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

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2012-004083-21-DE
• Date of registration: 12/02/2016
• Prospective Registration: Yes
• Primary sponsor: Epizyme, Inc.
• Public title: A Study on the Effect of Tazametostat (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 and Tazemetostat in Combination With Prednisolone in Subjects With Diffuse Large B Cell Lymphoma
• Date of first enrolment: 04/07/2016
• Target sample size: 350
• 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, 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 [ß-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG). 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 n
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 (combination cohort only), or inability to be treated with a Pneumocystis prophylaxis medication (combination cohort 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 disease-free for 5 years, or subjects with a history of a completely resected non-melanoma 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
MedDRA version: 20.0 Level: LLT Classification code 10065252 Term: Solid tumor System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: PT Classification code 10003899 Term: B-cell lymphoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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

Intervention(s)

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

Primary Outcome(s)

Primary end point(s): Phase 1:
The MTD and/or RP2D of tazemetostat 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 tazemetostat 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 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 monotherapy and tazemetostat in combination with prednisolone on progression-free survival (PFS)
? To assess the effect of tazemetostat monotherapy and tazemetostat in combination with prednisolone on duration of response (DOR)
All Phases and Cohorts
? To assess the safety and tolerability of tazemetostat monotherapy and tazemetostat in combination with prednisolone
? To assess the pharmacokinetic (PK) profile of tazemetostat monotherapy and tazemetostat in combination with prednisolone

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 and the ORR of tazemetostat in combination with prednisolone in subjects with EZH2 wild-type DLBCL

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 tazemetostat.
• Effect of tazemetostat 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

2012-004083-21-GB

Source(s) of Monetary Support

Epizyme, Inc.

Ethics review

Status: Approved
Approval date:
Contact: