A Study on the Effect of Tazemetostat (study drug) in Patients with Advanced Solid Tumors or with B Cell Lymphomas

• Register: EUCTR
• Last refreshed on: 27 July 2020
• Main ID: EUCTR2012-004083-21-GB
• Date of registration: 19/11/2013
• Prospective Registration: Yes
• Primary sponsor: Epizyme, Inc.
• Public title: A Study on the Effect of Tazemetostat (study drug) in Patients with Advanced Solid Tumors or with B Cell Lymphomas
• Scientific title: An Open-Label, Multicenter, Phase 1/2 Study of Tazemetostat (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Advanced Solid Tumors or With B Cell Lymphomas
• Date of first enrolment: 02/02/2015
• Target sample size: 420
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-004083-21
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 6
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Canada, France, Germany, Italy, Netherlands, Poland, Taiwan, United Kingdom, United States

Contacts

• Name: Clinical Trials Information
• Affiliation: Epizyme, Inc.

• Name: Clinical Trials Information
• Affiliation: Epizyme, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
All Subjects:
1. Phase 1: Eastern Cooperative Oncology Group (ECOG) performance
status of 0 to 1. Phase 2: ECOG performance status of 0 to 2.
2. Life expectancy = 3 months before starting tazemetostat.
3. Subjects with a history of Hepatitis B or C are eligible on the condition
that subjects have adequate liver function as defined by Inclusion
Criterion #6 and are hepatitis B surface antigen negative and/or have
undetectable hepatitis C virus (HCV RNA).
4. Adequate renal function defined as calculated creatinine clearance =
40 mL/min per the Cockcroft and Gault formula or local institutional
standard formula.
5. Adequate bone marrow function:
a. Absolute neutrophil count (ANC)= 750/mm3 (= 0.75 × 109/L)
b. Platelets = 75,000/mm3 (= 75 × 10*9/L)
c. Hemoglobin = 9.0 g/dL
6. Adequate liver function:
a. Total bilirubin = 1.5 × the upper limit of normal (ULN) except for
unconjugated hyperbilirubinemia of Gilbert's syndrome
b. Alkaline phosphatase (ALP) (in the absence of bone disease), alanine
aminotransferase (ALT), and aspartate aminotransferase (AST) = 3 ×
ULN (= 5 × ULN if subject has liver metastases)
7. Time between prior anticancer therapy and first dose of tazemetostat
as indicated in the protocol.
8. Males or females aged =18 years at the time of informed consent
(Phase 2). Males and females aged =16 years of age at time of informed
consent (Phase 1).
9. Females must not be lactating or pregnant at screening or baseline
(as documented by a negative beta-human chorionic gonadotropin [ßhCG]
test with a minimum sensitivity of 25 IU/L or equivalent units of ßhCG).
A separate baseline assessment is required if a negative screening
pregnancy test was obtained more than 72 hours before the first dose of
study drug. All females will be considered to be of childbearing potential
unless they are postmenopausal (at least 12 months consecutively
amenorrheic, in the appropriate age group, and without other known or
suspected cause) or have been sterilized surgically (ie, bilateral tubal
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery
at least 1 month before dosing). Females of childbearing potential must
not have had unprotected sexual intercourse within 30 days prior to
study entry and must agree to use a highly effective method of
contraception(as per protocol), from the last menstrual period prior to
randomization, during Treatment Cycles, and for 30 days after the final
dose of study drug, and have a male partner who uses a condom.
10. Male subjects must have had either a successful vasectomy OR they
and their female partner must meet the criteria above (ie, not of
childbearing potential OR practicing highly effective contraception and
use a condom throughout the study period and for 30 days after study
drug discontinuation).
11. Voluntary agreement to provide written informed consent and the
willingness and ability to comply with all aspects of the protocol.
Phase 1 only (IGR and IB sites in France only):
12. Histologically and/or cytologically confirmed advanced or metastatic
solid tumor or B cell lymphomas that have progressed after treatment
with approved therapies or for which there are no standard therapies
available.
Phase 2:
13. Subjects must satisfy all of the following criteria:
a. Have histologically confirmed DLBCL (including primary mediastinal B
cell lymphoma), with relapsed or refractory disease following at least 2
lines of prior standard ther
Exclusion criteria:
All Subjects:
1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
2. Subjects with known leptomeningeal metastases or brain metastases
or history of previously treated brain metastases.
3. Has thrombocytopenia, neutropenia, or anemia of Grade =3 (per
CTCAE 4.03 criteria) and any prior history of myeloid malignancies,
including myelodysplastic syndrome (MDS).
4. Has a prior history of T-LBL/T-ALL.
5. Subjects taking medications that are known potent CYP3A4
inducers/inhibitors (including St John's Wort)
6. Subjects unwilling to exclude Seville oranges, grapefruit juice, and
grapefruit from their diet.
7. Any prior treatment-related (ie, chemotherapy, immunotherapy,
radiotherapy), clinically significant toxicities have not resolved to =
Grade 1 per CTCAE version 4.03, or prior treatment-related toxicities are
clinically unstable and clinically significant at time of enrollment.
8. Major surgery within 4 weeks before the first dose of study drug.
9. Inability to take oral medication, or malabsorption syndrome or any
other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or
vomiting) that might impair the bioavailability of tazemetostat.
10. Significant cardiovascular impairment: history of congestive heart
failure greater than New York Heart Association (NYHA) Class II,
uncontrolled arterial hypertension, unstable angina, myocardial
infarction, or stroke within 6 months of the first dose of study drug; or
cardiac ventricular arrhythmia.
11. Prolongation of corrected QT interval using Fridericia's formula (QTcF)
to > 480 msec.
12. Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat.
13. Active infection requiring systemic therapy.
14. Known hypersensitivity to any component of tazemetostat,
prednisolone/prednisone (cohort 6 only), or inability to be
treated with a Pneumocystis prophylaxis medication (cohort 6 only).
15. Immunocompromised subjects, including subjects known to be
infected with human immunodeficiency virus (HIV).
16. Any other major illness that, in the investigator's judgment, will
substantially increase the risk associated with the subject's participation
in this study.
17. Females who are pregnant or breastfeeding.
18. Subjects who have undergone a solid organ transplant.
Phase 2 only:
19. Subjects with noncutaneous malignancies other than B cell
lymphomas.
? Exception: Subjects with another malignancy who have been diseasefree
for 5 years, or subjects with a history of a completely resected nonmelanoma
skin cancer or successfully treated in situ carcinoma are eligible.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Relapsed or refractory Diffuse Large B Cell Lymphoma, Follicular Lymphoma, Advanced solid tumor

