Clinical trials could lead to new options for colorectal cancer patients
April 22, 2015 | by Tami Dennis
Patients with metastatic colorectal cancer often stop responding to the primary drugs used against the disease, leaving them with few options and little hope. Determined to increase those options, doctors and researchers at City of Hope are conducting two clinical trials that could lead to new treatments for people with colorectal cancer, currently the third most common cancer in the U.S.
Marwan Fakih, co-director of the Gastrointestinal Cancer Program at City of Hope, highlighted those studies in a recent conversation, explaining how they show particular promise for patients with metastatic colorectal cancer. The first study will assess the potential impact of a new drug – one that targets a specific activated gene product, Fakih says – when used with a standard two-drug chemotherapy regimen. The second study will assess the maximum dosage of an investigational drug when used with a well-known three-drug chemotherapy regimen in patients who haven’t been helped by other therapies.
Here, Fakih answers questions about the two trials.
Thwarting a mutation-plagued protein
What is the purpose of this trial?
This study is evaluating a new combination of treatment for patients with advanced colorectal cancer with a BRAF gene mutation that causes tumors. This type of BRAF mutation is found in 10 percent of patients with colorectal cancer and is associated with chemotherapy resistance and with a poor overall survival. This trial is evaluating whether the addition of vemurafenib to standard chemotherapy, specifically irinotecan and cetuximab, improves overall outcome.
Vemurafenib is what’s known as a BRAF inhibitor, meaning it blocks the action of a protein made abnormal by the BRAF mutation. In BRAF-linked cancer, the protein tells cancer cells to multiply; vemurafenib stops the action of that protein, slowing the spread of cancer.
Why is that important?
The current second line treatment for BRAF-mutant colorectal cancer is associated with only a modest benefit. The use of cetuximab and irinotecan in this setting, while considered a standard approach, leads to minimal improvements because of inherent tumor resistance. Preliminary clinical data from a phase I clinical trial suggest that the addition of vemurafenib to standard therapy leads to major tumor shrinkage that lasts a long time. This trial will determine if the addition of vemurafenib to cetuximab and irinotecan is a better option of treatment.
What might the impact be?
The addition of this drug, or similar drugs, in this population may improve response rates, disease control and overall survival of patients with a BRAF mutant colorectal cancer, therefore becoming the new standard of care.
Potential treatment for patients failed by standard therapy
The second study highlighted by Fakih is a phase I study of the investigational drug MEK162. The drug will be administered with the standard FOLFOX combination in patients who have not responded to standard therapy.
What is the purpose of this trial?**
The purpose of this study is to determine what is the highest dose of MEK162 that can be given safely with FOLFOX chemotherapy (a combination of the drugs leucovorin calcium, fluorouracil and oxaliplatin).
Why is that important?
Chemotherapy resistance occurs in all patients with metastatic colorectal cancer. Therefore, it is important to determine how to overcome chemotherapy resistance in order to delay tumor progression and improve overall survival. Oxaliplatin, a common chemotherapy drug for metastatic colorectal cancer, can lose effectiveness against colorectal cancer after approximately six to 10 months of treatment. Tumor resistance to platinum chemotherapy drugs such as oxaliplatin has been associated with the activation of MEK, an intratumor kinase that drives tumor growth and proliferation. MEK162 inhibits MEK and augments oxaliplatin antitumor activity and 5-FU anti-tumor activity. It is hoped that the combination of MEK162 and FOLFOX (5-FU and oxaliplatin) will overcome prior resistance to oxaliplatin and 5-FU and improve tumor responses.
What might the impact be?
The above combination may overcome tumor resistance.
Next steps? (Or, a synopsis of your perspective)
If this study suggests that the drug is effective, and can be tolerated by patients, doctors and researchers would investigate the combination earlier in the treatment process, rather than waiting until patients have been failed by existing therapies.
Learn more about colorectal cancer treatment and research at City of Hope.
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