Testing the Addition of Anti-Cancer Drug, ZEN003694 (ZEN-3694) and PD-1 Inhibitor (Pembrolizumab), to Standard Chemotherapy (Nab-Paclitaxel) Treatment in Patients With Advanced Triple-Negative Breast Cancer

Recruiting now · Phase 1

Conditions studied: Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Locally Advanced Triple-Negative Breast Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Unresectable Triple-Negative Breast Carcinoma

In brief

This phase Ib trial tests the safety and tolerability of ZEN003694 in combination with an immunotherapy drug called pembrolizumab and the usual chemotherapy approach with nab-paclitaxel for the treatment of patients with triple negative-negative breast cancer that has spread to other parts of the body (advanced). Paclitaxel is in a class of medications called antimicrotubule agents. It stops cancer cells from growing and dividing and may kill them. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. Immunotherapy with monoclonal antibodies, such as pembrolizumab may help the body's immune system attach the cancer and may interfere with the ability of tumor cells to grow and spread. ZEN003694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). It may prevent the growth of tumor cells that over produce BET protein. Combination therapy with ZEN003694 pembrolizumab immunotherapy and nab-paclitaxel chemotherapy may help shrink or stabilize cancer for longer than chemotherapy alone.

Key facts

Study ID

NCT05422794

Run by

National Cancer Institute (NCI)

People needed

57

Starts

2023-05-18

Expected to finish

2027-03-31

Last updated by the study team

2026-08-05

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Participants must have a histologically or cytologically confirmed diagnosis of TNBC based on standard criteria for the disease:
• Estrogen receptor (ER) and progesterone receptor (PR) < 10% by immunohistochemistry (IHC), and HER2-negative (per current American Society of Clinical Oncology [ASCO]/College of American Pathologists [CAP] guidelines)
• If there is more than one histological result available, the most recent sample with ER, PR and HER2 results will be considered for inclusion
• Patients who have not had ER, PR and HER2 testing and thus, ER, PR and HER2 status is unknown, are not eligible
• Participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation
• Participants must have disease that is unresectable locally advanced or metastatic
• DOSE ESCALATION COHORT: Known PD-L1 status is not required prior to study enrollment. Central PD-L1 testing (on archival tumor tissue) will occur retrospectively
• DOSE ESCALATION COHORT: Any number of prior lines of therapy are allowed in the metastatic setting. Prior immune checkpoint inhibitor allowed in any setting
• DOSE ESCALATION COHORT: Evaluable or measurable disease per RECIST 1.1 criteria
• DOSE EXPANSION COHORT: PD-L1 status must be negative. Standard local testing with any PD-L1 antibody that has been validated in a Clinical Laboratory Improvement Act (CLIA)- certified environment will be acceptable for including patients on trial. Primary or metastatic samples may be tested for PD-L1 status. Central confirmation will occur retrospectively. For patients in whom a baseline research tumor tissue biopsy is not performed (e.g. site of disease is not safely accessible), archival tissue should be provided for central confirmatory PD-L1 testing
• DOSE EXPANSION COHORT: 0-1 prior lines of systemic therapy in the metastatic setting
• DOSE EXPANSION COHORT: Participants must have measurable disease per RECIST 1.1 criteria
• DOSE EXPANSION COHORT: Participants must have disease that is amenable to biopsy as judged by the treating investigator and must be willing to undergo pre- and on-treatment tumor biopsies, if safely accessible
• Age >= 18 years
• Because no dosing or adverse event data are currently available on the use of ZEN003694 (ZEN-3694) in combination with nab-paclitaxel and pembrolizumab (MK-3475) in patients < 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Absolute neutrophil count >= 1,000/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (or =< 2.0 x ULN in patients with documented Gilbert's Syndrome)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3.0 x institutional ULN or ≤ 5.0 x institutional ULN for participants with documented liver metastases
• Serum or plasma creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 60 mL/min (based on the calculated chronic kidney disease epidemiology (CKD-EPI) glomerular filtration rate estimation
• International normalized ratio (INR) or prothrombin time (PT): =< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
• Activated partial thromboplastin time (aPTT): =< 1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial as long as their anti-retroviral therapy does not have the potential for drug-drug interactions as judged by the treating investigator

You may not qualify if…

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 (ZEN-3694), nab-paclitaxel, or pembrolizumab
• Patients with uncontrolled intercurrent illness
• Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Any gastrointestinal (GI) disorder that may affect absorption of oral medications in the opinion of the treating investigator, such as malabsorption syndrome or major bowel or stomach resection
• Pregnant women are excluded from this study because ZEN003694 (a BETi agent) and MK-3475 have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ZEN003694 (ZEN-3694), breastfeeding should be discontinued if the mother is treated with ZEN003694 (ZEN-3694). These potential risks may also apply to MK-3475 and nab-paclitaxel
• Patients who have previously received ZEN003694 (ZEN-3694) or who have been treated with an investigational BET inhibitor
• DOSE EXPANSION COHORT: Prior exposure to immune checkpoint inhibitors in the metastatic setting. PD-1 or PD-L1 inhibitors in the neo-/adjuvant setting are allowed if at least 12 months have elapsed since the end of adjuvant systemic treatment to development of metastatic disease
• DOSE EXPANSION COHORT: Prior exposure to taxane-based therapy in the metastatic setting. Taxane in the neo-/adjuvant setting is allowed if at least 12 months have elapsed since the end of adjuvant systemic treatment to development of metastatic disease
• Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible. Strong inhibitors or inducers of CYP3A4 must be discontinued at least 7 days prior to the first dose of ZEN003694 (ZEN-3694). Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Patients receiving any medications or substances that are 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
• Patients who have had a bone-targeted radionuclide within 6 weeks of the first dose of ZEN003694 (ZEN-3694)
• Myocardial infarction or unstable angina within 6 months prior to the first dose of ZEN003694 (ZEN-3694)
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the study principal investigator (PI)
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Has a known history of active tuberculosis (TB)
• Has received a live vaccine within 30 days of planned treatment start. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacille Calmette-Guerin (BCG), and typhoid vaccine. Seasonal flu vaccines that do not contain live virus are permitted. Coronavirus disease-2019 (COVID-19) vaccines received within the last 30 days are also permitted
• Participants with known or suspected extensive bone marrow infiltration per radiographic assessment, laboratory assessment, or bone marrow sampling (e.g., aspiration or biopsy), determined to be clinically significant by the treating investigator

Where it is running

• Boston Medical Center — Boston, Massachusetts, United States (enrolling)
• Dana-Farber Cancer Institute — Boston, Massachusetts, United States (enrolling)
• NYU Langone Hospital - Long Island — Mineola, New York, United States (enrolling)
• Laura and Isaac Perlmutter Cancer Center at NYU Langone — New York, New York, United States (enrolling)
• Ohio State University Comprehensive Cancer Center — Columbus, Ohio, United States (enrolling)
• Vanderbilt Breast Center at One Hundred Oaks — Nashville, Tennessee, United States (enrolling)

Full record on ClinicalTrials.gov

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