Combining propranolol and pembrolizumab for advanced soft tissue sarcoma

An Open Label Phase 2 Study on Propranolol and Pembrolizumab in Advanced Angiosarcoma and Undifferentiated Pleomorphic Sarcoma - a Scandinavian Sarcoma Group Collaboration

This study is testing a new combination of two medications, propranolol and pembrolizumab, to see if it can help people with advanced angiosarcoma or undifferentiated pleomorphic sarcoma live longer and feel better.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 80 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Herlev and Gentofte Hospital (Academic / other)
• Drugs / interventions: chemotherapy, radiation, prednisone, pembrolizumab, doxorubicin
• Locations: 4 sites (Aarhus and 3 other locations)
• Trial ID: NCT05961761 on ClinicalTrials.gov

What this trial studies

This phase 2 clinical trial aims to evaluate the efficacy and tolerability of a combination treatment using propranolol and pembrolizumab in patients with advanced angiosarcoma or undifferentiated pleomorphic sarcoma. The study will assess the progression-free survival rate at 3 months as the primary endpoint, while secondary objectives include measuring the objective response rate, duration of response, overall survival, and quality of life. Participants will receive propranolol and pembrolizumab while undergoing evaluations, including biopsies and blood tests for biomarkers. The trial seeks to address the urgent need for new therapeutic options in this patient population, which has limited treatment choices and poor prognosis.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with unresectable locally advanced or metastatic angiosarcoma or undifferentiated pleomorphic sarcoma who have not benefited from first-line chemotherapy.

Not a fit: Patients with resectable tumors or those who have not progressed after first-line chemotherapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment combination could improve survival rates and quality of life for patients with advanced soft tissue sarcoma.

How similar studies have performed: Emerging results from other studies using immune checkpoint inhibitors in soft tissue sarcomas suggest potential benefits, indicating this approach is promising but still requires further validation.

Eligibility criteria

Inclusion Criteria:

* Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject 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 metastatic Angiosarcoma or Undifferentiated Pleomorphic Sarcoma, who has progressed/failed to provide clinical benefit on first line standard chemotherapy.
* Age ≥18 years
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of ≤2 at the time of enrollment.
* Evaluable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).
* Available material from archived formalin-fixed paraffin-embedded tumor tissue obtained within 3 months of study enrollment for biomarker related studies. If not sufficient or available, a newly obtained core or excisional biopsy of a tumor lesion may 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 Syndrome must 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 the Cockcroft-Gault formula)
* Women of childbearing potential (WOCBP): Agreement to use contraceptive methods with a failure rate of \< 1 % per year during the treatment period and for at least 120 days after the treatment. Safe contraceptive methods for women are birth control pills, intrauterine device, contraceptive injection, contraceptive implant,contraceptive patch or contraceptive vaginal ring.
* Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year during the treatment period and for at least 120 days after the treatment.
* Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile) 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 pulmonary disease.
* Acute or non-stable congestive heart failure
* Any other condition listed as contraindication for treatment with propranolol according to SPC
* Have received any previous systemic therapy targeting the PD-1/PDL-1 signaling pathway or other immune checkpoint inhibitors.
* Have received propranolol within 4 weeks prior to treatment.
* Prior to study day one received radiation therapy, chemotherapy or targeted small molecule 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 drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
* Participants with active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism Inclusion criteria
* Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject 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 metastatic Angiosarcoma or Undifferentiated Pleomorphic Sarcoma, who has progressed/failed to provide clinical benefit on first line standard chemotherapy.
* Age ≥18 years
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of ≤2 at the time of enrollment.
* Evaluable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).
* Available material from archived formalin-fixed paraffin-embedded tumor tissue obtained within 3 months of study enrollment for biomarker related studies. If not sufficient or available, a newly obtained core or excisional biopsy of a tumor lesion may 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 Syndrome must 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 the Cockcroft-Gault formula)
* Women of childbearing potential (WOCBP): Agreement to use contraceptive methods with a failure rate of \< 1 % per year during the treatment period and for at least 120 days after the treatment. Safe contraceptive methods for women are birth control pills, intrauterine device, contraceptive injection, contraceptive implant,contraceptive patch or contraceptive vaginal ring.
* Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year during the treatment period and for at least 120 days after the treatment.
* Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile) 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 pulmonary disease.
* Acute or non-stable congestive heart failure
* Any other condition listed as contraindication for treatment with propranolol according to SPC
* Have received any previous systemic therapy targeting the PD-1/PDL-1 signaling pathway or other immune checkpoint inhibitors.
* Have received propranolol within 4 weeks prior to treatment.
* Prior to study day one received radiation therapy, chemotherapy or targeted small molecule 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 drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
* Participants with active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
* Participants with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
* Patients should be excluded if they have known history of testing positive for human immunodeficiency 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

Where this trial is running

Aarhus and 3 other locations

• Aarhus University Hospital — Aarhus, Denmark (Not_yet_recruiting)
• Herlev Gentofte Hospital — Herlev, Denmark (Recruiting)
• Oslo University Hospital — Oslo, Norway (Recruiting)
• Karolinska University Hospital — Stockholm, Sweden (Not_yet_recruiting)

Study contacts

• Principal investigator: Niels Junker, MD, PhD — Herlev and Gentofte Hospital
• Study coordinator: Niels Junker, MD, PhD

Conditions Soft Tissue Sarcoma Adult; Angiosarcoma; Undifferentiated Pleomorphic Sarcoma; Immunotherapy; Propranolol; Pembrolizumab; PD-1 inhibitor; Sarcoma