Selumetinib and Akt Inhibitor MK2206 in Treating Patients With Stage III or Stage IV Melanoma Who Failed Prior Therapy With Vemurafenib or Dabrafenib
|Recurrent Melanoma Stage IIIA Melanoma Stage IIIB Melanoma Stage IIIC Melanoma Stage IV Melanoma||Drug: Akt inhibitor MK2206 Drug: selumetinib Other: laboratory biomarker analysis||Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||A Phase II Trial of MAP Kinase Inhibition With AZD6244 Hydrogen Sulfate in Combination With MK-2206 (Akt Inhibitor) in Patients With BRAF V600-Mutant Advanced Melanoma Whose Disease Has Progressed on Prior Therapy With a Selective BRAF Inhibitor (i.e., Vemurafenib, Dabrafenib, LGX818)|
- Objective Response [ Time Frame: On-treatment date to date of progressive disease (assessed up to 30 days after end of treatment) ]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.
- Changes in Biomarker Expression [ Time Frame: Before initiation of treatment and at 7-14 days, up to 2 years ]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
- Progression-free Survival (PFS) [ Time Frame: On-study to lesser of date of progression or date of death from any cause, up to 2 years ]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
- Overall Survival [ Time Frame: On-study date to date of death from any cause, up to 2 years ]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).
|Study Start Date:||January 2012|
|Study Completion Date:||May 2013|
|Primary Completion Date:||May 2013 (Final data collection date for primary outcome measure)|
Experimental: Treatment (selumetinib and Akt inhibitor MK2206)
Patients receive selumetinib PO BID on days 1-21 and Akt inhibitor MK2206 PO once weekly.
Drug: Akt inhibitor MK2206
Other Name: MK2206Drug: selumetinib
Other Names:Other: laboratory biomarker analysis
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.
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).
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01519427
|United States, Georgia|
|Atlanta, Georgia, United States, 30322|
|United States, New Jersey|
|Cancer Institute of New Jersey|
|New Brunswick, New Jersey, United States, 08903|
|United States, Tennessee|
|Vanderbilt-Ingram Cancer Center|
|Nashville, Tennessee, United States, 37232|
|United States, Virginia|
|Virginia Commonwealth University/Massey Cancer Center|
|Richmond, Virginia, United States, 23298|
|Principal Investigator:||Jeffrey Sosman||H. Lee Moffitt Cancer Center and Research Institute|