Clinical Trials /

Tazemetostat in Treating Patients With Metastatic or Unresectable Solid Tumors or B-Cell Lymphomas With Liver Dysfunction

NCT03217253

Description:

This phase I trial studies the best dose and side effects of tazemetostat in treating patients with solid tumors or B-cell lymphomas with liver dysfunction that have spread to other places in the body or cannot be removed by surgery. Tazemetostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Hepatocellular Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Suspended

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Tazemetostat in Treating Patients With Metastatic or Unresectable Solid Tumors or B-Cell Lymphomas With Liver Dysfunction
  • Official Title: A Phase I Study of Single Agent Tazemetostat in Subjects With Advanced Solid Tumors and B-Cell Lymphomas With Hepatic Dysfunction

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01231
  • SECONDARY ID: NCI-2017-01231
  • SECONDARY ID: PJC-025
  • SECONDARY ID: 10130
  • SECONDARY ID: 10130
  • SECONDARY ID: UM1CA186644
  • NCT ID: NCT03217253

Conditions

  • Ann Arbor Stage III B-Cell Non-Hodgkin Lymphoma
  • Ann Arbor Stage IV B-Cell Non-Hodgkin Lymphoma
  • Liver Dysfunction
  • Metastatic Malignant Solid Neoplasm
  • Stage III Hepatocellular Carcinoma AJCC v7
  • Stage IIIA Hepatocellular Carcinoma AJCC v7
  • Stage IIIB Hepatocellular Carcinoma AJCC v7
  • Stage IIIC Hepatocellular Carcinoma AJCC v7
  • Stage IV Hepatocellular Carcinoma AJCC v7
  • Stage IVA Hepatocellular Carcinoma AJCC v7
  • Stage IVB Hepatocellular Carcinoma AJCC v7
  • Unresectable Solid Neoplasm

Interventions

DrugSynonymsArms
TazemetostatE7438, EPZ-6438, EPZ6438Treatment (tazemetostat)

Purpose

This phase I trial studies the best dose and side effects of tazemetostat in treating patients with solid tumors or B-cell lymphomas with liver dysfunction that have spread to other places in the body or cannot be removed by surgery. Tazemetostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine safety, tolerability and recommended phase 2 dose (RP2D) of tazemetostat in
      patients with varying degrees of hepatic dysfunction.

      SECONDARY OBJECTIVES:

      I. To assess the pharmacokinetics (PK) profiles of tazemetostat in patients with varying
      degrees of hepatic dysfunction.

      II. To observe preliminary antitumor activity of tazemetostat in this population, especially
      in tumors with aberrations in EZH2 or SWI/SNF complex pathways.

      OUTLINE: This is a dose escalation study.

      Patients receive tazemetostat orally (PO) twice daily (BID) on days 1-28. Courses repeat
      every 28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 4 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (tazemetostat)ExperimentalPatients receive tazemetostat PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Tazemetostat

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically and/or cytologically confirmed solid tumors or B
             cell lymphoma that are metastatic or unresectable and for which standard treatment
             options do not exist; patients with hepatocellular carcinoma are eligible without
             pathological diagnosis if diagnosed on the basis of blood work and imaging

          -  Patients with evaluable disease will be eligible

          -  All patients must have completed any prior chemotherapy, targeted therapy and major
             surgery, >= 28 days before study entry; for daily or weekly chemotherapy without the
             potential for delayed toxicity, a washout period of 14 days may be acceptable, and
             questions related to this can be discussed with study principal investigator

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Life expectancy of greater than 3 months

          -  Able to swallow and retain orally-administered medication and does not have any
             clinically significant gastrointestinal abnormalities that may alter absorption such
             as malabsorption syndrome or major resection of the stomach or bowels

          -  All prior treatment-related toxicities must be Common Terminology Criteria for Adverse
             Events (CTCAE) version 5.0 grade =< 1 (except alopecia) at the time of enrollment

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Hemoglobin >= 90 g/L (9.0 g/dL)

