A Study of ZEN003694 in Combination With Enzalutamide in Patients With Metastatic Castration-Resistant Prostate Cancer
Sponsor
Zenith Epigenetics (Industry)
Overall Status
Completed
CT.gov ID
NCT02711956
Collaborator
(none)
75
8
1
35
9.4
0.3
Study Details
Study Description
Brief Summary
This is an open label, non-randomized, Phase 1b/2a, dose escalation and dose confirmation study of ZEN003694 in combination with enzalutamide in patients with mCRPC.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
75 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1b/2a Safety and Tolerability Study of ZEN003694 in Combination With Enzalutamide in Patients With Metastatic Castration-Resistant Prostate Cancer
Actual Study Start Date
:
Dec 1, 2016
Actual Primary Completion Date
:
Nov 1, 2019
Actual Study Completion Date
:
Nov 1, 2019
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: DE and DC - ZEN003694 in Combination with Enzalutamide Dose Escalation (DE) and Dose Confirmation (DC): ZEN003694 will be administered orally once daily with enzalutamide in 28-day cycles, enrolling mCRPC patients. Two patient populations will be enrolled in DE and DC. Cohort A: Patients with prior progression on enzalutamide or apalutamide by PCWG2 criteria who were receiving a stable dose of enzalutamide at the time of study entry. Cohort B: Patients who were enzalutamide-naïve with prior progression on abiraterone by Prostate Cancer Working Group 2 (PCWG2) criteria. |
Drug: ZEN003694
Drug: Enzalutamide
Other Names:
|
Outcome Measures
Primary Outcome Measures
- For Dose Escalation: Incidence of Dose-limiting Toxicities (DLT) to Determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of ZEN003694 in Combination With Enzalutamide. [Cycle 1 (Day 1 thru Day 28)]
Determination of DLT was made during the first 28 days of treatment in the dose escalation phase. A DLT is defined as a clinically significant AE or laboratory abnormality that is considered possibly, probably, or definitely related to study drug. The MTD reflects the highest dose of ZEN003694 in combination with enzalutamide that did not cause a DLT in more than 1 of 6 patients. The RP2D is the recommended dose of ZEN003694 in combination with enzalutamide as determined in the dose confirmation phase of the study.
- For Dose Escalation and Dose Confirmation: Incidence of Treatment-emergent Adverse Events (TEAE) and Treatment-related Serious Adverse Events (SAE) [Cycle 1 Day 1 to 30 days post last dose]
Treatment-emergent adverse events (TEAEs) were defined as any adverse events (AEs) that begin or worsen on or after the start of study drug through 30 days after the last dose of study drug. The severity of AEs was graded based on the National Cancer Institute's Common Terminology for Adverse Events (V4.03). A serious adverse event (SAE) was any AE that was: fatal; life-threatening; required in-patient hospitalization or prolonged an existing hospitalization; disabling or incapacitating; a congenital anomaly or birth defect; or any other important medical event.
Secondary Outcome Measures
- Evaluate Prostate-specific Antigen (PSA) Response Rate by PCWG2 Criteria [Screening up to 35 months]
The PSA response rate will be evaluated using PCWG2 criteria and defined as the proportion of patients with a PSA decline of at least 50%. Any change from baseline is confirmed by a second measurement at least 3 weeks later. PSA Response Rate will be evaluated using PCWG2 criteria and defined as following: Percentage change from baseline in PSA to 12 weeks post ZEN003694 dose. Only evaluate for patients with at least 12 weeks of treatment, the PSA assessment at 12 weeks (84 days +/-3 days) will be used; Maximum percent decrease in PSA from baseline that occurs at any point after treatment. Evaluable for all patients with post-baseline PSA. Arms will be combined to analyze efficacy in Cohort A and Cohort B.
- Evaluate Radiographic Response Rate (Overall Response Rate) by PCWG2 Criteria [Screening up to 35 months]
Tumor response will be evaluated using the PCWG2 criteria. Patients with measurable disease will be evaluated for clinical benefit as determined by tumor response using RECIST v1.1. Patients with non-measurable bone disease will be evaluated for progression based on the presence of any new lesions by bone scans. Radiographic tumor evaluation will be performed at screening and every 3 cycles or more frequently as determined by the investigator. Using the tumor response that is determined by the investigator, best overall response will be determined using RECIST v1.1. Best overall response is defined as the best response recorded from the start of treatment until disease progression or study exit. Arms will be combined to analyze efficacy in Cohort A and Cohort B.
- Evaluate Overall Median Progression-free Survival by PCWG2 Criteria [Screening up to 35 months]
Overall progression free survival (PFS) is determined using the PCWG2 criteria. Overall PFS is measured from screening until the time that disease progression (radiographic progressive disease or clinical deterioration) or death is documented, whichever occurs first. Arms will be combined to analyze efficacy in Cohort A and Cohort B.
- Evaluate Median Radiographic Progression-Free Survival by PCWG2 Criteria [Screening up to 35 months]
Radiographic progression-free survival (rPFS) is determined using the PCWG2 criteria to assess both soft-tissue and bone assessments. The rPFS is measured from screening until the time the first radiographic scan shows disease progression, or until the time of death, whichever occurs first. If radiographic disease progression is identified at the first on-treatment radiographic assessment at Cycle 3 Day 1 (8 weeks), radiographic progression must be confirmed by a second assessment 6 or more weeks later. Patients who do not progress radiographically or did not die prior to study exit are censored on the date of their last dose of ZEN003694. Arms will be combined to analyze efficacy in Cohort A and Cohort B.
