Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma

Study Description

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Brief Summary:

This randomized phase III trial studies how well initial treatment with ipilimumab and nivolumab followed by dabrafenib and trametinib works and compares it to initial treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab in treating patients with stage III-IV melanoma that contains a mutation known as BRAFV600 and cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Dabrafenib and trametinib may block tumor growth by targeting the BRAFV600 gene. It is not yet known whether treating patients with ipilimumab and nivolumab followed by dabrafenib and trametinib is more effective than treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab.

Condition or disease	Intervention/treatment	Phase
BRAF NP_004324.2:p.V600X; Metastatic Melanoma; Recurrent 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	Drug: Dabrafenib; Biological: Ipilimumab; Other: Laboratory Biomarker Analysis; Biological: Nivolumab; Other: Quality-of-Life Assessment; Drug: Trametinib	Phase 3

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Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	300 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a Phase III Trial
Actual Study Start Date :	July 13, 2015
Estimated Primary Completion Date :	October 2, 2022

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Arm A (immunotherapy); IMMUNOTHERAPY INDUCTION (COURSES 1-2): Patients receive nivolumab IV over 30-60 minutes and ipilimumab IV over 30-60 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. IMMUNOTHERAPY MAINTENANCE (COURSES 3-14): Patients receive nivolumab IV over 30-60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients re-register and cross over to Arm C.	Biological: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment
Experimental: Arm B (BRAF inhibitor therapy); Patients receive dabrafenib PO BID and trametinib PO daily on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients re-register and cross over to Arm D.	Drug: Dabrafenib; Given PO; Other Names: BRAF Inhibitor GSK2118436; GSK-2118436A; GSK2118436; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment; Drug: Trametinib; Given PO; Other Names: GSK1120212; JTP-74057; MEK Inhibitor GSK1120212; Mekinist
Experimental: Arm C (BRAF inhibitor therapy); Patients receive dabrafenib PO BID and trametinib PO daily on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.	Drug: Dabrafenib; Given PO; Other Names: BRAF Inhibitor GSK2118436; GSK-2118436A; GSK2118436; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment; Drug: Trametinib; Given PO; Other Names: GSK1120212; JTP-74057; MEK Inhibitor GSK1120212; Mekinist
Experimental: Arm D (immunotherapy); IMMUNOTHERAPY INDUCTION (COURSES 1-2): Patients receive nivolumab IV over 30-60 minutes and ipilimumab IV over 30-60 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. IMMUNOTHERAPY MAINTENANCE (COURSES 3-14): Patients receive nivolumab IV over 30-60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.	Biological: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment

Outcome Measures

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Primary Outcome Measures :

1. Overall survival (OS) rate, defined as the proportion of patients alive after 2 years of follow-up time [ Time Frame: The time from randomization to death from any cause, assessed for up to 2 years ]
   Will be estimated and compared between the two arms using the Mantel-Haenszel test based (stratified by Eastern Cooperative Oncology Group (ECOG) performance status [PS] and LDH) based on two-sided overall type I error rate of 0.05 adjusting for two-interim analysis. Mantel-Haenszel test will compare the 2-year OS rates while controlling for the stratification factors. The difference in 2-year OS rates in arms A and B will be estimated and presented with 95% repeated confidence interval of Jennison-Turnbull. In addition, OS distribution will be estimated using the Kaplan-Meier method. The distribution of OS will be compared using the stratified log rank test. Hazard of OS will be estimated as a function of time in arm A and in arm B (as randomized in step 1 to arm A versus [vs.] B) and presented graphically.

Secondary Outcome Measures :

1. Progression-free survival (PFS), evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [ Time Frame: The time from randomization to disease progression or death (whichever occurs first), assessed up to 5 years ]
   Distribution will be estimated using the Kaplan-Meier method. PFS will be compared using the log-rank test.
2. Response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [ Time Frame: Up to 5 years ]
   Response rates will be compared using the Mantel-Haenszel test (stratified by ECOG PS and LDH) test in arms A vs. B. Response rate for patients who are treated with ipilimumab/nivolumab before crossover (arm A) vs. for patients who were initially treated with dabrafenib/trametinib and crossed over to ipilimumab/nivolumab will be compared (arm D). Response rates will be compared using the Fisher's exact test.
3. Toxicity rate for individual adverse events (AEs) [ Time Frame: Up to 5 years ]
   Compared using the chi-square of Fisher's exact test. Two-sided p-values will be reported for these comparisons.
4. Toxicity rate for categorized adverse events (AEs) [ Time Frame: Up to 5 years ]
   Compared using the chi-square of Fisher's exact test. Two-sided p-values will be reported for these comparisons.
5. Toxicity rate for worst degree adverse events (AEs) [ Time Frame: Up to 5 years ]
   Compared using the chi-square of Fisher's exact test. Two-sided p-values will be reported for these comparisons.

