A Study of ZEN003694 and Talazoparib in Patients With Triple Negative Breast Cancer (TNBC)

• ClinicalTrials.gov Identifier: NCT03901469
• Recruitment Status: Terminated
• First Posted: April 3, 2019
• Last Update Posted: May 3, 2024
• Sponsor: Zenith Epigenetics
• Collaborators: Pfizer; Newsoara Biopharma Co., Ltd.
• Information provided by (Responsible Party): Zenith Epigenetics

Tracking Information

• First Submitted Date: March 22, 2019
• First Posted Date: April 3, 2019
• Last Update Posted Date: May 3, 2024
• Actual Study Start Date: June 26, 2019
• Actual Primary Completion Date: March 7, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 7, 2022)

• Part 1 and Part 2: Incidence of 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) ]
• Part 1: Incidence of dose-limiting toxicities (DLT) [ Time Frame: 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) [ Time Frame: From screening up to 18 months ]
  CBR defined as a 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) [ Time Frame: From screening up to 18 months ]
  ORR defined as a confirmed complete response (CR) or partial response (PR) by RECIST 1.1

Original Primary Outcome Measures (submitted: April 1, 2019)

• Part 1 and Part 2: Incidence of of treatment-related adverse events (AE) and treatment-related serious adverse events (SAE) [ Time Frame: From screening up to 18 months ]
• Part 1: Incidence of dose-limiting toxicities (DLT) [ Time Frame: Cycle 1, Up to 1 month ]
  A DLT is a treatment-related, clinically significant adverse event or laboratory abnormality occurring during the first cycle of treatment
• Part 2: Objective response rate (ORR) defined as a complete response (CR), partial response (PR) or stable disease (SD ≥ 4 cycles) by RECIST 1.1 [ Time Frame: From screening up to 12 months ]

Current Secondary Outcome Measures (submitted: June 7, 2022)

• Part 1, Expansion Cohorts A and C: Clinical benefit rate (CBR) [ Time Frame: From screening up to 18 months ]
  CBR defined as a confirmed complete response (CR), partial response (PR), or stable disease (SD ≥ 4 cycles) by RECIST 1.1
• Part 1, Part 2, and Expansion Cohort C: Objective response rate (ORR) [ Time Frame: From screening up to 18 months ]
  ORR defined as a confirmed complete response (CR) or partial response (PR) by RECIST 1.1
• Part 1, Part 2, Expansion Cohorts A and C: Evaluate median progression-free survival [ Time Frame: From screening up to 18 months ]
  Time from randomization to documented disease progression or death
• Part 2, Expansion Cohorts A and C: Evaluate duration of response (DOR) [ Time Frame: 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: Measure plasma concentrations of ZEN003694 and the active metabolite ZEN003791. [ Time Frame: Cycle 1 Day 1: Pre-dose, 15 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose; Cycle 1 Day 15: Pre-dose; Cycle 2 Day1: 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: Measure plasma concentrations of talazoparib. [ Time Frame: Cycle 1 Day 15: Pre-dose; 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, B, and C: Measure plasma concentrations of ZEN003694 and the active metabolite ZEN003791. [ 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) ]
  Plasma concentrations of ZEN003694 and the active metabolite ZEN003791 will be measured.
• Part 2, Expansion Cohorts A and C: Measure plasma concentrations of talazoparib. [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
• Part 2, Expansion Cohorts A and C: Safety profile of ZEN003694 in combination with talazoparib. [ Time Frame: From screening up to 18 months ]

Original Secondary Outcome Measures (submitted: April 1, 2019)

• Part 1 and Part 2: Measure the pharmacokinetic (PK) parameter: AUC of ZEN003694 administered in combination with talazoparib [ Time Frame: From screening up to 6 months ]
• Part 1 and Part 2: Measure the pharmacokinetic (PK) parameter: Cmax of ZEN003694 administered in combination with talazoparib [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, and Cycle 2 Day 15 ]
• Part 1: Measure the pharmacokinetic (PK) parameter: Cmin of ZEN003694 administered in combination with talazoparib [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, and Cycle 2 Day 15 ]
• Part 1 and Part 2: Measure the pharmacokinetic (PK) parameter: Tmax of ZEN003694 administered in combination with talazoparib [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, and Cycle 2 Day 15 ]
• Part 1 and Part 2: Measure the pharmacokinetic (PK) parameter: t1/2 of ZEN003694 administered in combination with talazoparib [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, and Cycle 2 Day 15 ]
• Part 1: Objective response rate (ORR) defined as a complete response (CR), partial response (PR) or stable disease (SD ≥ 4 cycles) by RECIST 1.1 [ Time Frame: From screening up to 6 months ]
• Part 1 and Part 2: Evaluate median radiographic progression-free survival [ Time Frame: From screening up to 18 months ]
  Time to radiographic progression by RECIST 1.1 or death
• Part 1 and Part 2: Evaluate median progression-free survival [ Time Frame: From screening up to 12 months ]
  Time to radiographic progression by RECIST 1.1, clinical progression, or death
• Part 1 and Part 2: Evaluate duration of response (DOR) [ Time Frame: From screening up to 12 months ]
  Time from first dose to last dose of ZEN-3694
• Part 1 and Part 2: Change From Baseline in Global Health Status/Quality of Life (QoL) Measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) for Overall Duration [ Time Frame: Screening and Day 1 of every 28-day Cycle, up to 18 months (Overall Duration) ]
  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 1 and Part 2: Change from Baseline in Breast Symptoms Scale as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer Module (EORTC-QLQ-BR23) [ Time Frame: Screening and Day 1 of every 28-day Cycle, up to 18 months (Overall Duration) ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of ZEN003694 and Talazoparib in Patients With Triple Negative Breast Cancer
• Official Title: A Phase 2b Study of ZEN003694 in Combination With Talazoparib in Patients With Triple-Negative Breast Cancer
• 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:

None (Open Label)

Primary Purpose: Treatment

• Condition: Triple Negative Breast Cancer

Intervention

• Drug: ZEN003694
  PO QD
  Other Name: ZEN-3694
• Drug: Talazoparib
  PO QD
  Other Name: Talzenna

Study Arms

• Experimental: Part 1 and Part 2
  ZEN003694 will be administered PO QD with Talazoparib 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.
  Interventions:

  • Drug: ZEN003694
  • Drug: Talazoparib
• Experimental: Expansion Cohort A - Combination Treatment in post-TROP2-ADC patients
  ZEN003694 will be administered PO QD with Talazoparib PO QD at the 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.
  Interventions:

  • Drug: ZEN003694
  • Drug: Talazoparib
• Experimental: Expansion Cohort B - ZEN003694 Monotherapy
  ZEN003694 will be administered PO QD as monotherapy at the RP2D in 28-day cycles with the option to cross-over to combination treatment of ZEN003694 PO QD with 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.
  Intervention: Drug: ZEN003694
• Experimental: Expansion Cohort C - Combination Treatment in TROP2-ADC-naïve patients
  ZEN003694 will be administered PO QD with Talazoparib PO QD at the 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.
  Interventions:

  • Drug: ZEN003694
  • Drug: Talazoparib

• Publications *: Kharenko OA, Patel RG, Calosing C, van der Horst EH. Combination of ZEN-3694 with CDK4/6 inhibitors reverses acquired resistance to CDK4/6 inhibitors in ER-positive breast cancer. Cancer Gene Ther. 2022 Jun;29(6):859-869. doi: 10.1038/s41417-021-00375-9. Epub 2021 Aug 12.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: February 6, 2024): 115
• Original Estimated Enrollment (submitted: April 1, 2019): 49
• Actual Study Completion Date: March 7, 2024
• Actual Primary Completion Date: March 7, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, China, Spain, United States

Administrative Information

• NCT Number: NCT03901469
• Other Study ID Numbers: ZEN003694-004; 2018-003906-26 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Zenith Epigenetics
• Original Responsible Party: Same as current
• Current Study Sponsor: Zenith Epigenetics
• Original Study Sponsor: Same as current

Collaborators

• Pfizer
• Newsoara Biopharma Co., Ltd.

• Investigators: Not Provided
• PRS Account: Zenith Epigenetics
• Verification Date: May 2024