A Study of the GSK MEK Inhibitor GSK1120212 and Everolimus in Cancer Subjects

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00955773
First received: August 6, 2009
Last updated: July 12, 2012
Last verified: July 2012

August 6, 2009
July 12, 2012
August 2009
November 2011   (final data collection date for primary outcome measure)
  • AEs and changes in laboratory values and vital signs [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Response rate, CR + PR of GSK1120212 and everolimus in KRAS-mutant NSCLC. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • For Phase IB: AEs and changes in laboratory values and vital signs [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • For Phase II: Response rate, CR + PR of GSK1120212 and everolimus in KRAS-mutant NSCLC. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00955773 on ClinicalTrials.gov Archive Site
  • GSK1120212 and everolimus PK parameters following repeat-dose (Day 15) administration of GSK1120212 and everolimus, including AUC(0-tau), Ct, Cmax, tmax, and t1/2, data permitting [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Tumor response as defined by RECIST 1.1. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • CA 19-9 levels compared to radiological response, per RECIST 1.1, over time for each pancreatic cancer subject [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Population PK parameters, oral clearance and oral volume of distribution of GSK1120212 and everolimus will be determined. Dependant upon the final compartmental model describing GSK1120212 + everolimus, add. PK may also be estimated. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Clinical benefit response rate CR+PR+SD greater than 4mos [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Duration of response [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Phase IB: GSK1120212 and everolimus PK parameters following repeat-dose (Day 15) administration of GSK1120212 and everolimus, including AUC(0-tau), Ct, Cmax, tmax, and t1/2, data permitting [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Phase IB: Tumor response as defined by RECIST 1.1. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Phase IB: CA 19-9 levels compared to radiological response, per RECIST 1.1, over time for each subject [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Phase II: Population PK parameters, oral clearance and oral volume of distribution of GSK1120212 and everolimus will be determined. Dependant upon the final compartmental model describing GSK1120212 + everolimus, add. PK may also be estimated. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Phase II: Clinical benefit response rate CR+PR+SD greater than 4mos [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Phase II: Duration of response [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
A Study of the GSK MEK Inhibitor GSK1120212 and Everolimus in Cancer Subjects
An Open-Label, Dose-Escalation, Phase IB II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the MEK Inhibitor GSK1120212 in Combination With Oral Everolimus in Subjects With Solid Tumors

The purpose of this study is to determine the recommended dose and regimen for the orally administered MEK inhibitor GSK1120212 dosed in combination with everolimus in subjects with solid tumors. The escalation part of the study will determine the MTD. The combination will be further explored in the expansion part in subjects with metastatic pancreatic cancer. In addition, subjects with KRAS mutant non-small cell lung cancer will be enrolled.

MEK112110 is a dose-escalation, open-label study to determine the recommended dose and regimen for the orally administered MEK inhibitor GSK1120212 dosed in combination with everolimus in subjects with solid tumors. This will be accomplished using a dose-escalation procedure starting at low doses of GSK1120212 and everolimus. Dose escalation will continue based on predefined parameters until the maximum tolerated dose is identified. The recommended doses and regimens will be selected based on the safety and pharmacokinetic profiles. The clinical activity of GSK1120212 dosed in combination with everolimus will be explored further in an expansion cohort consisting of 20 subjects with metastatic pancreatic cancer. In addition a substudy will be conducted in 40 subjects with KRAS-mutant non-small cell lung cancer.

Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Cancer
Drug: GSK1120212 plus everolimus
Dose escalation will begin at low doses of GSK1120212 and everolimus, then gradually increase in future cohorts. Dose escalation will continue until a recommended combination dose is identified. The recommended combination dose will be used to treat pancreatic and lung cancer patients in later groups in this study.
  • Experimental: Group I
    20 to 30 solid tumor subjects will be dosed with GSK1120212 in combination with everolimus to identify Maximum Tolerated Dose. Subjects will continue on study drug until disease progression or withdraw consent.
    Intervention: Drug: GSK1120212 plus everolimus
  • Experimental: Group II
    20 subjects with pancreatic cancer will receive the recommended dose identified in group I. Subjects will remain on study drug until disease progression or withdrawal from consent.
    Intervention: Drug: GSK1120212 plus everolimus
  • Experimental: Group III
    Approximately 40 lung cancer subjects will receive the recommended dose identified in group I. Subjects will remain on study until disease progression or withdrawal of consent.
    Intervention: Drug: GSK1120212 plus everolimus
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
90
November 2011
November 2011   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
  • Age 18 years old or older and able to swallow oral medication.
  • Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology (ECOG) scale for Dose Escalation Cohort. Subjects with ECOG of 2 can be enrolled for expansion cohort.
  • Tumor Type criteria as listed in the protocol
  • Fasting glucose < 126mg/dL
  • Male subjects must agree to use one of the contraception methods listed in the protocol.
  • A female subject is eligible to participate if she is of non-childbearing potential, and if she is of childbearing potential she must use protocol defined contraception methods.
  • Calcium phosphate product less than or equal to 4.0 mmol2/L2 (50 mg2/dL2)
  • Adequate organ system function as defined below in the protocol.

Exclusion Criteria:

  • Malignancies related to HIV or solid organ transplant.
  • Primary malignant brain tumors.
  • Chemotherapy, radiotherapy, or immunotherapy within 28 days (or 42 days for prior nitrosoureas or mitomycin C) prior to the first dose of GSK1120212. Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity are permitted with approval of a GSK Medical Monitor if dosing of that agent is terminated at least 14 days prior to the first dose of GSK1120212.
  • Use of an investigational anti-cancer drug within 28 days or 5 half-lives, whichever is shorter preceding the first dose of GSK1120212 - as long as a minimum of 14 days has passed between the last dose of the prior investigational anti-cancer drug and the first dose of GSK1120212.
  • Previous treatment with an mTOR inhibitor unless approved by GSK Medical Monitor.
  • Previous treatment with GSK1120212.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug, DMSO, or excipients. (To date there are no known FDA approved drugs chemically related to GSK1120212).
  • Use of a prohibited medication (as defined in the protocol).
  • Current use of anticoagulants (e.g. warfarin, heparin) at therapeutic levels within seven days prior to the first dose of GSK1120212. Low dose (prophylactic) low molecular weight heparin (LMWH) is permitted provided that subject's PT and PTT meet entry criteria. Subjects required therapeutic levels of LMWH must receive approval from GSK Medical Monitor and monitored appropriately as clinically indicated.
  • Gastrointestinal disease predicted to interfere with absorption of an oral drug, systemic disease, major surgery, or social/psychological issues that in the opinion of investigators would jeopardize compliance with protocol.
  • History of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
  • Predisposing factors to RVO including uncontrolled hypertension, uncontrolled diabetes, uncontrolled hyperlipidemia, and coagulopathy.
  • Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for RVO or CSR.
  • Intraocular pressure > 21mm Hg as measured by tonography.
  • Glaucoma diagnosed within 1 month prior to study Day 1.
  • Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. Subjects previously treated for these conditions that are asymptomatic and off corticosteroids for at least two weeks are permitted. Subjects are not permitted to receive enzyme inducing anti-epileptic drugs (EIAEDs).
  • Unresolved toxicity greater than common terminology criteria for adverse events (CTCAE) grade 1 from previous anti-cancer therapy except alopecia (if applicable) unless agreed to by a GSK Medical Monitor and the Investigator.
  • History of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks.
  • QTc interval ≥ 480 msecs.
  • Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
  • Pregnant or lactating female.
  • History or active hepatitis B or C.
  • History of HIV infection.
  • Subjects on chronic antifungal therapy.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00955773
112110
No
GlaxoSmithKline
GlaxoSmithKline
Not Provided
Study Director: GSK Clinical Trials GlaxoSmithKline
GlaxoSmithKline
July 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP