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

Phase 2TerminatedNCT03901469

Zenith Epigenetics115 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

115

Conditions

Triple Negative Breast Cancer

Interventions

ZEN003694DRUG

PO QD

TalazoparibDRUG

PO QD

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (19)

Banner MD Anderson Cancer Center

Gilbert, Arizona, United States

Emory University Winship Cancer Institute

Atlanta, Georgia, United States

Outcomes

Primary Outcomes

Part 1 and Part 2: Number of Participants With 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) up to 22 months

Part 1: Number of Participants With 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.

Time frame: Cycle 1, Up to 1 month

Part 2: Clinical Benefit Rate (CBR)

Percentage of patients with a best overall response of confirmed complete response (CR), partial response (PR), or stable disease (SD ≥ 4 cycles) by RECIST v1.1

Time frame: From screening up to 18 months

Expansion Cohort A: Objective Response Rate (ORR) by RECIST v1.1 (CR or PR)

Percentage of participants with a confirmed complete response (CR) or partial response (PR) by RECIST 1.1

Time frame: From screening up to 18 months

Secondary Outcomes

Part 1, Expansion Cohorts A and C: Clinical Benefit Rate (CBR)

Percentage of participants with a confirmed complete response (CR), partial response (PR), or stable disease (SD ≥ 4 cycles) by RECIST 1.1

Time frame: From screening up to 18 months

Part 1, Part 2, and Expansion Cohort C: Objective Response Rate (ORR)

Percentage of participants with a confirmed complete response (CR) or partial response (PR) by RECIST 1.1

Time frame: From screening up to 18 months

Data from ClinicalTrials.gov

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University of Kansas Cancer Center

Westwood, Kansas, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Tennessee Oncology (Sarah Cannon)

Nashville, Tennessee, United States

MD Anderson

Houston, Texas, United States

Institut Jules Bordet

Anderlecht, Belgium

UZ Leuven

Leuven, Belgium

...and 9 more locations

Part 2, Expansion Cohorts A and C: Safety Profile of ZEN003694 in Combination With Talazoparib.

Incidence of Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE) in Part 2, Expansion Cohorts A and C

Time frame: From screening up to 18 months

Part 1, Part 2, Expansion Cohorts A & C: Evaluate Median Progression-free Survival

Median progression-free survival is the time from randomization to documented disease progression or death

Time frame: From screening up to 18 months

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.

Time frame: From screening up to 18 months

Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite)

Cmax is defined as the maximum or peak plasma concentration of drug (calculated from samples taken over a 4-hour or 8-hour time period). Cmax(0-8h) was calculated for Cycle 1, Day 1. Cmax(0-4h) was calculated for Cycle 2, Day 1. Pre-dose is time 0 for calculations.

Time frame: Part 1: Cycle 1 Day 1: Pre-dose, 15 min, 30 min, 1 hour, 2 hour, 4 hour, 6 hour, and 8 hours post-dose. Parts 1 & 2: Cycle 2 Day 1: Pre-dose, 1 hour, 2 hour, and 4 hours post-dose. (cycles are 28 days)

Part 1 and Part 2: Measure the Pharmacokinetic (PK) Parameter of Combined AUC(0-4h or 0-8h) of ZEN003694 and ZEN003791 (Active Metabolite)

AUC(0-4h or 0-8h) is defined as the area under the curve (plasma concentration of drug calculated from samples taken over a 4-hour or 8-hour time period). AUC(0-8h) was calculated for Cycle 1, Day 1. AUC(0-4h) was calculated for Cycle 2, Day 1. Pre-dose is time 0 for calculations.

Part 1 & 2: Measure Plasma Concentrations of Talazoparib.

Plasma concentrations of talazoparib will be measured.

Time frame: Part 1: Cycle 1 Day 15: Pre-dose; Parts 1& 2 Cycle 2 Day 1: Pre-dose; Cycle 2 Day 15: Pre-dose (each cycle is 28 days)

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.

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)

Expansion Cohorts A and C: Measure Plasma Concentrations of Talazoparib.

Plasma concentrations of talazoparib will be measured.

Time frame: Cycle 2 Day 1: Pre-dose, Cycle 2 Day 15: Pre-dose (each cycle is 28 days)

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.

Time frame: Screening and Day 1 of every 28-day Cycle, up to 18 months (Overall Duration)

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.

Time frame: Screening and Day 1 of every 28-day Cycle, up to 18 months (Overall Duration)