Cancer
Conditions
Keywords
Oncology, GSK1120212, MEK inhibitor, hematological malignancies, AML, CMML, MDS
Brief summary
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.
Interventions
DRUGGSK1120212
Starting dose based on GSK protocol MEK111054 and then dose escalation based on Dose Limiting Toxicities per protocol.
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Phase I * Written informed consent provided. * 18 years old or older. * Subjects must have relapsed/refractory leukemias for which no standard therapies are anticipated to result in a durable remission. Subjects with poor-risk myelodysplasia (MDS) and chronic melomonocytic leukemia (CMML) are also eligible. Relapsed/refractory leukemias include acute non-lymphocytic leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML) in blast crisis. Subjects with agnogenic myeloid metaplasia (AMM) are also eligible. Subjects with a haematological malignancy associated with human immunodeficiency virus (HIV) infection or solid organ transplant are NOT eligible. * Subjects who have previously received an autologous stem cell transplant are allowed if a minimum of three months has elapsed from the time of transplant (T0) and the subject has recovered from transplant-associated toxicities prior to the first dose of GSK1120212. * Subjects with a history of allogeneic stem cell transplant are eligible for study participation provided the following eligibility criteria are met: transplant was greater than 100 days prior to study enrolment, subject has not taken immunosuppressive medications (per protocol) for at least 1 month, no signs or symptoms of graft versus host disease other than Grade 1 skin involvement, no active infection, subject meets the remainder of the eligibility criteria outlined in this protocol. * Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2. * Life expectancy of at least four weeks. * Able to swallow and retain oral medication. * Male subjects must agree to use one of the contraception methods listed in the protocol. * Female subjects must be of non-childbearing potential as listed in the protocol or using a contraception method listed in the protocol. * Calcium Phosphate Product less than or equal to 4.0 mmol (squared)/L (squared) or 50mg (squared)/dL (squared). * Subjects must have adequate organ function as specified in the protocol. * Phase II * Confirmed diagnosis of one of the following: Relapsed or refractory acute myeloid leukemia (AML), Secondary AML including AML arising from antecedent hematologic diseases (e.g., myelodysplastic syndrome, myeloproliferative disorders, or therapyrelated AML), CMML, or MDS. Cohorts 1: RAS Positive AML/MDS Cohort 2: Wild Type AML/MDS/CMML Cohort 3: RAS Positive CMML
Exclusion criteria
* Phase I * Currently receiving cancer therapy as specified in the protocol. * Received corticosteroids or imatinib within 24h of GSK1120212 administration. * Received gemtuzumab ozogamicin (myelotarg) within two weeks of GSK1120212 adminstration. * Received an investigational anti-cancer drug within four weeks or five half-lives, whichever is shorter of GSK1120212 administration, as specified in the protocol. * Received major surgery, radiotherapy, or immunotherapy within four weeks of GSK1120212 administration. * Received chemotherapy regimens with delayed toxicity within the last four weeks (six weeks for prior nitrosourea or mitomycin C). Received chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last two weeks. * Received a MEK inhibitor. * Current use of a prohibited medication per protocol. * Current use of warfarin. Low molecular weight heparin and prophylactic low-dose warfarin are permitted per protocol. * Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs. * History of RVO. * Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for retinal vein thrombosis. * Intraocular pressure greater than 21mm Hg as measured by tonography. * Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol. * Condition that in the investigator's opinion would jeopardize compliance with the protocol. * Symptomatic or untreated central nervous system involvement by the hematologic malignancy, including primary CNS lymphoma. Subjects who were previously treated for CNS involvement, and are asymptomatic without anti-epileptic medications for at least two months are eligible. * Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, or cardiac disease). * Unresolved toxicity greater than Grade 1 from previous anti-cancer therapy except alopecia (if applicable) unless agreed to by a GSK Medical Monitor and the investigator. * QTc interval greater than 480 msecs. * History of acute coronary syndromes (including unstable angina), coronary angioplasty or stenting within the past 24 weeks. * Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system. * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug, dimethyl sulfoxide (DMSO), or excipients (See Section 3.10). (To date there are no known FDA approved drugs chemically related to GSK1120212). * Pregnant or lactating female. * Unwillingness or inability to follow the procedures outlined in the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | From the start of the study drug until the final study visit (up to approximately 407 days) | 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. |
| Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) by Dose | From the start of the study drug until the final study visit (up to approximately 407 days) | 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. |
| Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | From the start of the study drug until the final study visit (up to approximately 407 days) | 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. |
| Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | From the start of the study drug until the final study visit (up to approximately 407 days) | 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. |
| Number of Participants With a Change From Baseline in Heart Rate by Dose | From the start of the study drug until the final study visit (up to approximately 407 days) | 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. |
| Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose | From the start of the study drug until the final study visit (up to approximately 407 days) | 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. |
| Number of Participants With a Change From Baseline in Temperature by Dose | From the start of the study drug until the final study visit (up to approximately 407 days) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1 | Cycle 1 Day 1 and Cycle 1 Day 15 | 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). |
| Cmin and Cmax of GSK1120212 in Part 1 | Cycle 1 Day 1 and Cycle 1 Day 15 | 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 at C1D1 and t1/2 Effective (Eff.) at C1D15 of GSK1120212 in Part 1 | Cycle 1 Day 1 (t1/2) and Cycle 1 Day 15 (t1/2eff) | 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 of GSK1120212 in Part 1 | Cycle 1 Day 1 and Cycle 1 Day 15 | 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). |
| Accumulation Ratio (AR) of GSK1120212 in Part 1 | Cycle 1 Day 1 and Cycle 1 Day 15 | 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 of GSK1120212 in Part 2 | C1D15, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1 and C12D1 | 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 by Cohort | From the start of the study drug until the final study visit (up to approximately 407 days ) | 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. |
Countries
Belgium, France, Germany, United States
Participant flow
Pre-assignment details
This is a Phase I/II study. Phase I is a dose escalation phase in participants with relapsed or refractory leukaemias to identify the recommended dose of GSK1120212 for Phase II. Phase II further evaluates the safety and efficacy of the recommended dose.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 5 |
| GSK1120212 2 mg OD Participants with relapsed or refractory leukemias received GSK1120212 2 mg OD as a continuous dose. | 9 |
| Cohort 1: AML/MDS With RAS Mutation Participants with relapsed or refractory AML or MDS with RAS mutation received GSK1120212 2 mg OD as a continuous dose. | 50 |
| Cohort 2: AML/MDS/CMML With RAS wt/Unknown 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. | 22 |
| Cohort 3: CMML With RAS Mutation Participants with relapsed or refractory CMML with RAS mutation received GSK1120212 2 mg OD as a continuous dose. | 11 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Phase 1 (Dose Escalation) | Adverse Event | 3 | 3 | 0 | 0 | 0 |
| Phase 1 (Dose Escalation) | Lack of Efficacy | 2 | 4 | 0 | 0 | 0 |
| Phase 1 (Dose Escalation) | Withdrawal by Subject | 0 | 2 | 0 | 0 | 0 |
| Phase 2 | Adverse Event | 0 | 0 | 14 | 2 | 3 |
| Phase 2 | Lack of Efficacy | 0 | 0 | 29 | 14 | 5 |
| Phase 2 | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 |
| Phase 2 | Physician Decision | 0 | 0 | 3 | 3 | 2 |
| Phase 2 | Withdrawal by Subject | 0 | 0 | 4 | 2 | 1 |
Baseline characteristics
| Characteristic | GSK1120212 <2 mg OD | GSK1120212 2 mg OD | Cohort 1: AML/MDS With RAS Mutation | Cohort 2: AML/MDS/CMML With RAS wt/Unknown | Cohort 3: CMML With RAS Mutation | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 70.4 Years STANDARD_DEVIATION 15.71 | 60.2 Years STANDARD_DEVIATION 15.86 | 65.6 Years STANDARD_DEVIATION 10.71 | 59.6 Years STANDARD_DEVIATION 18.89 | 67.7 Years STANDARD_DEVIATION 6.87 | 64.2 Years STANDARD_DEVIATION 13.69 |
| Race/Ethnicity, Customized African American/African Heritage | 1 Participants | 0 Participants | 5 Participants | 2 Participants | 0 Participants | 8 Participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 4 Participants | 9 Participants | 40 Participants | 18 Participants | 9 Participants | 80 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 22 Participants | 7 Participants | 6 Participants | 41 Participants |
| Sex: Female, Male Male | 1 Participants | 7 Participants | 28 Participants | 15 Participants | 5 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 90 / 91 |
| serious Total, serious adverse events | 2 / 6 | 64 / 91 |
Outcome results
Primary
Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose
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.
