SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT01940809

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

A Sequential Safety and Biomarker Study of BRAF-MEK Inhibition on the Immune Response in the Context of Combined CTLA-4 Blockade and PD-1 Blockade for BRAF Mutant Melanoma

This randomized phase I trial studies the side effects and best way to give ipilimumab with or without dabrafenib, trametinib and/or nivolumab in treating patients with melanoma that has spread to other parts of the body (metastatic) or cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and nivolumab, may interfere with the ability of cancer cells to grow and spread. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether ipilimumab works better with or without dabrafenib, trametinib, and/or nivolumab in treating melanoma.

NCT01940809 BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Melanoma 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
MeSH: Melanoma Skin Neoplasms
HPO: Cutaneous melanoma Melanoma Neoplasm of the skin

5 Interventions

Name: Dabrafenib

Description: Given PO

Type: Drug

Arm A1 (ipilimumab, dabrafenib, trametinib) Arm C1 (ipilimumab, dabrafenib) Arm A2 (dabrafenib, trametinib, nivolumab, ipilimumab) Arm C2 (dabrafenib, nivolumab, ipilimumab)

Name: Ipilimumab

Description: Given IV

Type: Biological

Arm A1 (ipilimumab, dabrafenib, trametinib) Arm B1 (ipilimumab, trametinib) Arm C1 (ipilimumab, dabrafenib) Arm D1 (ipilimumab) Arm A2 (dabrafenib, trametinib, nivolumab, ipilimumab) Arm B2 (trametinib, nivolumab, ipilimumab) Arm C2 (dabrafenib, nivolumab, ipilimumab) Arm D2 (nivolumab, ipilimumab)

Name: Laboratory Biomarker Analysis

Description: Correlative studies

Type: Other

Arm A1 (ipilimumab, dabrafenib, trametinib) Arm B1 (ipilimumab, trametinib) Arm C1 (ipilimumab, dabrafenib) Arm D1 (ipilimumab) Arm A2 (dabrafenib, trametinib, nivolumab, ipilimumab) Arm B2 (trametinib, nivolumab, ipilimumab) Arm C2 (dabrafenib, nivolumab, ipilimumab) Arm D2 (nivolumab, ipilimumab)

Name: Nivolumab

Description: Given IV

Type: Biological

Arm A2 (dabrafenib, trametinib, nivolumab, ipilimumab) Arm B2 (trametinib, nivolumab, ipilimumab) Arm C2 (dabrafenib, nivolumab, ipilimumab) Arm D2 (nivolumab, ipilimumab)

Name: Trametinib

Description: Given PO

Type: Drug

Arm A1 (ipilimumab, dabrafenib, trametinib) Arm B1 (ipilimumab, trametinib) Arm A2 (dabrafenib, trametinib, nivolumab, ipilimumab) Arm B2 (trametinib, nivolumab, ipilimumab)


Primary Outcomes

Description: Presented with 90% confidence intervals calculated using exact binomial methods.

Measure: Incidence of grade 3 or higher immune-related adverse events (irAEs), graded according to the National Cancer Institute (NCI) CTCAE v4.0

Time: Up to 3 weeks after end of ipilimumab induction

Secondary Outcomes

Description: Presented with 90% confidence intervals calculated using exact binomial methods by randomized treatment arm.

Measure: Proportion of patients receiving dabrafenib and trametinib with grade 3 or higher irAEs after disease progression on ipilimumab, according to the NCI CTCAE v4.0

Time: Up to 4 weeks after completion of study treatment

Description: Summarized by treatment arm and presented with 90% exact binomial confidence intervals. Fisher's exact test will be used.

Measure: Response rate for the total treatment period according to Response Evaluation Criteria in Solid Tumors v1.1

Time: Up to 4 weeks after completion of study treatment

Description: Summarized by treatment arm and presented with 90% exact binomial confidence intervals. Fisher's exact test will be used.

Measure: Disease-control rate

Time: Up to 4 weeks after completion of study treatment

Other Outcomes

Description: The relationship between pre-treatment marker levels and response will be assessed according to expression cut-off between positive and negative. Fisher's exact test will be used to detect an increase in response rate and a secondary, sensitivity analysis will use a stratified Fisher's exact test.

Measure: Biomarker expression levels

Time: Baseline

Description: Biomarkers measured on a continuous scale will be summarized and compared across response categories using the Wilcoxon rank-sum test. For biomarkers measured categorically, pre/post response combinations will be compared between responders and non-responders using Fisher's exact test.

Measure: Fold-changes in biomarkers

Time: Baseline to 3 weeks after fourth ipilimumab dose

Description: Biomarkers measured on a continuous scale will be summarized and compared across response categories using the Wilcoxon rank-sum test. For biomarkers measured categorically, pre/post response combinations will be compared between responders and non-responders using Fisher's exact test.

