Clinical trial NCT01897571: Study of Tazemetostat as Single Agent in Solid Tumors or B-cell Lymphomas and in Combination With Prednisolone in DLBCL
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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)
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
First posted: 2013-07-12
Enrollment: 400
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Recommended Phase 2 Dose (RP2D) of Tazemetostat as a Single-Agent and in Combination With Prednisolone (Phase 1 Only)
timeFrame: The first 28-day cycle of therapy
measure: Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR]) (Phase 2)
timeFrame: 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:
measure: Duration of Response for Tazemetostat as a Single Agent or in Combination With Prednisolone (Phase 2 Only)
timeFrame: 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
measure: Progression Free Survival for Tazemetostat as a Single Agent or in Combination With Prednisolone (Phase 2 Only)
timeFrame: 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
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Duarte
country: United States
state: California
city: Santa Barbara
country: United States
state: California
city: Aurora
country: United States
state: Colorado
city: Washington
country: United States
state: District of Columbia
city: Ocala
country: United States
state: Florida
city: Ann Arbor
country: United States
state: Michigan
city: New York
country: United States
state: New York
city: Houston
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Fairfax
country: United States
state: Virginia
city: Seattle
country: United States
state: Washington
city: Clayton
country: Australia
city: Geelong
country: Australia
city: Melbourne
country: Australia
city: Montreal
country: Canada
city: Toronto
country: Canada
city: Bordeaux
country: France
city: Caen
country: France
city: Creteil
country: France
city: Lille
country: France
city: Lyon
country: France
city: Marseille
country: France
city: Montpellier
country: France
city: Nantes
country: France
city: Paris
country: France
city: Pierre Benite
country: France
city: Rennes
country: France
city: Rouen
country: France
city: Villejuif Cedex
country: France
city: Gottingen
country: Germany
city: Muenster
country: Germany
city: Bologna
country: Italy
city: Napoli
country: Italy
city: Krakow
country: Poland
city: Lublin
country: Poland
city: Poznan
country: Poland
city: Warsaw
country: Poland
city: Taipei City
country: Taiwan
city: Chernivtsi
country: Ukraine
city: Dnipro
country: Ukraine
city: Ivano-Frankivs'k
country: Ukraine
city: Kharkiv
country: Ukraine
city: Kyiv
country: Ukraine
city: Mykolayiv
country: Ukraine
city: Uzhgorod
country: Ukraine
city: Zaporizhzhya
country: Ukraine
city: Zhytomyr
country: Ukraine
city: Glasgow
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Southampton
country: United Kingdom
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.