MK-2206 and AZD6244 in Patients With Advanced Colorectal Carcinoma

NCT01333475 | Completed Phase 2 Results

• 2 other identifiers: 11011711-C-0117
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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....

Conditions

Colorectal Neoplasms

Keywords

Targeted Therapy; KRAS Mutation; Metastatic Colorectal Cancer; Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• 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

  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.

  C1D1 and C1D22 post administration of the combination of AZD6244 hydrogen sulfate and MK-2206

Secondary Outcomes (1)

• Number of Participants With Adverse Events

  29 months, 23 days

Study Arms (2)

TAC1:MK-2206 & AZD6244 in Pts with Colorectal Ca

EXPERIMENTAL

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.

Drug: MK-2206 + AZD6244

TAC1A:MK-2206 & AZD6244 in Pts with Colorectal Ca

EXPERIMENTAL

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.

Drug: MK-2206 + AZD6244

Interventions

MK-2206 + AZD6244 DRUG

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.

TAC1:MK-2206 & AZD6244 in Pts with Colorectal Ca; TAC1A:MK-2206 & AZD6244 in Pts with Colorectal Ca

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically confirmed metastatic colorectal cancer, which has recurred or progressed following oxaliplatin- and irinotecan-based chemotherapy regimens administered for the treatment of metastatic disease, except if the patient was not a candidate for either agent or refused treatment with oxaliplatin or irinotecan. The diagnosis must be confirmed by the Laboratory of Pathology at the Clinical Center, NIH (National Institutes of Health), prior to patient enrollment.
• Results of KRAS (Kirsten-Ras) mutation analysis must be available prior to patient enrollment.
• Patients must have disease amenable to biopsy, and must be willing to undergo pre- and post-treatment tumor biopsies.
• Patients must have completed any major surgery chemotherapy, radiation therapy, or biologic therapy greater than or equal to 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C). Patients must be greater than or equal to 2 weeks since any prior administration of a study drug in an exploratory IND (investigational new drug) /Phase 0 study. Patients must have recovered to eligibility levels from any prior surgery, toxicity, or adverse events.
• Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of MK-2206 in combination with AZD6244 in patients less than 18 years of age, children are excluded from this study.
• Life expectancy of greater than 3 months.
• ECOG (Eastern Cooperative Oncology Group) performance status less than 2.
• Patients must have normal organ and marrow function as defined below:
• Absolute neutrophil count greater than or equal to 1,500/microL
• Platelets greater than or equal to 100,000/microL
• Total bilirubin less than or equal to 1.5 times institutional ULN (upper limit of normal)
• AST (aspartate aminotransferase) /ALT (alanine aminotransferase) less than or equal to 3.0 times institutional ULN; less than or equal to 5.0 times institutional ULN if liver metastases
• Creatinine less than 1.5 times ULN; OR
• Measured creatinine greater than or equal to 60 mL/minute for patients with clearance creatinine levels greater than or equal to 1.5 times ULN
• INR (International Normalized Ratio) less than or equal to 1.4

You may not qualify if:

• Patients who are receiving any other investigational agents.
• Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for greater than or equal to 4 weeks after treatment of the brain metastases, without steroids. Patients on stable doses of antiseizure medications with no history of seizures in the past 4 weeks will be eligible.
• Poorly controlled diabetes defined as fasting blood glucose of greater than 160 mg/dL (CTCAE (Common Terminology Criteria for Adverse Events)) Grade greater than or equal to 2) or HgA1c (glycated hemoglobin) greater than 8%.
• QTc (corrected QT interval) prolongation greater than 450 msec (male) or QTc greater than 470 msec (female) by Bazetts formula or use of medications that may cause QTc interval prolongation. A comprehensive list of agents with the potential to cause QTc prolongation can be found at http://www.azcert.org/medical-pros/drug- lists/bycategory.cfm.
• Patients with clinically significant intercurrent illnesses, including but not limited to, interstitial pneumonitis, pulmonary fibrosis, uncontrolled infection, psychiatric illness or social situations that would limit compliance with study requirements.
• Patients with symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, myocardial infarction in the past 6 months, left ventricular ejection fraction (LVEF) less than or equal to 50%, are not eligible to participate.
• Uncontrolled hypertension (blood pressure \[BP\] of greater than or equal to 150/95 despite optimal therapy).
• Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.
• HIV (human immunodeficiency virus) -positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with MK-2206 and AZD6244.
• Patients currently on warfarin (Coumadin) are ineligible. Otherwise eligible patients requiring anticoagulant treatment should have their warfarin switched to a low molecular weight heparin such as enoxaparin injections.
• Patients on strong cytochrome P450 system inducers or inhibitors are ineligible.
• Both men and women of all races and ethnic groups are eligible for this trial.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Messa C, Russo F, Caruso MG, Di Leo A. EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta Oncol. 1998;37(3):285-9. doi: 10.1080/028418698429595.

  PMID: 9677101 BACKGROUND

• Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. doi: 10.1056/NEJMoa033025.

  PMID: 15269313 BACKGROUND

• Khosravi-Far R, Der CJ. The Ras signal transduction pathway. Cancer Metastasis Rev. 1994 Mar;13(1):67-89. doi: 10.1007/BF00690419.

  PMID: 8143346 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

MK 2206; AZD 6244

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Results Point of Contact

• Title: Dr. Shivaani Kummar
• Organization: National Cancer Institute

kummars@mail.nih.gov

301-435-0517

Study Officials

• Shivaani Kummar, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 9, 2011
• First Posted: April 12, 2011
• Study Start: March 1, 2011
• Primary Completion: November 1, 2013
• Study Completion: September 1, 2014
• Last Updated: September 30, 2015
• Results First Posted: December 4, 2014

Record last verified: 2014-11

Locations

US (1)