Other Outcome Measures:

1. Genetic characteristics [ Time Frame: Baseline ]
   Genetic associations with immune-related adverse events (irAE) status will be assessed using Fisher's exact test, one-degree-of-freedom genotypic trend test or the two-degrees-of-freedom chi-squared test of independence at each individual SNP marker. Tests of association will be adjusted for age, sex, center or clinical protocol, and dose as well as American Joint Committee on Cancer stage, ulceration, performance status, LDH level, number of involved sites, BRAF mutation status (when available) and number of prior therapies using logistic regression modeling assuming an additive genetic model.
2. Immune-related adverse events (irAE) status [ Time Frame: Up to 2 years ]
   Genetic associations with irAE status will be assessed using Fisher's exact test, one-degree-of-freedom genotypic trend test or the two-degrees-of-freedom chi-squared test of independence at each individual SNP marker. Tests of association will be adjusted for age, sex, center or clinical protocol, and dose as well as American Joint Committee on Cancer stage, ulceration, performance status, LDH level, number of involved sites, BRAF mutation status (when available) and number of prior therapies using logistic regression modeling assuming an additive genetic model.
3. Quality-adjusted time without symptoms of disease progression or toxicity of treatment (Q-TWIST) [ Time Frame: Up to 2 years ]
   The restricted mean amount of time for each health state will be estimated using the Kaplan-Meier method, with time limit set at 2 years for computation of all restricted means. The mean amount of time for each health state and the average group utility scores will be summarized by initial treatment (i.e., arm A: ipilimumab + nivolumab [with subsequent dabrafenib + trametinib] vs. arm B: dabrafenib + trametinib [with subsequent ipilimumab + nivolumab]). The Q-TWiST subscore and the overall Q-TWiST score will then be reported by initial treatment. Differences between treatment groups in the mean Q-TWiST score (including the overall score and the subscore) will be calculated. For each score, a 95% confidence interval and two-sided P-value for testing the null hypothesis of no difference between treatment groups will be conducted using a Z-test (with normal approximation), with standard errors calculated by the bootstrap method.
4. Overall function, assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) PROFILE-29 [ Time Frame: Up to 24 months from study entry ]
   A log-normal survival model for analyzing longitudinal data which incorporates the non-ignorable censoring mechanism will be fitted for each short form T-score and pain intensity, separately, to assess initial treatment effect (i.e., arm A: ipilimumab + nivolumab [with subsequent dabrafenib + trametinib] vs. arm B: dabrafenib + trametinib [with subsequent ipilimumab + nivolumab]) on each function. To evaluate the effect of treatment sequence on patient function, each of the PROMIS short form T-score and pain intensity (with longitudinal data collected at baseline, 6-, 12-weeks, and 6-months after the initiation of treatment in each step) will be compared by treatment sequence for ipilimumab + nivolumab (arm A vs. D) and for dabrafenib + trametinib (arm B vs. C), using a log-normal survival model as described above.
5. Change in patient-reported symptoms, assessed using the Patient Reported Outcomes Common Terminology Criteria for Adverse Events [ Time Frame: Baseline to up to 6 months after the initiation of treatment in each step ]
   To evaluate the effect of treatment sequence on symptoms, summary statistics (frequency [N] and percentage [%]) will be reported with respect to presence, frequency and severity (if applicable) for each symptom by treatment sequence for ipilimumab + nivolumab (arm A vs. D), and for dabrafenib + trametinib (arm B vs. C) at baseline, 6-, 12-weeks, and 6-months after the initiation of the first treatment and the secondary treatment.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• STEP 1
• Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1

