History of Changes for Study: NCT04179864

Version	Submitted Date	Changes
1	November 25, 2019	None (earliest Version on record)
2	December 10, 2019	Outcome Measures, Conditions, Study Description, Study Status, Contacts/Locations and Eligibility
3	December 16, 2019	Study Status
4	February 3, 2020	Contacts/Locations, Outcome Measures, Study Status, Eligibility and Study Description
5	February 27, 2020	Contacts/Locations and Study Status
6	May 6, 2020	Contacts/Locations and Study Status
7	May 26, 2020	Contacts/Locations, Study Status and Study Identification
8	August 3, 2020	Contacts/Locations and Study Status
9	March 8, 2021	Outcome Measures, Arms and Interventions, Study Design, Study Status, Study Description, Contacts/Locations, Eligibility and Study Identification
10	May 12, 2021	Contacts/Locations and Study Status
11	May 20, 2021	Contacts/Locations and Study Status
12	May 24, 2021	Outcome Measures, Eligibility, Study Description and Study Status
13	June 29, 2021	Contacts/Locations and Study Status
14	December 8, 2021	Contacts/Locations, Study Status, Study Description and Study Identification
15	April 28, 2022	Study Status, Contacts/Locations, Eligibility, Outcome Measures, Study Description and Study Identification
16	May 9, 2023	Recruitment Status, Study Status, Contacts/Locations, Outcome Measures, Study Identification, Arms and Interventions, Study Description and Conditions
17	May 17, 2023	Study Status and Study Identification
18	July 13, 2023	Study Status
19	August 11, 2023	Study Status
20	September 21, 2023	Study Status
21	October 25, 2023	Study Status
22	November 30, 2023	Study Status
23	December 29, 2023	Study Status
24	January 30, 2024	Study Status
25	February 29, 2024	Study Status
26	March 4, 2024	Study Status and Study Design
27	April 26, 2024	Study Status and IPDSharing

Brief Summary:

A Phase 1b/2 Study to Examine Tazemetostat in Combination with Enzalutamide or Abiraterone/Prednisone in Patients with Metastatic Castration Resistant Prostate Cancer and Have Not Received Chemotherapy

Detailed Description:

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.

Arms

Assigned Interventions

Experimental: Phase 1b: Tazemetostat in Combination with Abiraterone/Prednisone

In Phase 1b, Abiraterone/prednisone will be administered on cycle 1 day 1 and Tazemetostat on cycle 1 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 Names:

Zytiga

Experimental: Phase 1b: Tazemetostat in Combination with Enzalutamide

In Phase 1b, Enzalutamide will be administered on cycle 1 day 1 and Tazemetostat on cycle 1 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 Names:

Xtandi

Experimental: Phase 2: Tazemetostat in Combination with Enzalutamide

In Phase 2, Enzalutamide and Tazemetostat will be administered on cycle 1 day 1

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 Names:

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 Names:

Xtandi

Outcome Measures


Primary Outcome Measures:
1.	Ph 1b: Determine the safety and tolerability of each of the combinations [ Time Frame: Assessed at end of Cycle 1 (each cycle is 28 days) ] Assess safety and tolerability of Tazemetostat in combination with enzalutamide or with abiraterone/prednisone by reviewing incidence and severity of treatment-emergent adverse events (AEs) qualifying as protocol-defined DLTs in Cycle 1
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: Determine the benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone by assessing change in radiographic progression free survival [ 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.	Determine benefit of combining tazemetostat with enzalutamide or abiraterone/prednisone (phase 1b) and benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone (phase 2) - PSA Change [ Time Frame: Assessed at Day 1 of every cycle for an average of one year (each cycle is 28 days) ] Confirmed prostate-specific antigen (PSA) responses will be defined as ≥50% reductions in PSA from baseline to lowest post baseline PSA result
2.	Determine benefit of combining tazemetostat with enzalutamide or abiraterone/prednisone (phase 1b) and benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone (phase 2) - PSA Change [ Time Frame: Assessed at Day 1 of every cycle for an average of one year (each cycle is 28 days) ] PSA progression is defined as a ≥25% increase from baseline to the day of PSA progression per PCWG3 criteria
3.	Determine benefit of combining tazemetostat with enzalutamide or abiraterone/prednisone (phase 1b) and benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone (phase 2) - 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.
4.	Determine benefit of combining tazemetostat with enzalutamide or abiraterone/prednisone (phase 1b) and benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone (phase 2) - ORR [ Time Frame: Assessed at Day 1 of every cycle for an average of one year (each cycle is 28 days) ] Assess objective response rate (ORR) per PCWG3 criteria and RECIST 1.1 guidelines
5.	Determine benefit of combining tazemetostat with enzalutamide or abiraterone/prednisone (phase 1b) and benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone (phase 2) - DCR [ Time Frame: Assessed at 6 months on treatment ] Assess disease control rate (DCR), no radiographic progression per PCWG3 criteria and no unequivocal clinical progression or death
6.	Evaluate the safety and tolerability of the combination of study drugs by assessing PK data [ Time Frame: Phase 1b PK of Tazemetostat will be assessed on Day 1 of Cycles 1 and 2. Phase 2 PK of Tazemetostat will be assessed on Day 1 of Cycles 2, 3, 5 and 10. (each cycle is 28 days) ] Assess the PK of tazemetostat from collection of blood draws
7.	Evaluate the safety and tolerability of the combination of study drugs by assessing PK data [ Time Frame: Phase 1b PK of enzalutamide will be assessed on Day 1 of Cycles 1 and 2. Phase 2 PK enzalutamide will be assessed on Day 1 of Cycles 2, 3, 5 and 10. (each cycle is 28 days) ] Assess the PK of enzalutamide from collection of blood draws
8.	Evaluate the safety and tolerability of the combination of study drugs by assessing PK data [ Time Frame: Phase 1b PK of abiraterone/prednisone will be assessed on Day 1 of Cycles 1 and 2. (each cycle is 28 days) ] Assess the PK of abiraterone/prednisone from collection of blood draws
9.	Assess the rate of reducing circulating tumor cells (CTC) [ Time Frame: Assessed at screening, on Day 1 of Cycles 1, 2, 3, 4, 5, 7, 10 and 13 (each cycle is 28 days) and post-treatment (30 days after last dose) ] 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
10.	Assess CTC response rate [ Time Frame: Assessed at screening, Day 1 of Cycles 1, 2, 3, 4, 5, 7, 10, 13 (each cycles is 28 days), and post-treatment (30 days after last dose) ] Assess CTC response rate as defined by a ≥30% reduction in CTC number from baseline.
11.	PHASE 2 ONLY: To determine the benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone, quality of life (QoL) will be assessed. [ Time Frame: Assessed at screening, Day 1 of Cycles 3, 5, 7, 10, 13 (each cycle is 28 days), and post-treatment (30 days after last dose).] ] Quality of Life (QoL) as assessed by changes from baseline in FACT-P Functional Well-being Subscale (FWB)
12.	PHASE 2 ONLY: To determine the benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone, quality of life (QoL) will be assessed. [ Time Frame: Assessed at screening, Day 1 of Cycles 3, 5, 7, 10, 13 (each cycle is 28 days), and post-treatment (30 days after last dose).] ] Quality of Life (QoL) as assessed by changes from baseline in Brief Pain Inventory (BPI) short form
13.	PHASE 2 ONLY: To determine the benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone, quality of life (QoL) will be assessed. [ Time Frame: Assessed at screening, Day 1 of Cycles 3, 5, 7, 10, 13 (each cycle is 28 days), and post-treatment (30 days after last dose).] ] Quality of Life (QoL) as assessed by changes from baseline in EQ-5D-5L visual analogue scale.

Minimum Age:

18 Years

Maximum Age:

Sex:

Male

Gender Based:

Accepts Healthy Volunteers:

Criteria:

Inclusion Criteria:

Age at the time of consent ≥ 18 years.
Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (Appendix
Life expectancy of > 3 months.
Histologically or cytologically confirmed adenocarcinoma of the prostate. Small cell or neuroendocrine tumors of the prostate are also permitted.
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.
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.
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.
No prior treatment with cytotoxic chemotherapy

Exclusion Criteria:

Known symptomatic brain metastases
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 progesterone's 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 inhibitor enzalutamide
Severe concurrent disease, infection, or comorbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment.
Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2.

Central Contact Person:

Shefali Agarwal, MD
Telephone: 617-229-7575
Email: clinicaltrials@epizyme.com

Central Contact Backup:

Daniel Powers, DO
Telephone: 978-289-8488

Locations:

United States, Arizona

Arizona Institute of Urology - Northwest
[Withdrawn]
Tucson, Arizona, United States, 85712

United States, California

San Bernardino Urological Associates
[Withdrawn]
San Bernardino, California, United States, 92404

United States, Colorado

The Urology Center Of Colorado
[Recruiting]
Denver, Colorado, United States, 80211
Contact:Contact: Lawrence Karsh
Contact:Principal Investigator: Lawrence Karsh, MD

United States, Florida

Hematology Oncology Associates of the Treasure Coast
[Recruiting]
Port Saint Lucie, Florida, United States, 34952
Contact:Contact: Nicholas Iannotti, MD 772-223-5982
Contact:Principal Investigator: Nicholas Iannotti, MD