Measure: Change in immune activation, measured by changes in biomarker levels

Time: Baseline to 3 weeks after fourth ipilimumab dose

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There are 2 SNPs

SNPs


1 V600E

For biomarkers measured categorically, pre/post response combinations will be compared between responders and non-responders using Fisher's exact test.. Inclusion Criteria: - Study participants must have histologically or cytologically confirmed unresectable or metastatic malignant melanoma - Study participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Study participants must have completed any prior treatment at least 3 weeks prior to treatment on this protocol; prior treatments may have included chemotherapy however may not have included BRAF or MEK inhibitors or immunotherapies (interleukin-2, ipilimumab, anti-programmed death [PD]1 antibodies etc.) excluding vaccine therapy; prior treatment with interferon in the adjuvant setting is allowed, though prior treatment with ipilimumab in the adjuvant setting is not; prior radiation therapy is allowed though must have included no more than 3000 centigray (cGy) to fields including substantial marrow - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 100 x 10^9/L - Albumin >= 2.5 g/dL - Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN - Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (lab); if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib or for 6 months after dabrafenib in combination with trametinib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of randomization - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - 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 study treatment and during the study - Study participants with a history of prior treatment with BRAF or MEK inhibitors - Study participants who had prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible - Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event) - Study participants who have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted - Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study - Study participants with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody and/or anti-PD-1 antibody - Study participants with brain metastases are excluded unless these have been definitively treated and are radiographically stable for at least 1 month; the study participant must also demonstrate a stable physical exam and must have discontinued systemic steroids for treatment of edema related to brain metastases or treatment for over 7 days - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History or evidence of cardiovascular risks including any of the following: - QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Any condition which in the investigator's opinion makes the subject unsuitable for study participation - History of retinal vein occlusion (RVO) - History of interstitial lung disease or pneumonitis Inclusion Criteria: - Study participants must have histologically or cytologically confirmed unresectable or metastatic malignant melanoma - Study participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Study participants must have completed any prior treatment at least 3 weeks prior to treatment on this protocol; prior treatments may have included chemotherapy however may not have included BRAF or MEK inhibitors or immunotherapies (interleukin-2, ipilimumab, anti-programmed death [PD]1 antibodies etc.) excluding vaccine therapy; prior treatment with interferon in the adjuvant setting is allowed, though prior treatment with ipilimumab in the adjuvant setting is not; prior radiation therapy is allowed though must have included no more than 3000 centigray (cGy) to fields including substantial marrow - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 100 x 10^9/L - Albumin >= 2.5 g/dL - Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN - Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (lab); if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib or for 6 months after dabrafenib in combination with trametinib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of randomization - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - 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 study treatment and during the study - Study participants with a history of prior treatment with BRAF or MEK inhibitors - Study participants who had prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible - Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event) - Study participants who have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted - Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study - Study participants with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody and/or anti-PD-1 antibody - Study participants with brain metastases are excluded unless these have been definitively treated and are radiographically stable for at least 1 month; the study participant must also demonstrate a stable physical exam and must have discontinued systemic steroids for treatment of edema related to brain metastases or treatment for over 7 days - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History or evidence of cardiovascular risks including any of the following: - QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Any condition which in the investigator's opinion makes the subject unsuitable for study participation - History of retinal vein occlusion (RVO) - History of interstitial lung disease or pneumonitis BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Melanoma 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 Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of ipilimumab (part 1) or ipilimumab plus nivolumab (part 2) following lead-in of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors, either alone or in combination, in patients with BRAFV600 mutant melanoma. --- V600E ---


