Propranolol and Pembrolizumab in Advanced Soft Tissue Sarcoma Patients — PROPANE  

Undifferentiated Pleomorphic Sarcoma Clinical Trial

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

Status Recruiting

Clinical Trial Summary

The goal of this phase 2 clinical trial is to test efficacy and tolerability of combining propranolol and pembrolizumab in patients with advanced angiosarcoma or undifferentiated pleomorphic sarcoma. The main questions aims to answer:

• Primary: determine the progression-free survival rate (PFSR) at 3 months

Secondary: determine the objective response rate (ORR), duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS). Ensure the safety and tolerability, Determine Quality of Life (QoL)

• Exploratory: Characterize the TME

Participants will be asked to ensure

• Baseline biopsy and further optional biopsies

• Treatment propranolol 40 mg BID and pembrolizumab 2 mg/kg Q3 weeks

• Evaluation, blood counts, QoL and blood samples for biomarkers according to schedule

Clinical Trial Description

Soft tissue sarcomas (STS) are mesenchymal derived tumors consisting of more than 50 subtypes, showing high metastatic features in approximately 50% of patients with intermediate and high-grade tumors. In spite of optimizing sequence of conventional systemic treatments with chemotherapy and tyrosine kinase inhibitors with an increase in overall survival from 12 to 18 months, the prognosis has not changed and is still a dismal 8% overall survival at 5 years. After four decades doxorubicin is still first line treatment as no new drugs has proven more effective and/or less toxic. Thus, new treatment modalities are needed.

Angiosarcomas (AS) and Undifferentiated Pleomorphic Sarcoma (UPS), comprising approximately 2% and 10% of STS respectively, are by definition high grade sarcomas characterized by an aggressive course. In the non-resectable advanced and metastatic setting treatment options are limited with short term palliative intent with median overall survival (OS) < 12 months. Patients are often elderly and with co-morbidities, increasing risk of severe toxicity from chemotherapy leading to significant deterioration of Quality of Life. New therapeutic options are needed.

Emerging results on immune modulating therapy with immune checkpoint inhibitors (ICI), have shown promising signals of potential benefit in certain subtypes of STS, especially in UPS and AS.

In tumors, neovascularization facilitate hypoxia, glucose deprivation and increased VEGF production leading to an immune suppressive tumor microenvironment (TME). This can in part be reverted by anti-angiogenic therapy including multitarget tyrosine kinase inhibitors. A proposed novel approach for targeting angiogenesis and potential immune modulatory mechanisms is through beta-adrenergic receptor (βAR) signaling. Preclinical data support combining βAR blockade with propranolol in combination with anti PD-1, and recently a phase 1 study showed the combination propranolol and pembrolizumab was well tolerated in melanoma patients.

This study is an open label, Simon two-stage single arm phase 2 study of pembrolizumab and propranolol in two separate cohorts. Patients will receive pembrolizumab 2 mg/kg every 3 weeks and propranolol 40 mg x2 daily until progression, unacceptable toxicity or patient withdrawal for a maximum of two years.

Up to 40 patients will be included in each separate cohort. Up to 18 patients in stage 1 and up to 22 patients in stage 2.

The primary objective is to determine progression-free survival rate (PFSR) at 3 months by Response Evaluation Criteria in Solid Tumors (RECIST v1.1)

The secondary objectives are to determine objective response rate (ORR) and duration of Response (DOR) using RECIST v 1.1, PFS and OS. Ensure safety and tolerability according to Common Terminology Criteria for Adverse Events (CTCAE version 5.0), and determine Quality of Life (QoL) using the 30 item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ C30) questionnaire

The explorative objective is to characterize the TME, immune cells and markers both in tumors and in peripheral blood. ;

Related Conditions & MeSH terms

• Angiosarcoma
• Histiocytoma, Malignant Fibrous
• Sarcoma
• Soft Tissue Sarcoma Adult
• Undifferentiated Pleomorphic Sarcoma

• NCT number: NCT05961761
• Study type: Interventional
• Source: Herlev and Gentofte Hospital
• Contact: Niels Junker, MD, PhD
• Phone: +4538682973
• Email: Niels.Junker@regionh.dk
• Status: Recruiting
• Phase: Phase 2
• Start date: August 17, 2021
• Completion date: December 2028