Propranolol and Pembrolizumab in Advanced Soft Tissue Sarcoma Patients

Inclusion Criteria:

• Subjects must have signed and dated an IRB/IEC approved written informed consent formin accordance with regulatory and institutional guidelines. This must be obtainedbefore the performance of any protocol related procedures that are not part of normalsubject care
• Subjects must be willing and able to comply with scheduled visits, treatment schedule,laboratory testing, and other requirements of the study
• Histologically confirmed diagnosis of unresectable locally advanced or metastaticAngiosarcoma or Undifferentiated Pleomorphic Sarcoma, who has progressed/failed toprovide clinical benefit on first line standard chemotherapy.
• Age ≥18 years
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of ≤2 at thetime of enrollment.
• Evaluable disease as defined by Response Evaluation Criteria in Solid Tumors (RECISTversion 1.1).
• Available material from archived formalin-fixed paraffin-embedded tumor tissueobtained within 3 months of study enrollment for biomarker related studies. If notsufficient or available, a newly obtained core or excisional biopsy of a tumor lesionmay be performed.
• Patients must have normal organ and marrow function as defined below:
• Absolute neutrophil count (ANC) ≥ 1 x 10⁹/L
• Platelet count ≥ 75 x 10⁹/L
• Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with Gilbert's Syndromemust have a total bilirubin ≤ 50 mmol/L)
• Aspartate transaminase (AST)/Alanine transaminase (ALT) ≤ 5 x ULN
• Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (using theCockcroft-Gault formula)
• Women of childbearing potential (WOCBP): Agreement to use contraceptive methods with afailure rate of < 1 % per year during the treatment period and for at least 120 daysafter the treatment. Safe contraceptive methods for women are birth control pills,intrauterine device, contraceptive injection, contraceptive implant,contraceptivepatch or contraceptive vaginal ring.
• Men who are sexually active with WOCBP must use any contraceptive method with afailure rate of less than 1% per year during the treatment period and for at least 120days after the treatment.
• Women who are not of childbearing potential (ie, who are postmenopausal or surgicallysterile) as well as azoospermic men do not require contraception

Exclusion Criteria:

• Have an anticipated life expectancy of <3 months.
• Moderate to severe degree of bronchial asthma or chronic obstructive pulmonarydisease.
• Acute or non-stable congestive heart failure
• Any other condition listed as contraindication for treatment with propranololaccording to SPC
• Have received any previous systemic therapy targeting the PD-1/PDL-1 signaling pathwayor other immune checkpoint inhibitors.
• Have received propranolol within 4 weeks prior to treatment.
• Prior to study day one received radiation therapy, chemotherapy or targeted smallmolecule therapy within 2 weeks and/or monoclonal antibody treatment within 4 weeks.
• Not recovered from the effects of previously administered agents
• Clinically active or unstable CNS metastases as assessed by the treating physician
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator,may increase the risk associated with study participation or study drugadministration, impair the ability of the subject to receive protocol therapy, orinterfere with the interpretation of study results
• Participants with active, known or suspected autoimmune disease. Participants withvitiligo, type I diabetes mellitus, residual hypothyroidism Inclusion criteria
• Subjects must have signed and dated an IRB/IEC approved written informed consent formin accordance with regulatory and institutional guidelines. This must be obtainedbefore the performance of any protocol related procedures that are not part of normalsubject care
• Subjects must be willing and able to comply with scheduled visits, treatment schedule,laboratory testing, and other requirements of the study
• Histologically confirmed diagnosis of unresectable locally advanced or metastaticAngiosarcoma or Undifferentiated Pleomorphic Sarcoma, who has progressed/failed toprovide clinical benefit on first line standard chemotherapy.
• Age ≥18 years
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of ≤2 at thetime of enrollment.
• Evaluable disease as defined by Response Evaluation Criteria in Solid Tumors (RECISTversion 1.1).
• Available material from archived formalin-fixed paraffin-embedded tumor tissueobtained within 3 months of study enrollment for biomarker related studies. If notsufficient or available, a newly obtained core or excisional biopsy of a tumor lesionmay be performed.
• Patients must have normal organ and marrow function as defined below:
• Absolute neutrophil count (ANC) ≥ 1 x 10⁹/L
• Platelet count ≥ 75 x 10⁹/L
• Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with Gilbert's Syndromemust have a total bilirubin ≤ 50 mmol/L)
• Aspartate transaminase (AST)/Alanine transaminase (ALT) ≤ 5 x ULN
• Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (using theCockcroft-Gault formula)
• Women of childbearing potential (WOCBP): Agreement to use contraceptive methods with afailure rate of < 1 % per year during the treatment period and for at least 120 daysafter the treatment. Safe contraceptive methods for women are birth control pills,intrauterine device, contraceptive injection, contraceptive implant,contraceptivepatch or contraceptive vaginal ring.
• Men who are sexually active with WOCBP must use any contraceptive method with afailure rate of less than 1% per year during the treatment period and for at least 120days after the treatment.
• Women who are not of childbearing potential (ie, who are postmenopausal or surgicallysterile) as well as azoospermic men do not require contraception Exclusion criteria
• Have an anticipated life expectancy of <3 months.
• Moderate to severe degree of bronchial asthma or chronic obstructive pulmonarydisease.
• Acute or non-stable congestive heart failure
• Any other condition listed as contraindication for treatment with propranololaccording to SPC
• Have received any previous systemic therapy targeting the PD-1/PDL-1 signaling pathwayor other immune checkpoint inhibitors.
• Have received propranolol within 4 weeks prior to treatment.
• Prior to study day one received radiation therapy, chemotherapy or targeted smallmolecule therapy within 2 weeks and/or monoclonal antibody treatment within 4 weeks.
• Not recovered from the effects of previously administered agents
• Clinically active or unstable CNS metastases as assessed by the treating physician
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator,may increase the risk associated with study participation or study drugadministration, impair the ability of the subject to receive protocol therapy, orinterfere with the interpretation of study results
• Participants with active, known or suspected autoimmune disease. Participants withvitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmunecondition only requiring hormone replacement, psoriasis not requiring systemictreatment, or conditions not expected to recur in the absence of an external triggerare permitted to enroll.
• Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications. Inhaledor topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalentsare permitted in the absence of active autoimmune disease.
• Patients should be excluded if they have known history of testing positive for humanimmunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Allergies and Adverse Drug Reaction
• History of allergy to study drug components
• History of severe hypersensitivity reaction to any monoclonal antibody
• WOCBP who are pregnant or breastfeeding