SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT02070549

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

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

This phase I trial studies the side effects and best dose of trametinib in treating patients with cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced) with or without liver (hepatic) dysfunction. Trametinib may stop the growth of tumor cells by blocking proteins needed for cell growth. When these proteins are blocked, the growth of cancer cells may be stopped and the cancer cells will then die. Hepatic dysfunction is frequently found in patients with advanced cancer and usually prevents patients from receiving standard treatments or from participating in clinical trials. Patients may also need dose adjustments or absorb drugs differently. Trametinib may be a better treatment for patients with advanced cancers and hepatic dysfunction.

NCT02070549 Advanced Malignant Solid Neoplasm Hepatic Complication Metastatic Malignant Neoplasm in the Liver Metastatic Malignant Solid Neoplasm Unresectable Solid Neoplasm
MeSH: Neoplasms Neoplasms, Second Primary Liver Neoplasms
HPO: Neoplasm Neoplasm of the liver

1 Interventions

Name: Trametinib

Description: Given PO

Type: Drug

Treatment (trametinib)


Primary Outcomes

Description: Dose escalation and determination of the maximum tolerated dose will be carried out separately for each cohort or stratum. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

Measure: Maximum tolerated dose of trametinib

Time: 28 days

Description: Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5.0 beginning April 1, 2018). Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

Measure: Dose-limiting toxicity

Time: 28 days

Description: Attempts to model associations between pharmacokinetic data with toxicity profiles will be performed primarily using descriptive statistics; however, logistic regression may be used if warranted.

Measure: Pharmacokinetic profile of trametinib

Time: Baseline and 0.5, 1, 2, 3, 4, 6, 10, and 24 hours on days 15 and 16 of cycle 1

Secondary Outcomes

Description: Will document in patients with varying degrees of hepatic dysfunction.

Measure: Non-dose-limiting toxicities associated with the administration of trametinib

Time: Up to 4 weeks post treatment

Description: Will be assessed using the Response Evaluation Criteria in Solid Tumors criteria 1.1. Summary statistics, such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics.

Measure: Objective response to treatment

Time: Up to 4 weeks post treatment

Description: Will be assessed by utilizing genomic sequencing technologies. Predictors of clinical outcomes will be investigated using logistic regression, Cox proportional hazards regression and/or generalized estimating equations as appropriate. Potential predictors include clinical predictors and molecular correlates. Descriptive statistics and plotting of data will also be used to better understand potential relationships.

Measure: Predictive biomarkers for individual cancer patients

Time: Up to 4 weeks post treatment

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 V600E

Descriptive statistics and plotting of data will also be used to better understand potential relationships.. Inclusion Criteria: - Patients 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 - Hepatocellular carcinoma (HCC) patients are not required to have histologically or cytologically confirmed malignancy, patients are considered eligible based on tumor markers and/or imaging assessment - Based on recent data that have shown limited trametinib benefit, patients with the following tumor types will be excluded from the normal and mild cohorts: - Pancreatic cancer patients - Colorectal cancer patients - BRAF V600E melanoma patients who have failed BRAF inhibitors - Note: Patients with pancreatic cancer, colorectal cancer, and BRAF V600E melanoma patients who have failed BRAF inhibitors are allowed to enroll in the moderate and severe cohorts provided the patients: 1) sign a separate consent form which outlines the extremely limited activity observed in prior studies, and 2) are consented to the study by a protocol-specified designee who is not their longitudinal oncologist - All patients 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 =< 2 (Karnofsky >= 60%) - Life expectancy of 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 (CTCAE) version 4.0 grade =< 1 (except alopecia) at the time of enrollment - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 75 x 10^9/L - Serum creatinine =< 1.5 mg/dL (=< 133 umol/L) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Proteinuria =< +1 on dipstick or =< 1 gram/24 hours - Prothrombin time (PT) =< 1.5 x institutional upper limit of normal (ULN) - International normalized ratio (INR) =< 1.5 x institutional ULN - Partial thromboplastin time (PTT) =< 1.5 x institutional ULN - Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) - 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 - Patients with abnormal hepatic function will be eligible and will be grouped according to criteria summarized below: - Group A: Normal hepatic function - Bilirubin =< ULN - Aspartate aminotransferase (AST) =< ULN - Group B: Mild hepatic dysfunction - B1: bilirubin =< ULN and AST > ULN - B2: ULN < bilirubin =< 1.5 x ULN and any AST - Group C: Moderate hepatic dysfunction - 1.5 x ULN < bilirubin =< 3 x ULN and any AST - Group D: Severe hepatic dysfunction - 3 x ULN < bilirubin =< 10 x ULN and any AST; hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Trametinib can cause fetal harm when administered to a pregnant woman; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to registration and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - History of another malignancy - Exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above - 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; multikinase antiangiogenic tyrosine kinase inhibitors such as regorafenib, sorafenib, sunitinib, etc. whose primary mechanism of action is not RAF inhibition, are allowed; if there are any questions, please contact study's principal investigator - Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression - Have a 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; the following medications or non-drug therapies are 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 - Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - History or current evidence/risk of retinal vein occlusion (RVO) - History or evidence of cardiovascular risk including any of the following: - LVEF < LLN - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 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 - Patients with intra-cardiac defibrillators - 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 cluster of differentiation (CD)4 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 - Animal reproductive studies have not been conducted with trametinib; therefore, 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; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable) - HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated - Any condition or medical problem in addition to the underlying malignancy and organ dysfunction which the investigator feels would pose unacceptable risk Inclusion Criteria: - Patients 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 - Hepatocellular carcinoma (HCC) patients are not required to have histologically or cytologically confirmed malignancy, patients are considered eligible based on tumor markers and/or imaging assessment - Based on recent data that have shown limited trametinib benefit, patients with the following tumor types will be excluded from the normal and mild cohorts: - Pancreatic cancer patients - Colorectal cancer patients - BRAF V600E melanoma patients who have failed BRAF inhibitors - Note: Patients with pancreatic cancer, colorectal cancer, and BRAF V600E melanoma patients who have failed BRAF inhibitors are allowed to enroll in the moderate and severe cohorts provided the patients: 1) sign a separate consent form which outlines the extremely limited activity observed in prior studies, and 2) are consented to the study by a protocol-specified designee who is not their longitudinal oncologist - All patients 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 =< 2 (Karnofsky >= 60%) - Life expectancy of 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 (CTCAE) version 4.0 grade =< 1 (except alopecia) at the time of enrollment - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 75 x 10^9/L - Serum creatinine =< 1.5 mg/dL (=< 133 umol/L) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Proteinuria =< +1 on dipstick or =< 1 gram/24 hours - Prothrombin time (PT) =< 1.5 x institutional upper limit of normal (ULN) - International normalized ratio (INR) =< 1.5 x institutional ULN - Partial thromboplastin time (PTT) =< 1.5 x institutional ULN - Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) - 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 - Patients with abnormal hepatic function will be eligible and will be grouped according to criteria summarized below: - Group A: Normal hepatic function - Bilirubin =< ULN - Aspartate aminotransferase (AST) =< ULN - Group B: Mild hepatic dysfunction - B1: bilirubin =< ULN and AST > ULN - B2: ULN < bilirubin =< 1.5 x ULN and any AST - Group C: Moderate hepatic dysfunction - 1.5 x ULN < bilirubin =< 3 x ULN and any AST - Group D: Severe hepatic dysfunction - 3 x ULN < bilirubin =< 10 x ULN and any AST; hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Trametinib can cause fetal harm when administered to a pregnant woman; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to registration and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - History of another malignancy - Exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above - 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; multikinase antiangiogenic tyrosine kinase inhibitors such as regorafenib, sorafenib, sunitinib, etc. whose primary mechanism of action is not RAF inhibition, are allowed; if there are any questions, please contact study's principal investigator - Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression - Have a 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; the following medications or non-drug therapies are 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 - Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - History or current evidence/risk of retinal vein occlusion (RVO) - History or evidence of cardiovascular risk including any of the following: - LVEF < LLN - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 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 - Patients with intra-cardiac defibrillators - 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 cluster of differentiation (CD)4 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 - Animal reproductive studies have not been conducted with trametinib; therefore, 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; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable) - HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated - Any condition or medical problem in addition to the underlying malignancy and organ dysfunction which the investigator feels would pose unacceptable risk Advanced Malignant Solid Neoplasm Hepatic Complication Metastatic Malignant Neoplasm in the Liver Metastatic Malignant Solid Neoplasm Unresectable Solid Neoplasm Neoplasms Neoplasms, Second Primary Liver Neoplasms PRIMARY OBJECTIVES: I. To provide appropriate dosing recommendations for patients with varying degree of hepatic dysfunction receiving trametinib (mild, moderate and severe). --- V600E ---

