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Study of Tazemetostat Together With Enzalutamide or With Abiraterone/Prednisone in Subjects With Castration Resistant Prostate Cancer That Has Spread Who Have Not Yet Received Chemotherapy

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ClinicalTrials.gov Identifier: NCT04179864
Recruitment Status : Recruiting
First Posted : November 27, 2019
Last Update Posted : August 4, 2020
Sponsor:
Information provided by (Responsible Party):
Epizyme, Inc.

Brief Summary:
This is a global, multi-center, open-label, randomized phase 1b, active-controlled safety and efficacy study of oral administration of tazemetostat in combination with enzalutamide or abiraterone/prednisone (phase 1b) versus enzalutamide or abiraterone/prednisone alone in asymptomatic or mildly symptomatic subjects with progressive, metastatic castration-resistant prostate cancer (mCRPC) who have progressed on either abiraterone acetate, enzalutamide, or apalutamide or who are second generation anti-androgen treatment naive, and who have not received chemotherapy for mCRPC. This study is designed to determine the recommended phase 2 doses (RP2D) of tazemetostat in combination with either enzalutamide or abiraterone/prednisone, based on safety, tolerability, pharmacokinetic, pharmacodynamic, and efficacy profiles.

Condition or disease Intervention/treatment Phase
Metastatic Prostate Cancer Drug: Tazemetostat Drug: Abiraterone/prednisone Drug: Enzalutamide Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Open-Label Study Evaluating Tazemetostat in Combination With Enzalutamide or Abiraterone/Prednisone in Chemotherapy Naive Subjects With Metastatic Castration-Resistant Prostate Cancer
Actual Study Start Date : September 26, 2019
Estimated Primary Completion Date : March 1, 2022
Estimated Study Completion Date : March 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Tazemetostat in Combination with Abiraterone/Prednisone
Abiraterone/prednisone will be administered on cycle 1 day 1 and Tazemetostat on day 2
Drug: Tazemetostat
Tazemetostat (EPZ-6438) is a selective small-molecule inhibitor of the histone-lysine methyltransferase EZH2 gene
Other Names:
  • EPZ-6438
  • E7438

Drug: Abiraterone/prednisone
1,000 mg (two 500 mg tablets or four 250 mg tablets) orally once daily in combination with prednisone 5 mg administered orally twice daily.
Other Name: Zytiga

Experimental: Tazemetostat in Combination with Enzalutamide
Enzalutamide will be administered on cycle 1 day 1 and Tazemetostat on day 2
Drug: Tazemetostat
Tazemetostat (EPZ-6438) is a selective small-molecule inhibitor of the histone-lysine methyltransferase EZH2 gene
Other Names:
  • EPZ-6438
  • E7438

Drug: Enzalutamide
enzalutamide 160 mg (four 40 mg capsules) orally once daily
Other Name: Xtandi




Primary Outcome Measures :
  1. Ph 1b: Determine the safety and tolerability of each of the combinations by reviewing dose limiting toxicities. [ Time Frame: The incidence and severity of treatment-emergent adverse events (AEs) qualifying as protocol-defined DLTs in Cycle 1 (28 days) ]
    Safety and tolerability of Tazemetostat in combination with enzalutamide or with abiraterone/prednisone

  2. Ph 1b: Select the recommended phase 2 doses (RP2D) of tazemetostat for each combination [ Time Frame: 1 cycle/28 days ]
    Based on pharmacokinetic (PK) and pharmacodynamic parameters as well as efficacy and the overall tolerability of each of the combinations


Secondary Outcome Measures :
  1. PSA ≥50% Response Rate [ Time Frame: Assessed every cycle for an average of one year. ]
    Confirmed prostate-specific antigen (PSA) responses will be defined as ≥50% reductions in PSA from baseline to lowest post baseline PSA result

  2. Time to PSA Progression [ Time Frame: Assessed every cycle for an average of one year. ]
    PSA progression is defined as a ≥25% increase and an absolute increase of ≥ 2 μg/L (2 ng/mL) above the nadir (or baseline value for subjects who did not have a decline in PSA value at week 17)

  3. Time to First Skeletal-Related Event (SRE) [ Time Frame: During screening and every 9 weeks if clinically indicated at baseline, average of one year. ]
    Time from randomization to first SRE will be assessed. An SRE is defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain

  4. Assess the rate of reducing circulating tumor cells (CTC) from a state of having a detectable number of CTCs to having an undetectable number of CTCs [ Time Frame: Assessed every cycle for duration of the study, an average of one year. ]
  5. Assess CTC 30% response rate [ Time Frame: Assessed every cycle for duration of the study, an average of one year. ]
    CTC 30% response is defined as a ≥30% reduction in CTC number from baseline



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age at the time of consent ≥ 18 years.
  2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (Appendix
  3. Life expectancy of > 3 months.
  4. Histologically or cytologically confirmed adenocarcinoma of the prostate. Small cell or neuroendocrine tumors of the prostate are also permitted.
  5. Progressive disease in the setting of medical or surgical castration (ie, castration- resistant prostate cancer [CRPC]) by PCWG3 criteria for study entry.

    • Evidence of disease progression by rising PSA or
    • Soft tissue progression per RECIST 1.1 or
    • Evidence of disease progression by observation of 2 new bone lesions since the initiation of last systemic therapy.
  6. Metastatic prostate cancer disease, documented by imaging.
  7. Must have undergone bilateral orchiectomy (surgical castration) or be willing to continue GnRH analog or antagonist (medical castration).
  8. Surgically or medically castrated, with serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening.
  9. Previously untreated with or progressed on a second generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide).
  10. No prior treatment with cytotoxic chemotherapy for mCRPC is permitted. Up to six prior cycles of docetaxel received for castration-sensitive disease is permitted for those subjects prior to receiving enzalutamide or abiraterone/prednisone.
  11. Subjects must refrain from donating sperm starting at the planned first dose of tazemetostat until 3 months following the last dose of tazemetostat, 3 weeks following the last dose of abiraterone/prednisone, and 3 months following the last dose of enzalutamide.
  12. Subjects with a female partner of childbearing potential as defined in the protocol must:

    1. Be vasectomized, or
    2. Remain abstinent or use a condom starting at the planned first dose of tazemetostat until 3 months following the last dose of tazemetostat, 3 weeks following the last dose of abiraterone/prednisone, and 3 months following the last dose of enzalutamide. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, sympto-thermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
  13. Female partners of subjects who are of child-fathering potential as defined in the protocol and who are, themselves, of childbearing potential as defined in the protocol must also adhere to one of the following:

    1. Placement of an intrauterine device or intrauterine system
    2. Established use of oral, injected, or implanted hormonal methods of contraception plus an additional barrier method
    3. Progesterone-only oral contraception, where inhibition of ovulation is not the primary mode of action.

Exclusion Criteria:

  1. Known symptomatic brain metastases.
  2. Untreated or impending spinal cord compression.
  3. Treatment with any of the following for prostate cancer within the indicated timeframe prior to day 1 of starting study treatment:

    • First generation: AR antagonists (eg, bicalutamide, nilutamide, flutamide) within 4 weeks.
    • 5-alpha-reductase inhibitors, ketoconazole, estrogens (including diethylstilbesterol), or progesterones within 2 weeks.
    • Chemotherapy (as permitted in inclusion criteria #10) within 3 weeks.
    • Prior radionuclide therapy within 4 weeks.
    • Another interventional product or standard agent in a clinical study within 28 days prior to the first planned dose of tazemetostat
  4. Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment.
  5. History of another invasive cancer within 3 years of randomization, with the exception of treated non-melanoma skin cancer, treated superficial bladder cancer, or fully treated cancers with a remote probability of recurrence in the opinion of both the Medical Monitor and Investigator.
  6. History of seizure or any condition that may predispose to seizure (eg, prior cortical stroke or significant brain trauma). History of sub clinical seizures manifested by loss of consciousness or transient ischemic attack within 12 months of randomization. However, subjects on medications with seizure lowering threshold will be admitted.
  7. Clinically significant cardiovascular disease including the following:

    • Myocardial infarction within 6 months before screening.
    • Uncontrolled angina within 3 months before screening.
    • Congestive heart failure (New York Heart Association class 3 or 4), or a history of congestive heart failure (New York Heart Association class 3 or 4), unless a screening echocardiogram or multigated acquisition scan performed within 3 months before randomization demonstrates a left ventricular ejection fraction

      • 50% (Appendix 2).
    • History of clinically significant ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes).
    • History of Mobitz 2 second-degree or third-degree heart block without a permanent pacemaker in place.
    • Hypotension as indicated by systolic blood pressure <86 millimeters of mercury (mmHg) at screening.
    • Bradycardia as indicated by a heart rate of <45 beats per minute on the screening ECG, and upon physical examination.
    • Uncontrolled hypertension as indicated by systolic blood pressure >170 mmHg or diastolic blood pressure >105 mmHg at screening.
  8. Gastrointestinal disorder affecting absorption (eg, gastrectomy, active peptic ulcer disease within 3 months before randomization).
  9. Major surgery within 4 weeks of randomization.
  10. For subjects taking abiraterone and prednisone, no evidence of hepatic impairment or classified as only Child-Pugh class A for hepatic impairment.
  11. Hypersensitivity reaction to the active pharmaceutical ingredient of tazemetostat, abiraterone, prednisone, or enzalutamide, or any of the other components of each individual agent under study.
  12. Is unwilling to exclude grapefruit juice, Seville oranges, and grapefruit from the diet and all foods that contain those fruits from time of enrollment to while on study.
  13. Is currently taking any prohibited medication(s) as described in Section 9.3.3.
  14. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2.
  15. Is immunocompromised (ie, has a congenital immunodeficiency). Subjects diagnosed with human immunodeficiency virus (HIV) are eligible to participate in the study if they meet the following criteria:

