Ivermectin and Balstilimab for the Treatment of Metastatic Triple Negative Breast Cancer

Inclusion Criteria:

• Age: ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) ≤ 1

• Life expectancy > 3 months

• Histologically confirmed metastatic triple negative breast cancer. Triple negativestatus will be defined as estrogen receptor (ER) and progesterone receptor (PR) ≤ 10% and HER2 negative (by immunohistochemistry [IHC] or fluorescence in situhybridization [FISH]), per American Society of Clinical Oncology (ASCO)/College ofAmerican Pathologists (CAP) guidelines

• Patients must have progressed on 1-2 prior lines of systemic therapy (chemotherapyand/or drug-antibody conjugate) in the metastatic setting

• Measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Lesions situated in a previously irradiated area are consideredmeasurable if progression has been demonstrated in such lesions

• Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 2 fromprior anti-cancer therapy

• For Phase 2 expansion only, must be PD-L1 negative. Note: For Phase 1 safety cohort,any PD-L1 status will be allowed to enroll.

• Patients must have adequate organ function as defined in the following:

• Absolute neutrophil count (ANC) ≥ 1,500/mm^3

• Platelets ≥ 100,000/mm^3

• Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L. Criteria must be met without erythropoietindependency and without packed red blood cell (pRBC) transfusion within last 2 weeks

• Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN) OR direct bilirubin ≤ ULNfor participants with total bilirubin levels > 1.5 x ULN

• Aspartate aminotransferase (AST) ≤ 1.5 x ULN or ≤ 3 x ULN with liver metastases

• Alanine aminotransferase (ALT) ≤ 1.5 x ULN or ≤ 3 x ULN with liver metastases

• Creatinine ≤ 1.5 x ULN OR calculated creatinine clearance ≥ 30 mL/min forparticipant with creatinine levels >1.5 x institutional ULN

• International normalized ratio (INR) or prothrombin time (PT), activated partialthromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is receiving anticoagulanttherapy as long as PT or aPTT is within therapeutic range of intended use ofanticoagulants

• Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

• If the urine test is positive or cannot be confirmed as negative, a serumpregnancy test will be required

• A male participant must agree to use a contraception during the treatment period andfor at least 120 days after the last dose of study treatment and refrain fromdonating sperm during this period

• A female participant is eligible to participate if she is not pregnant, notbreastfeeding, and at least one of the following conditions applies:

• Not a woman of childbearing potential (WOCBP) OR

• Females of child-bearing potential must be willing to use effectivecontraception during study and for 120 days after the last dose

• Written informed consent obtained from subject and ability for subject to complywith the requirements of the study.

Exclusion Criteria:

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of study drug

• Prohibited Treatments and/or Therapies:

• Chemotherapy, radiation therapy, biological therapy, immunotherapy within 28 daysprior to day 1 of protocol therapy

• Prior immune checkpoint inhibitor therapy in metastatic setting (Note: Prior use ofimmune checkpoint inhibitor in neoadjuvant or adjuvant setting only permitted iflast dose is at least 1 year from start of study intervention)

• Prior radiotherapy within 2 weeks of start of study intervention. Participants musthave recovered from all radiation-related toxicities, not require corticosteroids,and not have had radiation pneumonitis. A 1-week washout is permitted for palliativeradiation (≤2 weeks of radiotherapy) to non-CNS disease

• Any live vaccine within 30 days prior to the first dose of study drug. Examples oflive vaccines include, but are not limited to, the following: measles, mumps,rubella, varicella/zoster (chicken pox), yellow fever, rabies, BacillusCalmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines forinjection are generally killed virus vaccines and are allowed; however, intranasalinfluenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed

• Participants on any dose of warfarin. Use of low molecular weight heparin,antithrombin agents, anti-platelet agents or factor Xa inhibitors is allowed

• Participants may not be currently participating in or participated in a study of aninvestigational agent or has used an investigational device within 4 weeks prior tothe first dose of study intervention

• Issues with tolerating oral medication (e.g., inability to swallow pills,malabsorption issues, ongoing nausea or vomiting during screening)

• Women who are or are planning to become pregnant or breastfeed

• Known allergy to any of the components within the study agents and/or theirexcipients

• No other prior malignancy is allowed except for the following: adequately treatedbasal cell or squamous cell skin cancer, in situ cervical cancer, adequately treatedstage I or II cancer from which the patient is currently in complete remission, orany other cancer from which the patient has been disease free for at least threeyears

• Participants must not have known active CNS metastases and/or carcinomatousmeningitis. Participants with previously treated brain metastases may participateprovided they are radiologically stable, i.e., without evidence of progression forat least 4 weeks by repeat imaging (note that the repeat imaging should be performedduring study screening), clinically stable and without requirement of steroidtreatment for at least 14 days prior to first dose of study intervention

• History of (non-infectious) pneumonitis that required steroids or has currentpneumonitis

• Active infection requiring systemic therapy

• Known history of Human Immunodeficiency Virus (HIV) infection

• Known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] isdetected) infection. Note: no testing for Hepatitis B and Hepatitis C is requiredunless mandated by local health authority

• Known history of active TB (Mycobacterium tuberculosis)

• Intercurrent or historic medical condition that increases subject risk in theopinion of the Investigator. Eligibility may be revisited for intercurrent medicalconditions once resolution/recovery is deemed adequate by the investigator (e.g.,recovery from major surgery, completion of treatment for severe infection).

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thesubject's participation for the full duration of the study, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial

• Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of trial treatment

• Has had an allogenic tissue/solid organ transplant

• Significant cardiovascular impairment: history of congestive heart failure greaterthan New York Heart Association (NYHA) class II, unstable angina, myocardialinfarction, or stroke within 6 months of the first dose of study drug, or cardiacarrhythmia requiring medical treatment at screening

• Subjects having > 1+ proteinuria on urine dipstick testing unless a 24-hour urinecollection for quantitative assessment indicates that the urine protein is < 1 g/24hours

• Has active autoimmune disease that has required systemic treatment in the past 2years (i.e., with use of disease modifying agents, corticosteroids, orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment and is allowed

• Any other condition that would, in the Investigator's judgment, contraindicate thepatient's participation in the clinical study due to safety concerns with clinicalstudy procedures