The investigational EZH2 inhibitor tazemetostat was safe and shrank tumors in 38 percent of patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma who were included in the first part of a Phase 1/2 clinical trial, the therapy’s developer, Epizyme, announced.
The study (NCT01897571) established the recommended dose to be tested in future Phase 2 trials and is now recruiting participants for its second part.
The study, “Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study,” was published in the journal The Lancet Oncology.
Tazemetostat (EPZ-6438) is an inhibitor of the EZH2 enzyme, which participates in tumor progression by making changes in the DNA that affect gene expression.
The open label, dose-escalation Phase 1 trial (NCT01897571), conducted at centers in France, was designed to evaluate the maximum dose of tazemetostat tolerated by patients and determine the proportion of patients who experience a reduction in tumor size after treatment. Researchers also assessed the treatment’s safety and how it was metabolized and excreted in the body.
The study recruited 64 patients, including 21 with B-cell non-Hodgkin’s lymphoma (NHL) and 43 with other types of solid tumors. Participants received ascending doses of the treatment — ranging from 100 mg to 1600 mg — administered orally, twice daily, in 28-day cycles.
Thirteen patients with solid tumors had lost the expression of one of two proteins, INI1 or SMARCA4, which “have an extremely poor prognosis and do not have efficacious treatments,” researchers wrote.
The maximum tolerated dose, which will be used in the trial’s second phase, was established at 800 mg twice daily. The most frequent treatment-related adverse events included weakness, anorexia, anemia, muscle spasms, nausea, and vomiting.
Tazemetostat led to durable objective responses in eight NHL patients – including three complete responses, one in a diffuse large B-cell lymphoma patient and two in follicular lymphoma patients.
Among solid tumor patients, five experienced tumor shrinkage, including a complete tumor clearance in one patient with malignant rhabdoid tumor (a very aggressive kidney tumor that occurs mainly in children), and a partial response in one patient with SMARCA4-negative malignant rhabdoid tumor of the ovary (MRTO).
Durable stable disease (more than 20 months) was found in a patient with MRTO and two patients with epithelioid sarcoma (ES).
At the highest dose of 1600 mg only one toxicity of grade 4 was identified — thrombocytopenia (abnormally low levels of platelets in the blood).
These results support further clinical investigation of tazemetostat in larger trials for tumors that depend on the activity of EZH2 enzyme to grow. The Phase 2 part of the trial is currently recruiting adult participants with DLBCL and follicular lymphoma (more information here).
“… publication in The Lancet Oncology reports the safety and tolerability endpoints for tazemetostat in this study, which enabled further evaluation of EZH2 inhibition in INI1- and SMARCA4-negative solid tumors and NHL,” professor Antoine Italiano, MD, PhD, of Institut Bergonie, and lead author of the paper, said in a press release. “I’m also encouraged by the preliminary anti-tumor activity observed in this study.”
“We would like to thank the investigators, patients and caregivers for their participation in this study, and for contributing to our understanding of tazemetostat as we work to address a significant medical need,” said Robert Bazemore, president and CEO of Epizyme.