Time frame: From the start of the study drug until the final study visit (up to approximately 407 days)
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Magnesium (hypermagnesemia), Grade 3, n=6, 88 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Glucose (hypoglycemia), Grade 3, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Glucose (hypoglycemia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Albumin (Low), Grade 4, n=6, 90 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Albumin (Low), Grade 3, n=6, 90 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Alkaline Phosphatase (High), Grade 3, n=6, 89 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Alkaline Phosphatase (High), Grade 4, n=6, 89 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Alanine Amino Transferase (High), Grade 3, n=6, 89 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Alanine Amino Transferase (High), Grade 4, n=6, 89 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | AST (High), Grade 3, n=6, 86 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | AST (High), Grade 4, n=6, 86 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Total Bilirubin (High), Grade 3, n=6, 89 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Total Bilirubin (High), Grade 4, n=6, 89 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Potassium (hyperkalemia), Grade 3, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Magnesium (hypomagnesemia), Grade 3, n=6, 88 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Calcium (hypocalcemia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Creatinine (High), Grade 3, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Creatinine (High), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Glucose (hyperglycemia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Glucose (hyperglycemia), Grade 3, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Calcium (hypercalcemia), Grade 3, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Calcium (hypercalcemia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Calcium (hypocalcemia), Grade 3, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Potassium (hypokalemia), Grade 3, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Bicarbonate (Low), Grade 3, n=5, 82 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Bicarbonate (Low), Grade 4, n=5, 82 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Potassium (hyperkalemia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Potassium (hypokalemia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Magnesium (hypermagnesemia), Grade 4, n=6, 88 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Magnesium (hypomagnesemia), Grade 4, n=6, 88 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Sodium (hypernatremia), Grade 3, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Sodium (hypernatremia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Sodium (hyponatremia), Grade 3, n=6, 91 | 2 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Sodium (hyponatremia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Phosphorus, Grade 3, n=6, 88 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Phosphorus, Grade 4, n=6, 88 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | AST (High), Grade 4, n=6, 86 | 2 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Magnesium (hypermagnesemia), Grade 4, n=6, 88 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Calcium (hypercalcemia), Grade 3, n=6, 91 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Glucose (hypoglycemia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Magnesium (hypomagnesemia), Grade 3, n=6, 88 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Calcium (hypercalcemia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Albumin (Low), Grade 3, n=6, 90 | 9 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Albumin (Low), Grade 4, n=6, 90 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Sodium (hyponatremia), Grade 3, n=6, 91 | 9 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Alkaline Phosphatase (High), Grade 3, n=6, 89 | 2 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Magnesium (hypomagnesemia), Grade 4, n=6, 88 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Alkaline Phosphatase (High), Grade 4, n=6, 89 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Phosphorus, Grade 3, n=6, 88 | 5 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Alanine Amino Transferase (High), Grade 3, n=6, 89 | 6 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Bicarbonate (Low), Grade 3, n=5, 82 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Alanine Amino Transferase (High), Grade 4, n=6, 89 | 1 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Sodium (hypernatremia), Grade 3, n=6, 91 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | AST (High), Grade 3, n=6, 86 | 5 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Bicarbonate (Low), Grade 4, n=5, 82 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Potassium (hyperkalemia), Grade 3, n=6, 91 | 1 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Total Bilirubin (High), Grade 3, n=6, 89 | 3 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Sodium (hyponatremia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Total Bilirubin (High), Grade 4, n=6, 89 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Potassium (hyperkalemia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Potassium (hypokalemia), Grade 3, n=6, 91 | 7 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Creatinine (High), Grade 3, n=6, 91 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Calcium (hypocalcemia), Grade 4, n=6, 91 | 2 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Sodium (hypernatremia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Potassium (hypokalemia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Calcium (hypocalcemia), Grade 3, n=6, 91 | 8 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Magnesium (hypermagnesemia), Grade 3, n=6, 88 | 3 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Creatinine (High), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Glucose (hyperglycemia), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Glucose (hypoglycemia), Grade 3, n=6, 91 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Phosphorus, Grade 4, n=6, 88 | 1 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Clinical Chemistry Parameters by Dose | Glucose (hyperglycemia), Grade 3, n=6, 91 | 7 Participants |
Primary
Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose
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.