    • No history of AIDS-defining opportunistic infections, or have not had an opportunistic infection within the 12 months prior to enrollment.
    • No history of AIDS-defining cancers (eg, Kaposi's sarcoma, aggressive B-cell lymphoma, and invasive cervical cancer).
    • Subjects may take prophylactic antimicrobials; however, subjects taking specific antimicrobial drugs where there may be drug-drug interaction or overlapping toxicities with study drugs must be excluded from study participation.
    • Subjects should be on established anti-retroviral therapy for ≥4 weeks with an HIV viral load of < 400 copies/mL and/or CD4+ T-cell (CD4+) count ≥ 350 cells/uL prior to enrollment.
  16. Has a prior history of T-cell lymphoblastic lymphoma/ T-cell acute lymphoblastic leukemia.
  17. Is unable to take oral medications or has malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea or vomiting) that might impair the bioavailability of study treatments.
  18. Subjects with hepatitis B or hepatitis C are ineligible to participate in the study unless they meet the following criteria:

    • Do not have uncontrolled hepatitis B or C infection, are not on active immunosuppressive therapy, and do not have a history of autoimmune disease requiring ongoing systemic therapy.
    • Subjects taking therapy for hepatitis where there may be a drug-drug interaction or overlapping toxicities with study drugs must be excluded from study participation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04179864


Contacts
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Contact: Shefali Agarwal, MD 617-229-7575 clinicaltrials@epizyme.com

Locations
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United States, Arizona
Arizona Institute of Urology - Northwest Recruiting
Tucson, Arizona, United States, 85712
Contact: Kalpesh Patel, MD    916-734-3771      
Principal Investigator: Kalpesh Patel, MD         
United States, California
San Bernardino Urological Associates Recruiting
San Bernardino, California, United States, 92404
Contact: Franklin Chu, MD    909-882-2973      
Principal Investigator: Franklin Chu, MD         
United States, Colorado
The Urology Center Of Colorado Recruiting
Denver, Colorado, United States, 80211
Contact: Lawrence Karsh         
Principal Investigator: Lawrence Karsh, MD         
United States, Florida
Hematology Oncology Associates of the Treasure Coast Recruiting
Port Saint Lucie, Florida, United States, 34952
Contact: Nicholas Iannotti, MD    772-223-5982      
Principal Investigator: Nicholas Iannotti, MD         
United States, Kentucky
Norton Cancer Institute - Broadway Recruiting
Louisville, Kentucky, United States, 40202
Contact: Jaspreet Grewal         
Principal Investigator: Jaspreet Grewal         
United States, Nevada
Comprehensive Cancer Centers of Nevada - Central Valley Recruiting
Las Vegas, Nevada, United States, 89169
Contact: Nicholas Vogelzang, MD    702-953-3400      
Principal Investigator: Nicholas Vogelzang, MD         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Wassim Abida         
Principal Investigator: Wassim Abida, MD         
United States, Pennsylvania
University of Pittsburgh Medical Center - Hillman Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Leonard Appleman, MD    412-648-6538      
Principal Investigator: Leonard Appleman, MD         
United States, Texas
Mary Crowley Cancer Research Recruiting
Dallas, Texas, United States, 75230
Contact: Ashley Ross    972-566-3000      
Principal Investigator: Ashley Ross, MD         
Oncology Consultants - Texas Medical Center Recruiting
Houston, Texas, United States, 77030
Contact: Julio Peguero, MD    713-600-0968      
Principal Investigator: Julio Peguero, MD         
Urology San Antonio Recruiting
San Antonio, Texas, United States, 78229
Contact: Daniel Saltzstein, MD         
Principal Investigator: Daniel Saltzstein, MD         
Sponsors and Collaborators
Epizyme, Inc.
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Responsible Party: Epizyme, Inc.
ClinicalTrials.gov Identifier: NCT04179864    
Other Study ID Numbers: EZH-1101
First Posted: November 27, 2019    Key Record Dates
Last Update Posted: August 4, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Epizyme, Inc.:
metastatic castration resistant prostate cancer
tazemetostat
EPZ-6438
E7438
enzalutamide
abiraterone
Prednisone
Zytiga
Xtandi
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Prostatic Diseases
Prednisone
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents