ProAgio in Combination With Gemcitabine in Patients With Metastatic Triple Negative Breast Cancer

Inclusion Criteria:

• Adult participants, ≥ 18 years of age, with histologically or cytologicallyconfirmed metastatic breast cancer that is estrogen receptor (ER) negative (lessthan 10%), progesterone receptor (PR) negative (less than 10%), and HER2negative/unamplified as per ASCO/CAP guidelines (Wolff et al., 2018). If ER/PR lessthan 10%, prior endocrine therapy is permitted, and the participant is notconsidered appropriate for hormone based therapy. Participants must agree to providearchival tumor material from metastatic site (most recent archival tumor tissueimmediately prior to enrollment is strongly preferred) and must agree to undergoresearch tumor biopsy before treatment and during cycle 2 at the same site ofmetastatic disease, if presence of easily accessible lesion, at the discretion ofthe treating physician.

• Participants must have received at least two lines of prior systemic treatment foradvanced disease. If participants received systemic therapy in the operable settingand the tumor progressed within 12 months of the receipt of the last dose ofsystemic therapy, this will be considered one line of prior systemic therapy foradvance disease. Participants must be more than 14 days removed from most recentstandard of care or experimental drug treatment for their tumor.

• ECOG performance status ≤2

• Participants must have adequate organ and marrow function as defined below:

• Absolute neutrophil count ≥1,500/mcL

• Hemoglobin ≥9 g/ dL (recent transfusion allowed)

• Platelets ≥100,000/mcL

• AST(SGOT)/ALT(SGPT) ≤3 x ULN. AST and ALT (up to 5x ULN is permitted forparticipants with liver metastases)

• Total bilirubin ≤1.5 x institutional ULN

• Creatinine clearance ≥60 mL/min (measured using Cockcroft- Gault equation or theestimated glomerular filtration rate)

• Participants with CNS metastases must be treated and/or stable (no progression forat least 4 weeks after local prior therapy as ascertained by clinical examinationand brain imaging (MRI or CT) during the screening period). Those with symptomssuggestive of possible CNS metastases (such as new headaches) must undergo brain MRIas part of screening.

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial.

• The effects of ProAgio on the developing human fetus are unknown. For this reason,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, forthe duration of study participation and for the 6 months following the last dosingof study drug. Should a woman become pregnant or suspect she is pregnant while sheor her partner is participating in this study, she should inform her treatingphysician immediately.

• During dose escalation, participants with bone only and/or non-measurable diseaseare eligible. During dose expansion, only participants with measurable disease areeligible.

• Ability of subject to understand and the willingness to sign a written informedconsent document.

Exclusion Criteria:

• Participants who have had prior treatment with gemcitabine in the metastaticsetting.

• Platelet transfusion within 7 days prior to treatment start.

• Participants with known history or current symptoms of cardiac disease, or historyof treatment with cardiotoxic agents, should have a clinical risk assessment ofcardiac function using the New York Heart Association Functional Classification. Tobe eligible for this trial, patients should be class 2B or better. Patients withhistory of known congestive heart failure (left ventricular ejection fraction (LVEF) <50%) must have documented LVEF >50% within 12 months of study enrollment.

• Prolonged QTc interval >480 msec on screening EKG

• Participants with known diagnosis of a chronic neurologic disorders (such asmultiple sclerosis, Huntington's disease, Parkinson's disease, or uncontrolledepilepsy) which causes motor disturbance, visual disturbance, or seizure and couldconfound assessment of neurologic toxicity caused by the study drug.

• Pregnant or nursing women are excluded from this study because ProAgio is an agentwith the potential for teratogenic or abortifacient effects. Because there is anunknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with ProAgio, breastfeeding should be discontinued if themother is treated with ProAgio.

• Participants who have undergone a major surgical procedure (within < 28 days) areexcluded.

• Participants with uncontrolled bleeding episodes <28 days prior to enrollment areexcluded.