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

Inclusion Criteria:

• STEP 1

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of dabrafenib or dabrafenib + trametinib or nivolumab or nivolumab +ipilimumab therapy in patients < 18 years of age, children are excluded from thisstudy, but will be eligible for future pediatric trials

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

• The effects of dabrafenib and trametinib or ipilimumab and nivolumab on thedeveloping human fetus are unknown; furthermore, dabrafenib has been reported tointerfere with the effect of hormone based oral contraceptives; for this reason andbecause other therapeutic agents used in this trial are known to be teratogenic,women of child-bearing potential and sexually active males must agree to use atleast two other accepted and effective methods of contraception and/or to abstainfrom sexual intercourse for the duration of their participation in the study, andfor at least 4 weeks after treatment with dabrafenib or for 4 months afterdabrafenib in combination with trametinib; women of child-bearing potential must useat least two other accepted and effective methods of contraception and/or to abstainfrom sexual intercourse for at least 5 months after the last dose of nivolumaband/or ipilimumab and sexually active males must use at least two other accepted andeffective methods of contraception and/or abstain from sexual intercourse for atleast 7 months after the last dose of nivolumab and/or ipilimumab; should a womanbecome 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 ismetastatic or unresectable and clearly progressive

• NOTE: Any patient with BRAF V600 mutant melanoma (whether cutaneous, acral ormucosal primary) who meets the eligibility criteria is eligible forparticipation in this trial; patients with uveal melanoma are not eligible forthis 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 theassay must be provided (FDA approved tests for BRAF V600 mutations in melanomainclude: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test, FoundationMedicine); prompt information on tumor BRAF mutation status can also be obtained viaNovartis "knowNow" Program

• Patients may have had prior systemic therapy in the adjuvant setting; however thisadjuvant treatment must not have included a CTLA4 or PD1 pathway blocking antibodyor a BRAF/MEK inhibitor. Also, patients may not have had any prior systemictreatment for advanced (measurable metastatic) disease

• Patients must have discontinued chemotherapy, immunotherapy or other investigationalagents used in the adjuvant setting >= 4 weeks prior to entering the study andrecovered from adverse events due to those agents; mitomycin and nitrosoureas musthave been discontinued at least 6 weeks prior to entering the study; patients musthave discontinued radiation therapy >= 1 week prior to entering the study andrecovered from any adverse events associated with treatment; prior surgery must be >= 2 weeks from registration and patients must be fully recovered from post-surgicalcomplications

• Patients must not receive any other investigational agents while on study or withinfour weeks prior to registration

• Patients are ineligible if they have any currently known active and definitivecentral nervous system (CNS) metastases; patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery [SRS]) could beeligible; patients must not have taken any steroids =< 10 days prior torandomization for the purpose of managing their brain metastases; repeat imagingafter SRS or surgical resection is not required so long as baseline magneticresonance imaging (MRI) is within 4 weeks of registration; patients with multiplebrain metastases treated with SRS (with [w] or without [w/o] whole-brainradiotherapy [WBRT]), are not an exclusion; patients with definitive CNS metastasestreated with only WBRT are ineligible; patients with potential CNS metastases thatare too small for treatment with either SRS or surgery (e.g. 1-2 mm) and/or are ofuncertain etiology are potentially eligible, but need to be discussed with andapproved by the study principal investigator (PI)

• Patients must not have other current malignancies, other than basal cell skincancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobularcarcinoma in situ of the breast; patients with other malignancies are eligible ifthey have been continuously disease-free for > 2 years prior to the time ofregistration

• 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 torandomization)

• 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 (=< 5x ULN for patients with documented liver metastases) (obtained within 4 weeks priorto randomization)

• Alkaline phosphatase =< 2 x ULN (=< 5 x ULN for patients with known liverinvolvement and =< 7 x ULN for patients with known bone involvement) (obtainedwithin 4 weeks prior to randomization)

