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

NCT00920140 | Completed Phase 2 Results

• 1 other identifier: 111759
• Study Type: interventional
• Target: 97
• Locations: 4 countries
• Sites: 28

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.

Conditions

Cancer

Keywords

Oncology, GSK1120212, MEK inhibitor, hematological malignancies, AML; CMML; MDS

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (7)

• 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

Study Arms (2)

Phase I

EXPERIMENTAL

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

Phase II

EXPERIMENTAL

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

Drug: GSK1120212

Interventions

GSK1120212 DRUG

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

Phase I

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Phase I
• Written informed consent provided.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (28)

GSK Investigational Site

Birmingham, Alabama, 35249, United States

Location

GSK Investigational Site

Duarte, California, 91010, United States

Location

GSK Investigational Site

Los Angeles, California, 90095, United States

Location

GSK Investigational Site

San Francisco, California, 94143, United States

Location

GSK Investigational Site

Chicago, Illinois, 60611, United States

Location

GSK Investigational Site

Rochester, Minnesota, 55905, United States

Location

GSK Investigational Site

Bornx, New York, 10467, United States

Location

GSK Investigational Site

Lake Success, New York, 11042, United States

Location

GSK Investigational Site

New York, New York, 10032, United States

Location

GSK Investigational Site

Winston-Salem, North Carolina, 27157-1009, United States

Location

GSK Investigational Site

Portland, Oregon, 97239, United States

Location

GSK Investigational Site

Hershey, Pennsylvania, 17033, United States

Location

GSK Investigational Site

Pittsburgh, Pennsylvania, 15232, United States

Location

GSK Investigational Site

Houston, Texas, 77030, United States

Location

GSK Investigational Site

Seattle, Washington, 98109-1023, United States

Location

GSK Investigational Site

Ghent, 9000, Belgium

Location

GSK Investigational Site

Leuven, 3000, Belgium

Location

GSK Investigational Site

Bobigny, 93009, France

Location

GSK Investigational Site

Lille, 59037, France

Location

GSK Investigational Site

Marseille, 13273, France

Location

GSK Investigational Site

Pierre-Bénite, 69495, France

Location

GSK Investigational Site

Toulouse, 31059, France

Location

GSK Investigational Site

Frankfurt am Main, Hesse, 60590, Germany

Location

GSK Investigational Site

Duisburg, North Rhine-Westphalia, 47166, Germany

Location

GSK Investigational Site

Münster, North Rhine-Westphalia, 48149, Germany

Location

GSK Investigational Site

Mainz, Rhineland-Palatinate, 55131, Germany

Location

GSK Investigational Site

Dresden, Saxony, 01307, Germany

Location

GSK Investigational Site

Leipzig, Saxony, 04103, Germany

Location

MeSH Terms

Conditions

Neoplasms; Hematologic Neoplasms; Leukemia, Myeloid, Acute

Interventions

trametinib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 12, 2009
• First Posted: June 15, 2009
• Study Start: May 1, 2011
• Primary Completion: April 1, 2013
• Study Completion: April 1, 2013
• Last Updated: April 2, 2014
• Results First Posted: February 28, 2014

Record last verified: 2014-03

Locations

BE (2); DE (6); US (15); FR (5)