FDA Lifts Partial Clinical Hold on Tazemetostat Trials

Robert Bazemore

The FDA has lifted a partial clinical hold on tazemetostat trials, reopening enrollment to clinical studies examining the EZH2 inhibitor in patients with various solid tumors and hematologic malignancies.

The federal agency had placed the hold on the tazemetostat program after Epizyme, the manufacturer of the drug, provided a safety update detailing a pediatric patient with advanced poorly differentiated chordoma enrolled in a phase I trial who developed a secondary T-cell lymphoma.

The patient had been enrolled in the trial for around 15 months at the time of the safety update and had reached a confirmed partial response. Following the diagnosis of the secondary malignancy, the patient stopped tazemetostat and received therapy for T-cell lymphoma.

In a press release announcing the hold lift, Epizyme reported that an independent panel of experts had validated the efficacy and safety findings across all tazemetostat trials. The company also noted that its official response to the FDA also included a thorough analysis of the potential link between tazemetostat and secondary malignancies.

“The Epizyme team has worked diligently to provide a comprehensive response back to the FDA, and through constructive dialogue, we successfully resolved the partial clinical hold. This allows us to turn our full attention to our key priorities: preparing for our first new drug application submission for tazemetostat in epithelioid sarcoma and defining our registration path in follicular lymphoma,” Robert Bazemore, president and chief executive officer of Epizyme, said in the press release.

“We, along with our investigators and the global experts we consulted to support our complete response, continue to believe in the positive benefit/risk of tazemetostat as we move forward in our clinical development program. We remain steadfast in our commitment to bringing this potential therapeutic option to cancer patients in need of safe and effective new treatments,” added Bazemore.

Data from the trial on which the clinical hold was based were reported at the 2018 American Society of Pediatric Hematology/Oncology Conference.¹ In the study, tazemetostat demonstrated promising antitumor activity in pediatric patients with INI1-negative solid tumors.

In the dose-escalation part of a phase I study, 46 patients were treated with 7 dose levels, ranging from from 240 to 1200 mg/m² of twice-daily tazemetostat. At the conference, lead author Susan N. Chi, MD, director, Pediatric Neuro-Oncology and Clinical Trials, Dana-Farber Cancer Institute, presented results from patients treated with ≥520 mg/m². Four patients who were treated at doses from 520 to 900 mg/m² demonstrated RECIST/RANO-confirmed objective response.

In this study, eligible patients aged 6 months to 21 years with synovial sarcoma or INI1-negative tumors, including epithelioid sarcomas and chordoma, could enroll and receive tazemetostat in a “Rolling 6” design. Objective response was assessed every 8 weeks.

The median age was 3 years (range, 0.8-15.0). All patients were diagnosed with metastatic disease and the median number of prior lines of therapy was 2.

Three patients had a complete response and 1 had a partial response. Five patients had stable disease. The complete responses lasted 20, 24+, and 40+ weeks. The partial response lasted 24+ weeks.

Aside from the patient whose secondary cancer led to the clinical hold, Chi said adverse events (AEs) were generally mild. One patient in the 300 mg/m² cohort experienced dose-limiting toxicities (DLTs) of grade 4 dyspnea and grade 3 hypoxia. Investigators did not observe DLTs in any other cohort.

All patients in the 520 mg/m² (n = 7), 700 mg/m² (n = 6), and 900 mg/m² (n = 6) cohorts experienced treatment-emergent AEs (TEAEs) of any grade, as did 86% of the 1200 mg/m² cohort. In the total patient population, 34 (74%) patients experienced TEAEs. Vomiting (26%) and fatigue (20%) were the most common TEAEs. Overall, 7 (15%) patients experienced grade ≥3 TEAEs, the most common being decreased platelet count (7%) and neutropenia (4%).

Steady state concentrations were lower on day 15 compared with day 1 across all dose cohorts and plasma concentrations were dose proportional. Chi said that the mean systemic exposure in the 1200 mg/m² cohort was roughly 4-fold greater than with the adult recommended phase II dose of twice-daily 800 mg.

Investigators observed a PK:PD relationship between tazemetostat exposure and H3K27 trimethylation levels in peripheral blood monocytes and granulocytes, and found “consistent and significant” post-dose reductions in H3K27 at doses ≥900 mg/m².

Chi et al set the pediatric recommended phase II dose at 1200 mg/m² of tazemetostat twice daily based on clinical safety, efficacy, PK, and PD results.

“We chose the higher dose level, 1200 mg/m², to increase the potential for CNS penetration,” Chi said. “We saw similar reductions in H3K27 trimethylation levels at both the 900 and 1200 mg/m² dose levels, suggesting a plateau of the pharmacodynamic effect.”

In June 2017, the FDA granted orphan drug designation to tazemetostat for the treatment of adult patients with INI1-negative epithelioid sarcoma. The orphan drug designation program is reserved for the safe and effective treatment, diagnosis, or prevention of conditions that affect fewer than 200,000 people in the United States.

Phase II data from 31 patients treated with 800 mg of tazemetostat in continuous 28-day cycles were presented at the 2017 ASCO Annual Meeting.² The median progression-free survival was 5.7 months. The disease control rate (DCR) was 10%, with a confirmed response rate of 13% and a stable disease rate of 19% at ≥32 weeks. Seven (23%) patients had disease progression.

Best overall response was partial response (13%), and there were no complete responses recorded. Thirteen patients remain on treatment, and DCR and overall response outcomes will be updated as the data matures.

The FDA in April 2017 granted fast track status to tazemetostat for the treatment of patients with relapsed or refractory follicular lymphoma, either wild-type EZH2 or with EZH2 activating mutations. The agency granted the drug Fast Track status in November 2016 for patients with relapsed/refractory diffuse large B-cell lymphoma with EZH2-activating mutations.

The fast track designation is intended to expedite the regulatory review process for promising investigational agents that may fill an unmet medical need for patients with serious or life-threatening conditions.

References

1. Chi S, Fouladi M, Shukla N, et al. Phase 1 study of the EZH2 inhibitor, tazemetostat, in children with relapsed or refractory INI1-negative tumors including rhabdoid tumors, epithelioid sarcoma, chordoma; and synovial sarcoma. In: Proceedings from the 2018 ASPHO Conference; May 2-5, 2018; Pittsburgh, Pennsylvania. Abstract 2077.
2. Gounder MM, Stacchiotti S, Schöffski P, et al. Phase 2 multicenter study of the EZH2 inhibitor tazemetostat in adults with INI1 negative epithelioid sarcoma (NCT02601950). J Clin Oncol. 2017;35(suppl; abstr 11058).