Time frame: From the start of the study drug until the final study visit (up to approximately 407 days)
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | INR (High), Grade 4, n=6, 75 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Platelet count (Low), Grade 3, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Platelet count (Low), Grade 4, n=6, 91 | 1 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | PTT (High), Grade 3, n=5, 75 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | PTT (High), Grade 4, n=5, 75 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | White Blood Cell count (Low), Grade 3, n=6, 91 | 1 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | White Blood Cell count (Low), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Hemoglobin (Low), Grade 3, n=6, 91 | 3 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Hemoglobin (Low), Grade 4, n=6, 91 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | INR (High), Grade 3, n=6, 75 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Lymphocytes (Low), Grade 3, n=6, 90 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Lymphocytes (Low), Grade 4, n=6, 90 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Total Neutrophils (Low), Grade 3, n=6, 89 | 1 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Total Neutrophils (Low), Grade 4, n=6, 89 | 1 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Lymphocytes (Low), Grade 4, n=6, 90 | 7 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Hemoglobin (Low), Grade 4, n=6, 91 | 7 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Platelet count (Low), Grade 3, n=6, 91 | 5 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Platelet count (Low), Grade 4, n=6, 91 | 28 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | INR (High), Grade 3, n=6, 75 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | PTT (High), Grade 3, n=5, 75 | 1 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | INR (High), Grade 4, n=6, 75 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | PTT (High), Grade 4, n=5, 75 | 0 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Total Neutrophils (Low), Grade 3, n=6, 89 | 4 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | White Blood Cell count (Low), Grade 3, n=6, 91 | 13 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Lymphocytes (Low), Grade 3, n=6, 90 | 12 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | White Blood Cell count (Low), Grade 4, n=6, 91 | 15 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Total Neutrophils (Low), Grade 4, n=6, 89 | 21 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline Grade to Grade 3 and 4 for the Indicated Hematology Parameters by Dose | Hemoglobin (Low), Grade 3, n=6, 91 | 28 Participants |
Primary
Number of Participants With a Change From Baseline in Heart Rate by Dose
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.
Time frame: From the start of the study drug until the final study visit (up to approximately 407 days)
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline in Heart Rate by Dose | Decrease to <60, n=6, 90 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline in Heart Rate by Dose | No Change, n=6, 90 | 4 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline in Heart Rate by Dose | Increase to >100, n=6, 90 | 2 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline in Heart Rate by Dose | Increase to >100, n=6, 90 | 19 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline in Heart Rate by Dose | Decrease to <60, n=6, 90 | 10 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline in Heart Rate by Dose | No Change, n=6, 90 | 67 Participants |
Primary
Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose
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.
Time frame: From the start of the study drug until the final study visit (up to approximately 407 days)
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose | SBP, Increase to Grade 3/4, n=6, 90 | 1 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose | DBP, Increase to Grade 3/4, n=6, 90 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose | DBP, Increase to Grade 2, n=6, 90 | 1 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose | SBP, Increase to Grade 1, n=6, 90 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose | DBP, Increase to Grade 1, n=6, 90 | 1 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose | SBP, Increase to Grade 2, n=6, 90 | 2 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose | DBP, Increase to Grade 2, n=6, 90 | 13 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose | SBP, Increase to Grade 2, n=6, 90 | 19 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose | SBP, Increase to Grade 3/4, n=6, 90 | 13 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose | DBP, Increase to Grade 1, n=6, 90 | 23 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose | DBP, Increase to Grade 3/4, n=6, 90 | 4 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline in Systolic and Diastolic Blood Pressure by Dose | SBP, Increase to Grade 1, n=6, 90 | 16 Participants |
Primary
Number of Participants With a Change From Baseline in Temperature by Dose
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.
Time frame: From the start of the study drug until the final study visit (up to approximately 407 days)
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline in Temperature by Dose | Decrease to <=35, n=6, 90 | 0 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline in Temperature by Dose | No Change, n=6, 90 | 4 Participants |
| GSK1120212 <2 mg OD | Number of Participants With a Change From Baseline in Temperature by Dose | Increase to >=38, n=6, 90 | 2 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline in Temperature by Dose | Decrease to <=35, n=6, 90 | 4 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline in Temperature by Dose | No Change, n=6, 90 | 76 Participants |
| GSK1120212 2 mg OD | Number of Participants With a Change From Baseline in Temperature by Dose | Increase to >=38, n=6, 90 | 12 Participants |
Primary
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
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.
