A Phase 1b Trial of ZEN003694 (ZEN-3694) With Pembrolizumab and Nab-Paclitaxel in Patients With Metastatic Triple-Negative Breast Cancer

Status: Recruiting
Location: See all (5) locations...
Intervention Type: Procedure, Drug, Biological
Study Type: Interventional
Study Phase: Phase 1
SUMMARY

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.

Eligibility
Participation Requirements
Sex: All
Minimum Age: 18
Healthy Volunteers: f
View:

• 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

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Patients with history of treated central nervous system (CNS) metastases are eligible, provided they meet the following criteria:

‣ Disease outside the CNS is present

⁃ Recovery from acute toxicity associated with the treatment to =\< Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1 or baseline (with the exception of alopecia), with no requirement for escalating doses of corticosteroids over the past 7 days

• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer are allowed

• Patients should be New York Heart Association Functional Classification of class 2B or better

• Peripheral neuropathy grade =\< 1

• Ability to swallow and retain oral medications

• Participants may not have had cytotoxic chemotherapy, immunotherapy, major surgery (other than diagnostic surgery, dental surgery or stenting), or other investigational therapy within 3 weeks prior to entering the study

• Participants may not have had radiotherapy within 1 week prior to entering the study. Patients may not have had \> 25% of their bone marrow radiated. Stereotactic radiosurgery (SRS) within 1 week prior to entering the study will be allowed

• Participants may not have received tyrosine kinase inhibitors (TKIs) or small molecules within 5 half-lives or 2 weeks (whichever is shorter) of study entry

• Patients who have experienced adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) must have recovered, with the exception of alopecia or as otherwise specified in the eligibility criteria

• The effects of the combination of ZEN003694 (ZEN-3694) and MK-3475 on the developing human fetus are unknown. For this reason and because BETi and PD-1 blocking agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after study completion. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of ZEN003694 (ZEN-3694), MK-3475 and nab-Paclitaxel administration. Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to registration. Childbearing potential is defined as: participants who have not reached a postmenopausal state (\>= 12 continuous months of amenorrhea with no identified cause other than menopause) and have not undergone surgical sterilization (removal of ovaries and/or uterus)

• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Locations
United States
Massachusetts
Boston Medical Center
RECRUITING
Boston
Dana-Farber Cancer Institute
RECRUITING
Boston
New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone
RECRUITING
New York
Ohio
Ohio State University Comprehensive Cancer Center
RECRUITING
Columbus
Tennessee
Vanderbilt Breast Center at One Hundred Oaks
RECRUITING
Nashville
Time Frame
Start Date: 2023-05-18
Estimated Completion Date: 2027-03-31
Participants
Target number of participants: 57
Treatments
Experimental: Dose Escalation (ZEN003694, nab-paclitaxel, pembrolizumab)
Patients receive ZEN003694 PO QD on days 1-21, nab-paclitaxel IV over 30 minutes on day 1, 8, and 15, and pembrolizumab IV over 30 minutes every 21 days of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity with a maximum of 35 doses of pembrolizumab administered. Patients also undergo CT or MRI scan and collection of blood samples throughout the trial.
Experimental: Dose Expansion (ZEN003694, nab-paclitaxel, pembrolizumab)
Patients receive ZEN003694 PO QD on days 1-7 prior to combination therapy. Patients then receive ZEN003694 PO QD on days 1-21, nab-paclitaxel IV over 30 minutes on days 1, 8, and 15, and pembrolizumab IV over 30 minutes every 21 days of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity with a maximum of 35 doses of pembrolizumab administered. Patients also undergo biopsies on study, and CT or MRI scans and collection of blood samples throughout the trial.
Related Therapeutic Areas
Sponsors
Leads: National Cancer Institute (NCI)

This content was sourced from clinicaltrials.gov

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