A Study of Tazemetostat With Enzalutamide or Abiraterone/Prednisone in Participants With Advanced Prostate Cancer

Study Overview
=================
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.

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

Conditions
-----------------
Metastatic Prostate Cancer, Metastatic Castration-resistant Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Tazemetostat
* Drug: Abiraterone/prednisone
* Drug: Enzalutamide


Participation Criteria
=================
Eligibility 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. 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 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. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Tazemetostat in Combination with Abiraterone/Prednisone<br>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<br>* Tazemetostat (EPZ-6438) is a selective small-molecule inhibitor of the histone-lysine methyltransferase EZH2 gene<br>* Other names: IPN60200;Drug: Abiraterone/prednisone<br>* 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.<br>* Other names: Zytiga;|
| Experimental: Phase 1b: Tazemetostat in Combination with Enzalutamide<br>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<br>* Tazemetostat (EPZ-6438) is a selective small-molecule inhibitor of the histone-lysine methyltransferase EZH2 gene<br>* Other names: IPN60200;Drug: Enzalutamide<br>* enzalutamide 160 mg (four 40 mg capsules) orally once daily<br>* Other names: Xtandi;|
| Experimental: Phase 2: Tazemetostat in Combination with Enzalutamide<br>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<br>* Tazemetostat (EPZ-6438) is a selective small-molecule inhibitor of the histone-lysine methyltransferase EZH2 gene<br>* Other names: IPN60200;Drug: Enzalutamide<br>* enzalutamide 160 mg (four 40 mg capsules) orally once daily<br>* Other names: Xtandi;|
| Active Comparator: Phase 2: Enzalutamide only<br>In Phase 2, Enzalutamide will be administered on cycle 1 day 1 | Drug: Enzalutamide<br>* enzalutamide 160 mg (four 40 mg capsules) orally once daily<br>* Other names: Xtandi;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ph 1b: Percentage of Participants with Treatment Emergent Adverse Event (TEAEs) | 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. | At end of Cycle 1 (each cycle is 28 days) | 
| Ph 1b: Select the recommended phase 2 doses (RP2D) of tazemetostat for each combination | 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) | 1 cycle/28 days | 
| Ph 2: Change in radiographic progression free survival (rPFS) | 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 | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b and 2: Percentage of participants with a ≥50% decline of Prostate Specific-Antigen (PSA50). | For participants with a baseline PSA ≥2.0 ug/L (ng/mL) per PCWG3 criteria | From baseline at any time on study, an average of one year | 
| Phase 1b and 2: Objective response rate (ORR) and best overall response (BOR) in soft tissue | According to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) guidelines. | At 6 months on treatment. | 
| Phase 1b and 2: Disease control rate (DCR) | Assessed by radiographic progression per PCWG3 criteria, with no unequivocal clinical progression or death | At 6 months on treatment. | 
| Phase 1b and 2: Time to first skeletal-related event (SRE) |  | During screening and every 9 weeks if clinically indicated at baseline, average of one year | 
| Phase 1b and 2: Time to initiation of the next systemic treatment for prostate cancer (TTNT) | 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. | From baseline to end of study, an average of one year | 
| Phase 1b and 2: Time to PSA progression (TTPP) | Defined as the duration per PCWG3 criteria in months. | From baseline to the day of PSA progression, an average one one year. | 
| Phase 1b and 2: Reduction in circulating tumor cells (CTC) | From a state of having a detectable number of CTCs to having an undetectable number of CTCs | From screening to 30 days after last dose | 
| Phase 1b and 2: CTC response rate | Defined as the percentage of participants with a ≥30% reduction in CTC number | From baseline to end of study, an average of one year | 
| Phase 1b and Phase 2: Percentage of Participants with Treatment Emergent Adverse Event (TEAEs) | 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. | From baseline to end of study, an average of one year | 
| Phase 1b and 2: AUC0-last: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration. | AUClast is defined as the concentration of drug from time zero to the last observable concentration. | From baseline to end of study, an average of one year | 
| Phase 1b and 2:AUC0-24: area under the plasma concentration-time curve from time 0 to the time of 24 hours. | AUC_0-24 is defined as the concentration of drug over time from time zero to 24 hours. | From baseline to end of study, an average of one year | 
| Phase 1b and 2: Cmax: maximum plasma concentration. | Cmax is defined as the maximum observed concentration of drug. | From baseline to end of study, an average of one year | 
| Phase 2: Change in Functional Assessment of Cancer Therapy - Prostate (FACT-P) | Assessed by Well-being Subscale (FWB) and Prostate Cancer Subscale (PCS) scores | From baseline to end of study, an average of one year | 
| Phase 2: Time to definitive deterioration (TDD) in functional status and in prostate symptoms | Assessed by the FACT-P FWB and PCS scores. | From baseline to end of study, an average of one year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
metastatic castration resistant prostate cancer, tazemetostat, EPZ-6438, E7438, enzalutamide, abiraterone, Prednisone, Zytiga, Xtandi