Trial record 1 of 4 for:    7438
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Study of 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 August 2014 by Eisai Inc.
Sponsor:
Collaborator:
Epizyme, Inc.
Information provided by (Responsible Party):
Eisai Inc. ( Eisai Limited )
ClinicalTrials.gov Identifier:
NCT01897571
First received: June 21, 2013
Last updated: August 25, 2014
Last verified: August 2014
  Purpose

This is a multicenter, open-label, Phase 1/2 study that will be conducted in two parts. The Phase 1 part will comprise dose escalation and establishment of the maximum tolerated dose (MTD) when 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 E7438 will be evaluated as well as the drug-drug interaction (DDI) potential as evaluated by the effect of E7438 on the pharmacokinetics (PK) of midazolam, a CYP3A4 substrate.

Once the MTD has been confirmed and a Phase 2 dose has been recommended, the protocol will be amended with updated dosing instructions and safety instructions. The Phase 2 part will determine the safety and activity of E7438 in EZH2 mutation positive subjects with histologically confirmed diffuse large B cell lymphoma (DLBCL) or Grade 3 follicular lymphomas with relapsed or refractory disease following 1) high-dose therapy (HDT) and autologous stem cell transplant (ASCT), or 2) at least one combination chemotherapy containing rituximab and an anthracycline (unless anthracycline-based therapy is contraindicated), and are ineligible or unwilling to undergo HDT and ASCT.


Condition Intervention Phase
Diffuse Large B Cell Lymphoma
Drug: E7438
Phase 1
Phase 2

Study Type: Interventional
Study Design: 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 Eisai Inc.:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) [ 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 randomization until the date of first documented progression of disease, date of death from any cause, or a minimum of 6 cycles. Subjects were followed for an average of 5 years. ] [ 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 E7438 treatment withdrawal, or withdrawal of consent either for treatment or the entire study. Subjects who discontinue study treatment for reasons other than disease progression will be followed until disease progression, death, or initiation of another anticancer therapy.


Secondary Outcome Measures:
  • Food effect of a high fat meal on the bioavailability of E7438 [ Time Frame: Day -8 and -1, Cycle 1 (Day 1 and 15), Cycle 2 (Day 1) ] [ Designated as safety issue: No ]
    PK profile, after MTD is identified.

  • Effect of E7438 on exposure of midazolam, a CYP3A4 substrate [ Time Frame: Day -1, Cycle 1 (Day 15), Cycle 2 (Day 1) ] [ Designated as safety issue: No ]
    PK profile, after enrollment into the Food Effect Cohort is completed.

  • Progression-free survival (PFS) [ Time Frame: From date of randomization until the date of first documented progression of disease, date of death from any cause, or a minimum of 6 cycles. Subjects were followed for an average of 5 years. ] [ 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 E7438 treatment withdrawal, or withdrawal of consent either for treatment or the entire study. Subjects who discontinue study treatment for reasons other than disease progression will be followed until disease progression, death, or initiation of another anticancer therapy.

  • Disease Control Rate (DCR: complete response [CR] + partial response [PR] + stable disease[SD]) [ Time Frame: From date of randomization until the date of first documented progression of disease, date of death from any cause, or a minimum of 6 cycles. Subjects were followed for an average of 5 years. ] [ 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 E7438 treatment withdrawal, or withdrawal of consent either for treatment or the entire study. Subjects who discontinue study treatment for reasons other than disease progression will be followed until disease progression, death, or initiation of another anticancer therapy.

  • Clinical Benefit Rate (CBR: CR or PR or durable SD) [ Time Frame: From date of randomization until the date of first documented progression of disease, date of death from any cause, or a minimum of 6 cycles. Subjects were followed for an average of 5 years. ] [ 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 E7438 treatment withdrawal, or withdrawal of consent either for treatment or the entire study. Subjects who discontinue study treatment for reasons other than disease progression will be followed until disease progression, death, or initiation of another anticancer therapy.

  • Pharmacokinetics (PK) profile of E7438 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 E7438 will be tabulated and summarized by dose level, day and time. E7438 PK parameters will be derived from plasma concentrations by noncompartmental analysis using actual times.