- Measure the Pharmacokinetic (PK) Parameter: AUC(0-24h) of ZEN003694 and ZEN003791 (Active Metabolite) Administered in Combination With Enzalutamide. [Cycle 1 Day 1: pre-dose, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-dose; Cycle 1 Day 2: pre-dose; Cycle 1 Day 15: pre-dose, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-dose]
AUC(0-24h) is defined as the area under the curve (plasma concentration of drug over a 24-hour time period).
- Measure the Pharmacokinetic (PK) Parameter: Cmax of ZEN003694 and ZEN003791 (Active Metabolite) Administered in Combination With Enzalutamide [Cycle 1 Day 1: pre-dose, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-dose; Cycle 1 Day 2: pre-dose; Cycle 1 Day 15: pre-dose, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-dose]
Cmax is defined as the maximum or peak plasma concentration of drug.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
Male
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Males age ≥ 18 years
-
Metastatic, castrate resistant, histologically confirmed prostate cancer; surgically castrated or continuous medical castration for ≥ 8 weeks prior to screening
-
Serum testosterone < 50 ng/dL determined within 4 weeks of first administration of study drug
-
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
-
Adequate laboratory parameters [absolute neutrophil (ANC), platelets, asparate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, creatinine and coagulation parameters] at screening
-
Dose Escalation Cohort DE-A: Prior progression on enzalutamide or apalutamide at any time by PCWG2 criteria and receiving a stable dose of enzalutamide at the start of study treatment.
-
Dose Escalation Cohort DE-B: Enzalutamide-naïve and apalutamide-naïve patients following prior progression on abiraterone by PCWG2 criteria and receiving a stable dose of enzalutamide at the start of study treatment.
-
Dose Confirmation Cohort A (DC-A) only: Currently receiving enzalutamide as most recent systemic therapy for mCRPC and have experienced PSA progression by PCWG2 criteria in the absence of radiographic and/or clinical progression. Patients may or may not have experienced prior progression on abiraterone.
-
Dose Confirmation Cohort B (DC-B) only: Enzalutamide-naïve patients following prior progression on abiraterone by PCWG2 criteria and within 12 weeks of discontinuing abiraterone.
Exclusion Criteria:
-
Any history of brain metastases or prior seizure or conditions predisposing to seizure activity
-
Have previously received an investigational BET inhibitor (including previous participation in this study or Study ZEN003694-001)
-
Have received prior systemic anti-cancer therapy (including abiraterone) or investigational therapy within 2 weeks or five half-lives, whichever is shorter, prior to the first administration of study drug
-
Failure to recover to Grade 1 or lower toxicity related to prior systemic therapy (excluding alopecia and neuropathy) prior to study entry
-
Radiation therapy within 2 weeks of the first administration of study drug
-
Have received prior chemotherapy in the metastatic castration-resistant setting (prior chemotherapy in the hormone-sensitive setting is allowed provided last dose was at least 6 months prior to study entry)
-
Have received prior investigational anti-androgen therapy, including ARN-509
-
Currently receiving medications known to be strong inhibitors of CYP2C8, strong inducers (except enzalutamide) or inhibitors of CYP3A4 and substrates of CYP3A4, CYP2C9 and CYP2C19 with a narrow therapeutic window. Strong inducers, inhibitors and substrates must be discontinued at least 7 days prior to the first administration of study drug.
-
Not a candidate for enzalutamide treatment, in the opinion of the Investigator
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of California Los Angeles Medical Center | Los Angeles | California | United States | |
| 2 | University of California San Francisco Medical Center | San Francisco | California | United States | |
| 3 | Karmanos Cancer Institute | Detroit | Michigan | United States | |
| 4 | Karmanos Cancer Institute | Farmington Hills | Michigan | United States | |
| 5 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | |
| 6 | Weill Cornell Medicine - New York Presbyterian | New York | New York | United States | |
| 7 | Oregon Health & Science University | Portland | Oregon | United States | |
| 8 | Seattle Cancer Care Alliance | Seattle | Washington | United States |
Sponsors and Collaborators
- Zenith Epigenetics
Investigators
None specified.Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Zenith Epigenetics
ClinicalTrials.gov Identifier:
NCT02711956
Other Study ID Numbers:
- ZEN003694-002
First Posted:
Mar 17, 2016
Last Update Posted:
Nov 30, 2021
Last Verified:
Nov 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Keywords provided by Zenith Epigenetics
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | The study was conducted at seven investigational sites in the United States between December 2016 and November 2019 |
