| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration Resistant Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060862 |
| E.1.2 | Term | Prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone, as assessed by rPFS according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria for progression in bone and in soft tissue (the latter by Response Evaluation Criteria in Solid Tumors 1.1 [RECIST 1.1]). |
|
| E.2.2 | Secondary objectives of the trial |
- To determine the benefit of combining tazemetostat with enzalutamide or abiraterone/prednisone (in ph 1b) and the benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone (in ph 2) as assessed by [...] (see Protocol section 6.2)
- To further evaluate the safety and tolerability of the combination of tazemetostat with enzalutamide.
- To assess the PK of tazemetostat when administered in combination with enzalutamide (ph 1b and 2) and abiraterone/prednisone (ph 1b only) and the PK of enzalutamide (ph 1b and 2) and abiraterone (ph 1b only) when administered in combination with tazemetostat.
- To determine the benefit of combining tazemetostat with enzalutamide
when compared to enzalutamide alone to QoL as assessed by changes
from baseline in FACT-P Functional Well-being Subscale (FWB) and
Prostate Cancer Subscale (PCS) scores over the course of the study
[...] |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 sperm from first dose of
study drug, during study treatment (including during dose
interruptions), and for 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. |
|
| E.4 | Principal 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 [...] (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, 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 thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per
CTCAE 5.0 criteria) or any prior history of myeloid malignancies,
including MDS and AML. Has abnormalities known to be associated with
MDS (eg, del 5q, chr 7 abn) and MPN (eg, JAK2 V617F) observed in
cytogenetic testing and DNA sequencing
NOTE: Bone marrow aspirate/biopsy will be conducted following
abnormal peripheral blood smear morphology assessment conducted by
central laboratory. Cytogenetic testing and DNA sequencing will be
conducted following an abnormal result of bone marrow aspirate/biopsy.
17. Has a prior history of T-LBL/T-ALL
18. 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.
19. Subjects with hepatitis B or hepatitis C are ineligible to participate in the study unless they meet the following criteria [...] (see Protocol sec 8.2) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Radiographic progression-free survival (phase 2 randomized treatment
arms): The rPFS of tazemetostat in combination with enzalutamide will
be compared to the rPFS of enzalutamide alone. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The timing of primary analysis depends on reaching the target number of rPFS events. Monthly or bi-monthly forecasts will be conducted to determine when enough rPFS (e.g. 15) is accumulated |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include:
- PSA50: Confirmed PSA responses will be defined as ≥50% reductions
in PSA from baseline to lowest post-baseline PSA result with a
consecutive assessment conducted at least 3 weeks later required to
confirm the PSA response. PSA50 will be calculated by treatment group
for subjects with PSA values at the baseline assessment (cycle 1 day 1
predose) and at least 1 post baseline assessment. A Cochran-Mantel-
Haenszel mean score test will be used to compare the response rates
between tazemetostat in combination with enzalutamide and
enzalutamide treatment alone.
- Time to PSA Progression: 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). This increase must be confirmed by a second consecutive assessment conducted at least 3 weeks later. Time from
randomization to first observation of PSA progression will be assessed. A
log-rank test will be used to compare TTPP with tazemetostat in
combination with enzalutamide and enzalutamide treatment alone.
- Time to First SRE: 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. A log-rank test will be used to
compare time to SREs with tazemetostat in combination with
enzalutamide and enzalutamide or enzalutamide treatment alone.
- ORR and Best Overall Soft Tissue Response: ORR is defined per PCWG3
criteria and RECIST 1.1 guidelines. The best overall soft tissue response
as assessed by investigators using RECIST 1.1 will be summarized. Only
subjects with measurable soft tissue disease at screening (ie, at least 1
target lesion per RECIST 1.1) will be included in this analysis. The
Clopper-Pearson exact method will be used to compare the proportion of
subjects with an objective response (complete response or partial
response) per RECIST 1.1 between tazemetostat in combination with
enzalutamide and enzalutamide treatment alone.
- Disease Control Rate (no radiographic progression per PCWG3, and no
unequivocal clinical progression or death) at 6 months on study therapy.
A Cochran-Mantel-Haenszel test will be used to compare DCR between
tazemetostat in combination with enzalutamide and enzalutamide
treatment alone, with p-values. Also, the 95% CI will be provided for
each treatment group and the difference in proportion between the two
treatment groups, using Clopper-Pearson exact method and Newcombe
method, respectively.
- Time to Initiation of Subsequent Antineoplastic Cytotoxic
Chemotherapy: A log-rank test will be used to compare time to initiation
of subsequent antineoplastic cytotoxic chemotherapy between
tazemetostat in combination with enzalutamide and enzalutamide
treatment alone. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoint evaluation will happen at the same time as the primary |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Efficacy, Safety, Tolerability, Pharmacokinetic and Pharmacodynamic |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Belgium |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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