ARX788 for Treating Patients With HER2-low Locally Advanced Unresectable or Metastatic Breast Cancer

Inclusion Criteria:

• Male or female participants age 18 years or greater with ability to provide writteninformed consent for the study.

• Eastern Cooperative Oncology Group (ECOG) score of 0-2.

• Estimated life expectancy of at least at 6 months per investigator assessment.

• Ability to understand and the willingness to sign a written informed consentdocument.

• Pathologically documented HER2-low locally advanced unresectable or metastaticbreast cancer (MBC). NOTE: human epidermal growth factor receptor 2 (HER2)-lowstatus determined by HER2 immunohistochemistry (IHC) 1+ or 2+ and no evidence ofHER2 gene amplification by in situ hybridization (ISH)/fluorescence in situhybridization (FISH), which can be documented from any tumor sample during thepatient's cancer treatment history (early-stage or metastatic).

• Cohort 1: Participants with hormone receptor positive (HR+)/HER2-low locallyadvanced unresectable or MBC. HR+ status defined as estrogen receptor >= 10%and/or progesterone receptor ≥ 10% and HER2 low.

• Cohort 2: Participants with hormone receptor negative (HR-)/HER2-low locallyadvanced unresectable or MBC. Considered HR- if estrogen receptor (ER) andprogesterone receptor (PR) < 10% and HER2-low.

• Presence of at least one measurable lesion per Response Evaluation Criteria in SolidTumors (RECIST) version (v) 1.1. NOTE: Participant's with at least one measurablelytic bone lesion are eligible.

• Availability of tumor block or formalin-fixed paraffin-embedded (FFPE) tissue as 10precut unstained slides will be collected for the HER2 status evaluation andbiomarker analysis based on the most recent tumor tissue sample. NOTE: Newpretreatment biopsy tissue is preferred as HER2 status may change, but a freshbiopsy is not required. The study team and investigator will make every attempt toget archival tissue. Participants who do not have archival or new tumor tissueavailable may be eligible after discussion with the study principal investigator (PI).

• Participants with stable and treated brain metastases are eligible if theparticipants meet the following criteria:

• Prior stereotactic radiosurgery (SRS) should be completed >=7 days before studytreatment initiation.

• Prior whole-brain radiation therapy should be completed >=14 days before studytreatment initiation.

• Any ongoing use of systemic corticosteroids does not exceed 2 mg ofdexamethasone (or equivalent) daily.

• Participants must have received at least one prior line of chemotherapy or ADCtherapy for locally advanced unresectable or metastatic disease. Prior checkpointinhibitor therapy is allowed.

• Hemoglobin ≥ 8.0 g/dL

• Absolute neutrophil count ≥ 1.0 x 10^9/L

• Platelets ≥ 100,000 x 10^9/L

• Total bilirubin ≤ 1.5 x institutional upper limit of normal, unless elevated due toGilbert's syndrome and direct bilirubin is within normal limits

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) < 3 x institutional upper limit of normal. In participants with liver metastases, <= 5x institutional upper limit of normal is allowed.

• Alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase (SGPT)) < 3 xinstitutional upper limit of normal. In participants with liver metastases, <=5 xinstitutional upper limit of normal is allowed.

• Creatinine ≤ 1.5 x within institutional upper limit of normal OR creatinineclearance glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m, calculated using theCockcroft-Gault equation

• Adequate cardiac function as assessed by left ventricular ejection fraction ≥ 50% orinstitutional lower limit of normal.

• Human immunodeficiency virus (HIV)-infected individuals on effective antiretroviraltherapy with undetectable viral load within 6 months are eligible for this trial.

• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy.

• Individuals with a history of hepatitis C virus (HCV) infection must have beentreated without detectable HCV RNA.

• Participants must have recovered from all acute toxicities from prior therapies to ≤grade 1 or baseline (except for alopecia and neuropathy) per the National CancerInstitute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v 5.0.

• Male and female subjects of reproductive/childbearing potential must agree to use ahighly effective form of contraception or total sexual abstinence during and uponcompletion of the study; and for at least 3 months after the last dose of study drugfor women of childbearing potential (WOCBP) and at least 5 months after the lastdose of study drug for men whose partners are WOCBP.

• Male subjects must agree to not freeze or donate sperm starting at Screening andthroughout the study period, and at least 5 months after the final study drugadministration.

• Female subjects must agree to not donate, or retrieve for their own use, ova fromthe time of screening and throughout the study treatment period, and for at least 3months after the final study drug administration.

Exclusion Criteria:

• Has a prior history of treatment with ARX-788 or auristatin analogues.

• Has a history of allergic reaction to any component of ARX788.

• Has exposure to any other investigational or commercial anti-cancer agents ortherapies administered with the intention to treat malignancy within 14 days beforethe first dose of study treatment. NOTE: Anti-hormonal therapy may be administeredup to 7 days prior to the first dose of study treatment.

• Radiotherapy outside of the brain administered <7 days prior to first dose of ARX788

• Prior or current history of interstitial lung disease (ILD), pneumonitis, or otherclinically significant lung disease with the exception of disease that is directlyattributable to the presence of lung metastases from their underlying cancer.

• Participants with significant pulmonary conditions, defined as any of the following:

• Any prior history of drug-induced immune-mediated pneumonitis.

• Prior history of radiation therapy to the chest of > 18 gray (Gy) with residualsequelae considered clinically significant by investigator assessment.

• Radiographic evidence of radiation fibrosis involving > 15% of the lungparenchyma associated with clinical symptoms.

• Any requirement for supplemental oxygen.

• Clinically-significant ocular findings including history of keratitis, keratopathy,and/or active eye disease (excluding glaucoma).

• History of congestive heart failure, unstable angina pectoris, unstable cardiacarrhythmia, or myocardial infarction within 6 months prior to enrollment. QTcFprolongation of >470 msec (females) or >450 msec (males) based screening ECG.

• Has a diagnosis of leptomeningeal carcinomatosis. NOTE: Stable brain metastases areallowed.

• Has an active systemic or psychiatric illness that would impact the patient'sability to receive study therapy.

• Has an uncontrollable intercurrent illness, infection (including participants withactive, symptomatic Coronavirus disease of 2019 (COVID-19) infections), or otherconditions that could limit study compliance or interfere with study assessments.

• Has a history of an additional malignancy that is progressing or has required activetreatment within the past 3 years. NOTE: Participants with basal cell carcinoma ofthe skin, squamous cell carcinoma of the skin, carcinoma in situ (excludingcarcinoma in situ of the bladder or high-grade cervical dysplasia in the last threeyears), and thyroid cancer not requiring cytotoxic agents that have undergonepotentially curative therapy are not excluded.

• Pregnancy or breastfeeding.

• Has an active, uncontrolled hepatitis B, hepatitis C, and/or human immunodeficiencyvirus (HIV) infection. Participants with adequately controlled hepatitis B,hepatitis C, and/or HIV are allowed. NOTE: HIV and hepatitis B and C testing are notrequired for screening. Testing will only be done if clinically indicated.