Estimated Enrollment: 154
Study Start Date: June 2013
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: E7438
In Phase 1, subjects will be administered increasing doses of E7438 orally, starting at 100 mg BID (200 mg total daily dose), until MTD is reached. Once MTD is established, the effect of food on the bioavailability of E7438 will be evaluated beginning with a single dose on Days -8 and -1, then BID on a continuous basis for a DDI potential as evaluated by the effect of E7438 on the pharmacokinetic of midazolam, a CYP3A4 substrate. Phase 2 will be conducted in two stages and subjects will be randomized in a 2:1 manner to receive either E7439 or standard of care treatment. Subjects with confirmation of disease progression by the investigator and sponsor while receiving standard of care therapy will be eligible to receive optional E7438 treatment and enter into the optional E7438 Crossover Treatment Period of the Extension Phase (Stage 2b).
Drug: 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 #17, which is applicable only to Phase 2 Stage 2b subjects).
  2. Life expectancy greater than or equal to 3 months after starting E7438.
  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 serum creatinine less than 1.5 x ULN (or use SI units or 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 1500/mm3 (greater than or equal to 1.5 x 10^3/micro L)
    2. Platelets greater than or equal to 100,000/mm3 (greater than or equal to 100 x 10^9/L)
    3. Hemoglobin greater than or equal to 9.0 g/dL (see Inclusion Criterion #16)
  6. Adequate liver function:

    1. 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. Males or females aged greater than or equal to 18 years at the time of informed consent.
  9. 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 (i.e., 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, from the last menstrual period prior to randomization, during Treatment Cycles, and for 30 days after the 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 (revised per Amendment 01).

  10. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they and their female partner must meet the criteria above (i.e., 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) (revised per Amendment 01).
  11. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.

    Phase 1 only:

  12. Histologically and/or cytologically confirmed advanced or metastatic solid tumor or B cell lymphomas that has progressed after treatment with approved therapies or for which there are no standard therapies available.

    Phase 2 (EZH2-mutation positive) B cell lymphomas only:

  13. Subjects must satisfy all of the following criteria:

    1. Have histologically confirmed DLBCL or Grade 3 follicular lymphomas with relapsed or refractory disease following: 1) HDT and ASCT or 2) at least one combination chemotherapy containing rituximab and an anthracycline (unless anthracycline-based therapy contraindicated), and are ineligible or unwilling to undergo HDT and ASCT
    2. Must harbor a Y641 mutation in EZH2. (At the time of protocol amendment, before initiation of Phase 2, the specific methodology for detection of EZH2 mutation will be included in the amended protocol)
    3. Have measurable disease as defined by International Working Group-Non-Hodgkin's Lymphoma (IWG-NHL [Cheson, 2007])

Exclusion Criteria

All Subjects:

  1. Prior exposure to E7438 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. However, subjects may receive prednisone (at doses up to 20 mg daily) until 1 week before start of study drug.
  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 E7438.
  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. Active infection requiring systemic therapy.
  12. Known hypersensitivity to any component of E7438.
  13. Achlorhydria or use of antacids, proton-pump inhibitors, or other drugs known to raise gastric pH within 2 weeks before study drug administration.
  14. Immunocompromised patients, including patients known to be infected with human immunodeficiency virus (HIV).
  15. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency (added per Amendment 01).
  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.

    Phase 2 only:

  18. 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: Eisai Ltd EUMedInfo@eisai.net

Locations
France
Recruiting
Bordeaux, France
Recruiting
Villejuif Cedex, France
Sponsors and Collaborators
Eisai Limited
Epizyme, Inc.
  More Information

No publications provided

Responsible Party: Eisai Inc. ( Eisai Limited )
ClinicalTrials.gov Identifier: NCT01897571     History of Changes
Other Study ID Numbers: E7438-G000-101
Study First Received: June 21, 2013
Last Updated: August 25, 2014
Health Authority: France: L'Agence nationale de securite du medicament et des produits de sante

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

ClinicalTrials.gov processed this record on October 02, 2014