• Women must not be pregnant or breast-feeding

  • All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy
  • A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of child-bearing potential and sexually active males must agree to use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for the duration of their participation in the study, and for at least 4 weeks after treatment with dabrafenib or for 4 months after dabrafenib in combination with trametinib; women of child-bearing potential must use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for at least 5 months after the last dose of nivolumab and/or ipilimumab and sexually active males must use at least two other accepted and effective methods of contraception and/or abstain from sexual intercourse for at least 7 months after the last dose of nivolumab and/or ipilimumab; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
• Patients must have unresectable stage III or stage IV disease
• Patients must have measurable disease; all sites of disease must be evaluated within 4 weeks prior to randomization

• Patients must have histological or cytological confirmation of melanoma that is metastatic or unresectable and clearly progressive

  • NOTE: Any patient with BRAF V600 mutant melanoma (whether cutaneous, acral or mucosal primary) who meets the eligibility criteria is eligible for participation in this trial; patients with uveal melanoma are not eligible for this trial
• Patients must have BRAF V600 mutation, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Act (CLIA)-certified lab; if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test, Foundation Medicine); prompt information on tumor BRAF mutation status can also be obtained via Novartis "knowNow" Program
• Patients may have had prior systemic therapy in the adjuvant setting; however this adjuvant treatment must not have included a CTLA4 or PD1 pathway blocking antibody or a BRAF/MEK inhibitor; also, patients may not have had any prior systemic treatment for advanced (measurable metastatic) disease
• Patients must have discontinued chemotherapy, immunotherapy or other investigational agents used in the adjuvant setting >= 4 weeks prior to entering the study and recovered from adverse events due to those agents; mitomycin and nitrosoureas must have been discontinued at least 6 weeks prior to entering the study; patients must have discontinued radiation therapy >= 1 weeks prior to entering the study and recovered from any adverse events associated with treatment; prior surgery must be >= 2 weeks from registration and patients must be fully recovered from post-surgical complications
• Patients must not receive any other investigational agents while on study or within four weeks prior to registration
• Patients are ineligible if they have any currently active central nervous system (CNS) metastases; patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery [SRS]) could be eligible; patients must not have taken any steroids =< 10 days prior to randomization for the purpose of managing their brain metastases; repeat imaging after SRS or surgical resection is not required so long as baseline magnetic resonance imaging (MRI) is within 4 weeks of registration; multiple brain metastases treated with SRS (with [w] or without [w/o] whole-brain radiotherapy [WBRT]), untreated asymptomatic lesions are not an exclusion
• Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast; patients with other malignancies are eligible if they have been continuously disease-free for > 2 years prior to the time of registration
• White blood count >= 3,000/uL (obtained within 4 weeks prior to randomization)
• Absolute neutrophil count (ANC) >= 1,500/uL (obtained within 4 weeks prior to randomization)
• Platelet count >= 100,000/uL (obtained within 4 weeks prior to randomization)
• Hemoglobin > 8 g/dL (obtained within 4 weeks prior to randomization)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) >= 40 ml/min (obtained within 4 weeks prior to randomization)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (=< 5 x ULN for patients with documented liver metastases)
• Alkaline phosphatase =< 2 x ULN (=< 5 x ULN for patients with known liver involvement and =< 7 x ULN for patients with known bone involvement) (obtained within 4 weeks prior to randomization)
• Total bilirubin =< 1.5 x ULN except subjects with normal direct bilirubin or those with known Gilbert's syndrome (obtained within 4 weeks prior to randomization)
• Serum lactate dehydrogenase (LDH) < 10 X ULN (patients with LDH > 10 X ULN are felt to have aggressive disease and should be considered for BRAF inhibitor therapy off protocol) (obtained within 4 weeks prior to randomization)
• Patients must not have any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), including but not limited to, ongoing or active infection requiring parenteral antibiotics on day 1, or psychiatric illness/social situations that would limit compliance with study requirements, interfere with subject's safety, or obtaining informed consent; therapeutic level dosing of warfarin can be used with close monitoring of prothrombin time (PT)/international normalized ratio (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

• Patients must not have a history of or evidence of cardiovascular risks including any of the following:

