Epizyme said today it will halt a Phase II clinical trial assessing its lead candidate, the cancer treatment tazemetostat in cohorts of patients with relapsed and/or refractory diffuse large B-cell lymphoma (r/r DLBCL), but continue the study in follicular lymphoma (FL) cohorts.

The trial halt comes more than three months after the FDA imposed a partial clinical hold on tazemetostat stemming from a separate trial—a hold that the company said it is working to have lifted.

The company said it will end its Phase II trial evaluating tazemetostat as monotherapy in cohorts of patients with r/r DLBCL (NCT01897571). The cohorts include DLBCL patients who have received tazemetostat in combination with prednisolone; as well as cohorts of DLBCL patients with EZH2 activating mutations, and with wild-type EZH2 who have been receiving tazemetostat as monotherapy.

“Epizyme has conducted an interim assessment of data from this trial and concluded that the clinical activity seen in these cohorts is not sufficient to warrant further development of tazemetostat in DLBCL as a monotherapy or in combination with prednisolone,” the company said in a statement, tucked within its announcement of second-quarter results. Epizyme finished Q2 with a net loss of $29.128 million, up from a net loss of $28.024 million in the year-ago quarter.

Epizyme added that it plans to present clinical data from each of the study cohorts at a medical meeting later this year. The company has two additional combination studies in DLBCL ongoing and plans to evaluate other potential combinations in this aggressive and difficult-to-treat cancer longer term.

The terminated trial was designed to assess tazemetostat in non-Hodgkin lymphoma (NHL), of which DLBCL is the most common form. Patients with DLBCL in the NHL trial who are responding to treatment with tazemetostat are continuing on the trial, but none are being enrolled, the company told GEN.

Other trials of tazemetostat in NHL indications include a Phase I/II study evaluating tazemetostat in first-line DLBCL with the “R-CHOP” chemotherapy combination of rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (oncovin), and prednisone (NCT02889523); and a Phase I study in r/r DLBCL in combination with the Genentech (Roche) cancer immunotherapy Tecentriq (atezolizumab; NCT02220842).

Additionally, tazemetostat is in clinical trials that include a Phase II study as monotherapy in adults with INI1-negative tumors or r/r synovial sarcoma (NCT02601950); a Phase II trial in mesothelioma (NCT02860286); a Phase I/II study in non-small-cell-lung cancer, in combination with Tecentriq (part of Genentech’s Morpheus umbrella study; NCT03337698), a Phase II study in recurrent ovarian, primary peritoneal, or endometrial cancer (NCT03348631), and a Phase II study in molecularly-targeted tumors (NCT03155620). The last two trials are being carried out by the NIH’s National Cancer Institute.

Possible Protocol Changes

In April, the FDA imposed its partial clinical hold on U.S.-based enrollment of new patients in clinical trials of tazemetostat after a patient in a Phase I pediatric study (NCT02601937) developed a secondary T-cell lymphoblastic lymphoma (T-LBL).

Epizyme said today it has since reviewed the single T-LBL case in detail, and completed a comprehensive assessment of tazemetostat safety data and clinical activity observed to date across clinical trials. The company said it has also convened a panel of external experts to review and validate the assessment, and will include the information in a formal response to regulators.

In addition, Epizyme said, it has obtained new consent from all patients in its clinical trials and updated its informed consent form based on the safety report that followed the lymphoma case.

“Epizyme plans to continue its engagement with the [FDA] in the weeks ahead and then finalize its response to regulatory authorities, including changes that may be proposed to study protocols,” the company stated. “Once the company has gained alignment with regulators in the U.S., France and Germany, it is anticipated that the partial clinical hold would be lifted and that enrollment activities would be allowed to proceed in those countries.”

The company cited the “potential impact” of the partial clinical hold, and its need to include more mature durability data, in delaying a planned New Drug Application (NDA) submission for tazemetostat for the treatment of patients with epithelioid sarcoma (ES).

In October, Epizyme plans to present updated data from part of NCT02601950 evaluating tazemetostat as a monotherapy for ES. A recent assessment of interim data from the full 62-patient ES cohort in the study showed an objective response rate that remained consistent with what was observed in the initial 31 enrolled patients. Enrollment in the trial was completed in July 2017. In addition, durability data from the cohort continue to mature.

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