Triple Negative Breast Cancer
Conditions
Keywords
TNBC, ZEN003694, ZEN-3694, Talazoparib, Breast Cancer, PARPi, poly ADP ribose polymerase, bromodomain, BETi
Brief summary
This is a two-part open label, non-randomized, Phase 2, study of ZEN003694 in combination with Talazoparib in patients with TNBC without germline mutations of BRCA1 or BRCA2. Part 1 is a dose escalation and Part 2 is a Simon 2-Stage design. There are 3 expansion cohorts: Expansion Cohort A (combination treatment in post-TROP2-ADC patients), Expansion Cohort B (ZEN003694 monotherapy), and Expansion Cohort C (combination treatment in TROP2-ADC-naive patients).
Interventions
DRUGZEN003694
PO QD
DRUGTalazoparib
PO QD
Sponsors
Pfizer
Newsoara Biopharma Co., Ltd.
Zenith Epigenetics
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
None (Open Label)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Females or males age ≥ 18 years (at time of signing informed consent) 2. Parts 1 and 2 only: Histologically confirmed metastatic or recurrent or locally advanced triple-negative breast cancer (estrogen receptor (ER) ≤10%; progesterone receptor (PR) ≤10%; and HER2 negative by immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH) Expansion only: Histologically confirmed metastatic or recurrent, or locally advanced triple-negative breast cancer as defined by the most recent American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. 3. Patient is not a candidate for endocrine based therapy, based on Investigator judgement 4. Have a history of progressive disease despite prior therapy 5. Part 1: Have had at least 1 prior cytotoxic chemotherapy. Part 2: Have had no more than 2 prior chemotherapy-inclusive regimens for locally advanced or metastatic disease, unless approved by the Sponsor (no limit on prior targeted anticancer therapies such as mechanistic target or rapamycin (mTOR) or CDK4/6 inhibitors, immune-oncology agents, tyrosine kinase inhibitors, or monoclonal antibodies against CTL4 or VEGF.) Expansion Cohort A (combination treatment in post-TROP2-ADC patients): Have received TROP2-ADC therapy for unresectable locally advanced or metastatic disease. Expansion Cohort B (ZEN003694 monotherapy): Have had at least 1 prior systemic therapy for locally advanced or metastatic disease which may or may not have included a TROP2-ADC. Expansion Cohort C (combination treatment in TROP2-ADC-naive patients): Have had at least 1 prior systemic therapy for locally advanced or metastatic disease and who have not received prior TROP2-ADC therapy. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 7. Part 2 and Expansion only: Measurable disease per RECIST version 1.1
Exclusion criteria
1. Documented germline mutations of BRCA1 or BRCA2 2. Parts 1 and 2 only: Evidence of disease progression during platinum treatment either in the neoadjuvant or in the metastatic setting. For patients receiving platinum in the neoadjuvant setting, at least 6 months must have elapsed between the last dose of platinum-based treatment and enrollment 3. Part 2 only: Patients with inflammatory breast cancer 4. Current or anticipated use of medications known to be strong inhibitors or inducers of CYP3A4 or substrates of CYP1A2 with narrow therapeutic windows. Strong inhibitors, inducers or substrates must be discontinued at least 7 days prior to the first administration of study drug. 5. Current or anticipated use within 7 days prior to the first administration of study drug, or during the study, of strong P-gp inhibitors. 6. Use of oral Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) and Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed 7. Prior anticancer therapy (chemotherapy, radiation, hormone therapy, immunotherapy or investigational agent) within 3 weeks from the start of study drug (except for nitrosoureas and mitomycin C within 6 weeks from start of study drug) 8. Parts 1 and 2 only: Radiation to \>25% of the bone marrow 9. Treatment with a bone-targeted radionuclide within 6 weeks of first dose of study drug 10. Have previously received an investigational BET inhibitor (including previous participation in studies with the Sponsor's drug, ZEN003694); except for patients in Expansion Cohort B who received ZEN003694 monotherapy and are eligible to cross-over to combination treatment 11. Prior treatment with a PARP inhibitor 12. QTcF interval \> 470 msec 13. Insufficient recovery (i.e., has not recovered to at least Grade 1) from prior treatment-related toxicities except for alopecia, fatigue and Grade 2 neuropathy 14. Non-healing wound, ulcer or bone fracture (not including a pathological bone fracture caused by a pre-existing pathological bone lesion) 15. Parts 1 and 2 only: Brain metastases not adequately treated and clinically stable (at the discretion of the Investigator) for at least 3 months prior to the start of study treatment, unless a shorter interval is approved by the Sponsor's Medical Monitor Expansion only: Progressive, symptomatic, or untreated brain metastases. CNS metastases treated definitively with surgery and/or radiation must be radiographically stable based on imaging at least 3 months after definitive treatment. CNS metastases requiring steroid doses equivalent to prednisone doses \>10 mg daily or an increase in steroid doses due to CNS disease prior to consent are not eligible 16. Expansion only: Disease initially diagnosed with expression of estrogen receptor (ER) or progesterone receptor (PR) as ≥5% 17. Expansion only: Patients treated with prior endocrine therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 and Part 2: Number of Participants With Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE) | Cycle 1 Day 1 to 30 days post last dose (each cycle is 28 days) up to 22 months | — |