• Total bilirubin =< 1.5 x ULN except subjects with normal direct bilirubin or thosewith known Gilbert's syndrome (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, orpsychiatric illness/social situations that would limit compliance with studyrequirements, interfere with subject's safety, or obtaining informed consent;therapeutic level dosing of warfarin can be used with close monitoring ofprothrombin time (PT)/international normalized ratio (INR) by the site; exposure maybe decreased due to enzyme induction when on treatment, thus warfarin dosing mayneed to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib,warfarin exposure may be increased and thus close monitoring via PT/INR and warfarindose adjustments must be made as clinically appropriate; prophylactic low dosewarfarin may be given to maintain central catheter patency

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

• QT interval corrected for heart rate using the Bazett's formula (QTcB) >= 480msec. at baseline

• History of acute coronary syndromes (including myocardial infarction orunstable angina), coronary angioplasty, or stenting within the past 24 weeksprior to registration

• History prior to registration or evidence of current >= class II congestiveheart failure as defined by the New York Heart Association (NYHA) functionalclassification 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 areineligible (note: HIV testing is not required for entry into the study)

• Patients with active autoimmune disease or history of autoimmune disease that mightrecur, which may affect vital organ function or require immune suppressive treatmentincluding systemic corticosteroids, should be excluded; these include but are notlimited to patients with a history of immune related neurologic disease, multiplesclerosis, 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 toxicepidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndromeshould be excluded because of the risk of recurrence or exacerbation of disease;patients with vitiligo, endocrine deficiencies including thyroiditis managed withreplacement hormones including physiologic corticosteroids are eligible; patientswith rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasiscontrolled with topical medication and patients with positive serology, such asantinuclear antibodies (ANA), should be evaluated for the presence of target organinvolvement and potential need for systemic treatment; if no systemic immunesuppression is deemed necessary they can be eligible

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

• Other anti-cancer therapies

• Other investigational drugs

• Patients taking any medications or substances that are strong inhibitors orinducers 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 conditionsthat would interfere with the ingestion or absorption of dabrafenib or trametinib

• STEP 2 (CROSSOVER ARMS): The patient must have met all eligibility criteria (exceptas 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 receivedallowed systemic therapy in the adjuvant setting prior to Step 1 and wereeligible for Step 1 are not excluded from proceeding to Step 2 if they meetother eligibility criteria

• Malabsorption, swallowing difficulty, or other conditions that would interferewith the ingestion or absorption of dabrafenib or trametinib, or history ofretinal vein occlusion are acceptable for patients crossing over to Arm D (ipilimumab + nivolumab) treatment

• History of autoimmune disease, excluding interstitial lung disease orpneumonitis, is allowed in patients crossing over to Arm C (dabrafenib/trametinib) therapy

• Patients crossing over from Arm A (nivolumab/ipilimumab) to Arm C (dabrafenib/trametinib) who underwent surgery or SRS to CNS metastases need notbe off of steroids to start treatment

• There is no restriction on serum lactate dehydrogenase (LDH) at crossover

• Patients with a history of cardiovascular risks that developed during step 1 oftherapy should be discussed with study principal investigator (PI) at time ofcrossover

• STEP 2 (CROSSOVER ARMS): Patients randomized to Arm A on Step 1 must have melanomathat is metastatic and clearly progressive on Step 1 therapy prior to crossing overto Arm C

• NOTE: Patients should (if possible) be at least 1 week from documented PD onStep 1 of current study. All sites of disease must be evaluated within 4 weeksprior to registration

• STEP 2 (CROSSOVER ARMS): Patients randomized to Arm B on Step 1 may cross over toArm D at or prior to disease progression

• NOTE: If possible, patients should wait to cross over until after the cyclewith the next protocol-required imaging assessment is completed; all sites ofdisease must be evaluated within 4 weeks prior to Step 2 registration

