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A Study of Tazemetostat With Enzalutamide or Abiraterone/Prednisone in Participants With Advanced Prostate Cancer (CELLO-1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04179864
Recruitment Status : Active, not recruiting
First Posted : November 27, 2019
Last Update Posted : May 18, 2023
Sponsor:
Information provided by (Responsible Party):
Ipsen ( Epizyme, Inc. )

Brief Summary:

This is a global, multi-center, open-label, randomized phase 1b/2, 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 Metastatic Castration-resistant Prostate Cancer Drug: Tazemetostat Drug: Abiraterone/prednisone Drug: Enzalutamide Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 104 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: CELLO-1: 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 : November 18, 2019
Estimated Primary Completion Date : February 2024
Estimated Study Completion Date : March 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase 1b: Tazemetostat in Combination with Abiraterone/Prednisone
In Phase 1b, abiraterone/prednisone will be administered in combination with tazemetostat in cycle 1 (28 days) to establish the recommended dose of tazemetostat in this combination; participants may continue treatment in additional 28-day cycles, as tolerated, until progression or unacceptable toxicity
Drug: Tazemetostat
Tazemetostat (EPZ-6438) is a selective small-molecule inhibitor of the histone-lysine methyltransferase EZH2 gene
Other Names:
  • EPZ-6438
  • E7438
  • IPN60200

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: Phase 1b: Tazemetostat in Combination with Enzalutamide
In Phase 1b, enzalutamide will be administered in combination with tazemetostat in cycle 1 (28 days) to establish the recommended dose of tazemetostat in this combination; participants may continue treatment in additional 28-day cycles, as tolerated, until progression or unacceptable toxicity
Drug: Tazemetostat
Tazemetostat (EPZ-6438) is a selective small-molecule inhibitor of the histone-lysine methyltransferase EZH2 gene
Other Names:
  • EPZ-6438
  • E7438
  • IPN60200

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

Experimental: Phase 2: Tazemetostat in Combination with Enzalutamide

Participants will receive the newly established recommended phase 2 dose, orally twice daily when given in combination with enzalutamide) as determined in phase 1b part of the study) or enzalutamide alone.

All participants will receive treatment in 28-day cycles.

Drug: Tazemetostat
Tazemetostat (EPZ-6438) is a selective small-molecule inhibitor of the histone-lysine methyltransferase EZH2 gene
Other Names:
  • EPZ-6438
  • E7438
  • IPN60200

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

Active Comparator: Phase 2: Enzalutamide only
In Phase 2, Enzalutamide will be administered on cycle 1 day 1
Drug: Enzalutamide
enzalutamide 160 mg (four 40 mg capsules) orally once daily
Other Name: Xtandi




Primary Outcome Measures :
  1. Ph 1b: Percentage of Participants with Treatment Emergent Adverse Event (TEAEs) [ Time Frame: At end of Cycle 1 (each cycle is 28 days) ]
    An Adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.

  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 (tazemetost with enzalutamide or tazemetostat with abiraterone/prednisone)

  3. Ph 2: Change in radiographic progression free survival (rPFS) [ Time Frame: Day 1 of Cycles 3, 5, 7, 10, and 13, and every 12 weeks after Cycle 13 for 1 year (each cycle is 28 days) ]
    Assessed by change radiographic progression free survival (rPFS) according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria for progression in bone or in soft tissue


Secondary Outcome Measures :
  1. Phase 1b and 2: Percentage of participants with a ≥50% decline of Prostate Specific-Antigen (PSA50). [ Time Frame: From baseline at any time on study, an average of one year ]
    For participants with a baseline PSA ≥2.0 ug/L (ng/mL) per PCWG3 criteria

  2. Phase 1b and 2: Objective response rate (ORR) and best overall response (BOR) in soft tissue [ Time Frame: At 6 months on treatment. ]
    According to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) guidelines.

