S1320: Intermittent Versus Continuous Dosing of Dabrafenib and Trametinib in BRAFV600E/K Mutant Melanoma

Inclusion Criteria:

• Histologically or cytologically confirmed Stage IV or unresectable Stage III BRAFV600E or BRAF V600K mutant melanoma

• BRAF mutation must be determined by FDA approved BRAF mutation detection assay

• BRAFV600 mutant status must be documented by a CLIA-certified laboratory

• CT scan of neck, chest, abdomen and pelvis within 28 days prior to registration

• A whole body PET/CT scan with diagnostic quality images and intravenous iodinatedcontrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomenand pelvis within 28 days prior to registration.

• Tests to assess non-measurable disease must be performed with 42 days prior toregistration

• Patients with treated brain metastases who are asymptomatic with no residualneurological dysfunction and have not received enzyme-reducting anti-epileptic drugsor corticosteroids for at least 7 dyas prior to registration are eligible

• Age ≥ 18 years

• ANC ≥ 1,500 / µl, platelets ≥ 100,000 /µl, hemoglobin ≥ 9 g/dL within 28 days priorto registration

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN), AST and ALT ≤ 2.5x IULN (or < 5 x IULN for patients with known liver metastases) within 28 days priorto registration

• ONE of the following: serum creatinine ≤ 1.5 x IULN OR measured or calculatedcreatinine clearance ≥ 60 mL/min within 28 days prior to registration

• serum LDH within 28 days prior to registration

• LVEF ≥ ILLN by ECHO or MUGA within 28 days prior to registration

• QTc ≤ 480 msec by ECG (corrected using the Bazett's formula) within 28 days prior toregistration

• Patients with known HIV may be eligible providing they meet all of the followingcriteria:

• CD4 cells ≤ 500/uL

• Serum HIV viral load of < 25,000 IU/ml

• No current antiretroviral therapy Tests must be obtained within 28 days prior toregistration

• Prestudy history and physical obtained with 28 days prior to registration

• Dermatology exam obtained within 28 days prior to registration

• Zubrod Performance Status of 0 or 1

Exclusion Criteria:

• Prior BRAF or MEK inhibitor

• Brain metastases

• Any anti-cancer drug within 28 days prior to registration

• Nitrosureas or mitomycin C within 42 days prior to registration

• Major surgery, radiotherapy or immunotherapy within 28 days prior to registration

• Unresolved toxicities (according to NCI-CTCAEv4.0) > Grade 1 from previousanti-cancer therapy (except alopecia) within 7 days prior to registration

• Known history or current evidence of retinal vein occlusion (RVO) or central serousretinopathy (CSR)

• Inability to take oral medications or impairment of gastrointestinal function orgastrointestinal disease that may significantly alter the absorption of protocoltreatment

• Use of warfarin within 14 days prior to planned first dose of trametinib (patientsmust not be planning to receive therapeutic warfarin while on protocol treatment)

• History of pneumonitis or interstitial lung disease

• Grade II/III/IV cardiac disease as defined by the New York Heart Association Criteria (Abnormal cardiac valve morphology (≥ Grade 2) documented by echocardiogram (subjectswith Grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered onstudy. Subjects with moderate valvular thickening should not be entered on study.

• Known Hepatitis B or Hepatitis C

• Prior malignancy (except for adequately treated basal cell or squamous cell skincancer, in situ cervical cancer, adequately treated Stage I or II cancer from whichthe patient is currently in complete remission, or any other cancer from which thepatient has been disease free for three years. Exception: Patients with knownhistory of colon cancer, cancer of the pancreas, or any cancer known to harbor anactivating RAS mutation are ineligible regardless of stage or time since diagnosis.)

• Pregnant or nursing