Doxorubicin Plus Dual Checkpoint Blockade for Soft Tissue Sarcomas

Inclusion Criteria:

Part One:

1. Provision to sign and date the consent form.

2. Stated willingness to comply with all study procedures and be available for theduration of the study.

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

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

5. 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 addressedwill be reviewed by the principal investigator and pathologist for finaldetermination of eligibility.

6. Have measurable or nonmeasurable but evaluable disease as defined by the ResponseEvaluation Criteria in Solid Tumors (RECIST 1.1). Tumors within a previouslyirradiated field will be designated as "nontarget" lesions unless progression isdocumented or a biopsy is obtained to confirm persistence at least 90 days followingcompletion of radiotherapy.

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

8. Adequate organ function as defined in protocol. Absolute neutrophil count (ANC) ≥1,000 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥8g/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 totalbilirubin levels > 1.5 ULN Exception: Subjects with known history of Gilbert'sdisease 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 iswithin therapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receivinganticoagulant therapy as long as PT or PTT is within therapeutic range of intendeduse of anticoagulants Creatinine clearance should be calculated per institutional standard.

9. ECOG performance status of 0 or 1.

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

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

12. Females of child bearing potential that are sexually active must agree to eitherpractice 2 medically accepted highly effective methods of contraception at the sametime or abstain from heterosexual intercourse from the time of signing the informedconsent through 120 days after the last dose of study drug. See Appendix B forprotocol-approved highly effective methods of contraceptive combinations. Subjectsof childbearing potential are those who have not been surgically sterilized or havenot 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 sexualorientation or whether they have undergone tubal ligation, who meets thefollowing criteria: 1. Has not undergone a hysterectomy or bilateraloophorectomy; or 2. Has not been naturally postmenopausal for at least 24consecutive months (ie, has had menses at any time in the preceding 24consecutive months or 730 days.)

• Conception while on treatment must be avoided.

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

14. 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:

1. Provision to sign and date the consent form.

2. Stated willingness to comply with all study procedures and be available for theduration of the study.

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

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

5. 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 addressedwill be reviewed by the principal investigator in consultation with pathologyas needed for final determination of eligibility.

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

7. Have received any number of prior systemic therapies for metastatic sarcoma but NOprior anthracyclines or checkpoint inhibitors. Re-treatment with the same drug orregimen after interruption (i.e. chemotherapy holiday) is not considered a new lineof treatment, and those patients are eligible.

8. Adequate organ function as defined in protocol. Absolute neutrophil count (ANC) ≥1,000 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥8g/dL without EPO dependency Serum creatinine OR Measured or calculated creatinine clearance (GFR can also beused 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 totalbilirubin levels > 1.5 ULN. Exception: Subjects with known history of Gilbert'sdisease 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 livermetastases Albumin >2.5 mg/dL International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unlesssubject is receiving anticoagulant therapy as long as PT or PTT is withintherapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receivinganticoagulant therapy as long as PT or PTT is within therapeutic range of intendeduse of anticoagulants Creatinine clearance should be calculated per institutionalstandard.

9. ECOG performance status of 0 or 1.

10. Patients must consent and be willing to undergo tumor core needle biopsies at twotimepoints: 1. Baseline, 2. Cycle 2 Day 5; a third biopsy for off-study/progressionis optional but advised. At least one tumor site must be amenable to biopsy in thejudgment of the investigator, with consultation with the interventional radiologistas needed.

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

12. Females of child bearing potential that are sexually active must agree to eitherpractice 2 medically accepted highly effective methods of contraception at the sametime or abstain from heterosexual intercourse from the time of signing the informedconsent through 120 days after the last dose of study drug. See Appendix B forprotocol-approved highly effective methods of contraceptive combinations. Subjectsof childbearing potential are those who have not been surgically sterilized or havenot 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 sexualorientation or whether they have undergone tubal ligation, who meets thefollowing criteria: 1. Has not undergone a hysterectomy or bilateraloophorectomy; or 2. Has not been naturally postmenopausal for at least 24consecutive months (ie, has had menses at any time in the preceding 24consecutive months or 730 days.)

• Conception while on treatment must be avoided.

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

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

Exclusion Criteria:

Part One:

1. Prior therapy with anthracycline or checkpoint inhibitors.

2. Hypersensitivity to doxorubicin or any excipients.

3. Patients may not be receiving any other investigational agents (within 4 weeks priorto Cycle 1, Day 1).

4. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Cycle 1, Day 1or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due toagents administered more than 4 weeks earlier.

5. Patient has had prior chemotherapy, targeted small molecule therapy, or radiationtherapy within 2 weeks prior to Cycle 1, Day 1 or has not recovered (i.e., ≤ Grade 1or at baseline) from adverse events due to agents administered more than 4 weeksearlier. Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to thiscriterion and may qualify for the study. Note: If subject received major surgery,they must have recovered adequately from the toxicity and/or complications from theintervention prior to starting therapy.

6. Additional known malignancy that is progressing or requires active treatment.Exceptions include basal cell carcinoma of the skin, or squamous cell carcinoma ofthe skin that has undergone potentially curative therapy, or in situ cervicalcancer.

7. Patients with underlying immune deficiency, chronic infections including HIV,hepatitis, or tuberculosis (TB) or autoimmune disease.

