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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03901469
Recruitment Status : Recruiting
First Posted : April 3, 2019
Last Update Posted : July 14, 2022
Sponsor:
Collaborators:
Pfizer
Newsoara Biopharma Co., Ltd.
Information provided by (Responsible Party):
Zenith Epigenetics

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).

Condition or disease Intervention/treatment Phase
Triple Negative Breast Cancer Drug: ZEN003694 Drug: Talazoparib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 179 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2b Study of ZEN003694 in Combination With Talazoparib in Patients With Triple-Negative Breast Cancer
Actual Study Start Date : June 26, 2019
Estimated Primary Completion Date : November 2023
Estimated Study Completion Date : May 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Talazoparib

Arm Intervention/treatment
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.
Drug: ZEN003694
PO QD
Other Name: ZEN-3694

Drug: Talazoparib
PO QD
Other Name: Talzenna

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.
Drug: ZEN003694
PO QD
Other Name: ZEN-3694

Drug: Talazoparib
PO QD
Other Name: Talzenna

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.
Drug: ZEN003694
PO QD
Other Name: ZEN-3694

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.
Drug: ZEN003694
PO QD
Other Name: ZEN-3694

Drug: Talazoparib
PO QD
Other Name: Talzenna




Primary Outcome Measures :
  1. 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) ]
  2. 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.

  3. 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

  4. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Part 2, Expansion Cohorts A and C: Safety profile of ZEN003694 in combination with talazoparib. [ Time Frame: From screening up to 18 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03901469


Contacts
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Contact: Zenith Study Team 587-390-7865 ZEN003694-004@zenithepigenetics.com

Locations
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United States, Arizona
Banner MD Anderson Cancer Center Recruiting
Gilbert, Arizona, United States, 85234
United States, Kansas
University of Kansas Cancer Center Recruiting
Westwood, Kansas, United States, 66203
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Tennessee Oncology (Sarah Cannon) Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
MD Anderson Recruiting
Houston, Texas, United States, 77030
Belgium
Institut Jules Bordet Recruiting
Anderlecht, Belgium, 1070
UZ Leuven Recruiting
Leuven, Belgium, 3000
Spain
Vall d'Hebron Institute of Oncology (VHIO) Recruiting
Barcelona, Spain, 08035
START Madrid Recruiting
Madrid, Spain, 28050
Sponsors and Collaborators
Zenith Epigenetics
Pfizer
Newsoara Biopharma Co., Ltd.
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Zenith Epigenetics
ClinicalTrials.gov Identifier: NCT03901469    
Other Study ID Numbers: ZEN003694-004
2018-003906-26 ( EudraCT Number )
First Posted: April 3, 2019    Key Record Dates
Last Update Posted: July 14, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Zenith Epigenetics:
TNBC
ZEN003694
ZEN-3694
Talazoparib
Breast Cancer
PARPi
poly ADP ribose polymerase
bromodomain
BETi
Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Talazoparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents