Study of Tazemetostat as Single Agent in Solid Tumors or B-cell Lymphomas and in Combination With Prednisolone in DLBCL

NCT ID: NCT01897571

Last Updated: 2024-03-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 400 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-06-13
• Study Completion Date: 2021-11-02

Brief Summary

This is an open-label, multicenter, Phase 1/2 study of tazemetostat 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 (DLBCL).

Detailed Description

This is a multicenter, open-label, Phase 1/2 study conducted in two parts: The Phase 1 part comprised dose escalation and expansion to establish the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) when tazemetostat was given twice daily (BID) orally on a continuous basis. Additionally, in separate cohorts in Phase 1, the effect of food on the bioavailability of tazemetostat as well as the drug-drug interaction (DDI) potential of tazemetostat were evaluated. The Phase 2 part was initiated once the RP2D was established. Phase 2 enrolled subjects with relapsed/ refectory (R/R) DLBCL (Cohorts 1-3 and 6) and subjects with R/R FL (Cohorts 4 and 5) for the determination of efficacy and safety of tazemetostat monotherapy (Cohorts 1-5) and of tazemetostat in combination with prednisolone (Cohort 6) with placement determined by centrally confirmed histology, cell of origin (COO), and enhancer of zeste homologue 2 (EZH2) mutation status.

Conditions

B-cell Lymphomas (Phase 1); Advanced Solid Tumors (Phase 1); Diffuse Large B-cell Lymphoma (Phase 2); Follicular Lymphoma (Phase 2); Transformed Follicular Lymphoma; Primary Mediastinal Large B-Cell Lymphoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase 1

Patients in the Phase 1 portion of the study.

Group Type: EXPERIMENTAL

Tazemetostat

Intervention Type: DRUG

Patients who received 100 mg to 1600 mg of tazemetostat, BID, administered in continuous 28-day cycles.

Phase 2 Group 1: Tazemetostat in R/R FL with Mutant EZH2

Patients with R/R FL with mutant EZH2 treated with tazemetostat as a single agent in Phase 2 of the study.

Group Type: EXPERIMENTAL

Tazemetostat

Intervention Type: DRUG

Patients who received 800 mg of tazemetostat, BID, administered in continuous 28-day cycles.

Phase 2 Group 2: Tazemetostat in R/R FL with Wild-Type EZH2

Patients with R/R FL with wild-type EZH2 treated with tazemetostat as a single agent in Phase 2 of the study.

Group Type: EXPERIMENTAL

Tazemetostat

Intervention Type: DRUG

Patients who received 800 mg of tazemetostat, BID, administered in continuous 28-day cycles.

Phase 2 Group 3: Tazemetostat in R/R DLBCL

Patients with R/R DLBCL treated with tazemetostat as a single agent or tazemetostat in combination with prednisolone in Phase 2 of the study.

Group Type: EXPERIMENTAL

Tazemetostat

Intervention Type: DRUG

Patients who received 800 mg of tazemetostat, BID, administered in continuous 28-day cycles.

Prednisolone

Intervention Type: DRUG

Patients who received 40 mg/m\^2 prednisolone once daily on Days 1-5 and 15-19 of Cycles 1-4.

Interventions

Tazemetostat

Patients who received 800 mg of tazemetostat, BID, administered in continuous 28-day cycles.

Intervention Type: DRUG

Prednisolone

Patients who received 40 mg/m\^2 prednisolone once daily on Days 1-5 and 15-19 of Cycles 1-4.

Intervention Type: DRUG

Tazemetostat

Patients who received 100 mg to 1600 mg of tazemetostat, BID, administered in continuous 28-day cycles.

Intervention Type: DRUG

Other Intervention Names

EPZ-6438; E7438; Pediapred; Omnipred; Pred Mild; Pred Forte,; Orapred ODT,; Veripred 20,; Millipred DP; EPZ-6438; E7438

Eligibility Criteria

Inclusion Criteria

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 of at least 3 months before starting tazemetostat.

3. Voluntary agreement to provide written informed consent and willing to adhere to all protocol requirements

4. Subjects with Hepatitis B or C are eligible on the condition that subjects have adequate liver function and are hepatitis B surface antigen negative and/or have undetectable hepatitis C virus (HCV) RNA.

5. Adequate renal and liver function

6. Phase 1: Males or females aged ≥ 16 years at time of informed consent. Phase 2: Males or females aged ≥ 18 years at the time of informed consent .

7. Females must not be lactating or pregnant at screening or baseline as documented by a negative pregnancy test All females will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutive 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 dose). 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, from the last menstrual period prior to randomization, during Treatment Cycles, and for 6 months after the last final dose of study drug; any male partner must use a condom.

