EZH-102 - Paediatric
Research type
Research Study
Full title
A Phase I Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects with Relapsed or Refractory INI1-Negative Tumours or Synovial Sarcoma
IRAS ID
190625
Contact name
Darren Hargrave
Contact email
Sponsor organisation
Epizyme, Inc
Eudract number
2015-002468-18
Clinicaltrials.gov Identifier
Duration of Study in the UK
5 years, 0 months, 1 days
Research summary
Research summary:
This phase 1 study is an exploratory evaluation of an oral suspension in a pediatric population with relapsed/refractory selected tumours. The study is designed to answer if tazemetostat can be safely administered to this population.
To determine the maximum tolerated dose (MTD) or the recommended Phase II dose (RP2D) of tazemetostat when administered as an oral suspension twice daily (BID) in pediatric subjects with relapsed/refractory INI1-negative tumours or synovial sarcoma. Also (after dose expansion period) to evaluate the antitumour activity of tazemetostat as assessed by overall response rate (ORR) in selected pediatric subjects using disease appropriate standardized response criteria.Tazemetostat is a selective small molecule inhibitor of histone-lysine methyltransferase enzyme EZH2. Sponsor research has shown that inhibition of EZH2 with tazemetostat results in the death of EZH2-dependent genetically defined cancer cells. For example, laboratory studies have demonstrated that tazemetostat inhibits the growth of cancer cells lacking the INI1 protein in vitro and in vivo. Tazemetostat has been shown to provide clinical benefit in patients with Malignant Rhabdoid Tumours in terms of disease progression and remission. To date no patients with synovial sarcoma have shown significant response but as synovial sarcomas also display decreased expression of the INI1 protein it is hoped that further testing will show results similar to those seen in MRT patients.
Clinical benefit for tazemetostat has not yet been established in paediatric patients: this study will identify a RP2D for tazemetostat in pediatric subjects and characterize the safety profile and PK in this population. This study will have 2 main stages:
• Dose Escalation:
The starting dose will be 240 mg/m2/dose administered orally BID for a total of 480 mg/m2/day.
Dose escalation will proceed in increments of 25-33% and dose de-escalation will proceed in decrements of 50%.
(see protocol 3.1 table 2)
• Dose Expansion:
Once the Max Tolerated Dose is determined and a Recommended Phase 2 Dose is determined in the dose escalation part, accrual of subjects in Dose Expansion will be allowed.
Approximately 44 patients (aged ≥ 6 months to ≤ 21 years) will be recruited into the study at locations worldwide.
In the UK, subjects under the age of 5 years will not be enrolled until at least 4 subjects study wide have been exposed to study drug for > 4 weeks.Summary of Results:
In total, 109 patients participated in the EZH-102 trial. In the dose escalation phase, 46 patients were enrolled. The dose escalation phase is the part of the study where the dose of the test drug is increased a little at a time in different groups of people until the highest dose that does not cause harmful side effects is found. This is also called the dose finding phase. In the dose expansion phase, 63 patients were enrolled. The dose expansion phase is the part of the study where additional information for the drug is collected at the dose level identified in the preceding dose escalation phase.
We looked at the data from patients in the dose escalation and dose expansion phase separately.
When looking at how well a drug works, we check if the tumor is shrinking. There are criteria how much a tumor needs to shrink until we can use the formal definition of “Partial Response.” If the tumor disappears, it is called a “Complete Response”. Another way to look at this is to see how long patients live with a response (duration of response=DOR), or how long patients live without their tumor getting worse (progression-fee survival=PFS). An additional way to look at this is to see how long patient survive from the time they received their tumor diagnosis or from the time they started the new treatment. This is also called overall survival or OS.According to the response criteria used in our protocol we saw the following responses:
Dose Escalation Phase, Response Rate:
• 6.5% (3 out of 46 patients) of patients had a response.
• 4.3% (2 out of 46 patients) of patients had a complete response.
• 2.2% (1 out of 46 patients) of patients had a partial response.Dose Escalation Phase, Duration of Response:
• The 3 patients with a response had a response that was longer than 18 weeks.Dose Expansion Phase, Response Rate:
• 14.3% (9 out of 63 patients) of patients had a response.
• 3.2% (2 out of 63 patients) of patients had a complete response.
• 11.1% (7 out of 63 patients) of patients had a partial response.Dose Expansion Phase, Duration of Response:
• The duration of response (DOR), available for 8 patients, was longer than 18 weeks.
• From all patients with a progression-free survival (PFS) time recorded, the middle (median) time of response was 8 weeks.
• From all patients with an overall survival (OS) time recorded, the middle (median) OS time was 21.3 weeks.
Main symptoms on study:
These symptoms occurred during the trial and were not necessarily linked to the new study drug.
Patients on the study had mostly (≥50%) symptoms from the following organ systems:
• Digestive system (e.g stomach) with symptoms like eg vomiting or nausea
• Respiratory system (e.g. lungs) with symptoms like eg cough or nasal congestion
• General symptoms like eg raised body temperature or fatigue.
Has the registry been updated to include summary results?: Yes
If yes - please enter the URL to summary results: Results have been posted on EudraCT on 23DEC2021 and will be made public within the next 2 weeks. For clinicaltrials.gov, results will be published in Q2-2022.
If no – why not?:
Did you follow your dissemination plan submitted in the IRAS application form (Q A51)?: Yes
If yes, describe or provide URLs to disseminated materials: "Results have been posted on EudraCT on 23DEC2021 and will be made public within the next 2 weeks.
For clinicaltrials.gov, results will be published in Q2-2022."If pending, date when dissemination is expected:
If no, explain why you didn't follow it:
Have participants been informed of the results of the study?: Yes
If yes, describe and/or provide URLs to materials shared and how they were shared: Results have been posted on EudraCT on 23DEC2021 and will be made public within the next 2 weeks.
For clinicaltrials.gov, results will be published in Q2-2022.REC name
South Central - Oxford A Research Ethics Committee
REC reference
16/SC/0049
Date of REC Opinion
19 Feb 2016
REC opinion
Further Information Favourable Opinion