United States, Kentucky

Norton Cancer Institute - Broadway
[Withdrawn]
Louisville, Kentucky, United States, 40202

United States, Massachusetts

Dana Farber Cancer Institute
[Recruiting]
Boston, Massachusetts, United States, 02115
Contact:Contact: Mary Taplin, MD
Contact:Principal Investigator: Mary Taplin, MD

Beth Israel Deaconess Medical Center
[Not yet recruiting]
Boston, Massachusetts, United States, 02215
Contact:Contact: David Einstein, MD
Contact:Principal Investigator: David Einstein, MD

United States, Nevada

Comprehensive Cancer Centers of Nevada - Central Valley
[Recruiting]
Las Vegas, Nevada, United States, 89169
Contact:Contact: Nicholas Vogelzang, MD 702-953-3400
Contact:Principal Investigator: Nicholas Vogelzang, MD

United States, New York

Montefiore Einstein Center for Cancer Care
[Not yet recruiting]
Bronx, New York, United States, 10461
Contact:Contact: Anna Ferrari, MD
Contact:Principal Investigator: Anna Ferrari, MD

Memorial Sloan Kettering Cancer Center
[Recruiting]
New York, New York, United States, 10065
Contact:Contact: Wassim Abida
Contact:Principal Investigator: Wassim Abida, MD

Associated Medical Professionals of NY, PLLC - Urology
[Not yet recruiting]
Syracuse, New York, United States, 13210
Contact:Contact: Christopher Pieczonka, MD
Contact:Principal Investigator: Christopher Pieczonka, MD

United States, Pennsylvania

University of Pittsburgh Medical Center - Hillman Cancer Center
[Recruiting]
Pittsburgh, Pennsylvania, United States, 15232
Contact:Contact: Leonard Appleman, MD 412-648-6538
Contact:Principal Investigator: Leonard Appleman, MD

United States, Tennessee

Urology Associates P.C.
[Not yet recruiting]
Hendersonville, Tennessee, United States, 37075
Contact:Contact: David Morris, MD
Contact:Principal Investigator: David Morris, MD

United States, Texas

Mary Crowley Cancer Research
[Withdrawn]
Dallas, Texas, United States, 75230

Oncology Consultants - Texas Medical Center
[Withdrawn]
Houston, Texas, United States, 77030

Urology San Antonio
[Recruiting]
San Antonio, Texas, United States, 78229
Contact:Contact: Daniel Saltzstein, MD
Contact:Principal Investigator: Daniel Saltzstein, MD

Belgium, West Vlaanderen

Academisch Ziekenhuis Groeninge Campus Kennedylaan
[Not yet recruiting]
Kortrijk, West Vlaanderen, Belgium
Contact:Contact: Siska Van Bruwaene, MD
Contact:Principal Investigator: Siska Van Bruwaene, MD

Spain

Hospital de la Santa Creu i. Sant Pau
[Recruiting]
Barcelona, Spain
Contact:Contact: Jose Pablo Maroto Rey, MD
Contact:Principal Investigator: Jose Pablo Maroto Rey, MD

Hospital del Mar Parc de Salut Mar
[Recruiting]
Barcelona, Spain
Contact:Contact: Alejo Martin Rodriguez Vida Rodriguez, MD
Contact:Principal Investigator: Alejo Martin Rodriguez Vida Rodriguez, MD

Hospital Clinico San Carlos
[Not yet recruiting]
Madrid, Spain
Contact:Contact: Jose Luis Gonzalez Larriba, MD
Contact:Principal Investigator: Jose Luis Gonzalez Larriba, MD

Hospital Universitario 12 de Octubre
[Not yet recruiting]
Madrid, Spain
Contact:Contact: Daniel Ernesto Castellano Gauna, MD
Contact:Principal Investigator: Daniel Ernesto Castellano Gauna, MD

Hospital Universitario La Paz
[Not yet recruiting]
Madrid, Spain
Contact:Contact: Alvaro Pinto Marin, MD
Contact:Principal Investigator: Alvaro Pinto Marin, MD

Clinica Universidad de Navarra
[Not yet recruiting]
Pamplona, Spain
Contact:Contact: Jose Luis Perez Garcia, MD
Contact:Principal Investigator: Jose Luis Perez Garcia, MD

Spain, Cadiz

Hospital Universitario de Jerez de la Frontera
[Not yet recruiting]
Jerez De La Frontera, Cadiz, Spain
Contact:Contact: Alvaro Juarez Soto, MD
Contact:Principal Investigator: Alvaro Juarez Soto, MD