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Report for Clinical Trial NCT02196181

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Randomized Phase II Trial of Intermittent Versus Continuous Dosing of Dabrafenib (NSC-763760) and Trametinib (NSC-763093) in BRAF V600E/K Mutant Melanoma

This randomized phase II trial studies how well dabrafenib and trametinib work in treating patients with stage III-IV melanoma that cannot be removed by surgery and contains a B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02196181 Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Melanoma
MeSH:Melanoma Skin Neoplasms
HPO:Cutaneous melanoma Melanoma Neoplasm of the skin

4 Interventions

Name: Dabrafenib

Description: Given PO
Type: Drug
Group Labels: 2

Arm I (continuous dosing) Arm II (intermittent dosing)

Name: Dabrafenib Mesylate

Description: Given PO
Type: Drug
Group Labels: 2

Arm I (continuous dosing) Arm II (intermittent dosing)

Name: Trametinib

Description: Given PO
Type: Drug
Group Labels: 2

Arm I (continuous dosing) Arm II (intermittent dosing)

Name: Trametinib Dimethyl Sulfoxide

Description: Given PO
Type: Drug
Group Labels: 2

Arm I (continuous dosing) Arm II (intermittent dosing)


Primary Outcomes

Description: Testing of the superiority of intermittent dosing of dabrafenib and trametinib compared to continuous dosing with these two same agents will be based on progression-free survival. Stratified Cox regression models stratified by stratification factors will be used for all analyses.

Measure: Progression-free survival (PFS)

Time: Measured from date of randomization, assessed up to 5 years

Secondary Outcomes

Description: Overall survival between patients on each arm and survival after progression will be compared using Cox regression models.

Measure: Overall survival

Time: Up to 5 years

Description: Response rates between arms will be compared using Fisher's exact test.

Measure: Response rates

Time: Up to 5 years

Description: Defined as >= grade 3 per Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 with attribution possibly, probably, or definitely related to treatment; or any >= grade 1 per CTCAE v4.0 with attribution possibly, probably, or definitely related to treatment with chills, dehydration, hypotension, dizziness, or muscle weakness per CTCAE v4.0 with attribution possibly, probably, or definitely related to treatment reported during the same course. Rates of fever between arms will also be compared using Fisher's exact test.

Measure: Rates of fever

Time: Up to 5 years

Other Outcomes

Description: Compared between patients of the two treatment groups.

Measure: Molecular events leading to reactivation of the MAPK pathway

Time: Up to 5 years

Description: Cox regression analyses will be used to evaluate biomarkers' associations with PFS.

Measure: Change in biomarkers associated with PFS of archived tissue

Time: Baseline up to 5 years

Description: Cox regression analyses will be used to evaluate biomarkers' associations with PFS.

Measure: Interaction between baseline biomarkers and treatment arm

Time: Baseline up to 5 years

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There are 2 SNPs

SNPs


1 V600E

A Randomized Phase II Trial of Intermittent Versus Continuous Dosing of Dabrafenib (NSC-763760) and Trametinib (NSC-763093) in BRAF V600E/K Mutant Melanoma. --- V600E ---

Cox regression analyses will be used to evaluate biomarkers' associations with PFS.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E ---

Cox regression analyses will be used to evaluate biomarkers' associations with PFS.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K --- --- V600E ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K --- --- V600E ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVE: I. To compare progression-free survival with intermittent dosing and continuous dosing of dabrafenib and trametinib among patients with metastatic BRAF V600E/K mutant melanoma. --- V600E ---


2 V600K

Cox regression analyses will be used to evaluate biomarkers' associations with PFS.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K ---

Cox regression analyses will be used to evaluate biomarkers' associations with PFS.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K --- --- V600E --- --- V600K ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K --- --- V600E --- --- V600K ---



HPO Nodes


HPO:
HP:0008069: Neoplasm of the skin
Genes 277
TGFBR2 DOCK8 KRT17 PORCN ERCC4 OCA2 PTEN SDHC SUFU RNF6 KRT6B PIK3CA TNFRSF1B DDB2 KRT14 SDHD FASLG COL1A1 CARMIL2 LRRC8A BAP1 NF1 FLT4 NRAS LAMC2 RSPO1 OCRL TP53 NTHL1 PTEN NF1 FH LAMB3 COL7A1 PERP FH NRAS TINF2 SLC17A9 RECQL4 PTCH2 RPS20 CD79B KRT17 BMPR1A MLH1 NF1 GJB3 LZTS1 MSH3 SUFU GNA14 IKBKG PTCH1 KIT HRAS BRAF APC PRKAR1A MMP1 KRT17 TP53 KEAP1 SMO PTCH1 ERCC5 MVD TERC PTEN SEMA4A CD79A SMARCB1 GJB2 KIT FLT4 KRT9 MC1R SEC23B VEGFC ERCC3 FGFR1 BLNK TNFRSF1B MSH6 TCF3 PLCD1 MEN1 FAS KRAS CTSC RECQL4 CD28 CDKN2B WWOX CTLA4 COL7A1 HRAS CDKN2A TP53 WNT10A NLRP1 ERCC2 IFNG MBTPS2 MDM2 KRAS GTF2E2 MLH1 STAT1 TMC8 SNAI2 BMPR1A CDKN1A KDSR CD28 CYLD ERCC2 ERCC4 NRAS DCLRE1C SLC45A2 PMS1 MITF MSH3 NUTM1 IL7 PIK3CA ERCC3 SDHC PTCH2 MLH1 CIB1 MSH6 CDKN2A NF1 CIB1 TNFRSF10B NF2 APC SLCO2A1 BLM GJA1 GTF2H5 PIK3CA TARS1 CXCR4 CDK4 PIK3R1 CYLD GJC2 GPR143 DDB2 LAMA3 SDHB MVK PMVK PIK3CA EPCAM GJB2 NF2 MSH2 WRAP53 MEN1 RASA1 KRAS LMNA CTNNB1 CDKN1B POLH GJB6 MPLKIP IL6 CXCR4 NOTCH3 TSC2 AKT1 PSENEN PMS2 RASGRP1 CASP10 ERCC3 MC1R SDHB KIT RMRP PTEN TGFBR2 PDGFRB CYLD RNF113A ALX3 BLM CTNNB1 FH KIT STIM1 TYR TMC6 HRAS CHEK2 KRT1 DICER1 DKC1 MSH2 COL7A1 NRAS PTEN FDPS PRKCD NRAS CDKN2A XPC WNT10A SEC23B XPA CDKN1B ERCC2 HPGD ERCC5 SLX4 TNFRSF4 FCN3 MMP1 ECM1 USF3 LMNA XPC NTHL1 KRT16 KIT PDGFB FAN1 ERCC4 SPRED1 PDGFB ING1 FERMT1 MLH1 KLLN ERCC2 GJB4 MSH6 APC TERT POLH BRD4 WRN SASH1 TMC6 MSH2 HRAS APC PMS2 ERCC3 KIT CTLA4 KLLN IGHM STK4 FAS GJB2 MLH3 TRPV3 CDKN2C IGLL1 TYR MSH2 NF2 COL7A1 AKT1 DCC FLCN PTCH1 TSC1 CDKN2A KRT5 PRKAR1A
Protein Mutations 4
D299G P13K V600E V600K
SNP 0