Trial record 1 of 6 for:    7438
Previous Study | Return to List | Next Study

Study of EPZ-6438 Formerly Known as E7438 (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Advanced Solid Tumors or With B-cell Lymphomas

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2015 by Epizyme, Inc.
Sponsor:
Information provided by (Responsible Party):
Epizyme, Inc.
ClinicalTrials.gov Identifier:
NCT01897571
First received: June 21, 2013
Last updated: June 15, 2015
Last verified: June 2015
  Purpose

This is a multicenter, open-label, Phase 1/2 study that is being conducted in two parts. The Phase 1 portion comprises dose escalation and establishment of the recommended Phase 2 dose (RP2D) when EPZ-6438 (E7438) is given BID (twice daily) orally on a continuous basis. Additionally, in separate cohorts in Phase 1, the effect of food on the bioavailability of EPZ-6438 as well as the drug-drug interaction (DDI) potential of EPZ-6438 are being evaluated. When maximum tolerated dose (MTD) has been identified and the RP2D confirmed, the Phase 2 portion will enroll subjects that have relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphomas (FL) that have either mutant or wild-type EZH2.


Condition Intervention Phase
B-cell Lymphomas (Phase 1)
Advanced Solid Tumors (Phase 1)
Diffuse Large B-cell Lymphoma (Phase 2)
Follicular Lymphoma (Phase 2)
Drug: EPZ-6438
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Multicenter, Phase 1/2 Study of E7438 (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Advanced Solid Tumors or With B-cell Lymphomas

Resource links provided by NLM:


Further study details as provided by Epizyme, Inc.:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) (Phase 1 only) [ Time Frame: 28 day cycle of therapy ] [ Designated as safety issue: No ]
    The MTD will be determined based on the incidence of Dose-Limiting Toxicities (DLT) in Cycle 1, although toxicities occurring during subsequent cycles will also be reviewed. If serious toxicities are observed at this dose level in later cycles, a reduction of the MTD may be considered.

  • Objective response rate (ORR; complete response + partial response [CR + PR]) [ Time Frame: From date of enrollment until the date of first documented progression of disease or date of death from any cause. ] [ Designated as safety issue: No ]
    Every 8 weeks or sooner, if clinically indicated, until documentation of disease progression, development of unacceptable toxicity that leads to EPZ-6438 treatment withdrawal, or withdrawal of consent either for treatment or the entire study.


Secondary Outcome Measures:
  • Duration of Response (DOR) [ Time Frame: From date of enrollment until the date of first documented progression of disease, or date of death from any cause. ] [ Designated as safety issue: No ]
    Every 8 weeks or sooner, if clinically indicated, until documentation of disease progression, development of unacceptable toxicity that leads to EPZ-6438 treatment withdrawal, or withdrawal of consent either for treatment or the entire study.

  • Progression-free survival (PFS) [ Time Frame: From date of enrollment until the date of first documented progression of disease or date of death from any cause. ] [ Designated as safety issue: No ]
    Every 8 weeks or sooner, if clinically indicated, until documentation of disease progression, development of unacceptable toxicity that leads to EPZ-6438 treatment withdrawal, or withdrawal of consent either for treatment or the entire study.

  • Pharmacokinetics (PK) profile of EPZ-6438 characterizing the absorption, distribution, metabolism, and elimination properties of the drug. [ Time Frame: Cycle 1 (Day 1 and 15), Cycle 2 (Day 1) ] [ Designated as safety issue: No ]
    Plasma and urine concentrations of EPZ-6438 will be tabulated and summarized by dose level, day and time.

  • Food effect of a high fat meal on the bioavailability of EPZ-6438 [ Time Frame: Day -8 and -1 ] [ Designated as safety issue: No ]
    PK profile

  • Effect of EPZ-6438 on exposure of a CYP3A4 substrate [ Time Frame: Day -1, all cycles (Day 1 and Day 15) ] [ Designated as safety issue: No ]
    PK profile

  • Clinical Benefit Rate (CBR: CR or PR or durable SD) [ Time Frame: From date of enrollment until the date of first documented progression of disease or date of death from any cause. ] [ Designated as safety issue: No ]
    Durable SD is considered greater than or equal to 23 weeks. Every 8 weeks or sooner, if clinically indicated, until documentation of disease progression, development of unacceptable toxicity that leads to EPZ-6438 treatment withdrawal, or withdrawal of consent either for treatment or the entire study.


Estimated Enrollment: 225
Study Start Date: June 2013
Estimated Study Completion Date: September 2017
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: EPZ-6438 (formerly known as E7438): Phase 1
The Phase 1 portion comprises dose escalation and establishment of the recommended Phase 2 dose (RP2D) when EPZ-6438 (E7438) is given BID (twice daily) orally on a continuous basis. Additionally, in separate cohorts in Phase 1, the effect of food on the bioavailability of EPZ-6438 as well as the drug-drug interaction (DDI) potential of EPZ-6438 are being evaluated
Drug: EPZ-6438
Other Name: E7438
Experimental: EPZ-6438 (formerly known as E7438): Phase 2
In Phase 2, subjects will be DLBCL or FL for the determination of efficacy and safety or EPZ-6438 in 5 independent cohorts determined by histology, cell of origin and EZH2 mutation status.
Drug: EPZ-6438
Other Name: E7438

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

All Subjects:

