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.
PRIMARY OBJECTIVES: I. To determine the frequency of objective clinical responses by RECIST 1.1 for these melanoma patients who have previously progressed on selective BRAF inhibitors when treated with MEK inhibitor, AZD6244 hydrogen sulfate plus Akt inhibitor, MK-2206. II. To further characterize toxicities of both regimens in these patients who have progressed after BRAF inhibitor therapy. SECONDARY OBJECTIVES: I. With required fresh pretreatment biopsies on all patients, we plan to characterize the molecular state (genetic and proteomic) associated with BRAF inhibitor resistance. This may include an analysis of pathway activation, PI3/Akt or MAP kinase pathway; loss of expression of PTEN, secondary mutations in BRAF, other mutations in the MAP kinase pathway (NRAS, KRAS, HRAS, CRAF, MEK), activation of other RTKs (amplification, over expression, phosphorylation). OUTLINE: Patients receive selumetinib orally (PO) twice daily (BID) on days 1-21 and Akt inhibitor MK2206 PO once weekly. After completion of study treatment, patients are followed up every 12 weeks.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
2
Emory University
Atlanta, Georgia, United States
Cancer Institute of New Jersey
New Brunswick, New Jersey, United States
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States
Virginia Commonwealth University/Massey Cancer Center
Richmond, Virginia, United States
Objective Response
Number of patients in each response category, per Response Evaluation in Solid Tumors (RECIST) v.1.1: complete response (CR), disappearance of target lesions; partial response (PR) \>=30% decrease in sum of longest diameter (LD) of target lesions; progressive disease (PD), \>=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or PR. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR\>PR\>SD\>PD.
Time frame: On-treatment date to date of progressive disease (assessed up to 30 days after end of treatment)
Changes in Biomarker Expression
Pre-treatment tumor biopsy tissue and blood and day 7-14 tumor biopsy tissue and blood will be examined by immunohistochemistry for expression and phosphorylation of the proteins pERK, pMEK, pAKT, Ki67, pRpS6, CRAF, cyclin D, PDGFr, pPDGFr. IGFr1, and COT/Tp12 for changes from baseline
Time frame: Before initiation of treatment and at 7-14 days, up to 2 years
Progression-free Survival (PFS)
Estimated probable duration of life without disease progression, from on-study date to earlier of progression date, or date of death from any cause, using the Kaplan-Meier method with censoring (see Analysis Population Description for additional details). Disease progression is defined by Response Evaluation in Solid Tumors (RECIST) v.1.1: \>= 20% increase in sum of the longest diameter of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions
Time frame: On-study to lesser of date of progression or date of death from any cause, up to 2 years
Overall Survival
Estimated probable duration of life from on-study date to date of death from any cause, using Kaplan-Meier method with censoring (see Analysis Population Description for additional details).
Time frame: On-study date to date of death from any cause, up to 2 years
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