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Tazemetostat (Formerly called: EPZ-6438, E7438)
Pharmaceutical Form: Tablet
INN or Proposed INN: Tazemetostat
Current Sponsor code: EPZ-6438
Other descriptive name: ESQR
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Phase 1: Dose escalation will continue until the MTD is reached, or up to a maximum feasible dose of 1600 mg BID, whichever comes first. If no DLTs are observed, the RP2D will be determined based on safety, tolerability, activity, PK, and PD assessments.
Phase 2: after end of trial database lock.

Main Objective: Phase 1
To determine the maximum tolerated dose (MTD) and/or
recommended Phase 2 dose (RP2D) of tazemetostat as a single agent
administered orally twice daily (BID), continuously in 28-day cycles, in
subjects with advanced solid tumors or with relapsed and/or refractory
B cell lymphomas
Phase 2
To determine the objective response rate (ORR; complete response +
partial response [CR + PR]) of tazemetostat in subjects with enhancer of
zeste homolog 2 (EZH2) gene mutation positive or negative (wild-type)
with histologically confirmed diffuse large B cell lymphoma (DLBCL) or
follicular lymphomas (FL), with relapsed or refractory disease.

Secondary Objective: Phase 1
? To assess the effect of a high-fat meal on the bioavailability of tazemetostat
? To assess the effect of tazemetostat on exposure of midazolam, a cytochrome P450 (CYP)3A4 substrate
? To assess the preliminary activity of tazemetostat
Phase 2
? To assess the effect of tazemetostat on progression-free survival (PFS)
? To assess the effect of tazemetostat on duration of response (DOR)
All Phases and Cohorts
? To assess the safety and tolerability of tazemetostat
? To assess the pharmacokinetic (PK) profile of tazemetostat

Primary end point(s): Phase 1:
The MTD and/or RP2D of EPZ-6438 as a single agent administered orally, b.i.d. continuously in 28-day cycles in subjects with advanced solid tumors or with relapsed and/or refractory B cell lymphomas.
Phase 2:
The objective response rate (ORR), defined as the proportion of complete response + partial response [CR + PR]) with EPZ-6438 in EZH2 mutation positive and negative (wild-type) subjects with histologically confirmed DLBCL or FL with relapsed or refractory disease. The 95% confidence interval (CI) of ORR will be based on a Clopper–Pearson exact formula. Each cohort will be evaluated separately.

Secondary Outcome(s)

Secondary end point(s): Phase 1:
• Preliminary efficacy (e.g., best overall response [BOR]) will be assessed in subjects in the Safety Analysis Set.
• Food effect on bioavailability (AUC and Cmax) of EPZ-6438.
• Effect of EPZ-6438 on exposure (AUC and Cmax) to midazolam, its metabolites and 4ß-hydroxycholesterol, an endogenous biomarker of CYP3A4 activity.
Phase 2:
- PFS, defined as the time from the date of first dose to the date of first documentation of relapse, disease
progression, or date of death, whichever occurs first.
- DOR, defined as time from the first date of response (CR or PR, whichever is first recorded) to recurrence, objectively documented disease progression, or death.

Timepoint(s) of evaluation of this end point: The food effect and drug-drug interaction will be assessed after cycle 1.

Other endpoints assessed after end of trial database lock.

Secondary ID(s)

E7438-G000-101

Source(s) of Monetary Support

Epizyme, Inc.

Ethics review

Status: Approved
Approval date: 02/02/2015
Contact: