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

The primary objective of this study is to compare progression-free survival with
intermittent dosing and continuous dosing of dabrafenib and trametinib among patients with
metastatic BRAFV600E/K mutant melanoma.

Inclusion Criteria:

- Histologically or cytologically confirmed Stage IV or unresectable Stage III BRAF
V600E 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 iodinated
contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen
and pelvis within 28 days prior to registration.

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

- Patients with treated brain metastases who are asymptomatic with no residual
neurological dysfunction and have not received enzyme-reducting anti-epileptic drugs
or 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 prior
to registration

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

- ONE of the following: serum creatinine ≤ 1.5 x IULN OR measured or calculated
creatinine 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 to
registration

- Patients with known HIV may be eligible providing they meet all of the following
criteria:

- 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 to
registration

- 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 previous
anti-cancer therapy (except alopecia) within 7 days prior to registration

- Known history or current evidence of retinal vein occlusion (RVO) or central serous
retinopathy (CSR)

- Inability to take oral medications or impairment of gastrointestinal function or
gastrointestinal disease that may significantly alter the absorption of protocol
treatment

- Use of warfarin within 14 days prior to planned first dose of trametinib (patients
must 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 (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.

- Known Hepatitis B or Hepatitis C

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

- Pregnant or nursing