Clinical trial NCT03901469: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Triple Negative Breast Cancer
Keywords: TNBC
ZEN003694
ZEN-3694
Talazoparib
Breast Cancer
PARPi
poly ADP ribose polymerase
bromodomain
BETi
Lead sponsor: Zenith Epigenetics
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
name: Newsoara Biopharma Co., Ltd.
First posted: 2019-04-03
Enrollment: 115
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


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

Primary outcomes:
measure: Part 1 and Part 2: Incidence of treatment-related adverse events (AE) and treatment-related serious adverse events (SAE)
timeFrame: Cycle 1 Day 1 to 30 days post last dose (each cycle is 28 days)
measure: Part 1: Incidence of dose-limiting toxicities (DLT)
timeFrame: Cycle 1, Up to 1 month
measure: Part 2: Clinical benefit rate (CBR)
timeFrame: From screening up to 18 months
measure: Expansion Cohort A: Objective response rate (ORR) by RECIST v1.1 (CR or PR)
timeFrame: From screening up to 18 months
Secondary outcomes:
measure: Part 1, Expansion Cohorts A and C: Clinical benefit rate (CBR)
timeFrame: From screening up to 18 months
measure: Part 1, Part 2, and Expansion Cohort C: Objective response rate (ORR)
timeFrame: From screening up to 18 months
measure: Part 1, Part 2, Expansion Cohorts A and C: Evaluate median progression-free survival
timeFrame: From screening up to 18 months
measure: Part 2, Expansion Cohorts A and C: Evaluate duration of response (DOR)
timeFrame: From screening up to 18 months
measure: Part 1: Measure plasma concentrations of ZEN003694 and the active metabolite ZEN003791.
timeFrame: 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)
measure: Part 1: Measure plasma concentrations of talazoparib.
timeFrame: Cycle 1 Day 15: Pre-dose; Cycle 2 Day 1: Pre-dose; Cycle 2 Day 15: Pre-dose (each cycle is 28 days)
measure: Part 2, Expansion Cohorts A, B, and C: Measure plasma concentrations of ZEN003694 and the active metabolite ZEN003791.
timeFrame: 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)
measure: Part 2, Expansion Cohorts A and C: Measure plasma concentrations of talazoparib.
timeFrame: Cycle 2 Day 1: Pre-dose, Cycle 2 Day 15: Pre-dose (each cycle is 28 days)
measure: 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
timeFrame: Screening and Day 1 of every 28-day Cycle, up to 18 months (Overall Duration)
measure: Part 2, Expansion Cohorts A and C: Change from Baseline in Breast Symptoms Scale as Assessed by the EORTC-QLQ-BR23
timeFrame: Screening and Day 1 of every 28-day Cycle, up to 18 months (Overall Duration)
measure: Part 2, Expansion Cohorts A and C: Safety profile of ZEN003694 in combination with talazoparib.
timeFrame: From screening up to 18 months
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Atlanta
country: United States
facility: Emory University Winship Cancer Institute
state: Georgia
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Oncology (Sarah Cannon)
state: Tennessee
city: Houston
country: United States
facility: MD Anderson
state: Texas
city: Anderlecht
country: Belgium
facility: Institut Jules Bordet
city: Leuven
country: Belgium
facility: UZ Leuven
city: Bengbu
country: China
facility: The First Affiliated Hosptial of Bengbu Medical College
state: Anhui
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
city: Guangzhou
country: China
facility: Sun Yat-sen Memorial Hospital, Sun Yat-sen University
state: Guangdong
city: Changsha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: Jining
country: China
facility: Affliated Hospital of Jining Medical University
state: Shandong
city: Neijiang
country: China
facility: The Second People's Hospital of Neijiang
state: Sichuan
city: Tianjin
country: China
facility: Tianjing Medical University Cancer Institute & Hospital
state: Tianjin
city: Barcelona
country: Spain
facility: Vall d'Hebron Institute of Oncology (VHIO)
city: Madrid
country: Spain
facility: START Madrid
Study officials:
References:
citation: 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.