MK-2206 and AZD6244 in Patients With Advanced Colorectal Carcinoma
- Registration Number
- NCT01333475
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
- MK-2206 and AZD6244 (Selumetinib) 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.
Objectives:
- To evaluate the safety and effectiveness of MK-2206 and AZD6244 in individuals with advanced colorectal carcinoma that has not responded to standard treatments.
Eligibility:
- 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.
Design:
* 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....
- Detailed Description
Background:
* The PI3K-AKT (protein kinase B) and RAF/MEK (methyl ethyl ketone)/ERK (extracellular-signal regulated kinase) pathways are two of the most frequently activated signaling pathways in cancer, including colorectal cancer (CRC). KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) mutations are detected in approximately 40% of patients with CRC and predict for resistance to EGFR (epidermal growth factor receptor) 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 (Rat Sarcoma) 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.
Primary Objectives:
* Determine reduction of pERK and pAKT in tumor biopsies on C1D1 (cycle 1 day 1) 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 (cycle 1, day 4) 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.
Secondary Objectives:
* 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.
Eligibility:
-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.
Study Design:
* MK-2206 135 mg PO (by mouth) once weekly and AZD6244 hydrogen sulfate 100 mg PO (by mouth) once daily will be administered in 28-day cycles, beginning on C1D1 (cycle 1, day 1).
* Patients will be stratified for KRAS mutation status.
* Blood samples and paired mandatory tumor biopsies will be obtained for pharmacodynamic studies.
* CT (computed tomography) scans will be performed every 2 cycles for restaging.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 21
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description TAC1:MK-2206 & AZD6244 in Pts with Colorectal Ca MK-2206 + AZD6244 Cycle = 28 days:MK-2206:90 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 75 mg PO QD (every day) MK-2206 + AZD6244: 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. TAC1A:MK-2206 & AZD6244 in Pts with Colorectal Ca MK-2206 + AZD6244 Cycle = 28 days:MK-2206:135 mg PO days 1, 8, 15, and 22 AZD6244 Hydrogen sulfate: 100 mg PO QD MK-2206 + AZD6244: 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.
- Primary Outcome Measures
Name Time Method pERK and pAKT Levels in Tumor Biopsies on C1D1 and C1D22 Post-administration of the Combination of AZD6244 Hydrogen Sulfate and MK-2206 in Participants With Advanced Colorectal Cancer C1D1 and C1D22 post administration of the combination of AZD6244 hydrogen sulfate and MK-2206 A predetermined target inhibition reduction of 70% of both pERK and pAKT was deemed significant, thus tumor biopsies were performed at C1D1 or C1D22 post administration and evaluated using quantitative chemiluminescence immunoassay to measure pERK and pAKT levels in human tissue.
- Secondary Outcome Measures
Name Time Method Number of Participants With Adverse Events 29 months, 23 days Here is the number of participants with adverse events. For the detailed list of adverse events, see the adverse event module.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States