• NOTE: Patients should start Arm D treatment at least 1 week after stoppingdabrafenib and trametinib, unless otherwise clinically indicated

• NOTE: Baseline labs and QOL assessments should be completed, and patientsshould follow the Arm D schedule

• STEP 2 (CROSSOVER ARMS): Patients must have recovered from adverse events (toxicities resolved to grade 1 or less) of prior therapy; patients with immunerelated toxicities from ipilimumab + nivolumab may continue onto Step 2 even ifstill on steroids to control side effects, so long as toxicity has resolved to grade 1 or less

• STEP 2 (CROSSOVER ARMS): Patients must have discontinued radiation therapy prior toregistering to Step 2 of the study and recovered from any adverse events associatedwith treatment; prior surgery must be >= 2 weeks from registration to Step 2 andpatients must be fully recovered from post-surgical complications

• STEP 2 (CROSSOVER ARMS): Patients are ineligible if they have any currently activeand definitive CNS metastases; patients who have treated brain metastases (witheither surgical resection or stereotactic radiosurgery [SRS]) could be eligible toproceed; patients crossing over from Arm B (dabrafenib/trametinib) to Arm D (nivolumab [nivo]/ipilimumab [ipi]) must not have taken any steroids =< 10 daysprior to Step 2 registration for the purpose of managing their brain metastases;patients with only whole brain irradiation for treatment of CNS metastases areineligible; patients with definitive CNS metastases treated with only WBRT areineligible; patients with potential CNS metastases that are too small for treatmentwith either SRS or surgery (e.g. 1-2 mm) and/or are of uncertain etiology arepotentially eligible, but need to be discussed with and approved by the study PI

• STEP 2 (CROSSOVER ARMS): Patients must not have other current malignancies

• STEP 2 (CROSSOVER ARMS): Women must not be pregnant or breast-feeding, as theeffects of ipilimumab + nivolumab or dabrafenib + trametinib on the developing humanfetus are unknown; all females of childbearing potential must have a blood test orurine study within 2 weeks prior to registration to Step 2 crossover to rule outpregnancy; a female of childbearing potential is any woman, regardless of sexualorientation or whether they have undergone tubal ligation, who meets the followingcriteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) hasnot been naturally postmenopausal for at least 24 consecutive months (i.e., has hadmenses at any time in the preceding 24 consecutive months

• STEP 2 (CROSSOVER ARMS): The effects of dabrafenib and trametinib or ipilimumab andnivolumab on the developing human fetus are unknown; furthermore, dabrafenib hasbeen reported to interfere with the effect of hormone based oral contraceptives; forthis reason and because other therapeutic agents used in this trial are known to beteratogenic, women of child-bearing potential and sexually active males must agreeto continue to use the same contraception requirements as on Step 1 of this study (i.e.: use at least two other accepted and effective methods of contraception and/orto abstain from sexual intercourse for the duration of their participation in thestudy, and for at least 4 weeks after treatment with dabrafenib or for 4 monthsafter dabrafenib in combination with trametinib; women of child-bearing potentialmust use at least two other accepted and effective methods of contraception and/orto abstain from sexual intercourse for at least 5 months after the last dose ofnivolumab and/or ipilimumab and sexually active males must use at least two otheraccepted and effective methods of contraception and/or to abstain from sexualintercourse for at least 7 months after the last dose of nivolumab and/oripilimumab); should a woman become pregnant or suspect she is pregnant while she isparticipating in this study, she should inform her treating physician immediately

Exclusion Criteria:

• 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 studywithin 2 weeks prior to registration to rule out pregnancy

• A female of childbearing potential is any woman, regardless of sexualorientation or whether they have undergone tubal ligation, who meets thefollowing criteria: 1) has not undergone a hysterectomy or bilateraloophorectomy; or 2) has not been naturally postmenopausal for at least 24consecutive months (i.e., has had menses at any time in the preceding 24consecutive months)