Testing the Addition of an Investigational Anti-Cancer Drug, ASTX660 (Tolinapant), to a Usual Chemotherapy Treatment (Eribulin) for Treatment of Advanced Triple Negative Breast Cancer

Patients must have histologically or cytologically confirmed invasive breast carcinoma.

* We limit the molecular subtype to triple negative (TNBC) and hormone receptor-low and Her2 negative (hormone receptor \[HR\]-low/Her2\[-\]) breast cancer. TNBC is defined as: HER2 expression 0 or 1+ on immunohistochemistry (IHC) or non-amplified (defined as HER2/CEP17 ratio \< 2 or copy number \< 6) on fluorescence in situ hybridization (FISH). If HER2 expression is 2+ on IHC, negative HER2 expression must be confirmed by FISH. Pathologic diagnosis of TNBC (negative HER2 status by cytogenetics, \< 1% of cells stained positive for estrogen receptor \[ER\] by IHC, and \< 1% of cells stained positive for progesterone receptor \[PR\] by IHC) (Allison et al., 2020, Wolff et al., 2013). HR-low/Her2(-) is defined as: HER2 expression 0 or 1+ on IHC or non-amplified (defined as HER2/CEP17 ratio \< 2 or copy number \< 6) on fluorescence in situ hybridization (FISH). If HER2 expression is 2+ on IHC, negative HER2 expression must be confirmed by FISH. 1-10% of cells stained positive for ER by IHC, and/or 1-10% of cells stained positive for PR by IHC) (Allison et al., 2020, Wolff et al., 2013)

Patients must have confirmed locally advanced and unresectable or metastatic disease by either imaging or tissue diagnosis

Patients must have received at least 2 lines of systemic treatment for metastatic disease

Patients must have measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) criteria

Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of ASTX660 (tolinapant) in combination with eribulin mesylate in patients \< 18 years of age, children are excluded from this study

Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)

Leukocytes ≥ 3,000/mcL

Absolute neutrophil count ≥ 1,500/mcL

Platelets ≥ 100,000/mcL

Hemoglobin ≥ 9 g/dL

Total bilirubin ≤ 1.8 mg/dL

Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x institutional upper limit of normal (ULN) or ≤ 5 x institutional ULN if known liver metastases

Alkaline phosphatase ≤ 3 x institutional ULN or ≤ 5 x institutional ULN if known liver and/or skeletal metastases

Lipase ≤ 1.5 x ULN

Creatinine ≤ 1.5 x institutional ULN OR glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m\^2

International normalized ratio (INR) ≤ 1.5 x ULN

Partial thromboplastin time (PTT) ≤ 1.5 x ULN

Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial provided they are on a stable regimen of anti-retroviral therapy (ART) with no medications otherwise prohibited by this protocol (e.g., drug-drug interactions)

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 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 known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better. Patients with history of known congestive heart failure (left ventricular ejection fraction \[LVEF\] \< 50%) must have documented LVEF ≥ 50% within 12 months of study enrollment

Patients with history of known type I or type II diabetes must have a fasting glucose level of \< 120 mg/dL on at least 2 separate occasions or glycosylated hemoglobin (HbA1c) \< 8.5% at screening within 14 days prior to registration

Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that their medication dose and INR/PTT is stable

Prophylactic antiemetics may be administered according to standard practice. The routine use of standard antiemetics, including 5-HT3 blockers, such as granisetron, ondansetron, or an equivalent agent, is allowed as needed, as long as corrected QT (QTc) interval on baseline electrocardiogram (ECG) \< 480 msec

Patients must be willing to have biopsies for this study in order to be enrolled in the dose expansion

The effects of ASTX660 (tolinapant) on the developing human fetus are unknown. For this reason and because dual IAP antagonist agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to practice 1 highly effective contraceptive measure of birth control (with a failure rate of \< 1% per year; preferably with low user dependency) during the study and for 6 months after the last dose of study treatment and must agree not to become pregnant for 6 months after completing treatment. Men with female partners of childbearing potential must agree to use a condom and advise their partners to practice 1 highly effective contraceptive measure of birth control (user dependent or with low user dependency) during the study and for at least 3 months after completing treatment, and must agree not to father a child while receiving study treatment and for at least 3 months after completing treatment

Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

What this study is about