Descriptive statistics and plotting of data will also be used to better understand potential relationships.. Inclusion Criteria: - Patients 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 - Hepatocellular carcinoma (HCC) patients are not required to have histologically or cytologically confirmed malignancy, patients are considered eligible based on tumor markers and/or imaging assessment - Based on recent data that have shown limited trametinib benefit, patients with the following tumor types will be excluded from the normal and mild cohorts: - Pancreatic cancer patients - Colorectal cancer patients - BRAF V600E melanoma patients who have failed BRAF inhibitors - Note: Patients with pancreatic cancer, colorectal cancer, and BRAF V600E melanoma patients who have failed BRAF inhibitors are allowed to enroll in the moderate and severe cohorts provided the patients: 1) sign a separate consent form which outlines the extremely limited activity observed in prior studies, and 2) are consented to the study by a protocol-specified designee who is not their longitudinal oncologist - All patients 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 =< 2 (Karnofsky >= 60%) - Life expectancy of 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 (CTCAE) version 4.0 grade =< 1 (except alopecia) at the time of enrollment - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 75 x 10^9/L - Serum creatinine =< 1.5 mg/dL (=< 133 umol/L) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Proteinuria =< +1 on dipstick or =< 1 gram/24 hours - Prothrombin time (PT) =< 1.5 x institutional upper limit of normal (ULN) - International normalized ratio (INR) =< 1.5 x institutional ULN - Partial thromboplastin time (PTT) =< 1.5 x institutional ULN - Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) - 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 - Patients with abnormal hepatic function will be eligible and will be grouped according to criteria summarized below: - Group A: Normal hepatic function - Bilirubin =< ULN - Aspartate aminotransferase (AST) =< ULN - Group B: Mild hepatic dysfunction - B1: bilirubin =< ULN and AST > ULN - B2: ULN < bilirubin =< 1.5 x ULN and any AST - Group C: Moderate hepatic dysfunction - 1.5 x ULN < bilirubin =< 3 x ULN and any AST - Group D: Severe hepatic dysfunction - 3 x ULN < bilirubin =< 10 x ULN and any AST; hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Trametinib can cause fetal harm when administered to a pregnant woman; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to registration and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - History of another malignancy - Exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above - 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; multikinase antiangiogenic tyrosine kinase inhibitors such as regorafenib, sorafenib, sunitinib, etc. whose primary mechanism of action is not RAF inhibition, are allowed; if there are any questions, please contact study's principal investigator - Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression - Have a 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; the following medications or non-drug therapies are 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 - Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - History or current evidence/risk of retinal vein occlusion (RVO) - History or evidence of cardiovascular risk including any of the following: - LVEF < LLN - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 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 - Patients with intra-cardiac defibrillators - 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 cluster of differentiation (CD)4 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 - Animal reproductive studies have not been conducted with trametinib; therefore, 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; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable) - HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated - Any condition or medical problem in addition to the underlying malignancy and organ dysfunction which the investigator feels would pose unacceptable risk Inclusion Criteria: - Patients 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 - Hepatocellular carcinoma (HCC) patients are not required to have histologically or cytologically confirmed malignancy, patients are considered eligible based on tumor markers and/or imaging assessment - Based on recent data that have shown limited trametinib benefit, patients with the following tumor types will be excluded from the normal and mild cohorts: - Pancreatic cancer patients - Colorectal cancer patients - BRAF V600E melanoma patients who have failed BRAF inhibitors - Note: Patients with pancreatic cancer, colorectal cancer, and BRAF V600E melanoma patients who have failed BRAF inhibitors are allowed to enroll in the moderate and severe cohorts provided the patients: 1) sign a separate consent form which outlines the extremely limited activity observed in prior studies, and 2) are consented to the study by a protocol-specified designee who is not their longitudinal oncologist - All patients 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 =< 2 (Karnofsky >= 60%) - Life expectancy of 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 (CTCAE) version 4.0 grade =< 1 (except alopecia) at the time of enrollment - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 75 x 10^9/L - Serum creatinine =< 1.5 mg/dL (=< 133 umol/L) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Proteinuria =< +1 on dipstick or =< 1 gram/24 hours - Prothrombin time (PT) =< 1.5 x institutional upper limit of normal (ULN) - International normalized ratio (INR) =< 1.5 x institutional ULN - Partial thromboplastin time (PTT) =< 1.5 x institutional ULN - Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) - 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 - Patients with abnormal hepatic function will be eligible and will be grouped according to criteria summarized below: - Group A: Normal hepatic function - Bilirubin =< ULN - Aspartate aminotransferase (AST) =< ULN - Group B: Mild hepatic dysfunction - B1: bilirubin =< ULN and AST > ULN - B2: ULN < bilirubin =< 1.5 x ULN and any AST - Group C: Moderate hepatic dysfunction - 1.5 x ULN < bilirubin =< 3 x ULN and any AST - Group D: Severe hepatic dysfunction - 3 x ULN < bilirubin =< 10 x ULN and any AST; hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Trametinib can cause fetal harm when administered to a pregnant woman; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to registration and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - History of another malignancy - Exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above - 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; multikinase antiangiogenic tyrosine kinase inhibitors such as regorafenib, sorafenib, sunitinib, etc. whose primary mechanism of action is not RAF inhibition, are allowed; if there are any questions, please contact study's principal investigator - Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression - Have a 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; the following medications or non-drug therapies are 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 - Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - History or current evidence/risk of retinal vein occlusion (RVO) - History or evidence of cardiovascular risk including any of the following: - LVEF < LLN - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 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 - Patients with intra-cardiac defibrillators - 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 cluster of differentiation (CD)4 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 - Animal reproductive studies have not been conducted with trametinib; therefore, 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; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable) - HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated - Any condition or medical problem in addition to the underlying malignancy and organ dysfunction which the investigator feels would pose unacceptable risk Advanced Malignant Solid Neoplasm Hepatic Complication Metastatic Malignant Neoplasm in the Liver Metastatic Malignant Solid Neoplasm Unresectable Solid Neoplasm Neoplasms Neoplasms, Second Primary Liver Neoplasms PRIMARY OBJECTIVES: I. To provide appropriate dosing recommendations for patients with varying degree of hepatic dysfunction receiving trametinib (mild, moderate and severe). --- V600E --- --- V600E ---

Descriptive statistics and plotting of data will also be used to better understand potential relationships.. Inclusion Criteria: - Patients 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 - Hepatocellular carcinoma (HCC) patients are not required to have histologically or cytologically confirmed malignancy, patients are considered eligible based on tumor markers and/or imaging assessment - Based on recent data that have shown limited trametinib benefit, patients with the following tumor types will be excluded from the normal and mild cohorts: - Pancreatic cancer patients - Colorectal cancer patients - BRAF V600E melanoma patients who have failed BRAF inhibitors - Note: Patients with pancreatic cancer, colorectal cancer, and BRAF V600E melanoma patients who have failed BRAF inhibitors are allowed to enroll in the moderate and severe cohorts provided the patients: 1) sign a separate consent form which outlines the extremely limited activity observed in prior studies, and 2) are consented to the study by a protocol-specified designee who is not their longitudinal oncologist - All patients 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 =< 2 (Karnofsky >= 60%) - Life expectancy of 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 (CTCAE) version 4.0 grade =< 1 (except alopecia) at the time of enrollment - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 75 x 10^9/L - Serum creatinine =< 1.5 mg/dL (=< 133 umol/L) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Proteinuria =< +1 on dipstick or =< 1 gram/24 hours - Prothrombin time (PT) =< 1.5 x institutional upper limit of normal (ULN) - International normalized ratio (INR) =< 1.5 x institutional ULN - Partial thromboplastin time (PTT) =< 1.5 x institutional ULN - Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) - 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 - Patients with abnormal hepatic function will be eligible and will be grouped according to criteria summarized below: - Group A: Normal hepatic function - Bilirubin =< ULN - Aspartate aminotransferase (AST) =< ULN - Group B: Mild hepatic dysfunction - B1: bilirubin =< ULN and AST > ULN - B2: ULN < bilirubin =< 1.5 x ULN and any AST - Group C: Moderate hepatic dysfunction - 1.5 x ULN < bilirubin =< 3 x ULN and any AST - Group D: Severe hepatic dysfunction - 3 x ULN < bilirubin =< 10 x ULN and any AST; hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Trametinib can cause fetal harm when administered to a pregnant woman; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to registration and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - History of another malignancy - Exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above - 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; multikinase antiangiogenic tyrosine kinase inhibitors such as regorafenib, sorafenib, sunitinib, etc. whose primary mechanism of action is not RAF inhibition, are allowed; if there are any questions, please contact study's principal investigator - Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression - Have a 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; the following medications or non-drug therapies are 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 - Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - History or current evidence/risk of retinal vein occlusion (RVO) - History or evidence of cardiovascular risk including any of the following: - LVEF < LLN - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 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 - Patients with intra-cardiac defibrillators - 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 cluster of differentiation (CD)4 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 - Animal reproductive studies have not been conducted with trametinib; therefore, 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; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable) - HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated - Any condition or medical problem in addition to the underlying malignancy and organ dysfunction which the investigator feels would pose unacceptable risk Inclusion Criteria: - Patients 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 - Hepatocellular carcinoma (HCC) patients are not required to have histologically or cytologically confirmed malignancy, patients are considered eligible based on tumor markers and/or imaging assessment - Based on recent data that have shown limited trametinib benefit, patients with the following tumor types will be excluded from the normal and mild cohorts: - Pancreatic cancer patients - Colorectal cancer patients - BRAF V600E melanoma patients who have failed BRAF inhibitors - Note: Patients with pancreatic cancer, colorectal cancer, and BRAF V600E melanoma patients who have failed BRAF inhibitors are allowed to enroll in the moderate and severe cohorts provided the patients: 1) sign a separate consent form which outlines the extremely limited activity observed in prior studies, and 2) are consented to the study by a protocol-specified designee who is not their longitudinal oncologist - All patients 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 =< 2 (Karnofsky >= 60%) - Life expectancy of 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 (CTCAE) version 4.0 grade =< 1 (except alopecia) at the time of enrollment - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 75 x 10^9/L - Serum creatinine =< 1.5 mg/dL (=< 133 umol/L) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Proteinuria =< +1 on dipstick or =< 1 gram/24 hours - Prothrombin time (PT) =< 1.5 x institutional upper limit of normal (ULN) - International normalized ratio (INR) =< 1.5 x institutional ULN - Partial thromboplastin time (PTT) =< 1.5 x institutional ULN - Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) - 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 - Patients with abnormal hepatic function will be eligible and will be grouped according to criteria summarized below: - Group A: Normal hepatic function - Bilirubin =< ULN - Aspartate aminotransferase (AST) =< ULN - Group B: Mild hepatic dysfunction - B1: bilirubin =< ULN and AST > ULN - B2: ULN < bilirubin =< 1.5 x ULN and any AST - Group C: Moderate hepatic dysfunction - 1.5 x ULN < bilirubin =< 3 x ULN and any AST - Group D: Severe hepatic dysfunction - 3 x ULN < bilirubin =< 10 x ULN and any AST; hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Trametinib can cause fetal harm when administered to a pregnant woman; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to registration and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - History of another malignancy - Exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above - 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; multikinase antiangiogenic tyrosine kinase inhibitors such as regorafenib, sorafenib, sunitinib, etc. whose primary mechanism of action is not RAF inhibition, are allowed; if there are any questions, please contact study's principal investigator - Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression - Have a 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; the following medications or non-drug therapies are 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 - Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - History or current evidence/risk of retinal vein occlusion (RVO) - History or evidence of cardiovascular risk including any of the following: - LVEF < LLN - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 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 - Patients with intra-cardiac defibrillators - 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 cluster of differentiation (CD)4 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 - Animal reproductive studies have not been conducted with trametinib; therefore, 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; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable) - HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated - Any condition or medical problem in addition to the underlying malignancy and organ dysfunction which the investigator feels would pose unacceptable risk Advanced Malignant Solid Neoplasm Hepatic Complication Metastatic Malignant Neoplasm in the Liver Metastatic Malignant Solid Neoplasm Unresectable Solid Neoplasm Neoplasms Neoplasms, Second Primary Liver Neoplasms PRIMARY OBJECTIVES: I. To provide appropriate dosing recommendations for patients with varying degree of hepatic dysfunction receiving trametinib (mild, moderate and severe). --- V600E --- --- V600E --- --- V600E ---