|---|---|
| Pre-assignment Detail | 75 participants were enrolled and treated in the study. |
| Arm/Group Title | DE-A - 48 mg ZEN003694 + Enzalutamide | DE-A - 60 mg ZEN003694 + Enzalutamide | DE-A - 72 mg ZEN003694 + Enzalutamide | DE-A - 96 mg ZEN003694 + Enzalutamide | DE-A - 120 mg ZEN003694 + Enzalutamide | DE-A - 144 mg ZEN003694 + Enzalutamide | DE-B - 36 mg ZEN003694 + Enzalutamide | DE-B - 48 mg ZEN003694 + Enzalutamide | DE-B 60 mg ZEN003694 + Enzalutamide | DE-B - 72 mg ZEN003694 + Enzalutamide | DE-B 96 mg ZEN003694 + Enzalutamide | DC-A 48 mg ZEN003694 + Enzalutamide | DC-A 96 mg ZEN003694 + Enzalutamide | DC-B 48 mg ZEN003694 + Enzalutamide | DC-B 96 mg ZEN003694 + Enzalutamide |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Dose Escalation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (60 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (72 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (120 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (60 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (72 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Confirmation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Confirmation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles | Dose Confirmation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles | Dose Confirmation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles |
| Period Title: Overall Study | |||||||||||||||
| STARTED | 2 | 2 | 3 | 5 | 4 | 3 | 4 | 4 | 4 | 3 | 1 | 9 | 17 | 6 | 8 |
| COMPLETED | 0 | 0 | 1 | 2 | 0 | 1 | 0 | 2 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| NOT COMPLETED | 2 | 2 | 2 | 3 | 4 | 2 | 4 | 2 | 4 | 3 | 1 | 9 | 16 | 5 | 8 |
Baseline Characteristics
| Arm/Group Title | DE-A - 48 mg ZEN003694 + Enzalutamide | DE-A - 60 mg ZEN003694 + Enzalutamide | DE-A - 72 mg ZEN003694 + Enzalutamide | DE-A - 96 mg ZEN003694 + Enzalutamide | DE-A - 120 mg ZEN003694 + Enzalutamide | DE-A - 144 mg ZEN003694 + Enzalutamide | DE-B - 36 mg ZEN003694 + Enzalutamide | DE-B - 48 mg ZEN003694 + Enzalutamide | DE-B - 60 mg ZEN003694 + Enzalutamide | DE-B - 72 mg ZEN003694 + Enzalutamide | DE-B - 96 mg ZEN003694 + Enzalutamide | DC-A - 48 mg ZEN003694 + Enzalutamide | DC-A - 96 mg ZEN003694 + Enzalutamide | DC-B - 48 mg ZEN003694 + Enzalutamide | DC-B - 96 mg ZEN003694 + Enzalutamide | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Dose Escalation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (60 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (72 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (120 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (60 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (72 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Confirmation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Confirmation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Confirmation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Confirmation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Total of all reporting groups |
| Overall Participants | 2 | 2 | 3 | 5 | 4 | 3 | 4 | 4 | 4 | 3 | 1 | 9 | 17 | 6 | 8 | 75 |
| Age (years) [Mean (Standard Deviation) ] | ||||||||||||||||
| Mean (Standard Deviation) [years] |
69.5
(0.71)
|
63.0
(1.41)
|
69.0
(18.03)
|
62.6
(10.26)
|
66.5
(5.80)
|
73.0
(3.61)
|
73.8
(3.50)
|
65.5
(11.33)
|
75.0
(13.49)
|
67.0
(12.49)
|
62
|
67.9
(9.20)
|
71.2
(7.59)
|
68.2
(6.71)
|
71.3
(7.98)
|
69.2
(8.68)
|
| Age (years) [Median (Full Range) ] | ||||||||||||||||
| Median (Full Range) [years] |
69.5
|
63
|
74
|
63
|
67.5
|
72
|
73.5
|
63.5
|
74.5
|
71
|
62
|
66
|
70
|
67
|
72
|
70
|
| Sex: Female, Male (Count of Participants) | ||||||||||||||||
| Female |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Male |
2
100%
|
2
100%
|
3
100%
|
5
100%
|
4
100%
|
3
100%
|
4
100%
|
4
100%
|
4
100%
|
3
100%
|
1
100%
|
9
100%
|
17
100%
|
6
100%
|
8
100%
|
75
100%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||||||||||||||
| Hispanic or Latino |
1
50%
|
0
0%
|
0
0%
|
1
20%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
33.3%
|
0
0%
|
1
11.1%
|
1
5.9%
|
0
0%
|
2
25%
|
7
9.3%
|
| Not Hispanic or Latino |
1
50%
|
2
100%
|
3
100%
|
4
80%
|
4
100%
|
3
100%
|
4
100%
|
4
100%
|
4
100%
|
2
66.7%
|
1
100%
|
8
88.9%
|
16
94.1%
|
6
100%
|
6
75%
|
68
90.7%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | ||||||||||||||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
4
23.5%
|
0
0%
|
0
0%
|
4
5.3%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
1
20%
|
0
0%
|
0
0%
|
0
0%
|
1
25%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
11.8%
|
0
0%
|
0
0%
|
4
5.3%
|
| White |
1
50%
|
2
100%
|
3
100%
|
4
80%
|
4
100%
|
3
100%
|
4
100%
|
3
75%
|
4
100%
|
2
66.7%
|
1
100%
|
7
77.8%
|
11
64.7%
|
6
100%
|
8
100%
|
63
84%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
1
50%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
33.3%
|
0
0%
|
2
22.2%
|
0
0%
|
0
0%
|
0
0%
|
4
5.3%
|
| Mean Body Mass Index (kg/m^2) [Mean (Standard Deviation) ] | ||||||||||||||||
| Mean (Standard Deviation) [kg/m^2] |
25.26
(1.854)