8. Male subjects must have had a successful vasectomy (with confirmed azoospermia) 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 3 months after study drug discontinuation). Nonvasectomized male subjects must also agree to refrain from donating sperm from first dose of tazemetostat until 3 months following the last dose of tazemetostat

9. Phase 1 only: 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.

10. Phase 2, Groups 1-6 only: Subjects must satisfy all of the following criteria:

1. Have histologically confirmed DLBCL (including primary mediastinal B-cell lymphoma), with relapsed or refractory disease following at least 2 lines of prior standard therapy, including alkylator/anthracycline (unless anthracycline-based chemotherapy is contraindicated)/anti-CD20-based therapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or equivalent) AND must be considered unable to benefit from intensification treatment with autologous hematopoietic stem cell transplantation (ASCT) as defined by meeting at least 1 of the following criteria:

• Relapsed following, or refractory to, previous ASCT
• Did not achieve at least a partial response to a standard salvage regimen (eg, rituximab, ifosfamide, carboplatin, and etoposide phosphate [R-ICE] or rituximab, dexamethasone, cytarabine, and cisplatin [R-DHAP])
• Ineligible for intensification treatment due to age or significant comorbidity
• Ineligible for intensification treatment due to failure to mobilize an acceptable number of hematopoietic stem cells
• Refused intensification treatment and/or ASCT or

2. Have histologically confirmed Follicular Lymphoma (FL), all grades. Subjects may have relapsed/refractory disease following at least 2 standard prior systemic treatment regimens where at least 1 anti-CD20-based regimen was used. Subjects with prior radiotherapy will be included; however, radiotherapy alone will not be considered a systemic treatment regimen.

3. Have provided sufficient archival tumor tissue that has been successfully tested for EZH2 mutation status and cell of origin (DLBCL only)

4. Have measurable disease as defined by International Working Group-Non-Hodgkin's Lymphoma (IWG-NHL)

Exclusion Criteria

1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2.

2. Subjects with 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-cell lymphoblastic lymphoma(T-LBL) or T-cell lymphoblastic leukemia (T-ALL).

5. Subjects taking medications that are known strong CYP3A inhibitors and strong or moderate CYP3A inducers (including St. Johns Wort) 6. Subjects unwilling to remove Seville oranges, grapefruit juice and grapefruit from their diet.

6. Any unstable or unresolved prior treatment-related (i.e. chemotherapy, immunotherapy, radiotherapy) toxicities at time of enrollment.

7. Major surgery within 4 weeks before the first dose of study drug. .

8. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, or vomiting) that might impair the bioavailability of tazemetostat.

9. 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.

10. Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat.

11. Active infection requiring systemic therapy.

12. Immunocompromised patients, including patients known to be infected with human immunodeficiency virus (HIV).

13. Any other major illness that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in this study.

14. Females who are pregnant or breastfeeding.

15. Phase 2 only: 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.

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Epizyme, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ipsen Medical Director

Role: STUDY_DIRECTOR

Ipsen

Locations

Birmingham, Alabama, United States

Duarte, California, United States

Santa Barbara, California, United States

Aurora, Colorado, United States

Washington D.C., District of Columbia, United States

Ocala, Florida, United States

Ann Arbor, Michigan, United States

New York, New York, United States

Houston, Texas, United States

San Antonio, Texas, United States

Fairfax, Virginia, United States

Seattle, Washington, United States

Clayton, , Australia

Geelong, , Australia

Melbourne, , Australia

Montreal, , Canada

Toronto, , Canada

Bordeaux, , France

Caen, , France

Créteil, , France

Lille, , France

Lyon, , France

Marseille, , France

Montpellier, , France

Nantes, , France

Paris, , France

Pierre-Bénite, , France

Rennes, , France

Rouen, , France

Villejuif, , France

Göttingen, , Germany

Münster, , Germany

Bologna, , Italy

Napoli, , Italy

Krakow, , Poland

Lublin, , Poland

Poznan, , Poland

Warsaw, , Poland

Taipei, , Taiwan

Chernivtsi, , Ukraine

Dnipro, , Ukraine

Ivano-Frankivsk, , Ukraine

Kharkiv, , Ukraine

Kyiv, , Ukraine

Mykolayiv, , Ukraine

Uzhhorod, , Ukraine

Zaporizhzhya, , Ukraine

Zhytomyr, , Ukraine

Glasgow, , United Kingdom

London, , United Kingdom

Manchester, , United Kingdom

Southampton, , United Kingdom

Countries

United States; Australia; Canada; France; Germany; Italy; Poland; Taiwan; Ukraine; United Kingdom

References

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Reference Type: DERIVED

PMID: 39563886 (View on PubMed)

Bosch F, Kuruvilla J, Vassilakopoulos TP, Maio DD, Wei MC, Zumofen MB, Nastoupil LJ. Indirect Treatment Comparisons of Mosunetuzumab With Third- and Later-Line Treatments for Relapsed/Refractory Follicular Lymphoma. Clin Lymphoma Myeloma Leuk. 2024 Feb;24(2):105-121. doi: 10.1016/j.clml.2023.09.007. Epub 2023 Sep 28.

Reference Type: DERIVED

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Morschhauser F, Tilly H, Chaidos A, McKay P, Phillips T, Assouline S, Batlevi CL, Campbell P, Ribrag V, Damaj GL, Dickinson M, Jurczak W, Kazmierczak M, Opat S, Radford J, Schmitt A, Yang J, Whalen J, Agarwal S, Adib D, Salles G. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020 Nov;21(11):1433-1442. doi: 10.1016/S1470-2045(20)30441-1. Epub 2020 Oct 6.

Reference Type: DERIVED

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Italiano A, Soria JC, Toulmonde M, Michot JM, Lucchesi C, Varga A, Coindre JM, Blakemore SJ, Clawson A, Suttle B, McDonald AA, Woodruff M, Ribich S, Hedrick E, Keilhack H, Thomson B, Owa T, Copeland RA, Ho PTC, Ribrag V. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 2018 May;19(5):649-659. doi: 10.1016/S1470-2045(18)30145-1. Epub 2018 Apr 9.

Reference Type: DERIVED

PMID: 29650362 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2012-004083-21

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

E7438-G000-101

Identifier Type: -

Identifier Source: org_study_id