Descriptive statistics and plotting of data will also be used to better understand potential relationships.. Inclusion Criteria: - Patients 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 - Hepatocellular carcinoma (HCC) patients are not required to have histologically or cytologically confirmed malignancy, patients are considered eligible based on tumor markers and/or imaging assessment - Based on recent data that have shown limited trametinib benefit, patients with the following tumor types will be excluded from the normal and mild cohorts: - Pancreatic cancer patients - Colorectal cancer patients - BRAF V600E melanoma patients who have failed BRAF inhibitors - Note: Patients with pancreatic cancer, colorectal cancer, and BRAF V600E melanoma patients who have failed BRAF inhibitors are allowed to enroll in the moderate and severe cohorts provided the patients: 1) sign a separate consent form which outlines the extremely limited activity observed in prior studies, and 2) are consented to the study by a protocol-specified designee who is not their longitudinal oncologist - All patients 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 =< 2 (Karnofsky >= 60%) - Life expectancy of 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 (CTCAE) version 4.0 grade =< 1 (except alopecia) at the time of enrollment - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 75 x 10^9/L - Serum creatinine =< 1.5 mg/dL (=< 133 umol/L) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Proteinuria =< +1 on dipstick or =< 1 gram/24 hours - Prothrombin time (PT) =< 1.5 x institutional upper limit of normal (ULN) - International normalized ratio (INR) =< 1.5 x institutional ULN - Partial thromboplastin time (PTT) =< 1.5 x institutional ULN - Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) - 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 - Patients with abnormal hepatic function will be eligible and will be grouped according to criteria summarized below: - Group A: Normal hepatic function - Bilirubin =< ULN - Aspartate aminotransferase (AST) =< ULN - Group B: Mild hepatic dysfunction - B1: bilirubin =< ULN and AST > ULN - B2: ULN < bilirubin =< 1.5 x ULN and any AST - Group C: Moderate hepatic dysfunction - 1.5 x ULN < bilirubin =< 3 x ULN and any AST - Group D: Severe hepatic dysfunction - 3 x ULN < bilirubin =< 10 x ULN and any AST; hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Trametinib can cause fetal harm when administered to a pregnant woman; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to registration and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - History of another malignancy - Exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above - 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; multikinase antiangiogenic tyrosine kinase inhibitors such as regorafenib, sorafenib, sunitinib, etc. whose primary mechanism of action is not RAF inhibition, are allowed; if there are any questions, please contact study's principal investigator - Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression - Have a 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; the following medications or non-drug therapies are 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 - Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - History or current evidence/risk of retinal vein occlusion (RVO) - History or evidence of cardiovascular risk including any of the following: - LVEF < LLN - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 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 - Patients with intra-cardiac defibrillators - 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 cluster of differentiation (CD)4 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 - Animal reproductive studies have not been conducted with trametinib; therefore, 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; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable) - HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated - Any condition or medical problem in addition to the underlying malignancy and organ dysfunction which the investigator feels would pose unacceptable risk Inclusion Criteria: - Patients 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 - Hepatocellular carcinoma (HCC) patients are not required to have histologically or cytologically confirmed malignancy, patients are considered eligible based on tumor markers and/or imaging assessment - Based on recent data that have shown limited trametinib benefit, patients with the following tumor types will be excluded from the normal and mild cohorts: - Pancreatic cancer patients - Colorectal cancer patients - BRAF V600E melanoma patients who have failed BRAF inhibitors - Note: Patients with pancreatic cancer, colorectal cancer, and BRAF V600E melanoma patients who have failed BRAF inhibitors are allowed to enroll in the moderate and severe cohorts provided the patients: 1) sign a separate consent form which outlines the extremely limited activity observed in prior studies, and 2) are consented to the study by a protocol-specified designee who is not their longitudinal oncologist - All patients 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 =< 2 (Karnofsky >= 60%) - Life expectancy of 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 (CTCAE) version 4.0 grade =< 1 (except alopecia) at the time of enrollment - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 75 x 10^9/L - Serum creatinine =< 1.5 mg/dL (=< 133 umol/L) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Proteinuria =< +1 on dipstick or =< 1 gram/24 hours - Prothrombin time (PT) =< 1.5 x institutional upper limit of normal (ULN) - International normalized ratio (INR) =< 1.5 x institutional ULN - Partial thromboplastin time (PTT) =< 1.5 x institutional ULN - Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) - 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 - Patients with abnormal hepatic function will be eligible and will be grouped according to criteria summarized below: - Group A: Normal hepatic function - Bilirubin =< ULN - Aspartate aminotransferase (AST) =< ULN - Group B: Mild hepatic dysfunction - B1: bilirubin =< ULN and AST > ULN - B2: ULN < bilirubin =< 1.5 x ULN and any AST - Group C: Moderate hepatic dysfunction - 1.5 x ULN < bilirubin =< 3 x ULN and any AST - Group D: Severe hepatic dysfunction - 3 x ULN < bilirubin =< 10 x ULN and any AST; hepatic function tests should be repeated within 24 hours prior to starting initial therapy and may result in patients' group assignment being altered if different to registration test results - Trametinib can cause fetal harm when administered to a pregnant woman; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to registration and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - History of another malignancy - Exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second malignancies meet the requirements specified above - 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; multikinase antiangiogenic tyrosine kinase inhibitors such as regorafenib, sorafenib, sunitinib, etc. whose primary mechanism of action is not RAF inhibition, are allowed; if there are any questions, please contact study's principal investigator - Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression - Have a 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; the following medications or non-drug therapies are 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 - Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - History or current evidence/risk of retinal vein occlusion (RVO) - History or evidence of cardiovascular risk including any of the following: - LVEF < LLN - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 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 - Patients with intra-cardiac defibrillators - 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 cluster of differentiation (CD)4 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 - Animal reproductive studies have not been conducted with trametinib; therefore, 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; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable) - HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated - Any condition or medical problem in addition to the underlying malignancy and organ dysfunction which the investigator feels would pose unacceptable risk Advanced Malignant Solid Neoplasm Hepatic Complication Metastatic Malignant Neoplasm in the Liver Metastatic Malignant Solid Neoplasm Unresectable Solid Neoplasm Neoplasms Neoplasms, Second Primary Liver Neoplasms PRIMARY OBJECTIVES: I. To provide appropriate dosing recommendations for patients with varying degree of hepatic dysfunction receiving trametinib (mild, moderate and severe). --- V600E --- --- V600E --- --- V600E --- --- V600E ---



HPO Nodes


HPO:
Neoplasm
Genes 762
CDKN1A CDKN1B CDKN1C CDKN2A HFE CDKN2B CDKN2C GDF5 TSR2 CDKN2D H19-ICR TMEM67 RPL26 RPL27 TREX1 ASXL1 ERBB2 SCN11A POU6F2 ERCC2 RPL35A ERCC3 BRIP1 ERCC4 ABL1 ERCC5 CEBPA ERCC6 PDE6D GCM2 CEL PDGFB PDGFRA PDGFRL MNX1 PDGFRB LEMD3 ENPP1 CTSC ESR1 HLA-DRB1 SLC26A4 MAX APC2 RPS7 TMC6 TMEM216 TRPS1 ACTB RPS10 MC1R MC2R BLNK RPS14 RPS15A ACTG2 ETV6 TCIRG1 DNAJC21 EVC HMBS L2HGDH RPS17 MCM4 RPS19 RPS20 TSC1 TSC2 EWSR1 EXT1 EXT2 RPS24 RPS26 RPS27 ACVR1 EYA1 RPS28 RPS29 MAGT1 ACVRL1 MDH2 MDM2 ADA HNF4A ADAR TRIP13 LYST PICALM ALX4 F13A1 TERF2IP PHF21A F13B RYR1 MAP3K1 AXIN1 TBC1D24 AXIN2 BAP1 CHRNG TWIST1 MEN1 TNFRSF4 FANCA FANCC FANCD2 FANCE TYR GFI1B FAH MET TYROBP FANCB FANCF FANCG SERPINA1 ARID1B SAMD9L AP2S1 MGAT2 DLC1 ICOS DMRT3 SFTPA2 PIGA MGMT MBTPS2 CLCNKB HOXD13 PIK3CA PIK3R1 ACAN FDPS HPGD JAG1 RNASEH2C RECQL4 SCN4A HACE1 RAD54B NR0B1 MITF AHCY GPC4 SCN9A SCN10A HRAS MLF1 MLH1 CTHRC1 TJP2 GTF2H5 FGF3 CC2D2A ANTXR1 LMOD1 PLAG1 FGF8 COL14A1 AKT1 NOP10 ASPSCR1 FGFR1 PLCB4 FGFR3 PLCD1 FGFR2 HAX1 MMP1 MAD2L2 UROD FH MN1 ALK HSPA9 SEC23B SEC23A CARD14 SDHA RAD54L SDHB SDHC SDHD FOXI1 COL1A1 FOXC2 COL2A1 FOXE1 MPL VEGFC ALX3 PMS1 FOXO1 VHL COL4A5 FLI1 MRE11 HSPG2 FLNA KLF11 COL7A1 PIGL SEMA3C BIN1 FLT3 PMS2 FLT4 COL11A2 CIB1 CCDC22 WAS COMP FN1 WIPF1 OFD1 KLF6 ADAMTS3 RNASEH2A LIN28B SFTPC CTC1 PUF60 WHCR NSD2 PPM1D NELFA MAP3K8 INPP5E POLD1 POLE WNT5A POLH GNPTAB SH3GL1 POT1 SH3KBP1 FERMT1 POLR1C WRN TUBB KCNAB2 WT1 APC IKBKG SHH PORCN SHOX BIRC3 POU2AF1 XIAP NLRP1 SAMHD1 XPA MSH2 CHD7 XPC MSH3 ZSWIM6 IDH1 MINPP1 IDH2 TMEM107 TXNRD2 XRCC2 XRCC4 SIX1 SIX3 FANCM SKI FAS FCN3 NHP2 FASLG CR2 CTSA TMEM127 CREB1 CREBBP AR ZAP70 ABCC6 CRKL ZIC2 FAN1 MSR1 MST1 PPP2R1B SETD2 C2CD3 MLH3 PIEZO2 IGF2 ARSA IGF2R MTAP MMEL1 STS GNA14 PMVK SLC12A3 COX1 COX2 UBE2T COX3 IGH SLC17A9 DYNC2LI1 PRCC ELMO2 ASCL1 PRF1 TP63 SLCO2A1 IGHM MTM1 ND1 SETBP1 ND4 ND5 ND6 SNAI2 PTCH2 RNR1 MPLKIP PRKAR1A SMARCB1 ABCB11 WNT10A FLCN SMARCD2 APPL1 PRKCD FOXP1 TRNF C11ORF95 CTBP1 SMO NR5A1 TRNH CTLA4 TRNK IGLL1 TRNL1 ATM RERE MAPK1 CTNNB1 TRNP TRNQ TRNS1 TRNS2 TRNW KDSR SUFU MAP2K1 MAP2K2 CEP57 FZD2 PRDM16 IL2RG G6PC SLC37A4 STAG3 PALLD TRIM37 SLX4 PRLR MUTYH H19 MVD IL7 MVK IL7R SOS1 MYC SOX2 GABRD CYLD MYCN TET2 SOX9 MYD88 IL12A IL12RB1 MYF6 TCTN3 ATP6V1B2 INTU MYH8 MYH11 SAMD9 ATP7A DIS3L2 ATP7B PSAP WWOX MYLK HDAC4 ATR SPIB ACD ATRX SPINK1 ING1 TNFSF12 RTEL1 INHBA PSENEN INS GJB4 CYP11B1 CYP11B2 GJB6 ARHGAP26 KIF1B MAFA RNF113A SRC GAS1 GATA1 CPLX1 GATA2 GATA4 PDX1 BARD1 GBA CDH23 SRP54 FGFRL1 