| Part 1: Number of Participants With Dose-limiting Toxicities (DLT) | Cycle 1, Up to 1 month | Determination of DLT will be made during the first 28 days of treatment (i.e., Cycle 1) 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. |
| Part 2: Clinical Benefit Rate (CBR) | From screening up to 18 months | Percentage of patients with a best overall response of confirmed complete response (CR), partial response (PR), or stable disease (SD ≥ 4 cycles) by RECIST v1.1 |
| Expansion Cohort A: Objective Response Rate (ORR) by RECIST v1.1 (CR or PR) | From screening up to 18 months | Percentage of participants with a confirmed complete response (CR) or partial response (PR) by RECIST 1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2, Expansion Cohorts A and C: Evaluate Duration of Response (DOR) | From screening up to 18 months | For subjects with a confirmed response of PR or CR, duration of response is measured from the date of the first response until the time that overall disease progression (radiographic progressive disease or clinical deterioration) or death is documented. |
| Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Part 1: Cycle 1 Day 1: Pre-dose, 15 min, 30 min, 1 hour, 2 hour, 4 hour, 6 hour, and 8 hours post-dose. Parts 1 & 2: Cycle 2 Day 1: Pre-dose, 1 hour, 2 hour, and 4 hours post-dose. (cycles are 28 days) | Cmax is defined as the maximum or peak plasma concentration of drug (calculated from samples taken over a 4-hour or 8-hour time period). Cmax(0-8h) was calculated for Cycle 1, Day 1. Cmax(0-4h) was calculated for Cycle 2, Day 1. Pre-dose is time 0 for calculations. |
| Part 1 and Part 2: Measure the Pharmacokinetic (PK) Parameter of Combined AUC(0-4h or 0-8h) of ZEN003694 and ZEN003791 (Active Metabolite) | Part 1: Cycle 1 Day 1: Pre-dose, 15 min, 30 min, 1 hour, 2 hour, 4 hour, 6 hour, and 8 hours post-dose. Parts 1 & 2: Cycle 2 Day 1: Pre-dose, 1 hour, 2 hour, and 4 hours post-dose. (cycles are 28 days) | AUC(0-4h or 0-8h) is defined as the area under the curve (plasma concentration of drug calculated from samples taken over a 4-hour or 8-hour time period). AUC(0-8h) was calculated for Cycle 1, Day 1. AUC(0-4h) was calculated for Cycle 2, Day 1. Pre-dose is time 0 for calculations. |
| Part 1 & 2: Measure Plasma Concentrations of Talazoparib. | Part 1: Cycle 1 Day 15: Pre-dose; Parts 1& 2 Cycle 2 Day 1: Pre-dose; Cycle 2 Day 15: Pre-dose (each cycle is 28 days) | Plasma concentrations of talazoparib will be measured. |
| Part 1, Part 2, and Expansion Cohort C: Objective Response Rate (ORR) | From screening up to 18 months | Percentage of participants with a confirmed complete response (CR) or partial response (PR) by RECIST 1.1 |
| Expansion Cohorts A and C: Measure Plasma Concentrations of Talazoparib. | Cycle 2 Day 1: Pre-dose, Cycle 2 Day 15: Pre-dose (each cycle is 28 days) | Plasma concentrations of talazoparib will be measured. |
| Part 2, Expansion Cohorts A and C: Change From Baseline in Global Health Status/Quality of Life (QoL) Measured by EORTC QLQ-C30 for Overall Duration | Screening and Day 1 of every 28-day Cycle, up to 18 months (Overall Duration) | European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30): cancer-specific instrument with 30 questions to assess the participant QoL. First 28 questions used to evaluate 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, nausea and vomiting, pain) and other single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Each question assessed on 4-point scale (1= not at all, 2= a little, 3= quite a bit, 4= very much); functional scales: higher score = better level of functioning; symptom scale: higher score = more severe symptoms; for single items: higher score= more severe problem. Last 2 questions used to evaluate global health status (GHS)/QoL. Each question was assessed on 7-point scale (1= very poor to 7= excellent). Scores averaged, transformed to 0-100 scale; higher score=better quality of life/better level of functioning. |
| Part 2, Expansion Cohorts A and C: Change From Baseline in Breast Symptoms Scale as Assessed by the EORTC-QLQ-BR23 | Screening and Day 1 of every 28-day Cycle, up to 18 months (Overall Duration) | European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer Module (EORTC-QLQ-BR23) is a disease-specific module for breast cancer developed as a supplement for the EORTC-QLQ-C30 to assess the quality of life of participants with breast cancer. EORTC-QLQ-BR23 symptoms subscale includes 4 items: systemic therapy side effects, breast symptoms, arm symptoms, upset by hair loss. Each item is rated by choosing 1 of 4 possible responses that record the level of intensity (1= not at all, 2= a little, 3= quite a bit, and 4= very much), higher scores=high level of symptom/problems. |
| Expansion Cohorts A, B, and C: Measure Plasma Concentrations of ZEN003694 and the Active Metabolite ZEN003791. | Cycle 2 Day 1: Pre-dose, 1 hour, 2 hours, and 4 hours post-dose; Cycle 2 Day 15: Pre-dose (each cycle is 28 days) | Plasma concentrations of ZEN003694 and the active metabolite ZEN003791 will be measured. |
| Part 1, Expansion Cohorts A and C: Clinical Benefit Rate (CBR) | From screening up to 18 months | Percentage of participants with a confirmed complete response (CR), partial response (PR), or stable disease (SD ≥ 4 cycles) by RECIST 1.1 |
| Part 2, Expansion Cohorts A and C: Safety Profile of ZEN003694 in Combination With Talazoparib. | From screening up to 18 months | Incidence of Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE) in Part 2, Expansion Cohorts A and C |
| Part 1, Part 2, Expansion Cohorts A & C: Evaluate Median Progression-free Survival | From screening up to 18 months | Median progression-free survival is the time from randomization to documented disease progression or death |
Countries
Belgium, China, Spain, United States
Participant flow
Recruitment details
The study was conducted at nineteen investigational sites in the United States (eight), Belgium (two), Spain (two), and China (seven) between June 2019 and March 2024
Pre-assignment details
115 participants were enrolled and treated in the study.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 Dose Escalation: Cohort 1 ZEN003694 48 mg PO QD with Talazoparib 1 mg PO QD in 28-day cycles. Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in the US and EU. | 6 |
| Part 1 Dose Escalation: Cohort 2 ZEN003694 48 mg PO QD with Talazoparib 0.75 mg PO QD in 28-day cycles. Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in the US and EU. | 8 |
| Part 1 Dose Escalation: Cohort 3 ZEN003694 36 mg PO QD with Talazoparib 1 mg PO QD in 28-day cycles. Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in the US and EU. | 3 |
| Part 2 Stages 1 & 2 ZEN003694 48 mg PO QD with Talazoparib 0.75 mg PO QD in 28-day cycles. Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in the US and EU. | 42 |
| Expansion Cohort A - Combination Treatment in Post-TROP2-ADC Patients ZEN003694 48 mg PO QD with Talazoparib 0.75 mg PO QD (RP2D) in 28-day cycles. Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in the US and EU. | 21 |
| Expansion Cohort B - ZEN003694 Monotherapy ZEN003694 48 mg PO QD as monotherapy at the in 28-day cycles with the option to cross-over to combination treatment of ZEN003694 48 mg PO QD with 0.75 mg Talazoparib PO QD at the time of disease progression (but no sooner than after 6 weeks of monotherapy). Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in the US and EU. | 3 |
| Expansion Cohort C - Combination Treatment in TROP2-ADC-naïve Patients ZEN003694 48 mg PO QD with Talazoparib PO QD (RP2D) in 28-day cycles. Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in China only. | 32 |
| Total | 115 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 | 9 |
| Overall Study | Clinical Progression | 0 | 2 | 0 | 7 | 6 | 0 | 2 |
| Overall Study | Death | 0 | 0 | 0 | 3 | 5 | 0 | 1 |
| Overall Study | Not Reported | 1 | 0 | 0 | 1 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Radiographic Progression | 4 | 6 | 3 | 30 | 7 | 2 | 11 |
| Overall Study | Termination of study by sponsor | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 2 | 0 | 8 |
Baseline characteristics
| Characteristic | Total | Part 1 Dose Escalation: Cohort 1 | Expansion Cohort C - Combination Treatment in TROP2-ADC-naïve Patients | Expansion Cohort B - ZEN003694 Monotherapy | Expansion Cohort A - Combination Treatment in Post-TROP2-ADC Patients | Part 2 Stages 1 & 2 | Part 1 Dose Escalation: Cohort 3 | Part 1 Dose Escalation: Cohort 2 |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 52 years | 55 years | 55 years | 50 years | 49 years | 51.5 years | 57 years | 53 years |
| BMI | 25.57 kg/m^2 | 24.61 kg/m^2 | 25.195 kg/m^2 | 21.70 kg/m^2 | 27.16 kg/m^2 | 25.90 kg/m^2 | 24.84 kg/m^2 | 27.65 kg/m^2 |
| ECOG Performance Status ECOG 0 | 66 Participants | 4 Participants | 15 Participants | 1 Participants | 14 Participants | 26 Participants | 2 Participants | 4 Participants |
| ECOG Performance Status ECOG 1 | 48 Participants | 2 Participants | 17 Participants | 2 Participants | 6 Participants | 16 Participants | 1 Participants | 4 Participants |
| ECOG Performance Status ECOG 2 | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 95 Participants | 5 Participants | 20 Participants | 3 Participants | 18 Participants | 40 Participants | 2 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 14 Participants | 0 Participants | 12 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Height | 162.5 cm | 164.60 cm STANDARD_DEVIATION 5.088 | 157.5 cm | 175.2 cm | 165.2 cm | 164.5 cm | 164.0 cm | 166.35 cm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 34 Participants | 0 Participants | 31 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 68 Participants | 5 Participants | 0 Participants | 2 Participants | 14 Participants | 38 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Female | 115 Participants | 6 Participants | 32 Participants | 3 Participants | 21 Participants | 42 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Weight | 68.07 kg STANDARD_DEVIATION 13.531 | 69.9 kg | 61.55 kg STANDARD_DEVIATION 10.212 | 62.30 kg STANDARD_DEVIATION 5.726 | 72.98 kg STANDARD_DEVIATION 14.325 | 67.25 kg STANDARD_DEVIATION 12.804 | 74.00 kg STANDARD_DEVIATION 18.672 | 79.35 kg STANDARD_DEVIATION 23.396 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 8 | 0 / 3 | 3 / 42 | 5 / 21 | 0 / 3 | 0 / 1 | 1 / 32 |
| other Total, other adverse events | 6 / 6 | 8 / 8 | 3 / 3 | 42 / 42 | 21 / 21 | 2 / 3 | 1 / 1 | 32 / 32 |
| serious Total, serious adverse events | 3 / 6 | 2 / 8 | 1 / 3 | 11 / 42 | 10 / 21 | 0 / 3 | 0 / 1 | 14 / 32 |
Outcome results
Primary
Expansion Cohort A: Objective Response Rate (ORR) by RECIST v1.1 (CR or PR)
Percentage of participants with a confirmed complete response (CR) or partial response (PR) by RECIST 1.1
Time frame: From screening up to 18 months
Population: Patients who have received at least 3 weeks of per-protocol treatment during Cycle 1, or \<3 weeks of treatment in Cycle 1 because of a DLT, will comprise the Efficacy Population. Patients who were determined to be unevaluable during Cycle 1 by the Sponsor and Investigator will not be included in the Efficacy Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Dose Escalation: Cohort 1 | Expansion Cohort A: Objective Response Rate (ORR) by RECIST v1.1 (CR or PR) | 0 Percentage of participants |
Primary
Part 1 and Part 2: Number of Participants With Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE)
Time frame: Cycle 1 Day 1 to 30 days post last dose (each cycle is 28 days) up to 22 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 Dose Escalation: Cohort 1 | Part 1 and Part 2: Number of Participants With Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE) | Patients Reporting at least one TEAE related to study treatment | 6 Participants |
| Part 1 Dose Escalation: Cohort 1 | Part 1 and Part 2: Number of Participants With Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE) | Patients reporting at least one Serious TEAE related to study treatment | 2 Participants |
| Part 1 Dose Escalation: Cohort 2 | Part 1 and Part 2: Number of Participants With Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE) | Patients reporting at least one Serious TEAE related to study treatment | 1 Participants |
| Part 1 Dose Escalation: Cohort 2 | Part 1 and Part 2: Number of Participants With Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE) | Patients Reporting at least one TEAE related to study treatment | 8 Participants |
| Part 1 Dose Escalation: Cohort 3 | Part 1 and Part 2: Number of Participants With Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE) | Patients Reporting at least one TEAE related to study treatment | 3 Participants |
| Part 1 Dose Escalation: Cohort 3 | Part 1 and Part 2: Number of Participants With Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE) | Patients reporting at least one Serious TEAE related to study treatment | 0 Participants |
| Part 2 Stages 1 & 2 | Part 1 and Part 2: Number of Participants With Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE) | Patients Reporting at least one TEAE related to study treatment | 41 Participants |
| Part 2 Stages 1 & 2 | Part 1 and Part 2: Number of Participants With Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE) | Patients reporting at least one Serious TEAE related to study treatment | 4 Participants |
Primary
Part 1: Number of Participants With Dose-limiting Toxicities (DLT)
Determination of DLT will be made during the first 28 days of treatment (i.e., Cycle 1) 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.
Time frame: Cycle 1, Up to 1 month
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1 Dose Escalation: Cohort 1 | Part 1: Number of Participants With Dose-limiting Toxicities (DLT) | Platelet count decreased | 1 participants |
| Part 1 Dose Escalation: Cohort 1 | Part 1: Number of Participants With Dose-limiting Toxicities (DLT) | Platelet count decreased/ Fatigue | 1 participants |
| Part 1 Dose Escalation: Cohort 2 | Part 1: Number of Participants With Dose-limiting Toxicities (DLT) | Platelet count decreased | 1 participants |
| Part 1 Dose Escalation: Cohort 2 | Part 1: Number of Participants With Dose-limiting Toxicities (DLT) | Platelet count decreased/ Fatigue | 0 participants |
| Part 1 Dose Escalation: Cohort 3 | Part 1: Number of Participants With Dose-limiting Toxicities (DLT) | Platelet count decreased | 0 participants |
| Part 1 Dose Escalation: Cohort 3 | Part 1: Number of Participants With Dose-limiting Toxicities (DLT) | Platelet count decreased/ Fatigue | 0 participants |
Primary
Part 2: Clinical Benefit Rate (CBR)
Percentage of patients with a best overall response of confirmed complete response (CR), partial response (PR), or stable disease (SD ≥ 4 cycles) by RECIST v1.1
Time frame: From screening up to 18 months
Population: Patients who have received at least 3 weeks of per-protocol treatment during Cycle 1, or \<3 weeks of treatment in Cycle 1 because of a DLT, will comprise the Efficacy Population. Patients who were determined to be unevaluable during Cycle 1 by the Sponsor and Investigator will not be included in the Efficacy Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Dose Escalation: Cohort 1 | Part 2: Clinical Benefit Rate (CBR) | 32.4 Percentage of participants |
Secondary
Expansion Cohorts A and C: Measure Plasma Concentrations of Talazoparib.
Plasma concentrations of talazoparib will be measured.
Time frame: Cycle 2 Day 1: Pre-dose, Cycle 2 Day 15: Pre-dose (each cycle is 28 days)
Population: Cohorts A and B - Study was terminated prior to PK analysis for samples collected from cohorts A and B, therefore data was not obtained. Data will never be obtained and reported for this measure. Cohort C - All Evaluable Participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Dose Escalation: Cohort 2 | Expansion Cohorts A and C: Measure Plasma Concentrations of Talazoparib. | Talazoparib Cycle 2 Day 1 - Pre-dose | 2152.8 pg/mL | Standard Deviation 2031.9 |
| Part 1 Dose Escalation: Cohort 2 | Expansion Cohorts A and C: Measure Plasma Concentrations of Talazoparib. | Talazoparib Cycle 2 Day 15 - Pre-dose | 4494.1 pg/mL | Standard Deviation 3139.8 |
Secondary
Expansion Cohorts A, B, and C: Measure Plasma Concentrations of ZEN003694 and the Active Metabolite ZEN003791.
Plasma concentrations of ZEN003694 and the active metabolite ZEN003791 will be measured.
Time frame: Cycle 2 Day 1: Pre-dose, 1 hour, 2 hours, and 4 hours post-dose; Cycle 2 Day 15: Pre-dose (each cycle is 28 days)
Population: Cohorts A and B - Study was terminated prior to PK analysis for samples collected from cohorts A and B, therefore data was not obtained. Data will never be obtained and reported for this measure. Cohort C - All Evaluable Participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Dose Escalation: Cohort 3 | Expansion Cohorts A, B, and C: Measure Plasma Concentrations of ZEN003694 and the Active Metabolite ZEN003791. | ZEN003694 Cycle 2 Day 1 - Predose | 33.82 ng/mL | Standard Deviation 21.4 |
| Part 1 Dose Escalation: Cohort 3 | Expansion Cohorts A, B, and C: Measure Plasma Concentrations of ZEN003694 and the Active Metabolite ZEN003791. | ZEN003694 Cycle 2 Day 1 - 1 hour | 383.9 ng/mL | Standard Deviation 259.1 |
| Part 1 Dose Escalation: Cohort 3 | Expansion Cohorts A, B, and C: Measure Plasma Concentrations of ZEN003694 and the Active Metabolite ZEN003791. | ZEN003694 Cycle 2 Day 1 - 2 hours | 397.2 ng/mL | Standard Deviation 232.4 |
| Part 1 Dose Escalation: Cohort 3 | Expansion Cohorts A, B, and C: Measure Plasma Concentrations of ZEN003694 and the Active Metabolite ZEN003791. | ZEN003694 Cycle 2 Day 1 - 4 hours | 345.3 ng/mL | Standard Deviation 116.9 |
| Part 1 Dose Escalation: Cohort 3 | Expansion Cohorts A, B, and C: Measure Plasma Concentrations of ZEN003694 and the Active Metabolite ZEN003791. | ZEN003694 Cycle 2 Day 15 - Predose | 45.2 ng/mL | Standard Deviation 28.6 |
| Part 1 Dose Escalation: Cohort 3 | Expansion Cohorts A, B, and C: Measure Plasma Concentrations of ZEN003694 and the Active Metabolite ZEN003791. | ZEN003791 Cycle 2 Day 1 - Predose | 110.2 ng/mL | Standard Deviation 84.3 |
| Part 1 Dose Escalation: Cohort 3 | Expansion Cohorts A, B, and C: Measure Plasma Concentrations of ZEN003694 and the Active Metabolite ZEN003791. | ZEN003791 Cycle 2 Day 1 - 1 hour | 231.0 ng/mL | Standard Deviation 158.9 |
| Part 1 Dose Escalation: Cohort 3 | Expansion Cohorts A, B, and C: Measure Plasma Concentrations of ZEN003694 and the Active Metabolite ZEN003791. | ZEN003791 Cycle 2 Day 1 - 2 hours | 268.4 ng/mL | Standard Deviation 207 |
| Part 1 Dose Escalation: Cohort 3 | Expansion Cohorts A, B, and C: Measure Plasma Concentrations of ZEN003694 and the Active Metabolite ZEN003791. | ZEN003791 Cycle 2 Day 1 - 4 hours | 303.8 ng/mL | Standard Deviation 154.1 |
| Part 1 Dose Escalation: Cohort 3 | Expansion Cohorts A, B, and C: Measure Plasma Concentrations of ZEN003694 and the Active Metabolite ZEN003791. | ZEN003791 Cycle 2 Day 15 - Predose | 169.0 ng/mL | Standard Deviation 111.3 |
Secondary
Part 1 & 2: Measure Plasma Concentrations of Talazoparib.
Plasma concentrations of talazoparib will be measured.
Time frame: Part 1: Cycle 1 Day 15: Pre-dose; Parts 1& 2 Cycle 2 Day 1: Pre-dose; Cycle 2 Day 15: Pre-dose (each cycle is 28 days)
Population: Part 1 (All evaluable participants): C1D15; Parts 1 \& 2 (All evaluable participants): C2D1 \& C2D15
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Dose Escalation: Cohort 1 | Part 1 & 2: Measure Plasma Concentrations of Talazoparib. | Cycle 2 Day 15 Pre-dose | 3952.5 pg/mL | Standard Deviation 1348.7 |
| Part 1 Dose Escalation: Cohort 1 | Part 1 & 2: Measure Plasma Concentrations of Talazoparib. | Cycle 2 Day 1 Pre-dose | 3814 pg/mL | Standard Deviation 3092 |
| Part 1 Dose Escalation: Cohort 1 | Part 1 & 2: Measure Plasma Concentrations of Talazoparib. | Cycle 1 Day 15 Pre-dose | 4813.3 pg/mL | Standard Deviation 2278.1 |
| Part 1 Dose Escalation: Cohort 2 | Part 1 & 2: Measure Plasma Concentrations of Talazoparib. | Cycle 2 Day 15 Pre-dose | 4892.5 pg/mL | Standard Deviation 1957.5 |
| Part 1 Dose Escalation: Cohort 2 | Part 1 & 2: Measure Plasma Concentrations of Talazoparib. | Cycle 1 Day 15 Pre-dose | 4582 pg/mL | Standard Deviation 1562.5 |
| Part 1 Dose Escalation: Cohort 2 | Part 1 & 2: Measure Plasma Concentrations of Talazoparib. | Cycle 2 Day 1 Pre-dose | 3584.3 pg/mL | Standard Deviation 2819.4 |
| Part 1 Dose Escalation: Cohort 3 | Part 1 & 2: Measure Plasma Concentrations of Talazoparib. | Cycle 2 Day 1 Pre-dose | 8220 pg/mL | Standard Deviation 4073.1 |
| Part 1 Dose Escalation: Cohort 3 | Part 1 & 2: Measure Plasma Concentrations of Talazoparib. | Cycle 1 Day 15 Pre-dose | 5650 pg/mL | Standard Deviation 2714.1 |
| Part 1 Dose Escalation: Cohort 3 | Part 1 & 2: Measure Plasma Concentrations of Talazoparib. | Cycle 2 Day 15 Pre-dose | 4840 pg/mL | Standard Deviation 3097.1 |
| Part 2 Stages 1 & 2 | Part 1 & 2: Measure Plasma Concentrations of Talazoparib. | Cycle 2 Day 15 Pre-dose | 4240 pg/mL | Standard Deviation 2110.4 |
| Part 2 Stages 1 & 2 | Part 1 & 2: Measure Plasma Concentrations of Talazoparib. | Cycle 2 Day 1 Pre-dose | 3129.8 pg/mL | Standard Deviation 2190.2 |
Secondary
Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite)
Cmax is defined as the maximum or peak plasma concentration of drug (calculated from samples taken over a 4-hour or 8-hour time period). Cmax(0-8h) was calculated for Cycle 1, Day 1. Cmax(0-4h) was calculated for Cycle 2, Day 1. Pre-dose is time 0 for calculations.
Time frame: Part 1: Cycle 1 Day 1: Pre-dose, 15 min, 30 min, 1 hour, 2 hour, 4 hour, 6 hour, and 8 hours post-dose. Parts 1 & 2: Cycle 2 Day 1: Pre-dose, 1 hour, 2 hour, and 4 hours post-dose. (cycles are 28 days)
Population: Part 1 (All evaluable participants): C1D1; Parts 1 \& 2 (All evaluable participants): C2D1
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Dose Escalation: Cohort 1 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 1 Day 1 - ZEN003694 | 406 ng/ML | Standard Error 166 |
| Part 1 Dose Escalation: Cohort 1 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 2 Day 1 - ZEN003694 | 217 ng/ML | Standard Error 154 |
| Part 1 Dose Escalation: Cohort 1 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 1 Day 1 - ZEN003791 | 202 ng/ML | Standard Error 60 |
| Part 1 Dose Escalation: Cohort 1 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 2 Day 1 - ZEN003791 | 88 ng/ML | Standard Error 30 |
| Part 1 Dose Escalation: Cohort 2 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 2 Day 1 - ZEN003694 | 465 ng/ML | Standard Error 158 |
| Part 1 Dose Escalation: Cohort 2 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 1 Day 1 - ZEN003791 | 187 ng/ML | Standard Error 65 |
| Part 1 Dose Escalation: Cohort 2 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 1 Day 1 - ZEN003694 | 407 ng/ML | Standard Error 104 |
| Part 1 Dose Escalation: Cohort 2 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 2 Day 1 - ZEN003791 | 242 ng/ML | Standard Error 81 |
| Part 1 Dose Escalation: Cohort 3 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 1 Day 1 - ZEN003694 | 143 ng/ML | Standard Error 119 |
| Part 1 Dose Escalation: Cohort 3 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 1 Day 1 - ZEN003791 | 66 ng/ML | Standard Error 30 |
| Part 1 Dose Escalation: Cohort 3 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 2 Day 1 - ZEN003694 | 401 ng/ML | Standard Error 174 |
| Part 1 Dose Escalation: Cohort 3 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 2 Day 1 - ZEN003791 | 218 ng/ML | Standard Error 80 |
| Part 2 Stages 1 & 2 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 2 Day 1 - ZEN003791 | 285 ng/ML | Standard Error 127 |
| Part 2 Stages 1 & 2 | Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite) | Cycle 2 Day 1 - ZEN003694 | 513 ng/ML | Standard Error 196 |
Secondary
Part 1 and Part 2: Measure the Pharmacokinetic (PK) Parameter of Combined AUC(0-4h or 0-8h) of ZEN003694 and ZEN003791 (Active Metabolite)
AUC(0-4h or 0-8h) is defined as the area under the curve (plasma concentration of drug calculated from samples taken over a 4-hour or 8-hour time period). AUC(0-8h) was calculated for Cycle 1, Day 1. AUC(0-4h) was calculated for Cycle 2, Day 1. Pre-dose is time 0 for calculations.
Time frame: Part 1: Cycle 1 Day 1: Pre-dose, 15 min, 30 min, 1 hour, 2 hour, 4 hour, 6 hour, and 8 hours post-dose. Parts 1 & 2: Cycle 2 Day 1: Pre-dose, 1 hour, 2 hour, and 4 hours post-dose. (cycles are 28 days)
Population: Part 1 (All evaluable participants): C1D1; Parts 1 \& 2 (All evaluable participants): C2D1
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Dose Escalation: Cohort 1 | Part 1 and Part 2: Measure the Pharmacokinetic (PK) Parameter of Combined AUC(0-4h or 0-8h) of ZEN003694 and ZEN003791 (Active Metabolite) | AUC(0-4h) Cycle 2 Day 1 | 3067 ng*h/mL | Standard Error 1628 |
| Part 1 Dose Escalation: Cohort 1 | Part 1 and Part 2: Measure the Pharmacokinetic (PK) Parameter of Combined AUC(0-4h or 0-8h) of ZEN003694 and ZEN003791 (Active Metabolite) | AUC(0-8h) Cycle 1 Day 1 | 2680 ng*h/mL | Standard Error 894 |
| Part 1 Dose Escalation: Cohort 2 | Part 1 and Part 2: Measure the Pharmacokinetic (PK) Parameter of Combined AUC(0-4h or 0-8h) of ZEN003694 and ZEN003791 (Active Metabolite) | AUC(0-4h) Cycle 2 Day 1 | 5615 ng*h/mL | Standard Error 696 |
| Part 1 Dose Escalation: Cohort 2 | Part 1 and Part 2: Measure the Pharmacokinetic (PK) Parameter of Combined AUC(0-4h or 0-8h) of ZEN003694 and ZEN003791 (Active Metabolite) | AUC(0-8h) Cycle 1 Day 1 | 2502 ng*h/mL | Standard Error 994 |
| Part 1 Dose Escalation: Cohort 3 | Part 1 and Part 2: Measure the Pharmacokinetic (PK) Parameter of Combined AUC(0-4h or 0-8h) of ZEN003694 and ZEN003791 (Active Metabolite) | AUC(0-8h) Cycle 1 Day 1 | 1013 ng*h/mL | Standard Error 733 |
| Part 1 Dose Escalation: Cohort 3 | Part 1 and Part 2: Measure the Pharmacokinetic (PK) Parameter of Combined AUC(0-4h or 0-8h) of ZEN003694 and ZEN003791 (Active Metabolite) | AUC(0-4h) Cycle 2 Day 1 | 7375 ng*h/mL | Standard Error 3818 |
| Part 2 Stages 1 & 2 | Part 1 and Part 2: Measure the Pharmacokinetic (PK) Parameter of Combined AUC(0-4h or 0-8h) of ZEN003694 and ZEN003791 (Active Metabolite) | AUC(0-4h) Cycle 2 Day 1 | 1994 ng*h/mL | Standard Error 797 |
Secondary
Part 1, Expansion Cohorts A and C: Clinical Benefit Rate (CBR)
Percentage of participants with a confirmed complete response (CR), partial response (PR), or stable disease (SD ≥ 4 cycles) by RECIST 1.1
Time frame: From screening up to 18 months
Population: Patients who have received at least 3 weeks of per-protocol treatment during Cycle 1, or \<3 weeks of treatment in Cycle 1 because of a DLT, will comprise the Efficacy Population. Patients who were determined to be unevaluable during Cycle 1 by the Sponsor and Investigator will not be included in the Efficacy Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Dose Escalation: Cohort 1 | Part 1, Expansion Cohorts A and C: Clinical Benefit Rate (CBR) | 33.3 Percentage of participants |
| Part 1 Dose Escalation: Cohort 2 | Part 1, Expansion Cohorts A and C: Clinical Benefit Rate (CBR) | 66.7 Percentage of participants |
| Part 1 Dose Escalation: Cohort 3 | Part 1, Expansion Cohorts A and C: Clinical Benefit Rate (CBR) | 33.3 Percentage of participants |
| Part 2 Stages 1 & 2 | Part 1, Expansion Cohorts A and C: Clinical Benefit Rate (CBR) | 0 Percentage of participants |
| Expansion Cohort C - Combination Treatment in TROP2-ADC-naïve Patients | Part 1, Expansion Cohorts A and C: Clinical Benefit Rate (CBR) | 11.1 Percentage of participants |
Secondary
Part 1, Part 2, and Expansion Cohort C: Objective Response Rate (ORR)
Percentage of participants with a confirmed complete response (CR) or partial response (PR) by RECIST 1.1
Time frame: From screening up to 18 months
Population: Patients who have received at least 3 weeks of per-protocol treatment during Cycle 1, or \<3 weeks of treatment in Cycle 1 because of a DLT, will comprise the Efficacy Population. Patients who were determined to be unevaluable during Cycle 1 by the Sponsor and Investigator will not be included in the Efficacy Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Dose Escalation: Cohort 1 | Part 1, Part 2, and Expansion Cohort C: Objective Response Rate (ORR) | 33.3 Percentage of participants |
| Part 1 Dose Escalation: Cohort 2 | Part 1, Part 2, and Expansion Cohort C: Objective Response Rate (ORR) | 16.7 Percentage of participants |
| Part 1 Dose Escalation: Cohort 3 | Part 1, Part 2, and Expansion Cohort C: Objective Response Rate (ORR) | 33.3 Percentage of participants |
| Part 2 Stages 1 & 2 | Part 1, Part 2, and Expansion Cohort C: Objective Response Rate (ORR) | 21.6 Percentage of participants |
| Expansion Cohort C - Combination Treatment in TROP2-ADC-naïve Patients | Part 1, Part 2, and Expansion Cohort C: Objective Response Rate (ORR) | 5.6 Percentage of participants |
Secondary
Part 1, Part 2, Expansion Cohorts A & C: Evaluate Median Progression-free Survival
Median progression-free survival is the time from randomization to documented disease progression or death
Time frame: From screening up to 18 months
Population: Patients who have received at least 3 weeks of per-protocol treatment during Cycle 1, or \<3 weeks of treatment in Cycle 1 because of a DLT, will comprise the Efficacy Population. Patients who were determined to be unevaluable during Cycle 1 by the Sponsor and Investigator will not be included in the Efficacy Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Dose Escalation: Cohort 1 | Part 1, Part 2, Expansion Cohorts A & C: Evaluate Median Progression-free Survival | 5.42 months |
| Part 1 Dose Escalation: Cohort 2 | Part 1, Part 2, Expansion Cohorts A & C: Evaluate Median Progression-free Survival | 5.06 months |
| Part 1 Dose Escalation: Cohort 3 | Part 1, Part 2, Expansion Cohorts A & C: Evaluate Median Progression-free Survival | 1.51 months |
| Part 2 Stages 1 & 2 | Part 1, Part 2, Expansion Cohorts A & C: Evaluate Median Progression-free Survival | 3.25 months |
| Expansion Cohort C - Combination Treatment in TROP2-ADC-naïve Patients | Part 1, Part 2, Expansion Cohorts A & C: Evaluate Median Progression-free Survival | 1.38 months |
| Expansion Cohort C - Combination Treatment in TROP2-ADC-naïve Patients | Part 1, Part 2, Expansion Cohorts A & C: Evaluate Median Progression-free Survival | 1.71 months |
Secondary
Part 2, Expansion Cohorts A and C: Change From Baseline in Breast Symptoms Scale as Assessed by the EORTC-QLQ-BR23
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer Module (EORTC-QLQ-BR23) is a disease-specific module for breast cancer developed as a supplement for the EORTC-QLQ-C30 to assess the quality of life of participants with breast cancer. EORTC-QLQ-BR23 symptoms subscale includes 4 items: systemic therapy side effects, breast symptoms, arm symptoms, upset by hair loss. Each item is rated by choosing 1 of 4 possible responses that record the level of intensity (1= not at all, 2= a little, 3= quite a bit, and 4= very much), higher scores=high level of symptom/problems.
Time frame: Screening and Day 1 of every 28-day Cycle, up to 18 months (Overall Duration)
Secondary
Part 2, Expansion Cohorts A and C: Change From Baseline in Global Health Status/Quality of Life (QoL) Measured by EORTC QLQ-C30 for Overall Duration
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30): cancer-specific instrument with 30 questions to assess the participant QoL. First 28 questions used to evaluate 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, nausea and vomiting, pain) and other single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Each question assessed on 4-point scale (1= not at all, 2= a little, 3= quite a bit, 4= very much); functional scales: higher score = better level of functioning; symptom scale: higher score = more severe symptoms; for single items: higher score= more severe problem. Last 2 questions used to evaluate global health status (GHS)/QoL. Each question was assessed on 7-point scale (1= very poor to 7= excellent). Scores averaged, transformed to 0-100 scale; higher score=better quality of life/better level of functioning.
Time frame: Screening and Day 1 of every 28-day Cycle, up to 18 months (Overall Duration)
Secondary
Part 2, Expansion Cohorts A and C: Evaluate Duration of Response (DOR)
For subjects with a confirmed response of PR or CR, duration of response is measured from the date of the first response until the time that overall disease progression (radiographic progressive disease or clinical deterioration) or death is documented.
Time frame: From screening up to 18 months
Population: Participants with a confirmed response of PR or CR are included for the duration of response analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Dose Escalation: Cohort 1 | Part 2, Expansion Cohorts A and C: Evaluate Duration of Response (DOR) | 4.7 months |
| Part 1 Dose Escalation: Cohort 3 | Part 2, Expansion Cohorts A and C: Evaluate Duration of Response (DOR) | 8.3 months |
Secondary
Part 2, Expansion Cohorts A and C: Safety Profile of ZEN003694 in Combination With Talazoparib.
Incidence of Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE) in Part 2, Expansion Cohorts A and C
Time frame: From screening up to 18 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 Dose Escalation: Cohort 1 | Part 2, Expansion Cohorts A and C: Safety Profile of ZEN003694 in Combination With Talazoparib. | Patients reporting at least one TEAE related to study treatment | 41 Participants |
| Part 1 Dose Escalation: Cohort 1 | Part 2, Expansion Cohorts A and C: Safety Profile of ZEN003694 in Combination With Talazoparib. | Patients reporting at least one Serious TEAE related to study treatment | 4 Participants |
| Part 1 Dose Escalation: Cohort 2 | Part 2, Expansion Cohorts A and C: Safety Profile of ZEN003694 in Combination With Talazoparib. | Patients reporting at least one TEAE related to study treatment | 19 Participants |
| Part 1 Dose Escalation: Cohort 2 | Part 2, Expansion Cohorts A and C: Safety Profile of ZEN003694 in Combination With Talazoparib. | Patients reporting at least one Serious TEAE related to study treatment | 1 Participants |
| Part 1 Dose Escalation: Cohort 3 | Part 2, Expansion Cohorts A and C: Safety Profile of ZEN003694 in Combination With Talazoparib. | Patients reporting at least one TEAE related to study treatment | 32 Participants |
| Part 1 Dose Escalation: Cohort 3 | Part 2, Expansion Cohorts A and C: Safety Profile of ZEN003694 in Combination With Talazoparib. | Patients reporting at least one Serious TEAE related to study treatment | 13 Participants |