Tazemetostat Demonstrates Promising Results for Pediatric Patients with INI1-Negative Tumors

Susan N. Chi, MD

Susan N. Chi, MD

According to findings presented at the 2018 American Society of Pediatric Hematology/Oncology Conference, promising antitumor activity was found with tazemetostat in pediatric patients with INI1-negative solid tumors.¹

Forty-six patients were given treatments at 7 dose levels for the dose-escalation part of this phase I study, ranging from from 240 to 1200 mg/m²of twice-daily tazemetostat. Susan N. Chi, MD, lead author and director of the Pediatric Neuro-Oncology and Clinical Trials at Dana-Farber Cancer Institute, presented the findings from the patients treated with ≥520 mg/m². Of which, 4 patients that were treated at doses from 520 to 900 mg/m²showed RECIST/RANO-confirmed objective response.

“Tazemetostat monotherapy is generally well tolerated in children and it shows encouraging and promising antitumor activity, including complete responses with this very high-risk, INI1-negative tumor population,” said Chi.

A partial clinical hold was placed in April 2018 on the entire tazemetostat clinical trial program after Epizyme, the manufacturer of the EZH2 inhibitor, provided a safety update of a patient with advanced poorly differentiated chordoma enrolled on this study that had developed a secondary T-cell lymphoma. The company has placed a voluntary hold on pediatric tazemetostat trials happening outside of the United States.

The patient mentioned in this safety update was enrolled in the trial for about 15 months with a confirmed partial response. The patient stopped receieving treatment of tazemetostat after the diagnosis of the secondary malignancy. Therapy for T-cell lymphoma is now being administered.

This is the only incident of secondary lymphoma reported among more than 750 patients treated with tazemetostat in their clinical program, according to Epizyme.

Consent forms and study protocols will be updated before enrollment is reopened, Chi explained. Investigators hope to enrollment will begin for patients again within the next few months.

In this study, Eligible patients aged 6 months to 21 years with synovial sarcoma or INI1-negative tumors, including epithelioid sarcomas and chordoma, will be able to enroll and receive a “Rolling 6” design of tazemetostat. The objective responses will be assessed every 8 weeks.

Median age of the patients was 3 years (range, 0.8-15.0). All patients has been diagnosed with metastatic disease with a median number of prior lines of therapy as 2.

Also, 3 patients had a complete response and 1 had a partial response. Five patients had stable disease and the complete responses lasted 20, 24+, and 40+ weeks. Partial response lasted over 24 weeks or longer.

Chi said adverse events (AEs) were generally mild with the exception of the patient that had developed secondary cancer. It is also noted that 1 patient in the 300 mg/m²cohort experienced dose-limiting toxicities (DLTs) of grade 4 dyspnea and grade 3 hypoxia. DLTs were not observed 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 had experienced treatment-emergent AEs (TEAEs) of any grade. This was also noted in 86% of patients in the 1200 mg/m²cohort.

Overall, 34 (74%) patients in the experiment experienced TEAEs. The most common TAEs were vomiting (26%) and fatigue (20%). Seven (15%) patients experienced grade ≥3 TEAEs, while the most common were decreased platelet count (7%) and neutropenia (4%).

Investigators found the steady state concentrations were lower on day 15 versus day 1 across all cohorts. Plasma concentrations were dose proportional. Chi noted that the mean systemic exposure in the 1200 mg/m2 cohort was roughly 4-fold greater when compared to the adult recommended phase II dose of twice-daily 800 mg.

A PK:PD relationship was found between tazemetostat exposure and H3K27 trimethylation levels in peripheral blood monocytes and granulocytes. “Consistent and significant” post-dose reductions were also found in H3K27 at doses ≥900 mg/m².

Based on clinical safety, efficacy, PK, and PD results, Chi et al set the pediatric recommended phase II dose at 1200 mg/m²of tazemetostat 2 times daily.

“We chose the higher dose level, 1200 mg/m², to increase the potential for CNS penetration,” Chi explained. “We saw similar reductions in H3K27 trimethylation levels at both the 900 and 1200 mg/m²dose levels, suggesting a plateau of the pharmacodynamic effect.”

The FDA granted orphan drug designation in June 2017 to tazemetostat for 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 affecting less than 200,000 people in the United States.

At the 2017 ASCO Annual Meeting, phase II data from 31 patients treated with 800 mg of tazemetostat in continuous 28-day cycles were presented.²Median progression-free survival was 5.7 months, and the disease control rate (DCR) was 10%. The confirmed response rate was 13%, with a stable disease rate of 19% at ≥32 weeks. Disease progression was found in 7 (23%) of the patients.

Partial response (13%) was the best overall response, and no complete responses were recorded. Thirteen patients continued with treatment, and DCR and overall response outcomes will be updated in the future after data has matured.

In April 2017, the FDA granted fast track status to tazemetostat for treatment of patients with relapsed or refractory follicular lymphoma that have either wild-typeEZH2or withEZH2activating mutations. In November 2016, the drug was granted Fast Track status for treatment of patients with relapsed/refractory diffuse large B-cell lymphoma with EZH2-activating mutations.

The fast track designation is intended to speed up the regulatory review process for promising investigational agents with the potential to fit 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).