Time frame: From the start of the study drug until the final study visit (up to approximately 407 days)
Population: 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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK1120212 <2 mg OD | 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 | PR | 1 Participants |
| GSK1120212 <2 mg OD | 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 | MLFS | 3 Participants |
| GSK1120212 <2 mg OD | 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 | Marrow CR | 1 Participants |
| GSK1120212 <2 mg OD | 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 | ORR | 10 Participants |
| GSK1120212 <2 mg OD | 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 | CR | 4 Participants |
| GSK1120212 <2 mg OD | 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 | CRp | 1 Participants |
| GSK1120212 2 mg OD | 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 | Marrow CR | 0 Participants |
| GSK1120212 2 mg OD | 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 | CRp | 0 Participants |
| GSK1120212 2 mg OD | 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 | MLFS | 0 Participants |
| GSK1120212 2 mg OD | 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 | PR | 1 Participants |
| GSK1120212 2 mg OD | 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 | ORR | 1 Participants |
| GSK1120212 2 mg OD | 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 | CR | 0 Participants |
| Cohort 3: CMML With RAS Mutation | 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 | ORR | 3 Participants |
| Cohort 3: CMML With RAS Mutation | 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 | PR | 0 Participants |
| Cohort 3: CMML With RAS Mutation | 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 | CR | 1 Participants |
| Cohort 3: CMML With RAS Mutation | 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 | Marrow CR | 1 Participants |
| Cohort 3: CMML With RAS Mutation | 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 | MLFS | 0 Participants |
| Cohort 3: CMML With RAS Mutation | 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 | CRp | 1 Participants |
Primary
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) by Dose
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.
Time frame: From the start of the study drug until the final study visit (up to approximately 407 days)
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK1120212 <2 mg OD | Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) by Dose | Any AE | 6 Participants |
| GSK1120212 <2 mg OD | Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) by Dose | Any SAE | 2 Participants |
| GSK1120212 2 mg OD | Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) by Dose | Any AE | 91 Participants |
| GSK1120212 2 mg OD | Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) by Dose | Any SAE | 64 Participants |
Secondary
Accumulation Ratio (AR) of GSK1120212 in Part 1
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).
Time frame: Cycle 1 Day 1 and Cycle 1 Day 15
Population: Pharmacokinetic Population. Only participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| GSK1120212 <2 mg OD | Accumulation Ratio (AR) of GSK1120212 in Part 1 | 6.32 Ratio | Geometric Coefficient of Variation 16.5 |
| GSK1120212 2 mg OD | Accumulation Ratio (AR) of GSK1120212 in Part 1 | 8.19 Ratio | Geometric Coefficient of Variation 10.8 |
| Cohort 3: CMML With RAS Mutation | Accumulation Ratio (AR) of GSK1120212 in Part 1 | 11.1 Ratio | Geometric Coefficient of Variation 76.5 |
Secondary
AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1
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).
Time frame: Cycle 1 Day 1 and Cycle 1 Day 15
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GSK1120212 <2 mg OD | AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1 | C1D15, AUC(0-t), n=2, 2, 8 | 172 nanograms*hour/milliliter | Geometric Coefficient of Variation 18.4 |
| GSK1120212 <2 mg OD | AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1 | C1D15, AUC(0-tau), n=2, 2, 8 | 170 nanograms*hour/milliliter | Geometric Coefficient of Variation 17.2 |
| GSK1120212 <2 mg OD | AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1 | C1D1, AUC(0-t), n=3, 2, 9 | 77.6 nanograms*hour/milliliter | Geometric Coefficient of Variation 25.1 |
| GSK1120212 <2 mg OD | AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1 | C1D1, AUC(0-24), n=3, 2, 9 | 77.6 nanograms*hour/milliliter | Geometric Coefficient of Variation 25.1 |
| GSK1120212 2 mg OD | AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1 | C1D15, AUC(0-tau), n=2, 2, 8 | 241 nanograms*hour/milliliter | Geometric Coefficient of Variation 5.6 |
| GSK1120212 2 mg OD | AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1 | C1D15, AUC(0-t), n=2, 2, 8 | 155 nanograms*hour/milliliter | Geometric Coefficient of Variation 61.9 |
| GSK1120212 2 mg OD | AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1 | C1D1, AUC(0-t), n=3, 2, 9 | 29.4 nanograms*hour/milliliter | Geometric Coefficient of Variation 5.2 |
| GSK1120212 2 mg OD | AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1 | C1D1, AUC(0-24), n=3, 2, 9 | 29.4 nanograms*hour/milliliter | Geometric Coefficient of Variation 5.2 |
| Cohort 3: CMML With RAS Mutation | AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1 | C1D15, AUC(0-tau), n=2, 2, 8 | 330 nanograms*hour/milliliter | Geometric Coefficient of Variation 34.6 |
| Cohort 3: CMML With RAS Mutation | AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1 | C1D1, AUC(0-24), n=3, 2, 9 | 28.0 nanograms*hour/milliliter | Geometric Coefficient of Variation 51 |
| Cohort 3: CMML With RAS Mutation | AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1 | C1D1, AUC(0-t), n=3, 2, 9 | 28.0 nanograms*hour/milliliter | Geometric Coefficient of Variation 51 |
| Cohort 3: CMML With RAS Mutation | AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1 | C1D15, AUC(0-t), n=2, 2, 8 | 298 nanograms*hour/milliliter | Geometric Coefficient of Variation 58.8 |
Secondary
Cmin and Cmax of GSK1120212 in Part 1
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).