  3. Phase 1b and 2: Disease control rate (DCR) [ Time Frame: At 6 months on treatment. ]
    Assessed by radiographic progression per PCWG3 criteria, with no unequivocal clinical progression or death

  4. Phase 1b and 2: Time to first skeletal-related event (SRE) [ Time Frame: During screening and every 9 weeks if clinically indicated at baseline, average of one year ]
  5. Phase 1b and 2: Time to initiation of the next systemic treatment for prostate cancer (TTNT) [ Time Frame: From baseline to end of study, an average of one year ]
    TTNT is defined as the time from the date of randomization to date of first documented administration of the next systemic treatment for prostate cancer.

  6. Phase 1b and 2: Time to PSA progression (TTPP) [ Time Frame: From baseline to the day of PSA progression, an average one one year. ]
    Defined as the duration per PCWG3 criteria in months.

  7. Phase 1b and 2: Reduction in circulating tumor cells (CTC) [ Time Frame: From screening to 30 days after last dose ]
    From a state of having a detectable number of CTCs to having an undetectable number of CTCs

  8. Phase 1b and 2: CTC response rate [ Time Frame: From baseline to end of study, an average of one year ]
    Defined as the percentage of participants with a ≥30% reduction in CTC number

  9. Phase 1b and Phase 2: Percentage of Participants with Treatment Emergent Adverse Event (TEAEs) [ Time Frame: From baseline to end of study, an average of one year ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.

  10. Phase 1b and 2: AUC0-last: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration. [ Time Frame: From baseline to end of study, an average of one year ]
    AUClast is defined as the concentration of drug from time zero to the last observable concentration.

  11. Phase 1b and 2:AUC0-24: area under the plasma concentration-time curve from time 0 to the time of 24 hours. [ Time Frame: From baseline to end of study, an average of one year ]
    AUC_0-24 is defined as the concentration of drug over time from time zero to 24 hours.

  12. Phase 1b and 2: Cmax: maximum plasma concentration. [ Time Frame: From baseline to end of study, an average of one year ]
    Cmax is defined as the maximum observed concentration of drug.

  13. Phase 2: Change in Functional Assessment of Cancer Therapy - Prostate (FACT-P) [ Time Frame: From baseline to end of study, an average of one year ]
    Assessed by Well-being Subscale (FWB) and Prostate Cancer Subscale (PCS) scores

  14. Phase 2: Time to definitive deterioration (TDD) in functional status and in prostate symptoms [ Time Frame: From baseline to end of study, an average of one year ]
    Assessed by the FACT-P FWB and PCS scores.



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 the following imaging

    • Bone lesions on bone scan (per PCWG3) or by soft tissue disease (per RECIST 1.1) by CT/MRI imaging Must have undergone bilateral orchiectomy or be willing to continue GnRH analogue or antagonist.

  7. Prior treatment with a second-generation androgen inhibitor as follows:

    • For phase 1b, EITHER Previously untreated with or progressed on a second generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide) OR progressed on a second generation inhibitor (inhibitor (abiraterone, enzalutamide, or apalutamide)
    • For phase 2 randomized component (i.e, enzalutamide- containing treatment arms) of the study, previously progressed on abiraterone.

Exclusion Criteria:

  1. Known symptomatic brain metastases
  2. 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 (except 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
    • For phase 2 subjects to be randomized to one of the enzalutamide treatment arms only, prior treatment with the second-generation androgen antagonist including enzalutamide, apalutamide, darolutamide, and proxalutamide, etc.
  3. Severe concurrent disease, infection, or comorbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment
  4. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2.

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


Locations
Show Show 24 study locations
Sponsors and Collaborators
Epizyme, Inc.
Investigators
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Study Director: Ipsen Medical Director Ipsen
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Responsible Party: Epizyme, Inc.
ClinicalTrials.gov Identifier: NCT04179864    
Other Study ID Numbers: EZH-1101
2019-003649-14 ( EudraCT Number )
First Posted: November 27, 2019    Key Record Dates
Last Update Posted: May 18, 2023
Last Verified: May 2023

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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 Ipsen ( 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
Genital Diseases, Male
Genital Diseases
Urogenital Diseases
Prostatic Diseases
Male Urogenital Diseases
Prednisone
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents