ECOG-ACRIN launches new trial to evaluate nilotinib and paclitaxel for advanced cancers

The ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) has enrolled the first patient in a new treatment trial to evaluate the effectiveness of adding nilotinib to standard paclitaxel chemotherapy. The trial (EAY191-E4) is for the treatment of adults with cancers that are getting worse after being treated with taxane-based chemotherapy. It is a new addition to the recently launched ComboMATCH precision medicine initiative, which uses tumor biology as a guiding point for testing new combinations of cancer drugs. 

James M. Ford, MD, the ECOG-ACRIN Chair for ComboMATCH and Professor of Medicine (Oncology) and Genetics at Stanford University, states that "the pre-clinical experimental data supporting the use of nilotinib in overcoming taxane resistance in all solid tumor types is extremely compelling. I am confident the ComboMATCH E4 treatment trial will accrue quite rapidly given the excitement surrounding this approach and the broad eligibility for cancer patients."

Chemotherapy treatments are part of the standard-of-care options for adults with advanced cancers, either alone or in combination with other treatments. Taxane-based chemotherapy drugs, which contain chemicals that are toxic to living cells, have decades of use to prevent cancer cells from dividing. Cancer cell division leads to increasing tumor size and malignancy. However, when taxanes are used alone in patients with advanced disease, especially those who had prior taxane therapy, tumors will continue to grow and spread in about 90% of patients. 

One taxane used to treat cancer is paclitaxel. Sometimes proteins in tumors block this drug from working. In the EAY191-E4 trial, researchers want to see if another drug, nilotinib, helps paclitaxel work better. Nilotinib is part of a class of medications called kinase inhibitors. It is given in pill form and works by binding to and inhibiting the action of a protein that signals cancer cells to multiply-;essentially blocking the protein from blocking the paclitaxel. This helps slow or stop cancer cells. Nilotinib is FDA-approved to treat adults with certain types of chronic myeloid leukemia (CML).

Pre-clinical studies using human tumor cell lines recently showed that nilotinib and paclitaxel may be stronger and more effective together at killing cancer cells than either drug alone. A phase 1 clinical trial (NCT02379416) has tested the safety of the combination in a small group of patients with advanced cancers. The trial has demonstrated efficacy, including tumor reduction in patients who did not benefit from prior taxane-based therapy. 

Surprisingly, both this trial and the pre-clinical data found less nerve damage in hands and feet (peripheral neuropathy) from the combination compared to paclitaxel alone. Peripheral neuropathy is a common and painful side effect of paclitaxel. 

Based on these discoveries, researchers have opened the EAY191-E4 trial to evaluate the nilotinib-paclitaxel combination. Further, as they collect information on the side effects of the treatment, they hope to determine whether nilotinib may help make paclitaxel less toxic and more tolerable for patients. If this trial is successful, the combination would move on to a larger randomized phase 3 trial for confirmation outside of ComboMATCH. 

To be eligible for EAY191-E4, patients must have solid tumor cancers (not a liquid/blood cancer such as leukemia or lymphoma) that are progressing after being treated with taxane therapies. They must not have a mutation in the c-KIT or PDGFRA tumor genes. Patients must first enroll in the ComboMATCH registration trial (EAY191) to determine their eligibility for this trial. More information is available in this Study Summary for Patients.

The trial seeks to enroll 40 patients. All participants will receive nilotinib and paclitaxel together in cycles that will repeat every 28 days. Patients may stay on treatment so long as the tumors shrink or remain stable, and they are able to tolerate the side effects of treatment. Patients will have imaging (CT scans or MRI) before, during, and after treatment to measure tumor size and thus monitor which tumors respond to--or resist--the combination treatment.

Another goal of the trial is to gather information for future research. To that end, patients will undergo a tumor biopsy and submit blood samples before starting treatment. Blood samples are being collected to look for the presence of circulating tumor DNA. 

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