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Clinical Trial 17690

Cancer Type: Multiple
Study Type: Treatment
NCT#: NCT02070549

Phase: Phase I
Prinicipal Investigator:

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Study Title

A Phase I Trial of Single Agent Trametinib (GSK1120212) in Advanced Cancer Patients with Hepatic Dysfunction


The purpose of this study is to test the safety of trametinib at different doses in patients with cancer who have different degrees of abnormal liver function to find out what effects, if any, it has on people.


Primary Objectives: To provide appropriate dosing recommendations for patients with varying degree of hepatic dysfunction receiving trametinib (mild, moderate and severe). To establish the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of trametinib in advanced cancer patients with varying degrees of hepatic dysfunction. To characterize the PK profile of trametinib in advanced cancer patients with varying degrees of hepatic dysfunction. Secondary Objectives: To document the non-DLTs associated with the administration of trametinib in patients with varying degrees of hepatic dysfunction. To document any antitumor activity associated with trametinib treatment of patients enrolled on this study. To explore and characterize predictive biomarkers for individual cancer patients utilizing genomic sequencing technologies.




GSK1120212 (Trametinib); Trametinib ()

Inclusion Criteria

  • Must have a histologically or cytologically confirmed solid malignancy that is metastatic or unresectable for which standard curative or palliative treatments do not exist or are no longer effective. HCC patients not required to have histologically or cytologically confirmed malignancy, are considered eligible based on tumor markers/image assessment. Patients with the following tumor types will be excluded from the normal and mild cohorts (but are allowed to enroll in moderate/severe cohorts if additional criteria is met: Pancreatic cancer patients; Colorectal cancer patients; V-raf murine sarcoma viral oncogene homolog B (BRAF) V600E melanoma patients who have failed BRAF inhibitors.
  • Must have completed any prior chemotherapy, targeted therapy, radiotherapy (unless palliative doses which must be discussed with study Principal Investigator), surgery, anti-angiogenic therapy or interferon >= 28 days before study entry.
  • Eastern Cooperative Oncology Group (ECOG) performance status == 60%)
  • Life expectancy greater than 3 months
  • Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
  • All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events version 4 (CTCAE v4) grade => Absolute neutrophil count (ANC) >= 1.2 x 10^9/L
  • Hemoglobin >= 9 g/dL
  • Platelets >= 75 x 10^9/L
  • Serum creatinine == 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min
  • Proteinuria == 1 gram/24 hours
  • Prothrombin time (PT)/International normalized ratio (INR) and partial thromboplastin time (PTT) => Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA)
  • Patients with abnormal hepatic function will be eligible and will be grouped according to criteria summarized below: Group A: Normal hepatic function Bilirubin = ULN; B2: ULN > Patients with active hemolysis should be excluded
  • No distinction should be made between liver dysfunction due to metastases and liver dysfunction due to other causes.
  • Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception prior to study entry, during the study participation, and for four months after the last dose of the drug; WOCBP must have a negative serum pregnancy test within 14 days prior to registration.
  • Age 18 years and older
  • Ability to understand and willingness to sign written informed consent document

  • Exclusion Criteria

  • History of another malignancy. Exception: Patients who have been disease-free for 3 years, or with history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible.
  • History of interstitial lung disease or pneumonitis
  • Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 28 days prior to enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrollment
  • Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of trametinib and during the study; patients previously treated with v-raf murine sarcoma (RAF) and/or mitogen-activated protein kinase (MEK) inhibitors are excluded from the study
  • Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib or excipients or to dimethyl sulfoxide (DMSO)
  • Current use of a prohibited medication. Prohibited: Other anti-cancer therapy while on study treatment (Note: megestrol [Megace] if used as an appetite stimulant is allowed); Concurrent treatment with bisphosphonates is permitted, however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis; The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra, ginkgo biloba, [DHEA, yohimbe, saw palmetto, or ginseng)
  • History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): History of RVO or CSR, or predisposing factors to RVO or CSR
  • History or evidence of cardiovascular risk including any of the following: Left ventricular ejection fraction (LVEF) = 480 msec; History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible); History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization; History or evidence of current >= Class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system; Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy; Known cardiac metastases
  • Active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible)
  • Patients with known human immunodeficiency virus (HIV) infection are eligible if not on antiviral agents and CD4 counts are adequate (>= 500)
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • The study drug must not be administered to pregnant women or nursing mothers; women of childbearing potential should be advised to avoid pregnancy and use effective methods of contraception
  • HIV-positive patients on combination antiretroviral therapy are ineligible
  • Any condition or medical problem in addition to the underlying malignancy and organ dysfunction which the investigator feels would pose unacceptable risk

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