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

NCT01897571 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: E7438-G000-1012012-004083-21
• Study Type: interventional
• Target: 400
• Locations: 10 countries
• Sites: 52

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).

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

Keywords

Epizyme; Tazverik; Tazemetostat (EPZ-6438)

Outcome Measures

Primary Outcomes (2)

• Recommended Phase 2 Dose (RP2D) of Tazemetostat as a Single-Agent and in Combination With Prednisolone (Phase 1 Only)

  Recommended Phase 2 dose (RP2D) of tazemetostat as 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 as determined by incidence, seriousness, toxicity grade, and relatedness of treatment emergent dose limiting toxicities

  The first 28-day cycle of therapy

• Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR]) (Phase 2)

  Number of patients achieving an objective response (CR or PR)/number of patients treated x 100%. ORR was calculated as the percentage of patients with a confirmed complete response (CR) or partial response (PR) relative to the total number of patients in the analysis population per response evaluation criteria in solid tumors (RECIST) version (v)1.1. Complete Response (CR) was defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. Partial Response (PR) was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters.

  Radiologic tumor assessments performed at baseline(within 28 days before start of study treatment)and every 8 weeks during Cycles 2 to 6,and then every 12 weeks thereafter until confirmed disease progression (PD)/death,a maximum of approximately 82 months

Secondary Outcomes (2)

• Duration of Response for Tazemetostat as a Single Agent or in Combination With Prednisolone (Phase 2 Only)

  Radiologic tumor assessments performed at baseline (within 28 days before start of study treatment) and every 8 weeks during Cycles 2 to 6, and then every 12 weeks thereafter until confirmed PD/death, a maximum of approximately 82 months

• Progression Free Survival for Tazemetostat as a Single Agent or in Combination With Prednisolone (Phase 2 Only)

  Radiologic tumor assessments performed at baseline (within 28 days before start of study treatment) and every 8 weeks during Cycles 2 to 6, and then every 12 weeks thereafter until confirmed PD/death, a maximum of approximately 82 months

Study Arms (4)

Phase 1

EXPERIMENTAL

Patients in the Phase 1 portion of the study.

Drug: Tazemetostat

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

EXPERIMENTAL

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

Drug: Tazemetostat

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

EXPERIMENTAL

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

Drug: Tazemetostat

Phase 2 Group 3: Tazemetostat in R/R DLBCL

EXPERIMENTAL

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

Drug: Tazemetostat; Drug: Prednisolone

Interventions

Tazemetostat DRUG

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

Also known as: EPZ-6438, E7438

Phase 2 Group 1: Tazemetostat in R/R FL with Mutant EZH2; Phase 2 Group 2: Tazemetostat in R/R FL with Wild-Type EZH2; Phase 2 Group 3: Tazemetostat in R/R DLBCL

Prednisolone DRUG

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

Also known as: Pediapred, Omnipred, Pred Mild, Pred Forte,, Orapred ODT,, Veripred 20,, Millipred DP

Phase 2 Group 3: Tazemetostat in R/R DLBCL

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Phase 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Phase 2: ECOG performance status of 0 to 2.
• Life expectancy of at least 3 months before starting tazemetostat.
• Voluntary agreement to provide written informed consent and willing to adhere to all protocol requirements
• 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.
• Adequate renal and liver function
• 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 .
• 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.
• 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
• 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.
• Phase 2, Groups 1-6 only: Subjects must satisfy all of the following criteria:
• 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

You may not qualify if:

• Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
• Subjects with leptomeningeal metastases or brain metastases or history of previously treated brain metastases.
• Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) and any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).
• Has a prior history of T-cell lymphoblastic lymphoma(T-LBL) or T-cell lymphoblastic leukemia (T-ALL).
• 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.
• Any unstable or unresolved prior treatment-related (i.e. chemotherapy, immunotherapy, radiotherapy) toxicities at time of enrollment.
• Major surgery within 4 weeks before the first dose of study drug. .
• 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.
• 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.
• Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat.
• Active infection requiring systemic therapy.
• Immunocompromised patients, including patients known to be infected with human immunodeficiency virus (HIV).
• Any other major illness that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in this study.
• Females who are pregnant or breastfeeding.
• 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.

Sponsors & Collaborators

• Epizyme, Inc.: lead

Study Sites (52)

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Birmingham, Alabama, 35294, United States

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Duarte, California, 91010, United States

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Santa Barbara, California, 93105, United States

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Aurora, Colorado, 80012, United States

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Washington D.C., District of Columbia, 20057, United States

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Ocala, Florida, 34471, United States

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Ann Arbor, Michigan, 48109, United States

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New York, New York, 10065, United States

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Houston, Texas, 77030, United States

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San Antonio, Texas, 78217, United States

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Fairfax, Virginia, 22031, United States

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Seattle, Washington, 98122, United States

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Clayton, Australia

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Geelong, Australia

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Melbourne, Australia

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Montreal, Canada

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Toronto, Canada

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Bordeaux, France

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Caen, France

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Créteil, France

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Lille, France

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Lyon, France

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Marseille, France

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Montpellier, France

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Nantes, France

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Paris, France

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Pierre-Bénite, France

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Rennes, France

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Rouen, France

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Villejuif, France

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Göttingen, Germany

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Münster, Germany

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Bologna, Italy

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Napoli, Italy

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Krakow, Poland

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Lublin, Poland

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Poznan, Poland

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Warsaw, Poland

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Taipei, Taiwan

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Chernivtsi, Ukraine

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Dnipro, Ukraine

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Ivano-Frankivsk, Ukraine

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Kharkiv, Ukraine

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Kyiv, Ukraine

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Mykolayiv, Ukraine

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Uzhhorod, Ukraine

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Zaporizhzhya, Ukraine

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Zhytomyr, Ukraine

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Glasgow, United Kingdom

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London, United Kingdom

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Manchester, United Kingdom

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Southampton, United Kingdom

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Related Publications (4)

• Alfaifi A, Bahashwan S, Alsaadi M, Ageel AH, Ahmed HH, Fatima K, Malhan H, Qadri I, Almehdar H. Advancements in B-Cell Non-Hodgkin's Lymphoma: From Signaling Pathways to Targeted Therapies. Adv Hematol. 2024 Nov 12;2024:5948170. doi: 10.1155/2024/5948170. eCollection 2024.

  PMID: 39563886 DERIVED

• 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.

  PMID: 37981564 DERIVED

• 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.

  PMID: 33035457 DERIVED

• 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.

  PMID: 29650362 DERIVED

MeSH Terms

Conditions

Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular

Interventions

tazemetostat; Prednisolone; prednisolone phosphate; Methylprednisolone; prednisolone acetate

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Medical Lead or Designee
• Organization: Epizyme, Inc.

clinicaltrials@epizyme.com

(855) 500-1011

Study Officials

• Ipsen Medical Director

  Ipsen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 21, 2013
• First Posted: July 12, 2013
• Study Start: June 13, 2013
• Primary Completion: August 24, 2021
• Study Completion: November 2, 2021
• Last Updated: March 26, 2024
• Results First Posted: August 4, 2023

Record last verified: 2024-03

Locations

US (12); IT (2); AU (3); PL (4); TW (1); UA (9); DE (2); GB (4); FR (13); CA (2)