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

Phase 1

Conditions: Triple Negative Breast Cancer
MedDRA version: 21.0Level: LLTClassification code 10071115Term: Node-negative breast cancerSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2018-003906-26-BE

Lead Sponsor: Zenith Epigenetics Ltd.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 179

Inclusion Criteria

1. Females or males age = 18 years (at time of signing informed consent)
2. Parts 1 and 2: Histologically confirmed metastatic or recurrent or locally advanced triple-negative breast cancer (estrogen receptor (ER) =10%; progesterone receptor (PR) =10%; HER2 negative by immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH)
Expansion: 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. Parts 1 and 2 only: 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 unresecable 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 TROP2-ADC therapy.
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
8. Adequate laboratory parameters at Screening including:
a. Parts 1 and 2: Hemoglobin = 10.0 gm/dL without transfusions during the 4 weeks prior to Screening. Expansion: Hemoglobin = 9.0 gm/dL
b. Absolute neutrophil count (ANC) = 1.5 × 109/L
c. Platelet count = 150,000/mm3
d. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) = 2.0 x ULN or if liver function abnormalities due to liver metastases AST and ALT = 5.0 x ULN
e. Total bilirubin = 1.5 x ULN (= 3.0 x ULN for subjects with known Gilbert's syndrome)
f. Calculated (Cockcroft-Gault formula) or measured creatinine clearance = 60 mL/min
g. Prothrombin time (PT), international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.5 x ULN
9. Female subjects may be enrolled if they are not of childbearing potential, permanently sterile or who are post-menopausal, defined as no menses for at least 1 year without an alternative medical cause and FSH levels in the post-menopausal range. Female subjects of childbearing potential may be enrolled if they consistently and correctly use a highly effective form of contraception. from the time point of study drug administration until at least 7 months thereafter. Highly effective forms of contraception include: combined (estrogen and progestogen hormonal contraceptives (oral, intravaginal, transdermal) associated with inhibition of ovulation; progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized

Exclusion Criteria

1. Documented germline BRCA1 or BRCA2 mutations
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 (in Part 2 only)
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
18. Known impaired cardiac function or clinically significant cardiac disease such as uncontrolled supraventricular arrhythmia, ventricular
arrhythmia requiring therapy, or congestive heart failure (New York Heart Association functional class III or IV)).
19. Myocardial infarction or unstable angina within 6 months prior to the first administration of study drug.
20. Known myelodysplastic syndrome.
21. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous sy

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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