|
38.54
(0.882)
|
27.18
(5.505)
|
29.01
(5.201)
|
33.99
(6.138)
|
32.58
(6.447)
|
25.91
(1.557)
|
29.74
(6.805)
|
30.25
(6.699)
|
27.54
(0.825)
|
34.87
|
28.1
(3.763)
|
26.05
(4.183)
|
28.13
(2.523)
|
28.34
(3.670)
|
28.54
(4.895)
|
| Median Body Mass Index (kg/m^2) [Median (Full Range) ] | ||||||||||||||||
| Median (Full Range) [kg/m^2] |
25.26
|
38.54
|
27.8
|
29.24
|
32.83
|
29.49
|
25.98
|
29.02
|
29.62
|
27.53
|
34.87
|
27.09
|
25.81
|
27.66
|
29.38
|
27.69
|
| Mean PSA (ng/mL) [Mean (Standard Deviation) ] | ||||||||||||||||
| Mean (Standard Deviation) [ng/mL] |
37.295
(17.9534)
|
96.855
(132.7452)
|
10.383
(7.8450)
|
8.996
(7.0365)
|
90.718
(87.1840)
|
6.280
(4.7483)
|
149.423
(157.4893)
|
34.766
(10.52727)
|
53.404
(21.9723)
|
24.433
(5.2254)
|
12.720
|
38.358
(41.2016)
|
167.043
(274.6941)
|
112.449
(185.2442)
|
88.141
(78.4200)
|
84.364
(156.2876)
|
| Median PSA (ng/mL) [Median (Full Range) ] | ||||||||||||||||
| Median (Full Range) [ng/mL] |
37.295
|
96.855
|
8.090
|
10.449
|
90.850
|
5.500
|
130.866
|
29.881
|
53.697
|
23.722
|
12.720
|
25.600
|
29.750
|
52.043
|
87.518
|
28.700
|
| ECOG performance status (Count of Participants) | ||||||||||||||||
| 0 |
1
50%
|
1
50%
|
2
66.7%
|
4
80%
|
3
75%
|
3
100%
|
1
25%
|
3
75%
|
1
25%
|
1
33.3%
|
1
100%
|
6
66.7%
|
10
58.8%
|
4
66.7%
|
4
50%
|
45
60%
|
| 1 |
1
50%
|
1
50%
|
1
33.3%
|
1
20%
|
1
25%
|
0
0%
|
3
75%
|
1
25%
|
3
75%
|
2
66.7%
|
0
0%
|
3
33.3%
|
7
41.2%
|
2
33.3%
|
4
50%
|
30
40%
|
Outcome Measures
| Title | For Dose Escalation: Incidence of Dose-limiting Toxicities (DLT) to Determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of ZEN003694 in Combination With Enzalutamide. |
|---|---|
| Description | Determination of DLT was made during the first 28 days of treatment in the dose escalation phase. A DLT is defined as a clinically significant AE or laboratory abnormality that is considered possibly, probably, or definitely related to study drug. The MTD reflects the highest dose of ZEN003694 in combination with enzalutamide that did not cause a DLT in more than 1 of 6 patients. The RP2D is the recommended dose of ZEN003694 in combination with enzalutamide as determined in the dose confirmation phase of the study. |
| Time Frame | Cycle 1 (Day 1 thru Day 28) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in dose escalation |
| Arm/Group Title | DE A+B - 36 mg ZEN003694 + Enzalutamide | DE A+B - 48 mg ZEN003694 + Enzalutamide | DE A+B - 60 mg ZEN003694 + Enzalutamide | DE A+B - 72 mg ZEN003694 + Enzalutamide | DE A+B - 96 mg ZEN003694 + Enzalutamide | DE A+B - 120 mg ZEN003694 + Enzalutamide | DE A+B - 144 mg ZEN003694 + Enzalutamide |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A+B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (60 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (72 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (120 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. |
| Measure Participants | 4 | 6 | 6 | 6 | 6 | 4 | 3 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
25%
|
0
0%
|
0
0%
|
| Title | For Dose Escalation and Dose Confirmation: Incidence of Treatment-emergent Adverse Events (TEAE) and Treatment-related Serious Adverse Events (SAE) |
|---|---|
| Description | Treatment-emergent adverse events (TEAEs) were defined as any adverse events (AEs) that begin or worsen on or after the start of study drug through 30 days after the last dose of study drug. The severity of AEs was graded based on the National Cancer Institute's Common Terminology for Adverse Events (V4.03). A serious adverse event (SAE) was any AE that was: fatal; life-threatening; required in-patient hospitalization or prolonged an existing hospitalization; disabling or incapacitating; a congenital anomaly or birth defect; or any other important medical event. |
| Time Frame | Cycle 1 Day 1 to 30 days post last dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants |
| Arm/Group Title | DE - 36 mg ZEN003694 + Enzalutamide | DE/DC - 48 mg ZEN003694 + Enzalutamide | DE - 60 mg ZEN003694 + Enzalutamide | DE - 72 mg ZEN003694 + Enzalutamide | DE/DC - 96 mg ZEN003694 + Enzalutamide | DE - 120 mg ZEN003694 + Enzalutamide | DE - 144 mg ZEN003694 + Enzalutamide |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Dose Escalation - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation + Dose Confirmation - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (60 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (72 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation + Dose Confirmation - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (120 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. |
| Measure Participants | 4 | 21 | 6 | 6 | 31 | 4 | 3 |
| Blood creatinine increased |
0
0%
|
0
0%
|
2
66.7%
|
0
0%
|
3
75%
|
0
0%
|
0
0%
|
| Constipation |
0
0%
|
1
50%
|
0
0%
|
0
0%
|
3
75%
|
0
0%
|
0
0%
|
| Decreased appetite |
0
0%
|
2
100%
|
2
66.7%
|
1
20%
|
10
250%
|
3
100%
|
2
50%
|
| Diarrhea |
0
0%
|
0
0%
|
0
0%
|
1
20%
|
5
125%
|
0
0%
|
0
0%
|
| Dizziness |
0
0%
|
0
0%
|
0
0%
|
1
20%