8. Patients with underlying hematologic issues including bleeding diathesis, such asknown previous GI bleeding requiring intervention within the past 6 months. Newlydiagnosed pulmonary emboli or deep venous thrombosis must be clinically stable onanticoagulation regimen for ≥ 2 weeks as of Cycle 1 Day 1.

9. Has known history of non-infectious pneumonitis that required oral corticosteroidtherapy for resolution within 12 months prior to study entry, or evidence by imagingor symptoms of active non-infectious pneumonitis.

10. Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis or leptomeningeal disease. Subjects with previously treated brainmetastases may participate provided they are stable based on the following: 1) MRIbrain obtained during screening evaluations shows no radiographic evidence ofprogression or new lesions, 2) any neurologic symptoms have returned to baseline, 3)no requirement for steroids for at least 28 days prior to trial treatment. Thisexception does not include carcinomatous meningitis which is excluded regardless ofclinical stability. Patients without a known history of brain metastases do notrequire screening brain MRI prior to study enrollment.

11. Has received a live vaccine within 30 days of planned start of study therapy. Note:Seasonal influenza vaccines for injection are generally inactivated flu vaccines andare allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are liveattenuated vaccines, and are not allowed.

12. Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the trial, starting with the pre-screening or screening visitthrough 120 days after the last dose of trial treatment.

13. Any uncontrolled, intercurrent illness including but not limited to ongoing oractive infection, symptomatic congestive heart failure, unstable angina pectoris,cardiac arrhythmia

14. Prolonged QTc interval on Screening EKG >475 ms.

15. Ejection Fraction <50% by 2D ECHO at Screening.

16. Any serious medical or psychiatric illness/condition including substance usedisorders likely in the judgment of the Investigator(s) to interfere or limitcompliance with study requirements/treatment, including NYHA Class II or greaterheart disease (see Appendix C for definitions).

17. 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.

18. Had a previous severe hypersensitivity reaction to another monoclonal antibody.

19. Primary or secondary immunodeficiency (including immunosuppressive disease,autoimmune disease [excluding hypothyroidism, insulin dependent diabetes mellitus,or vitiligo], or usage of immunosuppressive medications).

Part Two: An individual who meets any of the following criteria will be excluded from participation in this study:

1. Prior therapy with anthracycline or checkpoint inhibitors.

2. Hypersensitivity to doxorubicin or any excipients.

3. Patients may not be receiving any other investigational agents (within 4 weeks priorto Cycle 1, Day 1).

4. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Cycle 1, Day 1or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due toagents administered more than 4 weeks earlier.

5. Patient has had prior chemotherapy, targeted small molecule therapy, or radiationtherapy within 2 weeks prior to Cycle 1, Day 1 or has not recovered (i.e., ≤ Grade 1or at baseline) from adverse events due to agents administered more than 4 weeksearlier. Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to thiscriterion and may qualify for the study. Note: If subject received major surgery,they must have recovered adequately from the toxicity and/or complications from theintervention prior to starting therapy.

6. Additional known malignancy that is progressing or requires active treatment.Exceptions include basal cell carcinoma of the skin, or squamous cell carcinoma ofthe skin that has undergone potentially curative therapy, or in situ cervicalcancer.

7. Patients with underlying immune deficiency, chronic infections including HIV,hepatitis, or tuberculosis (TB) or autoimmune disease.

8. Patients with underlying hematologic issues including bleeding diathesis, such asknown previous GI bleeding requiring intervention within the past 6 months. Newlydiagnosed pulmonary emboli or deep venous thrombosis must be clinically stable onanticoagulation regimen for ≥ 2 weeks as of Cycle 1 Day 1.

9. Has known history of non-infectious pneumonitis that required oral corticosteroidtherapy for resolution within 12 months prior to study entry, or evidence by imagingor symptoms of active non-infectious pneumonitis.

10. Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis or leptomeningeal disease. Subjects with previously treated brainmetastases may participate provided they are stable based on the following: 1) MRIbrain obtained during screening evaluations shows no radiographic evidence ofprogression or new lesions, 2) any neurologic symptoms have returned to baseline, 3)no requirement for steroids for at least 28 days prior to trial treatment. Thisexception does not include carcinomatous meningitis which is excluded regardless ofclinical stability. Patients without a known history of brain metastases do notrequire screening brain MRI prior to study enrollment.

11. Has received a live vaccine within 30 days of planned start of study therapy. Note:Seasonal influenza vaccines for injection are generally inactivated flu vaccines andare allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are liveattenuated vaccines, and are not allowed.

12. Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the trial, starting with the pre-screening or screening visitthrough 120 days after the last dose of trial treatment.

13. Any uncontrolled, intercurrent illness including but not limited to ongoing oractive infection, symptomatic congestive heart failure, unstable angina pectoris,cardiac arrhythmia

14. Prolonged QTc interval on Screening EKG >475 ms.

15. Ejection Fraction <50% by 2D ECHO at Screening.

16. Any serious medical or psychiatric illness/condition including substance usedisorders likely in the judgment of the Investigator(s) to interfere or limitcompliance with study requirements/treatment, including NYHA Class II or greaterheart disease (see Appendix C for definitions).

17. 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.

18. Had a previous severe hypersensitivity reaction to another monoclonal antibody.

19. Primary or secondary immunodeficiency (including immunosuppressive disease,autoimmune disease [excluding hypothyroidism, insulin dependent diabetes mellitus,or vitiligo], or usage of immunosuppressive medications).