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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 97
- 试验地点
- 1
- 主要终点
- Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) by Dose
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 GSK
- •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
- •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.
- •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
排除标准
- •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.
研究组 & 干预措施
Phase I
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.
干预措施: GSK1120212 (Drug)
Phase II
A dose determined by Phase I to further evaulate the safety profile, PK, PD, and clinical activity of GSK1120212.
干预措施: GSK1120212 (Drug)
结局指标
主要结局
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) by Dose
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
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
时间窗: 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.
次要结局
- Ctau of GSK1120212 in Part 2(C1D15, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1 and C12D1)
- AUC(0-24), AUC(0-t), and AUC(0-tau) of GSK1120212 in Part 1(Cycle 1 Day 1 and Cycle 1 Day 15)
- Cmin and Cmax of GSK1120212 in Part 1(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(Cycle 1 Day 1 (t1/2) and Cycle 1 Day 15 (t1/2eff))
- Tmax of GSK1120212 in Part 1(Cycle 1 Day 1 and Cycle 1 Day 15)
- Accumulation Ratio (AR) of GSK1120212 in Part 1(Cycle 1 Day 1 and Cycle 1 Day 15)
- Overall Survival by Cohort(From the start of the study drug until the final study visit (up to approximately 407 days ))