Phase 2 Study of Propranolol Hydrochloride and Pembrolizumab in Advanced Angiosarcoma and Undifferentiated Pleomorphic Sarcoma
- Trial ID
- 2024-513727-16-00
- Protocol
- SA2115
- Sponsor
- Region Hovedstaden
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **progression-free survival rate (PFSR)** at 3 months in patients with advanced Angiosarcoma and Undifferentiated Pleomorphic Sarcoma, utilizing the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). This is clinically relevant as it provides an early indicator of the treatment's efficacy in halting disease progression, which is crucial for assessing the potential benefit of the therapeutic regimen.
Secondary objectives include:
- Determining the **objective response rate (ORR)** and duration of response (DOR) using RECIST v1.1, which helps in evaluating the proportion of patients who experience a predefined amount of tumor size reduction and the duration of this response.
- Assessing **progression-free survival (PFS)** and **overall survival (OS)**, which are critical endpoints for understanding the long-term benefits of the treatment.
- Evaluating the **safety and tolerability** of the combination of pembrolizumab and propranolol, ensuring that the treatment is not only effective but also safe for patients.
- Determining the **quality of life (QoL)** of patients, which is essential for understanding the impact of the treatment on patients' daily living and well-being.
- Exploring the association between anti-tumor activity and specific **biomarker measures** in tumor tissue and peripheral blood, which may provide insights into the mechanisms of action and potential predictive markers of response.
Participants
The clinical trial involves participants diagnosed with **Advanced Angiosarcoma** and **Undifferentiated Pleomorphic Sarcoma**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically confirmed diagnosis of unresectable locally advanced or metastatic forms of the disease, having shown progression or lack of clinical benefit from first-line standard chemotherapy. The trial population was selected based on specific inclusion criteria, including an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 2 or less, and the ability to comply with study requirements. Participants must have evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). The trial also considers vulnerable populations. However, the sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **propranolol hydrochloride** in combination with **pembrolizumab** for the treatment of advanced **angiosarcoma** and **undifferentiated pleomorphic sarcoma**. This is a phase II, open-label study with a primary objective to determine the progression-free survival rate at three months, assessed by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The trial employs a randomized, controlled design to ensure the reliability of the results. The estimated duration of the trial is from December 2022 to December 2028, with a maximum treatment period of 104 weeks for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, performance status, and laboratory values. Following the screening, eligible participants will be enrolled and receive treatment according to the study protocol. Regular follow-up visits will be scheduled to monitor the participants' response to treatment, assess any adverse events, and ensure compliance with the study requirements. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, where final assessments will be conducted.
The expected length of participant involvement is up to 104 weeks, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent by the participant. The study will adhere to ethical guidelines, ensuring that all participants provide informed consent and are aware of their rights throughout the trial. The trial's endpoints include the percentage of patients achieving complete response, partial response, or stable disease at three months, as well as secondary endpoints such as median progression-free survival, overall survival, and quality of life assessments.
Treatment
The clinical trial involves the administration of **PROPRANOLOL HYDROCHLORIDE**, a beta-blocker, in the form of film-coated tablets. The active substance, propranolol hydrochloride, is of chemical origin. The maximum daily dose is 80 mg, with a total maximum dose of 58,240 mg over a treatment period of up to 104 weeks. The medication is administered orally. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.
**KEYTRUDA** (pembrolizumab) is also utilized in this trial. It is provided as a 25 mg/mL concentrate for solution for infusion. Pembrolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF02. The maximum daily dose is 2 mg/kg, with a total maximum dose of 68 mg/kg over the same treatment period of 104 weeks. The administration route is intravenous, and the infusion schedule will be closely monitored to ensure proper dosing and participant compliance.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this study. The trial aims to evaluate the efficacy of the experimental medications in achieving the main objective, which is to determine the progression-free survival rate at 3 months using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
Efficacy
Efficacy in the clinical trial will be assessed using several key endpoints. The primary endpoint is the percentage of patients alive with complete response (CR), partial response (PR), and stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) at 3 months. Secondary endpoints include the percentage of patients with CR and PR, including the duration of these responses using RECIST v1.1, median progression-free survival (PFS) and overall survival (OS), adverse events as per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, and patient-reported outcomes using the 30-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ C30).
The main objective of the trial is to determine the progression-free survival rate (PFSR) at 3 months, evaluated by RECIST v1.1. Efficacy assessments will be conducted at specified intervals throughout the trial, with the primary endpoint being evaluated at the 3-month mark. The trial will utilize validated scales and criteria, such as RECIST v1.1 and CTCAE v5.0, to ensure consistent and reliable measurement of efficacy parameters. The trial is designed to provide comprehensive data on the efficacy of the treatment regimen in patients with advanced **Angiosarcoma** and Undifferentiated Pleomorphic Sarcoma.
Inclusion and Exclusion 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 biomarkerrelated studies. If not sufficient or available, a newly obtained core or excisional biopsy of a tumor lesion may be performed.
- 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)
- History of allergy to study drug components
- History of severe hypersensitivity reaction to any monoclonal antibody
- WOCBP who are pregnant or breastfeeding
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Recruiting | 05 Dec 2022 | 50 |
 Norway | Recruiting | 05 Dec 2022 | 30 |
 Sweden | Not Yet Recruiting | 05 Dec 2022 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PROPRANOLOL HYDROCHLORIDE | Test | — | ORAL | 80 | 104 | SUB04091MIG |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 2 | 104 | PRD4323105 |
PROPRANOLOL HYDROCHLORIDE | Test | — | ORAL | 80 | 104 | SUB04091MIG |