Selumetinib and Akt Inhibitor MK2206 in Treating Patients With Stage III or Stage IV Melanoma Who Failed Prior Therapy With Vemurafenib or Dabrafenib
Condition: Recurrent Melanoma; Stage IIIA Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma
MeSH terms: Melanoma
Intervention: Akt inhibitor MK2206; selumetinib; laboratory biomarker analysis
Intervention description: Given PO; Given PO; Correlative studies
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well selumetinib and Akt inhibitor MK2206 works in treating
      patients with stage III or stage IV melanoma who failed prior therapy with vemurafenib or
      dabrafenib. Selumetinib and Akt inhibitor MK2206 stop the growth of tumor cells by blocking
      some of the enzymes needed for cell growth. It is not yet know whether giving selumetinib and
      Akt inhibitor MK2206 together is an effective treatment for advanced melanoma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have incurable unresectable stage III or IV histologically confirmed
             Melanoma with V600-mutant BRAF disease and must have progressed after therapy on
             selective BRAF inhibitor; all patients must have biopsiable tumor and a biopsy must be
             performed with the collection of FFPE and if possible FF prior to initiation of
             treatment on this protocol; archival tumor tissue must also be obtained if at all
             available; this required biopsy will not be necessary if a previous biopsy of
             progressing tumor after selective BRAF therapy had already been obtained and is
             adequate

          -  Patients 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

          -  Patients must have received prior therapy and progressed following a selective BRAF
             inhibitor (i.e., vemurafenib, dabrafenib, LGX818, etc.); patients must have completed
             prior therapy a minimum of 4 weeks previously (6 weeks for BCNU and/or mitomycin C), 4
             weeks for prior biologic therapy, and 2 weeks for localized radiation therapy; all
             treatment related toxicity must have resolved to grade 2 or less as well; patients may
             initiate the protocol treatment at 48 hours following the completion of BRAF
             inhibitor; patients must have had no more than 2 prior chemotherapy regimens; patients
             cannot receive chemotherapy after the BRAF inhibitor treatment and prior to enrollment
             on this protocol; up to two prior immunotherapy regimens for advanced disease are
             allowed and one may be given between BRAF inhibitor therapy and this trial

          -  Patients must not be refractory to the BRAF inhibitor; patients must demonstrate some
             degree of tumor regression initially on BRAF inhibitor prior to progression; (tumor
             regression does not require RECIST objective response); they cannot have progressive
             disease at the time of first evaluation (4 or 8 weeks) on the BRAF inhibitor

          -  Baseline Ophthalmologic exam must be done at screening to include slit lamp exam and
             fundoscopy; an OCT scan should be considered in case of retinal abnormality at exam

          -  Life expectancy of greater than or equal to 3 months

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (Karnofsky ≥ 70%)

          -  Absolute neutrophil count ≥ 1,500 mm³

          -  Hemoglobin ≥ 9.0 g/dL (patients may be transfused to achieve level)

          -  Platelet count ≥ 100,000/μL

          -  Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate
             transaminase(SGPT) < 2.5 X upper limit of normal (ULN)

          -  Total bilirubin < 1.5 mg/dL

          -  Serum creatinine ≤ 2.0 mg/dL OR creatinine clearance > 50 mL/min, determined by
             24-hour urine collection

          -  Fasting blood glucose < 160 mg/dL OR

          -  HgbA1C < 8% disease (uncontrolled diabetes)

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             the duration of study participation

          -  Patients must have a negative serum pregnancy test prior to being eligible to take
             part in the study

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with AZD6244 hydrogen sulfate and MK-2206

          -  Baseline echocardiogram or MUGA must be performed at screening and patients must have
             LVEF > 55%; additionally baseline EKG must be performed and corrected QTc must be <
             480 milliseconds

          -  Baseline electrocardiogram(EKG) must be performed and corrected QTc must be < 480
             milliseconds

          -  Patients must be able to swallow tablets and capsules to participate in the study

          -  No history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to AZD6244 hydrogen sulfate, MK-2206, or other agents used in the
             study

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, Uncontrolled intercurrent illness including, but not limited to, ongoing or
             active infection, psychiatric illness/social situations that would limit compliance
             with study requirements, symptomatic congestive heart failure, unstable angina
             pectoris, cardiac arrhythmia, uncontrolled hypertension (BP >= 150/95 despite optimal
             therapy), baseline ejection fraction < 55% or the lower limit of institutional normal,
             heart failure NYHA Class II or above, prior or current cardiomyopathy, atrial
             fibrillation with heart rate > 100 bpm, and uncontrolled angina (Canadian
             Cardiovascular society grade II-IV despite medical therapy); acute coronary syndrome
             within 6 months from starting therapy

          -  Patients must have completed prior therapy a minimum of 4 weeks previously (6 weeks
             for BCNU and/or mitomycin C), 4 weeks for prior biologic therapy, and 2 weeks for
             localized radiation therapy

          -  All treatment-related toxicity must have resolved to grade 2 or less

          -  No patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events due to agents administered more than 4 weeks earlier

          -  Patients must have had no more than 2 prior chemotherapy regimens

          -  Patients cannot receive chemotherapy after the BRAF-inhibitor treatment and prior to
             enrollment on this protocol

          -  Up to two prior immunotherapy regimens for advanced disease are allowed and one may be
             given between BRAF-inhibitor therapy and this trial

          -  Patients may not be receiving any other investigational agents at the same time as
             study treatment

          -  Patients receiving medications or substances that are strong inhibitors or inducers of
             cytochrome P450 3A4 (CYP3A4) are ineligible

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible

          -  Patients must not have received chemotherapy in the time between the failure of BRAF
             inhibitor and the enrollment onto the present trial