Time frame: Cycle 1 Day 1 and Cycle 1 Day 15
Population: Pharmacokinetic Population. Only participants with data available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GSK1120212 <2 mg OD | Cmin and Cmax of GSK1120212 in Part 1 | C1D15, Cmax , n=2, 2, 8 | 12.3 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 19.4 |
| GSK1120212 <2 mg OD | Cmin and Cmax of GSK1120212 in Part 1 | C1D1, Cmax, n=3, 2, 9 | 7.67 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 27.6 |
| GSK1120212 <2 mg OD | Cmin and Cmax of GSK1120212 in Part 1 | C1D15, Cmin, n=2, 2, 8 | 4.79 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 6.6 |
| GSK1120212 2 mg OD | Cmin and Cmax of GSK1120212 in Part 1 | C1D15, Cmax , n=2, 2, 8 | 15.1 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 15.6 |
| GSK1120212 2 mg OD | Cmin and Cmax of GSK1120212 in Part 1 | C1D1, Cmax, n=3, 2, 9 | 3.69 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 35.5 |
| GSK1120212 2 mg OD | Cmin and Cmax of GSK1120212 in Part 1 | C1D15, Cmin, n=2, 2, 8 | 8.50 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 19.4 |
| Cohort 3: CMML With RAS Mutation | Cmin and Cmax of GSK1120212 in Part 1 | C1D1, Cmax, n=3, 2, 9 | 3.27 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 93.2 |
| Cohort 3: CMML With RAS Mutation | Cmin and Cmax of GSK1120212 in Part 1 | C1D15, Cmin, n=2, 2, 8 | 10.8 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 36.8 |
| Cohort 3: CMML With RAS Mutation | Cmin and Cmax of GSK1120212 in Part 1 | C1D15, Cmax , n=2, 2, 8 | 18.7 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 36.1 |
Secondary
Ctau of GSK1120212 in Part 2
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).
Time frame: C1D15, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1 and C12D1
Population: Pharmacokinetic Population. Only participants with data available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GSK1120212 <2 mg OD | Ctau of GSK1120212 in Part 2 | C2D1, n=57 | 9.34 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 78.9 |
| GSK1120212 <2 mg OD | Ctau of GSK1120212 in Part 2 | C4D1, n=21 | 9.17 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 99.9 |
| GSK1120212 <2 mg OD | Ctau of GSK1120212 in Part 2 | C8D1, n=5 | 6.01 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 222.3 |
| GSK1120212 <2 mg OD | Ctau of GSK1120212 in Part 2 | C3D1, n=38 | 10.0 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 64.9 |
| GSK1120212 <2 mg OD | Ctau of GSK1120212 in Part 2 | C5D1, n=10 | 12.05 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 37.4 |
| GSK1120212 <2 mg OD | Ctau of GSK1120212 in Part 2 | C6D1, n=6 | 9.73 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 44.8 |
| GSK1120212 <2 mg OD | Ctau of GSK1120212 in Part 2 | C7D1, n=6 | 8.94 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 55 |
| GSK1120212 <2 mg OD | Ctau of GSK1120212 in Part 2 | C9D1, n=3 | 11.3 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 30.7 |
| GSK1120212 <2 mg OD | Ctau of GSK1120212 in Part 2 | C10D1, n=2 | 5.01 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 73.9 |
| GSK1120212 <2 mg OD | Ctau of GSK1120212 in Part 2 | C11D1, n=1 | 2.01 nanograms per milliliter (ng/mL) | — |
| GSK1120212 <2 mg OD | Ctau of GSK1120212 in Part 2 | C12D1, n=1 | 0.644 nanograms per milliliter (ng/mL) | — |
| GSK1120212 <2 mg OD | Ctau of GSK1120212 in Part 2 | C1D15, n=72 | 10.8 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 63.8 |
Secondary
Overall Survival by Cohort
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.
