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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Cancer

Intervention / Treatment
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* Drug: GSK1120212
* Drug: GSK1120212


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I<br>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. | Drug: GSK1120212<br>* Starting dose based on GSK protocol MEK111054 and then dose escalation based on Dose Limiting Toxicities per protocol.<br>|
| Experimental: Phase II<br>A dose determined by Phase I to further evaulate the safety profile, PK, PD, and clinical activity of GSK1120212. | Drug: GSK1120212<br>* Dose will be maximum tolerated dose based on Phase I results.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From the start of the study drug until the final study visit (up to approximately 407 days) | 
| 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. | From the start of the study drug until the final study visit (up to approximately 407 days) | 
| 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. | From the start of the study drug until the final study visit (up to approximately 407 days) | 
| 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. | From the start of the study drug until the final study visit (up to approximately 407 days) | 
| 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. | From the start of the study drug until the final study visit (up to approximately 407 days) | 
| 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. | From the start of the study drug until the final study visit (up to approximately 407 days) | 
| 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. | From the start of the study drug until the final study visit (up to approximately 407 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Cycle 1 Day 1 and Cycle 1 Day 15 | 
| 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). | Cycle 1 Day 1 and Cycle 1 Day 15 | 
| 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). | Cycle 1 Day 1 (t1/2) and Cycle 1 Day 15 (t1/2eff) | 
| 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). | Cycle 1 Day 1 and Cycle 1 Day 15 | 
| 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). | Cycle 1 Day 1 and Cycle 1 Day 15 | 
| 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). | C1D15, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1 and C12D1 | 
| 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. | From the start of the study drug until the final study visit (up to approximately 407 days ) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oncology, GSK1120212, MEK inhibitor, hematological malignancies, AML, CMML, MDS