A Phase 1b/2 open-label study to test if Tazemetostat together with Enzalutamide or with Abiraterone/prednisone is effective in subjects with castration resistant prostate cancer that has spread and who have not yet received chemotherapy.
- Conditions
- Metastatic Castration Resistant Prostate CancerMedDRA version: 20.0Level: PTClassification code 10060862Term: Prostate cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2019-003649-14-BE
- Lead Sponsor
- Epizyme, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- Male
- Target Recruitment
- 80
1. Age at the time of consent = 18 years.
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (Appendix 1)
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
NOTE: Enrollment of subjects without measurable disease will be capped
at 15 per treatment arm to ensure reflection of the prevalence of
measurable disease in the population (approximately 60%).
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. Prior treatment with a second-generation androgen inhibitor as
follows: ? For phase 1b, EITHER previously untreated with a second-generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide) OR progressed on a second generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide); ? For phase 2, randomized component (ie, enzalutamide-containing
treatment arms) of the study, previously progressed on abiraterone.
10. No prior treatment with cytotoxic chemotherapy for mCRPC except
as follows:
? For phase 1b, more than 6 cycles of docetaxel received for castrationsensitive
disease prior to having received enzalutamide or
abiraterone/prednisone is permitted
? For the phase 2 randomized component (ie, enzalutamide-containing
treatment arms) of the study, up to 6 prior cycles of docetaxel received
for castration-sensitive disease prior to having received
abiraterone/prednisone is permitted
11. Demonstrate adequate organ function as defined below:
• ANC = 1,000 /µL.
• Platelet Count = 100,000 /µL.
• Hemoglobin = 9 g/dL without a transfusion within 2 weeks of
screening.
• Serum creatinine = 2 × upper limit of normal (ULN) or
- Creatinine clearance = 40 mL/min as estimated by the Cockcroft and
Gault formula in subjects with creatinine > 2 × ULN.
• Bilirubin = 1.5 × ULN unless evidence of Gilbert's disease in which case
< 3 × ULN.
• AST = 2.5 × ULN without liver metastases; must be = 5 × ULN with
liver metastases.
• ALT = 2.5 × ULN without liver metastases; must be = 5 × ULN with
liver metastases.
• Albumin >3.0 g/dL (30 g/L) at screening
12. Subjects of child-fathering potential as defined in the protocol must
refrain either practice complete abstinence or agree to use a latex or
synthetic condom, even with a successful vasectomy (medically
confirmed azoospermia), or maintain medical castration during sexual
contact with a pregnant female or female partner of childbearing
potential (FCBP) during study treatment, for 3 weeks following the last
dose of abiraterone/prednisone, and for 3 months following the last
dose of enzalutamide. Males subjects with surgical castration are not
required to use condoms.
NOTE: Male subjects must not donate semen or
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 [...] (see Protocol sec. 8.2)
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%
? 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, according to the potential to be assigned to the agent(s)
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,
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method