|
3
75%
|
0
0%
|
0
0%
|
| Dysgeusia |
0
0%
|
2
100%
|
0
0%
|
0
0%
|
10
250%
|
1
33.3%
|
3
75%
|
| Dyspepsia |
0
0%
|
1
50%
|
0
0%
|
0
0%
|
2
50%
|
0
0%
|
0
0%
|
| Fatigue |
1
50%
|
8
400%
|
1
33.3%
|
2
40%
|
13
325%
|
3
100%
|
1
25%
|
| Nasal congestion |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
3
75%
|
0
0%
|
0
0%
|
| Nausea |
0
0%
|
7
350%
|
2
66.7%
|
3
60%
|
17
425%
|
3
100%
|
2
50%
|
| Photopsia |
0
0%
|
1
50%
|
0
0%
|
0
0%
|
3
75%
|
0
0%
|
0
0%
|
| Photosensitivity |
0
0%
|
2
100%
|
0
0%
|
0
0%
|
3
75%
|
0
0%
|
0
0%
|
| Rash |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
3
75%
|
0
0%
|
0
0%
|
| Rash maculopapular |
0
0%
|
3
150%
|
0
0%
|
0
0%
|
1
25%
|
0
0%
|
1
25%
|
| Taste disorder |
0
0%
|
0
0%
|
1
33.3%
|
1
20%
|
3
75%
|
0
0%
|
0
0%
|
| Thrombocytopenia |
0
0%
|
1
50%
|
1
33.3%
|
2
40%
|
6
150%
|
0
0%
|
1
25%
|
| Vision blurred |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
50%
|
1
33.3%
|
0
0%
|
| Visual symptoms |
3
150%
|
12
600%
|
4
133.3%
|
6
120%
|
17
425%
|
4
133.3%
|
2
50%
|
| Vomiting |
0
0%
|
1
50%
|
0
0%
|
0
0%
|
3
75%
|
1
33.3%
|
0
0%
|
| Weight loss and abnormal weight loss |
1
50%
|
0
0%
|
0
0%
|
1
20%
|
3
75%
|
1
33.3%
|
2
50%
|
| Title | Evaluate Prostate-specific Antigen (PSA) Response Rate by PCWG2 Criteria |
|---|---|
| Description | The PSA response rate will be evaluated using PCWG2 criteria and defined as the proportion of patients with a PSA decline of at least 50%. Any change from baseline is confirmed by a second measurement at least 3 weeks later. PSA Response Rate will be evaluated using PCWG2 criteria and defined as following: Percentage change from baseline in PSA to 12 weeks post ZEN003694 dose. Only evaluate for patients with at least 12 weeks of treatment, the PSA assessment at 12 weeks (84 days +/-3 days) will be used; Maximum percent decrease in PSA from baseline that occurs at any point after treatment. Evaluable for all patients with post-baseline PSA. Arms will be combined to analyze efficacy in Cohort A and Cohort B. |
| Time Frame | Screening up to 35 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Arms were combined to analyze efficacy based on Cohorts defined by protocol. Cohort A is defined as patients with prior progression on enzalutamide or apalutamide by PCWG2 criteria. Cohort B is defined as patients who were enzalutamide-naïve with prior progression on abiraterone by PCWG2 criteria. |
| Arm/Group Title | DE/DC-A ZEN003694 + Enzalutamide | DE/DC-B ZEN003694 + Enzalutamide |
|---|---|---|
| Arm/Group Description | Dose Escalation + Dose Confirmation - Cohort A - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 -144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation + Dose Confirmation - Cohort B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 - 96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. |
| Measure Participants | 45 | 30 |
| Number (95% Confidence Interval) [percentage of participants] |
4.4
220%
|
23.3
1165%
|
| Title | Evaluate Radiographic Response Rate (Overall Response Rate) by PCWG2 Criteria |
|---|---|
| Description | Tumor response will be evaluated using the PCWG2 criteria. Patients with measurable disease will be evaluated for clinical benefit as determined by tumor response using RECIST v1.1. Patients with non-measurable bone disease will be evaluated for progression based on the presence of any new lesions by bone scans. Radiographic tumor evaluation will be performed at screening and every 3 cycles or more frequently as determined by the investigator. Using the tumor response that is determined by the investigator, best overall response will be determined using RECIST v1.1. Best overall response is defined as the best response recorded from the start of treatment until disease progression or study exit. Arms will be combined to analyze efficacy in Cohort A and Cohort B. |
| Time Frame | Screening up to 35 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Arms were combined to analyze efficacy based on Cohorts defined by protocol. Cohort A is defined as patients with prior progression on enzalutamide or apalutamide by PCWG2 criteria. Cohort B is defined as patients who were enzalutamide-naïve with prior progression on abiraterone by PCWG2 criteria. |
| Arm/Group Title | DE/DC A ZEN003694 + Enzalutamide | DE/DC B ZEN003694 + Enzalutamide |
|---|---|---|
| Arm/Group Description | Dose Escalation + Dose Confirmation - Cohort A - Enzalutamide/Apalutamide Progressors - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 mg - 144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation + Dose Confirmation - Cohort B - Abiraterone Progressors - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 mg - 144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. |
| Measure Participants | 39 | 26 |
| Number (95% Confidence Interval) [percentage of participants] |
2.6
130%
|
3.8
190%
|
| Title | Evaluate Overall Median Progression-free Survival by PCWG2 Criteria |
|---|---|
| Description | Overall progression free survival (PFS) is determined using the PCWG2 criteria. Overall PFS is measured from screening until the time that disease progression (radiographic progressive disease or clinical deterioration) or death is documented, whichever occurs first. Arms will be combined to analyze efficacy in Cohort A and Cohort B. |
| Time Frame | Screening up to 35 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Arms were combined to analyze efficacy based on Cohorts defined by protocol. Cohort A is defined as patients with prior progression on enzalutamide or apalutamide by PCWG2 criteria. Cohort B is defined as patients who were enzalutamide-naïve with prior progression on abiraterone by PCWG2 criteria. |
| Arm/Group Title | DE/DC A ZEN003694 + Enzalutamide | DE/DC B ZEN003694 + Enzalutamide |
|---|---|---|
| Arm/Group Description | Dose Escalation + Dose Confirmation - Cohort A - Enzalutamide/Apalutamide Progressors - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 mg - 144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation + Dose Confirmation - Cohort B -Abiraterone Progressors - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 mg - 144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. |
| Measure Participants | 45 | 30 |
| Median (95% Confidence Interval) [months] |
4.7
|
6.2
|
| Title | Evaluate Median Radiographic Progression-Free Survival by PCWG2 Criteria |
|---|---|
| Description | Radiographic progression-free survival (rPFS) is determined using the PCWG2 criteria to assess both soft-tissue and bone assessments. The rPFS is measured from screening until the time the first radiographic scan shows disease progression, or until the time of death, whichever occurs first. If radiographic disease progression is identified at the first on-treatment radiographic assessment at Cycle 3 Day 1 (8 weeks), radiographic progression must be confirmed by a second assessment 6 or more weeks later. Patients who do not progress radiographically or did not die prior to study exit are censored on the date of their last dose of ZEN003694. Arms will be combined to analyze efficacy in Cohort A and Cohort B. |
| Time Frame | Screening up to 35 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Arms were combined to analyze efficacy based on Cohorts defined by protocol. Cohort A is defined as patients with prior progression on enzalutamide or apalutamide by PCWG2 criteria. Cohort B is defined as patients who were enzalutamide-naïve with prior progression on abiraterone by PCWG2 criteria. |
| Arm/Group Title | DE/DC A ZEN003694 + Enzalutamide | DE/DC B ZEN003694 + Enzalutamide |
|---|---|---|
| Arm/Group Description | Dose Escalation + Dose Confirmation - Cohort A - Enzalutamide/Apalutamide Progressors - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 mg -144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation + Dose Confirmation - Cohort B - Abiraterone Progressors - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 mg -144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. |
| Measure Participants | 45 | 30 |
| Median (95% Confidence Interval) [months] |
10.2
|
8.8
|
| Title | Measure the Pharmacokinetic (PK) Parameter: AUC(0-24h) of ZEN003694 and ZEN003791 (Active Metabolite) Administered in Combination With Enzalutamide. |
|---|---|
| Description | AUC(0-24h) is defined as the area under the curve (plasma concentration of drug over a 24-hour time period). |
| Time Frame | Cycle 1 Day 1: pre-dose, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-dose; Cycle 1 Day 2: pre-dose; Cycle 1 Day 15: pre-dose, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Evaluable Participants |
| Arm/Group Title | DE A+B 36 mg ZEN003694 + Enzalutamide | DE/DC A+B 48 mg ZEN003694 + Enzalutamide | DE A+B 60 mg ZEN003694 + Enzalutamide | DE A+B 72 mg ZEN003694 + Enzalutamide | DE/DC A+B 96 mg ZEN003694 + Enzalutamide | DE A+B 120 mg ZEN003694 + Enzalutamide | DE A+B 144 mg ZEN003694 + Enzalutamide |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation + Dose Confirmation - Cohorts A+B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (60 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (72 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation + Dose Confirmation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (120 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A +B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. |
| Measure Participants | 4 | 21 | 6 | 6 | 31 | 4 | 3 |
| ZEN003694 AUC(0-24h) Study Day 1 |
1001
(494)
|
985
(374)
|
2243
(848)
|
1966
(1067)
|
2424
(1450)
|
2153
(1529)
|
2119
(1547)
|
| ZEN003694 AUC(0-24h) Study Day 15; C24 (24h) inputed with Day 15 C0 (pre-dose) for AUC calculations |
867
(651)
|
1046
(512)
|
1487
(871)
|
1453
(967)
|
2138
(946)
|
2109
(578)
|
1641
(704)
|
| ZEN003791 AUC(0-24h) Study Day 1 |
1335
(659)
|
1874
(635)
|
3344
(1101)
|
3277
(1708)
|
4090
(1562)
|
3712
(2660)
|
3815
(2774)
|
| ZEN003791 AUC(0-24h) Study Day 15; C24 (24h) imputed with Day 15 C0 (pre-dose) for AUC calculations. |
1234
(606)
|
2216
(1187)
|
2979
(1583)
|
2586
(1265)
|
4478
(2449)
|
5275
(2369)
|
3155