          -  Creatinine within normal institutional limits OR calculated creatinine clearance >= 60
             mL/min/1.73 m^2 (Cockcroft-Gault formula) for patients with creatinine levels above
             institutional normal

          -  Patients with abnormal hepatic function will be eligible and will be grouped according
             to criteria; patients with active hemolysis should be excluded; no distinction should
             be made between liver dysfunction due to metastases and liver dysfunction due to other
             causes; this data will be captured in the case report form (CRF); registration
             laboratory investigations will be used to assign a patient to a hepatic function
             group; hepatic function tests should be repeated within 24 hours prior to starting
             initial therapy and may result in patients' group assignment being altered if
             different to registration test results

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use contraceptive methods that result in a failure rate
             of < 1% per year during the treatment period and for 30 days after tazemetostat
             discontinuation

               -  A woman is considered to be of childbearing potential if she is postmenarchal,
                  has not reached a postmenopausal state (>= 12 continuous months of amenorrhea
                  with no identified cause other than menopause), and has not undergone surgical
                  sterilization (removal of ovaries and/or uterus)

               -  Examples of contraceptive methods with a failure rate of < 1% per year include
                  bilateral tubal ligation, male sterilization, established, proper use of hormonal
                  contraceptives that inhibit ovulation, hormone-releasing intrauterine devices,
                  and copper intrauterine devices

               -  Female subjects who use hormonal contraceptives should use an additional barrier
                  method of birth control while on study treatment and for 30 days after
                  discontinuation of study treatment

               -  The reliability of sexual abstinence should be evaluated in relation to the
                  duration of the clinical study and the preferred and usual lifestyle of the
                  patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or
                  postovulation methods) and withdrawal are not acceptable methods of contraception

          -  For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
             contraceptive measures and agreement to refrain from donating sperm, as defined below:

               -  With female partners of childbearing potential or pregnant female partners, men
                  must remain abstinent or use a condom during the treatment period and for at
                  least 4 months after the last dose of study drug; men must refrain from donating
                  sperm during this same period; in addition, female partners of male subjects
                  should adhere to the following:

                    -  Intrauterine device (IUD)(must provide medical documentation of IUD)

                    -  Hormonal contraceptive (partner must be on a stable dose of the same
                       hormonal contraceptive product for at least 4 weeks before receiving study
                       drug) AND a condom (hormonal contraceptives must be supplemented with
                       condoms)

               -  The reliability of sexual abstinence should be evaluated in relation to the
                  duration of the clinical study and the preferred and usual lifestyle of the
                  patient; periodic abstinence and withdrawal are not acceptable methods of
                  contraception

          -  Females of childbearing potential must have a negative serum pregnancy test at
             screening

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Has a QT interval corrected by Fridericia's formula (QTcF) =< 450 msec

          -  Whenever available, archival tissue (block or minimum 10 slides) is requested for
             molecular characterization, e.g. detection of somatic mutations and/or candidate
             biomarkers of response; this is not mandatory and lack of available tissue would not
             be an exclusion criteria

        Exclusion Criteria:

          -  Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression
             as documented by computed tomography (CT) or magnetic resonance imaging (MRI) scan,
             analysis of cerebrospinal fluid or neurological exam; patients with primary
             glioblastoma multiforme are excluded

          -  Radiation therapy in the last 14 days; palliative radiation to a localized area
             without residual toxicity requires a washout of greater than 7 days

          -  Clinically significant bleeding diathesis or coagulopathy, including known platelet
             function disorders; patients on anticoagulation with low molecular weight heparin are
             allowed

          -  Known hypersensitivity to any of the components of tazemetostat

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to tazemetostat

          -  Concurrent investigational agent or anticancer therapy

               -  Note: megestrol [Megace] if used as an appetite stimulant is allowed

               -  Concurrent treatment with bisphosphonates is permitted; however, treatment must
                  be initiated prior to the first dose of study therapy; prophylactic use of
                  bisphosphonates in patients without bone disease is not permitted, except for the
                  treatment of osteoporosis