  • QT interval corrected for heart rate using the Bazett's formula (QTcB) >= 480 msec. at baseline
  • History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to registration
  • History prior to registration or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system
  • Left ventricular ejection fraction (LVEF) =< 45% on cardiac echocardiogram (echo) or multi gated acquisition scan (MUGA)
  • Intra-cardiac defibrillator
• Individuals who are known to be human immunodeficiency virus (HIV) infected are eligible (note: HIV testing is not required for entry into the study)
• 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, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), should be evaluated for the presence of target organ involvement and potential need for systemic treatment; if no systemic immune suppression is deemed necessary they can be eligible

• The following medications or non-drug therapies are also prohibited while on treatment in this study:

  • Other anti-cancer therapies
  • Other investigational drugs
  • Patients taking any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible
• Patients must not have history of retinal vein occlusion (RVO)
• Patients must not have evidence of interstitial lung disease or pneumonitis
• Patients must not have malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib
• STEP 2 (CROSSOVER ARM FOR PATIENTS WITH PROGRESSIVE DISEASE)

• The patient must have met all eligibility criteria (except as detailed below) at the time of crossover

  • RECIST defined measurable disease is not required
  • Only prior systemic therapy as part of step 1 is allowed; patients who received allowed systemic therapy in the adjuvant setting prior to Step 1 and were eligible for Step 1 are not excluded from proceeding to Step 2 if they meet other eligibility criteria
  • Malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib, or history of retinal vein occlusion are acceptable for patients crossing over to ipilimumab + nivolumab treatment
  • History of autoimmune disease, excluding interstitial lung disease or pneumonitis, is allowed in patients crossing over to dabrafenib/trametinib therapy
  • Patients crossing over from nivolumab/ipilimumab to dabrafenib/trametinib who underwent surgery or SRS to CNS metastases need not be off of steroids to start treatment
  • There is no restriction on serum LDH at crossover
  • Patients with a history of cardiovascular risks that developed during step 1 of therapy should be discussed with study principal investigator (PI) at time of crossover
• Patients must have melanoma that is metastatic and clearly progressive on prior therapy
• Patients must be at least 1 weeks from documented progressive disease (PD) on Step 1 of current study; all sites of disease must be evaluated within 4 weeks prior to registration
• Patients must have recovered from adverse events (toxicities resolved to grade 1 or less) of prior therapy; patients with immune related toxicities from ipilimumab + nivolumab may continue onto Step 2 even if still on steroids to control side effects, so long as toxicity has resolved to grade 1 or less
• Patients must have discontinued radiation therapy prior to registering to Step 2 of the study and recovered from any adverse events associated with treatment; prior surgery must be >= 2 weeks from registration to Step 2 and patients must be fully recovered from post-surgical complications
• Patients are ineligible if they have any currently active CNS metastases; patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery [SRS]) could be eligible to proceed; patients crossing over from dabrafenib/trametinib to nivolumab (nivo)/ipilimumab (ipi) must not have taken any steroids =< 10 days prior to registration for the purpose of managing their brain metastases; patients with only whole brain irradiation for treatment of CNS metastases are ineligible
• Patients must not have other current malignancies
• Women must not be pregnant or breast-feeding, as the effects of ipilimumab + nivolumab or dabrafenib + trametinib on the developing human fetus are unknown; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to Step 2 crossover to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months
• Women of child-bearing potential and sexually active males must agree to continue to use the same contraception requirements as on Step 1 of this study (ie: use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for the duration of their participation in the study, and for at least 4 weeks after treatment with dabrafenib or for 4 months after dabrafenib in combination with trametinib; women of child-bearing potential must use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for at least 5 months after the last dose of nivolumab and/or ipilimumab and sexually active males must use at least two other accepted and effective methods of contraception and/or to abstain from sexual intercourse for at least 7 months after the last dose of nivolumab and/or ipilimumab); should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately

Contacts and Locations

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Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Michael Atkins	ECOG-ACRIN Cancer Research Group

More Information

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Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT02224781 History of Changes
Other Study ID Numbers:	NCI-2014-01747; NCI-2014-01747 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); EA6134; EA6134 ( Other Identifier: ECOG-ACRIN Cancer Research Group ); EA6134 ( Other Identifier: CTEP ); U10CA180820 ( U.S. NIH Grant/Contract )
First Posted:	August 25, 2014
Last Update Posted:	January 18, 2019
Last Verified:	November 2018

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Nivolumab	Trametinib; Dabrafenib; Antibodies, Monoclonal; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action