IRF1 NBN SRP72 IRF5 DAXX SRY GCGR CCND1 BCL2 SMARCAD1 GCK NDP KEAP1 TNFRSF10B BCL6 RB1CC1 DCC GPR101 PTCH1 PTEN GDF2 SSX1 BCR SSX2 ADA2 NSUN2 NEK9 DDB2 GDNF DPM1 GINS1 RNF43 GFI1 PTH1R STAR BDNF NAGS STAT1 ITK STAT3 KIAA0753 NOD2 BLK BLM NUTM1 JAK2 STK4 IFIH1 GJA1 STK11 MALT1 NEK1 PTPN3 FAM20C BMPR1A BMPR1B GJB2 GJB3 CCM2 PTPN11 ARL6IP6 KARS NEUROD1 NF1 ANTXR2 DHH GPC3 BRCA1 BRAF BRCA2 NF2 TINF2 SDHAF2 WASHC5 KCNH1 CXCR4 SQSTM1 GLI1 GLI2 GLI3 ABCC8 NBEAL2 DHCR7 DHCR24 KCNJ10 NFKB1 BTK KCNJ11 NFKB2 BUB1 CYP26C1 BUB1B VAMP7 TMC8 MFN2 DKC1 KCNQ1 C1S GNA11 KDR TRPV3 BCL10 DLEC1 GNAI3 GNAQ CDC73 BMPER GNAS SEMA4A GNB1 NME1 TMEM231 FOXH1 PHOX2B CPLANE1 MAPRE2 NODAL TAL1 KIT TAL2 KCNQ1OT1 TNFSF15 DNASE1L3 NOTCH1 NOTCH3 KIF11 CDON DNM2 DNMT3A PNP RAD21 TBX2 RAD51 RAD51C RNASEH2B RAD51D KRAS NPM1 RAF1 KRT1 RAG1 RAG2 CACNA1S KRT5 TCF4 KRT6B EFL1 HNF1A FAT4 HNF1B KRT9 TCF3 CYSLTR2 KRT10 KRT14 EVC2 KCNE3 RARA RPGRIP1L KRT16 CARMIL2 NRAS SRD5A3 KRT17 SASH1 RASA1 RHBDF2 SH2B3 USB1 RB1 TCOF1 NRTN DOCK8 DYNC2H1 CALR GPR35 SLC26A2 NTHL1 NTRK1 MYO1H NUMA1 DVL1 ASCC1 DVL3 NSD1 LAMA3 AGGF1 GPR143 CASP8 B3GALT6 LAMB3 CASP10 GJC2 NR4A3 CASR LAMC2 FANCL RELA OCA2 TDGF1 NUP214 OCRL AIP REST RET MLLT10 RUNX1 WRAP53 CBFB ECE1 GPC6 DLL1 TEK CBL TERC ECM1 AAGAB TERT OGG1 TFAP2A DICER1 WDPCP PALB2 EDN1 LETM1 OPCML MSTO1 EDN3 EDNRB TFE3 ZFPM2 RFWD3 KRIT1 KIF7 SIX6 TG RAD50 ESCO2 VANGL2 RMRP TBX18 TGFBR2 POLR1D SLC22A18 TGIF1 MSH6 COL18A1 USP8 RASGRP1 LIG4 SEMA3D GTF2E2 KLLN RNASEL THPO SF3B1 HMGA2 ALX1 LMNA RNF6 CD19 MS4A1 MTMR14 EGFR LMO1 DCLRE1C ABCA5 LZTS1 LMX1B CD27 TRIM28 CD28 VANGL1 CCBE1 SBDS FANCI BRD4 SLC25A13 MRAP ARMC5 LPP SLC49A4 CHEK2 TREM2 TNFRSF13C FIBP LRRC8A ELANE TNFRSF13B LRP5 CD70 SPRED1 CD79A CD79B CD81 SLC45A2 PRKN PARN HABP2 TAF15 PAX3 EIF2AK4 PAX4 RPL35 PAX6 GREM1 PAX7 SPRTN TNFRSF1B BUB3 KAT6B HBB PDCD10 RNF139 SH2D1A ENG CDH1 EPCAM RSPO1 NNT RPL5 TNPO3 CD96 EP300 DISP1 TOP2A TP53 RPL10 RPL11 SMAD4 RPL15 CDK4 RPL18
Neoplasm of the liver
Genes 94
BLK PMS1 CDKN1C CDKN2A HFE KRAS MST1 FAH IL12A TGFBR2 H19-ICR MET TMEM67 IL12RB1 MSH6 RASGRP1 TCF4 KLF11 HNF1A BMPR1A POU6F2 SERPINA1 PMS2 MLH3 NEUROD1 IGF2 IGF2R DIS3L2 RPGRIP1L MMEL1 ATP7B GPC3 BRCA1 CEL SPIB BRCA2 PDGFRL PIK3CA TRIM28 GPR35 INS INPP5E ABCC8 SLC25A13 JAG1 KCNJ11 SETBP1 AHCY GPC4 WT1 PDX1 APC MLH1 PRKAR1A TJP2 ABCB11 KCNQ1 CC2D2A CASP8 HMBS POU2AF1 CASP10 APPL1 PRKCD C11ORF95 IRF5 RPS20 RELA MSH2 GCK PAX4 REST SEMA4A CTNNB1 SPRTN UROD FAS HBB FASLG HNF4A TRIP13 KCNQ1OT1 EPCAM G6PC TNFSF15 SLC37A4 PALLD TNPO3 PALB2 H19 TP53 AXIN1 SMAD4 FAN1