Response to new drug in patients with lymphomas and advanced solid tumors
Patients with B-cell non-Hodgkin lymphomas and advanced solid tumors have responded to a new drug that is being tested for the first time in humans in a phase I clinical trial. These preliminary results were presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain.
Reponses occurred in four lymphoma patients who have failed numerous previous treatments and also in one patient with a cancer for which there is no approved medical treatment at all. That patient has a malignant rhabdoid tumor in the brain.
The drug, E7438 (also known as EPZ6438), inhibits the action of a histone methyltransferase (a type of enzyme) known as EZH2. A mutant form of EZH2 is thought to be involved in the development of a number of cancers.
"In many human cancers, misregulated EZH2 enzyme activity results in misregulation of genes that control cell proliferation. Without these control mechanisms, cancer cells are free to grow rapidly. Targeting EZH2 is a novel approach under investigation in oncology. Preclinical work has shown that E7438 successfully targets EZH2 and causes cell death in a number of cancers," said Vincent Ribrag, MD, head of hematology molecular therapeutics in the drug development department (DITEP) at the Gustave Roussy Cancer Campus, France.
The trial, which started at two centers in France in July 2013, has recruited 24 patients (age 24 to 84 years) so far with a range of non-Hodgkin lymphomas and advanced solid tumors, including one malignant rhabdoid tumor.
The patients all had a poor prognosis after their cancers had failed to respond or had returned after several previous treatments. For many of them, this meant that they had no, or few, treatment options left.
The patients received E7438 orally at 1 of 5 dose levels tested: 100, 200, 400, 800, or 1,600 mg twice daily. The researchers assessed the tumors every 8 weeks and took blood and skin samples to assess the interaction of the drug with the body and its effect on the tumors.
Of 10 patients with lymphoma who had tumor measurements taken while being treated with E7438, one had a complete response (disappearance of all signs of cancer) and three had a partial response (tumor shrinkage) by the time of the EORTC-NCI-AACR Symposium. Anti-tumor effects were seen at different dose levels. In addition, one patient with a malignant rhabdoid tumor had a partial response in the group of 11 patients with advanced solid tumors.
Skin samples showed a decrease in skin cells expressing a protein called trimethylated H3K27 (H3K27Me3), which was related to exposure to the drug. A decrease in H3K27Me3 shows that E7438 is biologically active and is inhibiting EZH2, since higher levels of EZH2 promote higher levels of H3K27Me3.
The researchers found that E7438 was well tolerated by most patients at all dose levels up to 1,600 mg twice a day. The most common mild side effects considered as related to treatment with E7438 were weakness, decreased appetite, and nausea. The only severe side effect considered as related to the treatment was low platelet levels, and occurred in one patient.