               -  The concurrent use of all herbal supplements is prohibited during the study
                  (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo
                  biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng)

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, clinically significant bleeding diathesis or coagulopathy, including known
             platelet function disorders, symptomatic congestive heart failure, unstable angina
             pectoris, clinically significant cardiac arrhythmias, or psychiatric illness/social
             situations that would limit compliance with study requirements

          -  Active hepatitis B virus (HBV; hepatitis B surface antigen [HepBsAG] positive [+ve]
             and IgM anti-hepatitis B virus core antibody [HBc]), or hepatitis C virus (HCV;
             detectable HCV ribonucleic acid [RNA]) infection; patients with chronic or cleared HBV
             and HCV infection are eligible

          -  Patients with known human immunodeficiency virus (HIV) infection are eligible if being
             treated with non-interacting antiretroviral (ARV) agents or be willing to stop ARV for
             the protocol

          -  Treatment with strong inhibitors or inducers of CYP3A are prohibited from 14 days
             prior to the first dose of tazemetostat to the end of the study

          -  Active gastrointestinal tract disease with malabsorption syndrome or unable to swallow
             oral medications

          -  Any condition or medical problem in addition to the underlying malignancy and organ
             dysfunction that the investigator feels would pose unacceptable risk

          -  Has thrombocytopenia, neutropenia, or anemia of grade >= 3 (per CTCAE 5.0 criteria) or
             any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)

          -  Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and
             multiple primary neoplasms (MPN) (e.g. JAK2 V617F) observed in cytogenetic testing and
             DNA sequencing

          -  Has a prior history of T-acute lymphoblastic lymphoma (T-LBL)/T-acute lymphoblastic
             leukemia (ALL)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events of tazemetostat in patients with varying degrees of hepatic dysfunction assessed using Common Terminology Criteria for Adverse Events version 5.0
Time Frame:Up to 2 years
Safety Issue:
Description:Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to study treatment.

Secondary Outcome Measures

Measure:Pharmacokinetic (PK) profiles of tazemetostat in patients with varying degrees of hepatic dysfunction
Time Frame:Up to course 4 day 1 (day 85)
Safety Issue:
Description:Plasma concentrations will be measured by Q2 Solutions using a validated Liquid chromatography (LC)/mass spectrometry (MS)/MS assay. Molecular and clinical predictors of clinical outcomes will be investigated using logistic regression and Cox proportional hazards models. Potential predictors include clinical predictors and molecular correlates. Descriptive statistics and plotting of data will also be used to better understand potential relationships. Given the small sample size, and exploratory nature of these endpoints, all pharmacodynamic analyses conducted will be considered exploratory. All analyses will be considered exploratory and inference will be performed with appropriate caution.
Measure:Antitumor activity of tazemetostat
Time Frame:Up to 2 years
Safety Issue:
Description:Molecular and clinical predictors of clinical outcomes will be investigated using logistic regression and Cox proportional hazards models. Potential predictors include clinical predictors and molecular correlates. Descriptive statistics and plotting of data will also be used to better understand potential relationships. All analyses will be considered exploratory and inference will be performed with appropriate caution.
Measure:Antitumor activity of tazemetostat in population with tumors with aberrations in EZH2 or SWI/SNF complex pathways
Time Frame:Up to 2 years
Safety Issue:
Description:Molecular and clinical predictors of clinical outcomes will be investigated using logistic regression and Cox proportional hazards models. Potential predictors include clinical predictors and molecular correlates. Descriptive statistics and plotting of data will also be used to better understand potential relationships. All analyses will be considered exploratory and inference will be performed with appropriate caution.
Measure:Objective confirmed response
Time Frame:Up to 2 years
Safety Issue:
Description:Response will be assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1
Measure:Duration of response
Time Frame:Up to 2 years
Safety Issue:
Description:Response will be assessed using the RECIST criteria 1.1.
Measure:Best response
Time Frame:Up to 2 years
Safety Issue:
Description:Response will be assessed using the RECIST criteria 1.1.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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