Pilot Study of the Combination of MK-2206, an AKT Inhibitor, and AZD6244, a MEK Inhibitor, in Patients With Advanced Colorectal Carcinoma
- The PI3K-AKT and RAF/MEK/ERK pathways are two of the most frequently activated
signaling pathways in cancer, including colorectal cancer (CRC). KRAS mutations are
detected in approximately 40% of patients with CRC and predict for resistance to EGFR
inhibitors. AKT is upregulated in approximately 60% of CRC.
- Preclinical studies demonstrate that activating mutations in the PI3K-AKT pathway and
increased phosphorylated Akt through a MEK-EGFR-PI3K feedback loop are implicated in
resistance to the antitumor effect of MEK inhibition.
- MK-2206 and AZD6244 hydrogen sulfate are selective inhibitors of human AKT and MEK,
respectively, with preclinical and clinical anti-tumor activity as single agents and in
combination with a variety of drugs. Combination treatment in mouse cancer models
harboring mutations in both the PI3K and RAS pathways was more potent compared to
either agent used alone, and resulted in substantial tumor inhibition, including tumor
regression. The combination is being studied in a Phase I trial and appears tolerable.
- Determine reduction of pERK and pAKT in tumor biopsies on C1D1 post-administration of
the combination of AZD6244 hydrogen sulfate and MK-2206 in patients with advanced
colorectal cancer, stratified for KRAS mutation status.
- Evaluate for recovery of pAKT levels in tumor biopsy samples obtained on C1D4 after
administration of the combination of AZD6244 hydrogen sulfate and MK-2206 in patients
with advanced colorectal cancer, stratified for KRAS mutation status.
- Determine reduction of Ki-67 in tumor biopsies post-administration of the combination
of AZD6244 hydrogen sulfate and MK-2206 in patients with advanced colorectal cancer,
stratified for KRAS mutation status.
- Evaluate reduction of pERK and pAKT in peripheral blood mononuclear cells (PBMCs) after
administration of the combination of AZD6244 hydrogen sulfate and MK-2206 and correlate
these reductions with those seen in tumor biopsy samples.
- Evaluate antitumor activity of the combination of MK-2206 with AZD6244 hydrogen
-Patients with histologically documented colorectal cancer that has progressed or recurred
after oxaliplatin- and irinotecan-based chemotherapy for metastatic disease. KRAS mutation
analysis results must be available prior to enrollment. Patients must have disease amenable
to biopsy, and be willing to undergo pre-and post-treatment tumor biopsies.
- MK-2206 135 mg PO once weekly and AZD6244 hydrogen sulfate 100 mg PO once daily will be
administered in 28-day cycles, beginning on C1D1.
- Patients will be stratified for KRAS mutation status.
- Blood samples and paired mandatory tumor biopsies will be obtained for pharmacodynamic
- CT scans will be performed every 2 cycles for restaging.
Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Determine reduction of pERK, pAKT, and Ki-67 in tumor biopsies post-administration of AZD6244 and MK-2206 in patients with advanced colorectal cancer, stratified for KRAS mutation status.
Shivaani Kummar, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|