Overview

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

Status:
Not yet recruiting
Trial end date:
2023-02-28
Target enrollment:
0
Participant gender:
All
Summary
This phase Ib trial tests the safety and tolerability of ZEN003694 in combination with immunotherapy PD1 inhibitor (pembrolizumab) and standard chemotherapy (nab-paclitaxel) for the treatment of patients with triple negative-negative breast cancer that has spread to other parts of the body (advanced). Chemotherapy drugs, such as nab-paclitaxel, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with pembrolizumab may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. ZEN003694 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy in combination with ZEN003694 and standard treatment of chemotherapy may help shrink or stabilize cancer for longer than just chemotherapy alone.
Phase:
Phase 1
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
National Cancer Institute (NCI)
Treatments:
Paclitaxel
Pembrolizumab
Criteria
Inclusion Criteria:

- 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

- Note: 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

- Serum or plasma creatinine =< 1.5 x institutional ULN OR gglomerular 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 experience adverse events due to prior anti-cancer therapy (i.e.,
have residual toxicities > Grade 1) must have recovered, with the exception of
alopecia

- 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

Exclusion Criteria:

- 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 (ZEN-3694) (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