  1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (except as acceptable for Inclusion Criterion #15, which is applicable only to Phase 2 subjects).
  2. Life expectancy greater than or equal to 3 months before starting EPZ-6438.
  3. Subjects with Hepatitis B or C are eligible on the condition that subjects have adequate liver function as defined by Inclusion Criterion #6.
  4. Adequate renal function defined as calculated creatinine clearance greater than or equal to 50 mL/min per the Cockcroft and Gault formula.
  5. Adequate bone marrow function:

    1. Absolute neutrophil count (ANC) greater than or equal to 750/mm3
    2. Platelets greater than or equal to 75,000/mm3
    3. Hemoglobin greater than or equal to 9.0 g/dL
  6. Adequate liver function:

    1. Total bilirubin less than or equal to 1.5 x the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome
    2. Alkaline phosphatase (in the absence of bone disease), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 x ULN (less than or equal to 5 x ULN if subject has liver metastases)
  7. Left ventricular ejection fraction (LVEF) greater than 50% on echocardiography or multiple gate acquisition (MUGA) scan.
  8. Follicular lymphoma subjects who have received prior radioisotope therapy must wait at least 6 weeks before screening for eligibility.
  9. Males or females aged greater than or equal to 18 years at the time of informed consent.
  10. Females must not be lactating or pregnant at screening or baseline (as documented by a negative beta-human chorionic gonadotropin [beta-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of beta-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 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 30 days after the last final dose of study treatment, and have a male partner who uses a condom. Highly effective contraception includes:

    1. Double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide.
    2. Placement of an intrauterine device.
    3. Established hormonal contraceptive methods: oral, injectable, or implant. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks prior to dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation.

    Female subjects exempt from this requirement are subjects who practice total abstinence or have a male partner who is vasectomized with confirmed azoospermia. If currently abstinent, the subject must agree to use a double barrier method as described above if they become sexually active during the Treatment Cycles, and for 30 days after study drug discontinuation.

  11. Male subjects must have had a successful vasectomy (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 30 days after study drug discontinuation).
  12. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.

    Phase 1 only:

  13. 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 only:

  14. 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 (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, R-ICE or 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 have histologically confirmed FL. Subjects may have relapsed/refractory disease following at least 2 standard prior treatment regimens, including at least 1 anti-CD20-based regimen, as well as alkylating agents (eg, cyclophosphamide or bendamustine), and have no curative option with other available therapies OR have a contra-indication to their use. Subjects with prior ASCT may be included.

    2. Have sufficient tumor tissue available for central testing of EZH2 mutation status and confirmation of cell of origin status, as appropriate.
    3. Have measurable disease as defined by International Working Group-Non-Hodgkin's Lymphoma (IWG-NHL [Cheson, 2007]).
  15. ECOG performance status of 0 to 2.

Exclusion Criteria

All Subjects:

  1. Prior exposure to EPZ-6438 or other inhibitor(s) of EZH2 HMT.
  2. Subjects with leptomeningeal metastases or brain metastases or history of previously treated brain metastases.
  3. Subjects taking medications that are known potent CYP3A4 inducers/inhibitors or substrates with narrow therapeutic indices or St. John's Wort .
  4. Subjects unwilling to exclude grapefruit juice and grapefruit from their diet.
  5. Subjects taking medications that are CYP2C8, CYP2C9, and CYP2C19 substrates.
  6. Subjects who have received any anticancer treatment within 3 weeks or any investigational agent within 30 days before the first dose of study drug or who have not recovered from any acute toxicity greater than Grade 0 or 1 related to previous anticancer treatment excluding hematological toxicity as outlined in Inclusion Criteria #5. However, subjects may receive prednisone (at doses up to 10 mg daily) or equivalent corticosteroid prior to and while on study.
  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 EPZ-6438.
  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 arrhythmia requiring medical treatment (including oral anticoagulation).
  10. Prolongation of corrected QT (QTc) interval to greater than 480 msec when electrolytes balance is normal.
  11. Symptomatic venous thrombosis within the last 3 months before starting EPZ-6438; subjects with a deep vein thrombosis (DVT) who are on anticoagulation therapy with a low molecular weight heparin (LMWH) may be included.
  12. Active infection requiring systemic therapy.
  13. Known hypersensitivity to any component of EPZ-6438.
  14. Achlorhydria or use of antacids, proton-pump inhibitors, or other drugs known to raise gastric pH within 2 weeks before study drug administration.
  15. Immunocompromised patients, including patients known to be infected with human immunodeficiency virus (HIV).
  16. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency.
  17. Any other major illness that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in this study.
  18. Females who are pregnant or breastfeeding.

    Phase 2 only:

  19. Subjects with active noncutaneous malignancies other than B-cell lymphomas.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01897571

Contacts
Contact: Blythe Thomson, MD 855-500-1011 clintrials@epizyme.com
Contact: Peter Ho, MD, PhD 855-500-1011 clintrials@epizyme.com

Locations
Australia
Recruiting
Melbourne, Australia
France
Recruiting
Bordeaux, France, Phase 1 only
Recruiting
Montpellier, France
Recruiting
Villejuif Cedex, France
Sponsors and Collaborators
Epizyme, Inc.
  More Information

No publications provided

Responsible Party: Epizyme, Inc.
ClinicalTrials.gov Identifier: NCT01897571     History of Changes
Other Study ID Numbers: E7438-G000-101
Study First Received: June 21, 2013
Last Updated: June 15, 2015
Health Authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Australia: Department of Health Therapeutic Goods Administration

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Follicular
Lymphoma, Large B-Cell, Diffuse
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on July 27, 2015