• Part One:

• Provision to sign and date the consent form.

• Stated willingness to comply with all study procedures and be available for the duration of the study.

• Be male or female aged 18-100 years at the time of signing informed consent.

• Have a histological diagnosis of advanced or metastatic soft tissue sarcoma (STS) (by local pathology review), not curable by surgery, for which treatment with doxorubicin is deemed appropriate by the investigator.

• Has one of the following histologies:

‣ synovial sarcoma,

⁃ malignant peripheral nerve sheath tumors,

⁃ dedifferentiated, pleomorphic or myxoid/round cell liposarcoma,

⁃ uterine or soft tissue leiomyosarcoma,

⁃ malignant phylloides tumor,

⁃ high grade undifferentiated pleomorphic sarcomas (HGUPS/MFH),

⁃ myxofibrosarcoma,

⁃ fibrosarcoma,

⁃ angiosarcoma,

⁃ spindle cell or undifferentiated sarcoma NOS,

⁃ malignant myoepithelioma,

⁃ malignant solitary fibrous tumor/hemangiopericytoma,

⁃ epithelioid hemangioendothelioma,

⁃ Any other histology or standard of care treatment not specifically addressed will be reviewed by the principal investigator and pathologist for final determination of eligibility.

• Have measurable or nonmeasurable but evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Tumors within a previously irradiated field will be designated as nontarget lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiotherapy.

• Have received 0 or 1 prior systemic therapies for metastatic sarcoma and NO prior anthracyclines or checkpoint inhibitors.

• Adequate organ function as defined in protocol.

• Absolute neutrophil count (ANC) ≥1,000 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥8 g/dL without EPO dependency

• Serum creatinine OR Measured or calculated creatiniecclearance

• ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN

• Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN Exception: Subjects with known history of Gilbert's disease should be ≤ 1.5 X of the patient's prior baseline AST (SGOT) and ALT (SGPT) ≤2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases Albumin \>2.5 mg/dL

• International Normalized Ratio (INR) or Prothrombin Time (PT)

• ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

• Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

• Creatinine clearance should be calculated per institutional standard.

• ECOG performance status of 0 or 1.

⁃ Patients must consent and be willing to undergo tumor core needle biopsies at two timepoints: 1. Baseline, 2. Cycle 2 Day 5; a third biopsy for off-study/progression is optional but advised. At least one tumor site must be amenable to biopsy in the judgment of the interventional radiologist.

⁃ Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

⁃ Females of child bearing potential that are sexually active must agree to either practice 2 medically accepted highly effective methods of contraception at the same time or abstain from heterosexual intercourse from the time of signing the informed consent through 120 days after the last dose of study drug. See Appendix B for protocol-approved highly effective methods of contraceptive combinations. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.

∙ Negative test for pregnancy is required of females of child-bearing potential. A female of child-bearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1. Has not undergone a hysterectomy or bilateral oophorectomy; or 2. Has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months or 730 days.)

‣ Conception while on treatment must be avoided.

⁃ Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. Prior history of vasectomy does NOT replace requirement for contraceptive use.

⁃ Subjects must either possess or undergo placement of central venous catheter, including pheresis or trifusion catheter, PICC line, or port.

• Part Two: In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Provision to sign and date the consent form.

• Stated willingness to comply with all study procedures and be available for the duration of the study.

• Be male or female aged 18-100 years at the time of signing informed consent.

• Have a histological diagnosis of advanced or metastatic soft tissue sarcoma (STS) (by local pathology review), not curable by surgery, for which treatment with doxorubicin is deemed appropriate by the investigator.

• Has one of the following histologies:

‣ synovial sarcoma,

⁃ malignant peripheral nerve sheath tumors,

⁃ dedifferentiated, pleomorphic or myxoid/round cell liposarcoma,

⁃ uterine or soft tissue leiomyosarcoma,

⁃ malignant phylloides tumor,

⁃ high grade undifferentiated pleomorphic sarcomas (HGUPS/MFH),

⁃ myxofibrosarcoma,

⁃ fibrosarcoma,

⁃ angiosarcoma,

⁃ spindle cell or undifferentiated sarcoma NOS,

⁃ malignant myoepithelioma,

⁃ malignant solitary fibrous tumor/hemangiopericytoma,

⁃ epithelioid hemangioendothelioma,

⁃ Any other histology or standard of care treatment not specifically addressed will be reviewed by the principal investigator in consultation with pathology as needed for final determination of eligibility.

• Have measurable or nonmeasurable but evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (modified RECIST 1.1). Tumors within a previously irradiated field will be designated as nontarget lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiotherapy.

• Have received any number of prior systemic therapies for metastatic sarcoma but NO prior anthracyclines or checkpoint inhibitors. Re-treatment with the same drug or regimen after interruption (i.e. chemotherapy holiday) is not considered a new line of treatment, and those patients are eligible.

• Adequate organ function as defined in protocol.

• Absolute neutrophil count (ANC) ≥1,000 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥8 g/dL without EPO dependency

• Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl)

• ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN

• Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN. Exception: Subjects with known history of Gilbert's disease should be ≤ 1.5 X of the patient's prior baseline

• AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases Albumin \>2.5 mg/dL

• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

• Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Creatinine clearance should be calculated per institutional standard.

• ECOG performance status of 0 or 1.

⁃ Patients must consent and be willing to undergo tumor core needle biopsies at two timepoints: 1. Baseline, 2. Cycle 2 Day 5; a third biopsy for off-study/progression is optional but advised. At least one tumor site must be amenable to biopsy in the judgment of the investigator, with consultation with the interventional radiologist as needed.

⁃ Female subjects of childbearing potential must have a negative urine or serum pregnancy test at screening. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. In the rare case where the sarcoma is thought to be producing beta HCG, patients with a positive serum HCG test must have a uterine ultrasound for confirmation of negative pregnancy status.

⁃ Females of child bearing potential that are sexually active must agree to either practice 2 medically accepted highly effective methods of contraception at the same time or abstain from heterosexual intercourse from the time of signing the informed consent through 120 days after the last dose of study drug. See Appendix B for protocol-approved highly effective methods of contraceptive combinations. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.

∙ Negative test for pregnancy is required of females of child-bearing potential. A female of child-bearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1. Has not undergone a hysterectomy or bilateral oophorectomy; or 2. Has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months or 730 days.)

‣ Conception while on treatment must be avoided.

⁃ Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. Prior history of vasectomy does NOT replace requirement for contraceptive use.

⁃ Subjects must either possess or undergo placement of central venous catheter, including pheresis or trifusion catheter, PICC line, or port.