(1858)
|
| Title | Measure the Pharmacokinetic (PK) Parameter: Cmax of ZEN003694 and ZEN003791 (Active Metabolite) Administered in Combination With Enzalutamide |
|---|---|
| Description | Cmax is defined as the maximum or peak plasma concentration of drug. |
| Time Frame | Cycle 1 Day 1: pre-dose, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-dose; Cycle 1 Day 2: pre-dose; Cycle 1 Day 15: pre-dose, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Evaluable Participants |
| Arm/Group Title | DE A+B - 36 mg ZEN003694 + Enzalutamide | DE/DC A+B 48 mg ZEN003694 + Enzalutamide | DE A+B 60 mg ZEN003694 + Enzalutamide PO QD | DE A+B 72 mg ZEN003694 + Enzalutamide | DE/DC A+B 96 mg ZEN003694 + Enzalutamide | DE A+B 120 mg ZEN003694 + Enzalutamide PO QD | DE A+B 144 mg ZEN003694 + Enzalutamide |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation + Dose Confirmation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (60 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (72 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation + Dose Confirmation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (120 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. |
| Measure Participants | 4 | 21 | 6 | 6 | 31 | 4 | 3 |
| ZEN003694 Cmax Study Day 1 |
181
(83)
|
216
(103)
|
290
(102)
|
452
(279)
|
492
(277)
|
425
(306)
|
494
(424)
|
| ZEN003694 Cmax Study Day 15 |
184
(128)
|
236
(119)
|
289
(204)
|
392
(278)
|
484
(189)
|
458
(305)
|
457
(330)
|
| ZEN003791 Cmax Study Day 1 |
125
(83)
|
184
(62)
|
244
(79)
|
306
(196)
|
374
(143)
|
342
(202)
|
417
(362)
|
| ZEN003791 Cmax Study Day 15 |
129
(72)
|
220
(101)
|
259
(176)
|
319
(208)
|
477
(194)
|
552
(332)
|
432
(362)
|
Adverse Events
| Time Frame | For an event to be recorded as an AE, the onset must occur during or after the patient's first exposure to study drug and no later than 30 days after the last study drug dose. There is no limit on reporting SAEs considered reasonably related to ZEN003694. | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Adverse events were collected in all participants | |||||||||||||
| Arm/Group Title | DE A+B 36 mg ZEN003694 + Enzalutamide | DE/DC A+B 48 mg ZEN003694 + Enzalutamide | DE A+B 60 mg ZEN003694 + Enzalutamide | DE A+B 72 mg ZEN003694 + Enzalutamide | DE/DC A+B 96 mg ZEN003694 + Enzalutamide | DE A+B 120 mg ZEN003694 + Enzalutamide | DE A+B 144 mg ZEN003694 + Enzalutamide | |||||||
| Arm/Group Description | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (36 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation + Dose Confirmation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (48 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (60 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (72 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation + Dose Confirmation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (96 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (120 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | Dose Escalation - Cohorts A + B - Enzalutamide (160 mg) PO QD 14 days lead-in followed by the combination of ZEN003694 (144 mg) PO QD and enzalutamide (160 mg) PO QD in 28-day cycles. | |||||||
All Cause Mortality |
||||||||||||||
| DE A+B 36 mg ZEN003694 + Enzalutamide | DE/DC A+B 48 mg ZEN003694 + Enzalutamide | DE A+B 60 mg ZEN003694 + Enzalutamide | DE A+B 72 mg ZEN003694 + Enzalutamide | DE/DC A+B 96 mg ZEN003694 + Enzalutamide | DE A+B 120 mg ZEN003694 + Enzalutamide | DE A+B 144 mg ZEN003694 + Enzalutamide | ||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/4 (0%) | 0/21 (0%) | 0/6 (0%) | 0/6 (0%) | 0/31 (0%) | 0/4 (0%) | 0/3 (0%) | |||||||
Serious Adverse Events |
||||||||||||||
| DE A+B 36 mg ZEN003694 + Enzalutamide | DE/DC A+B 48 mg ZEN003694 + Enzalutamide | DE A+B 60 mg ZEN003694 + Enzalutamide | DE A+B 72 mg ZEN003694 + Enzalutamide | DE/DC A+B 96 mg ZEN003694 + Enzalutamide | DE A+B 120 mg ZEN003694 + Enzalutamide | DE A+B 144 mg ZEN003694 + Enzalutamide | ||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/4 (25%) | 3/21 (14.3%) | 1/6 (16.7%) | 2/6 (33.3%) | 6/31 (19.4%) | 1/4 (25%) | 3/3 (100%) | |||||||
| Blood and lymphatic system disorders | ||||||||||||||
| Disseminated intravascular coagulation | 0/4 (0%) | 0/21 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/31 (0%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Cardiac disorders | ||||||||||||||
| Myocardial ischaemia | 0/4 (0%) | 0/21 (0%) | 0/6 (0%) | 0/6 (0%) | 1/31 (3.2%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Eye disorders | ||||||||||||||
| Vision blurred | 0/4 (0%) | 0/21 (0%) | 0/6 (0%) | 0/6 (0%) | 0/31 (0%) | 0/4 (0%) | 1/3 (33.3%) | |||||||
| Gastrointestinal disorders | ||||||||||||||
| Nausea | 0/4 (0%) | 0/21 (0%) | 0/6 (0%) | 0/6 (0%) | 1/31 (3.2%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Small intestinal obstruction | 0/4 (0%) | 0/21 (0%) | 0/6 (0%) | 0/6 (0%) | 0/31 (0%) | 0/4 (0%) | 1/3 (33.3%) | |||||||
| Infections and infestations | ||||||||||||||
