg OD as a continuous dose.

GSK1120212 2 mg OD

Participants with relapsed or refractory leukemias received either GSK1120212 3 milligrams (mg) loading dose (LD) followed by 1 mg once daily (OD) (3/1 mg LD/OD), or 1 mg OD as a continuous dose.

Participants with relapsed or refractory AML or MDS with RAS mutation received GSK1120212 2 mg OD as a continuous dose.

Cohort 1: AML/MDS With RAS Mutation

Participants with relapsed or refractory AML or MDS or CMML with RAS wt or unknown mutation received GSK1120212 2 mg OD as a continuous dose.

Cohort 2: AML/MDS/CMML With RAS wt/Unknown

Participants with relapsed or refractory CMML with RAS mutation received GSK1120212 2 mg OD as a continuous dose.

Cohort 3: CMML With RAS Mutation

Total

Age, Continuous

Sex: Female, Male

African American/African Heritage

White - White/Caucasian/European Heritage

Asian - Central/South Asian Heritage

Asian - Japanese Heritage

Asian - South East Asian Heritage

Missing

Race/Ethnicity, Customized

GSK Response Center

Any AE

Any SAE

All Treated Population: all participants who received at least one dose of study medication. Safety data was evaluated based on this population. One Phase 2 par. was incorrectly dosed (received \<2 mg \[0.5 mg\]); thus, 6 par. receiving GSK1120212 \<2 mg OD were analyzed.

Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) by Dose

Hemoglobin (Low), Grade 3, n=6, 91

Hemoglobin (Low), Grade 4, n=6, 91

INR (High), Grade 3, n=6, 75

INR (High), Grade 4, n=6, 75

Lymphocytes (Low), Grade 3, n=6, 90

Lymphocytes (Low), Grade 4, n=6, 90

Total Neutrophils (Low), Grade 3, n=6, 89

Total Neutrophils (Low), Grade 4, n=6, 89

Platelet count (Low), Grade 3, n=6, 91

Platelet count (Low), Grade 4, n=6, 91

PTT (High), Grade 3, n=5, 75

PTT (High), Grade 4, n=5, 75

White Blood Cell count (Low), Grade 3, n=6, 91

White Blood Cell count (Low), Grade 4, n=6, 91

All Treated Population (ATP). Only those par. available at the specified time points were analyzed. Different par. may have been analyzed for different parameters; the overall number analyzed reflects everyone in the ATP. One Phase 2 par. was incorrectly dosed (received \<2 mg \[0.5 mg\]); thus, 6 par. receiving GSK1120212 \<2 mg OD were analyzed.

Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose

Albumin (Low), Grade 3, n=6, 90

Albumin (Low), Grade 4, n=6, 90

Alkaline Phosphatase (High), Grade 3, n=6, 89

Alkaline Phosphatase (High), Grade 4, n=6, 89

Alanine Amino Transferase (High), Grade 3, n=6, 89

Alanine Amino Transferase (High), Grade 4, n=6, 89

AST (High), Grade 3, n=6, 86

AST (High), Grade 4, n=6, 86

Total Bilirubin (High), Grade 3, n=6, 89

Total Bilirubin (High), Grade 4, n=6, 89

Calcium (hypercalcemia), Grade 3, n=6, 91

Calcium (hypercalcemia), Grade 4, n=6, 91

Calcium (hypocalcemia), Grade 3, n=6, 91

Calcium (hypocalcemia), Grade 4, n=6, 91

Creatinine (High), Grade 3, n=6, 91

Creatinine (High), Grade 4, n=6, 91

Glucose (hyperglycemia), Grade 3, n=6, 91

Glucose (hyperglycemia), Grade 4, n=6, 91

Glucose (hypoglycemia), Grade 3, n=6, 91

Glucose (hypoglycemia), Grade 4, n=6, 91

Bicarbonate (Low), Grade 3, n=5, 82

Bicarbonate (Low), Grade 4, n=5, 82

Potassium (hyperkalemia), Grade 3, n=6, 91

Potassium (hyperkalemia), Grade 4, n=6, 91

Potassium (hypokalemia), Grade 3, n=6, 91

Potassium (hypokalemia), Grade 4, n=6, 91

Magnesium (hypermagnesemia), Grade 3, n=6, 88

Magnesium (hypermagnesemia), Grade 4, n=6, 88

Magnesium (hypomagnesemia), Grade 3, n=6, 88

Magnesium (hypomagnesemia), Grade 4, n=6, 88

Sodium (hypernatremia), Grade 3, n=6, 91

Sodium (hypernatremia), Grade 4, n=6, 91

Sodium (hyponatremia), Grade 3, n=6, 91

Sodium (hyponatremia), Grade 4, n=6, 91

Phosphorus, Grade 3, n=6, 88

Phosphorus, Grade 4, n=6, 88

Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose

Decrease to <60, n=6, 90

No Change, n=6, 90

Increase to >100, n=6, 90

Number of Participants With a Change From Baseline in Heart Rate by Dose

DBP, Increase to Grade 1, n=6, 90

DBP, Increase to Grade 2, n=6, 90

DBP, Increase to Grade 3/4, n=6, 90

SBP, Increase to Grade 1, n=6, 90

SBP, Increase to Grade 2, n=6, 90

SBP, Increase to Grade 3/4, n=6, 90

Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose

Decrease to <=35, n=6, 90

Increase to >=38, n=6, 90

Number of Participants With a Change From Baseline in Temperature by Dose

Marrow CR

MLFS

Efficacy Population: all participants included in the All Treated Population who had received at least one dose of 2 mg of study drug in Phase 2. The number of participants for the Cohort 2: AML/MDS/CMML with RAS wt/Unknown treatment group is equal to the 8 participants from Phase 1 plus the 22 participants from Phase 2 (total of 30).

Number of Participants With an Investigator-assessed Best Response (Achieving Complete Response [CR], Marrow CR, Partial Response [PR], Complete Response Without Platelet Recovery [CRp] or Morphologic Leukaemia-free State[MLFS]) by Cohort

C1D1, AUC(0-24), n=3, 2, 9

C1D1, AUC(0-t), n=3, 2, 9

C1D15, AUC(0-t), n=2, 2, 8

C1D15, AUC(0-tau), n=2, 2, 8

Participants with relapsed or refractory leukemias received either GSK1120212 0.5 mg OD or 3/1 mg LD/OD as a continuous dose.

GSK1120212 0.5 mg OD/ 3/1 mg LD/OD

Participants with relapsed or refractory leukemias received GSK1120212 1 mg OD as a continuous dose.

GSK1120212 1 mg OD

Pharmacokinetic Population: all participants included in the All Treated Population for whom a PK sample was obtained and analyzed. Only participants with data available at the indicated time points were analyzed.

AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1

C1D1, Cmax, n=3, 2, 9

C1D15, Cmax , n=2, 2, 8

C1D15, Cmin, n=2, 2, 8

Pharmacokinetic Population. Only participants with data available at the indicated time points were analyzed.

Cmin and Cmax of GSK1120212 in Part 1

C1D1, t1/2, n=3, 1, 8

C1D15, t1/2 eff., n=2, 2, 8

t1/2 at C1D1 and t1/2 Effective (Eff.) at C1D15 of GSK1120212 in Part 1

C1D1, tmax, n=3, 2, 9

C1D15, tmax, n=2, 2, 8

Tmax of GSK1120212 in Part 1

Accumulation Ratio (AR) of GSK1120212 in Part 1

C1D15, n=72

C2D1, n=57

C3D1, n=38

C4D1, n=21

C5D1, n=10

C6D1, n=6

C7D1, n=6

C8D1, n=5

C9D1, n=3

C10D1, n=2

C11D1, n=1

C12D1, n=1

Ctau of GSK1120212 in Part 2

Efficacy Population. The number of participants for the Cohort 2: AML/MDS/CMML with RAS wt/Unknown treatment group is equal to the 8 participants from Phase 1 plus the 22 participants from Phase 2 (total of 30).

Overall Survival by Cohort

GSK1120212 < 2 mg OD

Participants with relapsed or refractory acute myeloid leukemia (AML) or myelodysplasia (MDS) with rat sarcoma (RAS) mutation received GSK1120212 2 mg OD as a continuous dose.

Participants with relapsed or refractory AML or MDS or chronic myelomonocytic leukemia (CMML) with RAS wild type (wt) or unknown mutation received GSK1120212 2 mg OD as a continuous dose.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Open-label Study to Evaluate the Safety, PK, and PD of MEK Inhibitor GSK1120212 in Subjects With Relapsed or Refractory Leukemias	NCT00920140	Cancer	GSK1120212 GSK1120212	18 Years -	GlaxoSmithKline
Open-label Study to Evaluate the Safety, PK, and PD of MEK Inhibitor GSK1120212 in Subjects With Relapsed or Refractory Leukemias	NCT00920140	Cancer	GSK1120212 GSK1120212	18 Years -	GlaxoSmithKline

Spots Global Cancer Trial Database for oncology, gsk1120212, mek inhibitor, hematological malignancies, aml