2 V600K

For biomarkers measured categorically, pre/post response combinations will be compared between responders and non-responders using Fisher's exact test.. Inclusion Criteria: - Study participants must have histologically or cytologically confirmed unresectable or metastatic malignant melanoma - Study participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Study participants must have completed any prior treatment at least 3 weeks prior to treatment on this protocol; prior treatments may have included chemotherapy however may not have included BRAF or MEK inhibitors or immunotherapies (interleukin-2, ipilimumab, anti-programmed death [PD]1 antibodies etc.) excluding vaccine therapy; prior treatment with interferon in the adjuvant setting is allowed, though prior treatment with ipilimumab in the adjuvant setting is not; prior radiation therapy is allowed though must have included no more than 3000 centigray (cGy) to fields including substantial marrow - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 100 x 10^9/L - Albumin >= 2.5 g/dL - Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN - Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (lab); if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib or for 6 months after dabrafenib in combination with trametinib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of randomization - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - 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 study treatment and during the study - Study participants with a history of prior treatment with BRAF or MEK inhibitors - Study participants who had prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible - Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event) - Study participants who have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted - Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study - Study participants with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody and/or anti-PD-1 antibody - Study participants with brain metastases are excluded unless these have been definitively treated and are radiographically stable for at least 1 month; the study participant must also demonstrate a stable physical exam and must have discontinued systemic steroids for treatment of edema related to brain metastases or treatment for over 7 days - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History or evidence of cardiovascular risks including any of the following: - QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Any condition which in the investigator's opinion makes the subject unsuitable for study participation - History of retinal vein occlusion (RVO) - History of interstitial lung disease or pneumonitis Inclusion Criteria: - Study participants must have histologically or cytologically confirmed unresectable or metastatic malignant melanoma - Study participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Study participants must have completed any prior treatment at least 3 weeks prior to treatment on this protocol; prior treatments may have included chemotherapy however may not have included BRAF or MEK inhibitors or immunotherapies (interleukin-2, ipilimumab, anti-programmed death [PD]1 antibodies etc.) excluding vaccine therapy; prior treatment with interferon in the adjuvant setting is allowed, though prior treatment with ipilimumab in the adjuvant setting is not; prior radiation therapy is allowed though must have included no more than 3000 centigray (cGy) to fields including substantial marrow - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 100 x 10^9/L - Albumin >= 2.5 g/dL - Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN - Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (lab); if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib or for 6 months after dabrafenib in combination with trametinib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of randomization - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - 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 study treatment and during the study - Study participants with a history of prior treatment with BRAF or MEK inhibitors - Study participants who had prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible - Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event) - Study participants who have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted - Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study - Study participants with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody and/or anti-PD-1 antibody - Study participants with brain metastases are excluded unless these have been definitively treated and are radiographically stable for at least 1 month; the study participant must also demonstrate a stable physical exam and must have discontinued systemic steroids for treatment of edema related to brain metastases or treatment for over 7 days - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History or evidence of cardiovascular risks including any of the following: - QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Any condition which in the investigator's opinion makes the subject unsuitable for study participation - History of retinal vein occlusion (RVO) - History of interstitial lung disease or pneumonitis BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Melanoma 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 Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of ipilimumab (part 1) or ipilimumab plus nivolumab (part 2) following lead-in of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors, either alone or in combination, in patients with BRAFV600 mutant melanoma. --- V600E --- --- V600K ---



HPO Nodes


HPO:
Cutaneous melanoma
Genes 11
BRAF HRAS XPC CDKN2A POLH ERCC3 BAP1 CXCR4 MC1R NRAS WRN
Melanoma
Genes 64
RAD51 RAD51C TYR RAD51D CDKN2A KRAS CDKN2B RAF1 CDKN2D MRE11 CYSLTR2 ERCC2 KLLN PTPN11 ERCC3 BRIP1 ERCC4 ERCC5 ERCC6 SF3B1 NRAS MGMT BRCA1 MBTPS2 BRAF ACD BRCA2 PIK3CA CXCR4 CTSC POLH POT1 MC1R MITF WRN CHEK2 HRAS BARD1 NBN AKT1 SLC45A2 GNA11 TRPV3 XPA OCA2 XPC GNAQ PTEN MDM2 TERT DDB2 RNF43 PALLD PALB2 TERF2IP SEC23B TP53 SDHB SDHC SDHD SMAD4 BAP1 CDK4 RAD50
Neoplasm of the skin
Genes 171
VEGFC ALX3 CDKN1A PMS1 CDKN1B CYLD CDKN2A KRAS CDKN2B CDKN2C KRT1 KRT5 COL7A1 KRT6B KRT9 TCF3 PMS2 ERCC2 FLT4 KRT14 ERCC3 CIB1 ERCC4 ERCC5 KRT16 CARMIL2 WWOX NRAS KRT17 SASH1 RASA1 PDGFB PDGFRA ING1 PDGFRB DOCK8 PSENEN GJB4 NTHL1 CTSC GJB6 POLH RNF113A TMC6 FERMT1 MC1R WRN BLNK APC IKBKG LAMA3 GPR143 PORCN LAMB3 CASP10 NLRP1 GJC2 LAMC2 RPS20 TSC1 TSC2 XPA MSH2 OCA2 XPC MSH3 OCRL KEAP1 TNFRSF10B DCC PTCH1 WRAP53 PTEN MDM2 FAS FCN3 FASLG TERC ECM1 TERT DDB2 DICER1 STAT1 BAP1 MEN1 FAN1 TNFRSF4 BLM TYR NUTM1 STK4 RMRP TGFBR2 GJA1 MSH6 RASGRP1 BMPR1A GTF2E2 GJB2 GJB3 KLLN MLH3 NF1 GNA14 PMVK MBTPS2 LMNA BRAF RNF6 NF2 TINF2 DCLRE1C SLC17A9 LZTS1 PIK3CA CD28 CXCR4 PIK3R1 FDPS HPGD SLCO2A1 IGHM BRD4 RECQL4 SNAI2 CHEK2 TMC8 HRAS PTCH2 MLH1 MPLKIP PRKAR1A GTF2H5 LRRC8A WNT10A DKC1 FLCN PRKCD SPRED1 CD79A CD79B AKT1 SLC45A2 SMO TRPV3 FGFR1 CTLA4 PLCD1 IGLL1 MMP1 SEMA4A CTNNB1 TNFRSF1B FH KDSR SUFU KIT EPCAM RSPO1 SLX4 SEC23B MUTYH MVD TP53 IL7 MVK NOTCH3 SDHB SDHC SDHD COL1A1