Time frame: From the start of the study drug until the final study visit (up to approximately 407 days )
Population: 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).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GSK1120212 <2 mg OD | Overall Survival by Cohort | 4.9 Months |
| GSK1120212 2 mg OD | Overall Survival by Cohort | 3.0 Months |
| Cohort 3: CMML With RAS Mutation | Overall Survival by Cohort | 14.5 Months |
Secondary
t1/2 at C1D1 and t1/2 Effective (Eff.) at C1D15 of GSK1120212 in Part 1
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).
Time frame: Cycle 1 Day 1 (t1/2) and Cycle 1 Day 15 (t1/2eff)
Population: Pharmacokinetic Population. Only participants with data available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GSK1120212 <2 mg OD | t1/2 at C1D1 and t1/2 Effective (Eff.) at C1D15 of GSK1120212 in Part 1 | C1D1, t1/2, n=3, 1, 8 | 33.5 Hours | Geometric Coefficient of Variation 43.7 |
| GSK1120212 <2 mg OD | t1/2 at C1D1 and t1/2 Effective (Eff.) at C1D15 of GSK1120212 in Part 1 | C1D15, t1/2 eff., n=2, 2, 8 | 96.41 Hours | Geometric Coefficient of Variation 18.1 |
| GSK1120212 2 mg OD | t1/2 at C1D1 and t1/2 Effective (Eff.) at C1D15 of GSK1120212 in Part 1 | C1D1, t1/2, n=3, 1, 8 | 25.0 Hours | — |
| GSK1120212 2 mg OD | t1/2 at C1D1 and t1/2 Effective (Eff.) at C1D15 of GSK1120212 in Part 1 | C1D15, t1/2 eff., n=2, 2, 8 | 128 Hours | Geometric Coefficient of Variation 11.6 |
| Cohort 3: CMML With RAS Mutation | t1/2 at C1D1 and t1/2 Effective (Eff.) at C1D15 of GSK1120212 in Part 1 | C1D1, t1/2, n=3, 1, 8 | 37.0 Hours | Geometric Coefficient of Variation 76.2 |
| Cohort 3: CMML With RAS Mutation | t1/2 at C1D1 and t1/2 Effective (Eff.) at C1D15 of GSK1120212 in Part 1 | C1D15, t1/2 eff., n=2, 2, 8 | 174 Hours | Geometric Coefficient of Variation 80.3 |
Secondary
Tmax of GSK1120212 in Part 1
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).
Time frame: Cycle 1 Day 1 and Cycle 1 Day 15
Population: Pharmacokinetic Population. Only participants with data available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| GSK1120212 <2 mg OD | Tmax of GSK1120212 in Part 1 | C1D15, tmax, n=2, 2, 8 | 1.75 Hours |
| GSK1120212 <2 mg OD | Tmax of GSK1120212 in Part 1 | C1D1, tmax, n=3, 2, 9 | 2.0 Hours |
| GSK1120212 2 mg OD | Tmax of GSK1120212 in Part 1 | C1D15, tmax, n=2, 2, 8 | 2.25 Hours |
| GSK1120212 2 mg OD | Tmax of GSK1120212 in Part 1 | C1D1, tmax, n=3, 2, 9 | 1.25 Hours |
| Cohort 3: CMML With RAS Mutation | Tmax of GSK1120212 in Part 1 | C1D1, tmax, n=3, 2, 9 | 3.0 Hours |
| Cohort 3: CMML With RAS Mutation | Tmax of GSK1120212 in Part 1 | C1D15, tmax, n=2, 2, 8 | 3.0 Hours |