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

Triple Negative Breast Cancer Clinical Trial

— TNBC  

Official title:

A Phase 2b Study of ZEN003694 in Combination With Talazoparib in Patients With Triple-Negative Breast Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03901469
• Other study ID #: ZEN003694-004
• Secondary ID: 2018-003906-26
• Status: Terminated
• Phase: Phase 2
• Start date: June 26, 2019
• Est. completion date: March 7, 2024

Study information

• Verified date: May 2024
• Source: Zenith Epigenetics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 115
• Est. completion date: March 7, 2024
• Est. primary completion date: March 7, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Neoplasms
• Triple Negative Breast Cancer
• Triple Negative Breast Neoplasms

Intervention

Drug:
• ZEN003694
PO QD
• Talazoparib
PO QD

Locations

Country	Name	City	State
Belgium	Institut Jules Bordet	Anderlecht
Belgium	UZ Leuven	Leuven
China	The First Affiliated Hosptial of Bengbu Medical College	Bengbu	Anhui
China	Hunan Cancer Hospital	Changsha	Hunan
China	Sun Yat-sen Memorial Hospital, Sun Yat-sen University	Guangzhou	Guangdong
China	Sun Yat-sen University Cancer Center	Guangzhou	Guangdong
China	Affliated Hospital of Jining Medical University	Jining	Shandong
China	The Second People's Hospital of Neijiang	Neijiang	Sichuan
China	Tianjing Medical University Cancer Institute & Hospital	Tianjin	Tianjin
Spain	Vall d'Hebron Institute of Oncology (VHIO)	Barcelona
Spain	START Madrid	Madrid
United States	Emory University Winship Cancer Institute	Atlanta	Georgia
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	MD Anderson	Houston	Texas
United States	Tennessee Oncology (Sarah Cannon)	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Kansas Cancer Center	Westwood	Kansas

Sponsors (3)

Lead Sponsor	Collaborator
Zenith Epigenetics	Newsoara Biopharma Co., Ltd., Pfizer

Countries where clinical trial is conducted

United States,  Belgium,  China,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1 and Part 2: Incidence of 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)
Primary	Part 1: Incidence of 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.	Cycle 1, Up to 1 month
Primary	Part 2: Clinical benefit rate (CBR)	CBR defined as a confirmed complete response (CR), partial response (PR), or stable disease (SD = 4 cycles) by RECIST v1.1	From screening up to 18 months
Primary	Expansion Cohort A: Objective response rate (ORR) by RECIST v1.1 (CR or PR)	ORR defined as a confirmed complete response (CR) or partial response (PR) by RECIST 1.1	From screening up to 18 months
Secondary	Part 1, Expansion Cohorts A and C: Clinical benefit rate (CBR)	CBR defined as a confirmed complete response (CR), partial response (PR), or stable disease (SD = 4 cycles) by RECIST 1.1	From screening up to 18 months
Secondary	Part 1, Part 2, and Expansion Cohort C: Objective response rate (ORR)	ORR defined as a confirmed complete response (CR) or partial response (PR) by RECIST 1.1	From screening up to 18 months
Secondary	Part 1, Part 2, Expansion Cohorts A and C: Evaluate median progression-free survival	Time from randomization to documented disease progression or death	From screening up to 18 months
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.	From screening up to 18 months
Secondary	Part 1: Measure plasma concentrations of ZEN003694 and the active metabolite ZEN003791.	Plasma concentrations of ZEN003694 and the active metabolite ZEN003791 will be measured.	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)
Secondary	Part 1: Measure plasma concentrations of talazoparib.	Plasma concentrations of talazoparib will be measured.	Cycle 1 Day 15: Pre-dose; Cycle 2 Day 1: Pre-dose; Cycle 2 Day 15: Pre-dose (each cycle is 28 days)
Secondary	Part 2, 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.	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)
Secondary	Part 2, Expansion Cohorts A and C: Measure plasma concentrations of talazoparib.	Plasma concentrations of talazoparib will be measured.	Cycle 2 Day 1: Pre-dose, Cycle 2 Day 15: Pre-dose (each cycle is 28 days)
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.	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 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.	Screening and Day 1 of every 28-day Cycle, up to 18 months (Overall Duration)
Secondary	Part 2, Expansion Cohorts A and C: Safety profile of ZEN003694 in combination with talazoparib.		From screening up to 18 months