MK-2206 and AZD6244 in Patients With Advanced Colorectal Carcinoma
- MK-2206 and AZD6244 are experimental cancer treatment drugs that block the effect of certain proteins that cancer cells need to grow and survive. These drugs may be effective treatments for some types of colorectal cancer that has not responded to or has relapsed after standard treatment. Researchers are interested in studying how MK-2206 and AZD6244 affect levels of certain proteins in colorectal cancer tumor, and how well the drugs work against cancer cells by examining cells from a tumor sample collected before the drugs are given and again after the drugs are given.
- To evaluate the safety and effectiveness of MK-2206 and AZD6244 in individuals with advanced colorectal carcinoma that has not responded to standard treatments.
- Individuals at least 18 years of age who have been diagnosed with advanced colorectal carcinoma that has not responded to at least one type of standard chemotherapy.
- Participants will be screened with a physical examination, medical history, blood tests, and tumor imaging studies.
- Participants will take MK-2206 and AZD6244 by mouth for 4-week cycles of treatment, with one dose of MK-2206 per week and one dose of AZD6244 every day. (If participants have negative side effects from the medications, the doses will be adjusted to a smaller dose). Participants will keep a diary to record doses and keep track of any side effects.
- During treatment, participants will have regular visits to the clinical center, involving blood and urine tests, tumor biopsies, and other examinations to monitor the effects of treatment. Participants will have imaging studies every two cycles (8 weeks) to study the cancer's response to the treatment.
- Participants will continue to have cycles of treatment for as long as the treatment continues to be effective and the side effects are not severe enough to stop participation in the study....
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Pilot Study of the Combination of MK-2206, an AKT Inhibitor, and AZD6244, a MEK Inhibitor, in Patients With Advanced Colorectal Carcinoma|
- 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. [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
- Evaluate reduction of pERK and pAKT in PBMCs after administration of AZD6244 and MK-2206 and correlate with reductions with reductions seen in tumor biopsies. Evaluate for recovery of pAKT levels in tumor biopsy samples. [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
|Study Start Date:||March 2011|
|Estimated Study Completion Date:||May 2015|
|Primary Completion Date:||November 2013 (Final data collection date for primary outcome measure)|
- 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 sulfate.
-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 studies.
- CT scans will be performed every 2 cycles for restaging.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01333475
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Shivaani Kummar, M.D.||National Cancer Institute (NCI)|