| Enterococcal bacteraemia | 1/4 (25%) | 0/21 (0%) | 0/6 (0%) | 0/6 (0%) | 0/31 (0%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Intervertebral discitis | 0/4 (0%) | 0/21 (0%) | 0/6 (0%) | 0/6 (0%) | 1/31 (3.2%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Leptospirosis | 0/4 (0%) | 0/21 (0%) | 0/6 (0%) | 0/6 (0%) | 0/31 (0%) | 0/4 (0%) | 1/3 (33.3%) | |||||||
| Proteus infection | 0/4 (0%) | 1/21 (4.8%) | 0/6 (0%) | 0/6 (0%) | 0/31 (0%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Pyelonephritis | 0/4 (0%) | 1/21 (4.8%) | 0/6 (0%) | 0/6 (0%) | 0/31 (0%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Urinary tract infection | 0/4 (0%) | 1/21 (4.8%) | 0/6 (0%) | 0/6 (0%) | 0/31 (0%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Injury, poisoning and procedural complications | ||||||||||||||
| Hip fracture | 0/4 (0%) | 1/21 (4.8%) | 0/6 (0%) | 0/6 (0%) | 0/31 (0%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||||
| Back pain | 0/4 (0%) | 1/21 (4.8%) | 0/6 (0%) | 0/6 (0%) | 0/31 (0%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Musculoskeletal pain | 0/4 (0%) | 0/21 (0%) | 0/6 (0%) | 0/6 (0%) | 1/31 (3.2%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Pathological fracture | 1/4 (25%) | 0/21 (0%) | 0/6 (0%) | 0/6 (0%) | 0/31 (0%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Nervous system disorders | ||||||||||||||
| Spinal cord compression | 0/4 (0%) | 0/21 (0%) | 0/6 (0%) | 1/6 (16.7%) | 1/31 (3.2%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Transient ischaemic attack | 0/4 (0%) | 0/21 (0%) | 0/6 (0%) | 0/6 (0%) | 0/31 (0%) | 1/4 (25%) | 0/3 (0%) | |||||||
| Renal and urinary disorders | ||||||||||||||
| Haematuria | 1/4 (25%) | 0/21 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/31 (0%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Acute kidney injury | 0/4 (0%) | 0/21 (0%) | 0/6 (0%) | 0/6 (0%) | 1/31 (3.2%) | 0/4 (0%) | 0/3 (0%) | |||||||
Other (Not Including Serious) Adverse Events |
||||||||||||||
| DE A+B 36 mg ZEN003694 + Enzalutamide | DE/DC A+B 48 mg ZEN003694 + Enzalutamide | DE A+B 60 mg ZEN003694 + Enzalutamide | DE A+B 72 mg ZEN003694 + Enzalutamide | DE/DC A+B 96 mg ZEN003694 + Enzalutamide | DE A+B 120 mg ZEN003694 + Enzalutamide | DE A+B 144 mg ZEN003694 + Enzalutamide | ||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/4 (75%) | 19/21 (90.5%) | 5/6 (83.3%) | 6/6 (100%) | 31/31 (100%) | 4/4 (100%) | 3/3 (100%) | |||||||
| Blood and lymphatic system disorders | ||||||||||||||
| Thrombocytopenia | 0/4 (0%) | 1/21 (4.8%) | 1/6 (16.7%) | 2/6 (33.3%) | 6/31 (19.4%) | 0/4 (0%) | 1/3 (33.3%) | |||||||
| Eye disorders | ||||||||||||||
| Visual impairment | 3/4 (75%) | 12/21 (57.1%) | 4/6 (66.7%) | 6/6 (100%) | 18/31 (58.1%) | 4/4 (100%) | 2/3 (66.7%) | |||||||
| Photosensitivity reaction | 0/4 (0%) | 2/21 (9.5%) | 0/6 (0%) | 0/6 (0%) | 3/31 (9.7%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Photopsia | 0/4 (0%) | 1/21 (4.8%) | 0/6 (0%) | 0/6 (0%) | 3/31 (9.7%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Gastrointestinal disorders | ||||||||||||||
| Nausea | 0/4 (0%) | 7/21 (33.3%) | 2/6 (33.3%) | 3/6 (50%) | 16/31 (51.6%) | 3/4 (75%) | 2/3 (66.7%) | |||||||
| Diarrhea | 0/4 (0%) | 0/21 (0%) | 0/6 (0%) | 1/6 (16.7%) | 5/31 (16.1%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Vomiting | 0/4 (0%) | 1/21 (4.8%) | 0/6 (0%) | 0/6 (0%) | 3/31 (9.7%) | 1/4 (25%) | 0/3 (0%) | |||||||
| Constipation | 0/4 (0%) | 1/21 (4.8%) | 0/6 (0%) | 0/6 (0%) | 3/31 (9.7%) | 0/4 (0%) | 0/3 (0%) | |||||||
| General disorders | ||||||||||||||
| Fatigue | 1/4 (25%) | 9/21 (42.9%) | 1/6 (16.7%) | 2/6 (33.3%) | 13/31 (41.9%) | 3/4 (75%) | 1/3 (33.3%) | |||||||
| Investigations | ||||||||||||||
| Weight decreased | 1/4 (25%) | 0/21 (0%) | 0/6 (0%) | 1/6 (16.7%) | 3/31 (9.7%) | 1/4 (25%) | 2/3 (66.7%) | |||||||
| Blood creatinine increased | 0/4 (0%) | 0/21 (0%) | 2/6 (33.3%) | 0/6 (0%) | 3/31 (9.7%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Metabolism and nutrition disorders | ||||||||||||||
| Decreased appetite | 0/4 (0%) | 2/21 (9.5%) | 2/6 (33.3%) | 1/6 (16.7%) | 10/31 (32.3%) | 3/4 (75%) | 2/3 (66.7%) | |||||||
| Nervous system disorders | ||||||||||||||
| Dysgeusia | 0/4 (0%) | 2/21 (9.5%) | 0/6 (0%) | 0/6 (0%) | 10/31 (32.3%) | 1/4 (25%) | 3/3 (100%) | |||||||
| Dizziness | 0/4 (0%) | 0/21 (0%) | 0/6 (0%) | 1/6 (16.7%) | 3/31 (9.7%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Taste disorder | 0/4 (0%) | 0/21 (0%) | 1/6 (16.7%) | 1/6 (16.7%) | 3/31 (9.7%) | 0/4 (0%) | 0/3 (0%) | |||||||
| Skin and subcutaneous tissue disorders | ||||||||||||||
| Rash maculopapular | 0/4 (0%) | 2/21 (9.5%) | 0/6 (0%) | 0/6 (0%) | 1/31 (3.2%) | 0/4 (0%) | 1/3 (33.3%) | |||||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Zenith Study Team |
|---|---|
| Organization | Zenith Epigenetics Ltd |
| Phone | (415) 470-5600 |
| ZEN003694-002@zenithepigenetics.com |
Responsible Party:
Zenith Epigenetics
ClinicalTrials.gov Identifier:
NCT02711956
Other Study ID Numbers:
- ZEN003694-002
First Posted:
Mar 17, 2016
Last Update Posted:
Nov 30, 2021
Last Verified:
Nov 1, 2021