Soft Tissue Sarcoma
Conditions
Brief summary
This phase I trial tests the safety, tolerability and impact of adding propranolol to standard radiation therapy (RT) before surgery for the treatment of patients with soft tissue sarcoma. Sarcomas are a diverse group of rare tumors arising from connective tissue. Approximately 13,000-16,000 new cases of sarcomas arise in the United States annually. Sarcoma management involves multidisciplinary team decision making and treatment is multimodal utilizing chemotherapy (if needed) and RT prior to surgical intervention. Propranolol is a drug that has been used for many years for high blood pressure by blocking both beta-1 and beta-2 adrenergic receptors. Preclinical data suggests that blocking the beta-2 adrenergic receptors can improve the response to both chemotherapy and radiation. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill tumor cells and shrink tumors. RT before surgery makes the tumor smaller and reduces the amount of tissue that needs to be removed during surgery. Surgery is the most common treatment for soft tissue sarcoma. Giving propranolol with standard RT before surgery may be safe, tolerable and impactful in treating patients with soft tissue carcinoma.
Detailed description
PRIMARY OBJECTIVE: I. To establish the safety and tolerability of adding propranolol to standard RT for soft tissue sarcoma. SECONDARY OBJECTIVE: I. To evaluate the response of tumor immune microenvironment to treatments for patients. OUTLINE: Patients receive propranolol orally (PO) twice daily (BID) for 2 weeks prior to standard of care RT (weeks 1 and 2) and then during and after standard of care RT (weeks 3-7). Treatment continues in the absence of disease progression or unacceptable toxicity until the time of standard of care surgery (week 8). Additionally, patients undergo positron emission tomography (PET) scan and/or computed tomography (CT) scan during screening and may undergo blood and tissue biopsy sample collection throughout the trial. After completion of study treatment, patients are followed up at 5 weeks.
Interventions
PROCEDUREBiopsy
Undergo tissue biopsy sample collection
PROCEDUREBiospecimen Collection
Undergo blood sample collection
PROCEDUREComputed Tomography
Undergo CT scan
PROCEDUREPositron Emission Tomography
Undergo PET scan
DRUGPropranolol
Given PO
RADIATIONRadiation Therapy
Undergo RT
PROCEDURESurgical Procedure
Undergo surgery
Sponsors
Roswell Park Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years old * Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 * Eligible for curative-intent radiation therapy for a soft tissue extremity sarcoma * Ability to swallow and retain oral medication * Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately * Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
Exclusion criteria
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Known hypersensitivity to propranolol * Contraindication to beta-blockers e.g.; uncontrolled depression, unstable angina pectoris, uncontrolled heart failure (New York Heart Association \[NYHA\] grade III or IV), hypotension (systolic blood pressure \< 85 or fasting plasma glucose \> 160 mg/dL at screening), symptomatic peripheral arterial disease or Raynaud's syndrome, untreated pheochromocytoma, current nondihydropyridines calcium channel blocker use (such as verapamil, diltiazem) or rhythm control agents such as digoxin and amiodarone. Patients with pacemakers will be excluded * Patients cannot be on propranolol and another beta-blocker simultaneously. Patients already on beta-blockers can (with approval and under supervision of their primary care physician and/or cardiologist) may choose to stop their current beta-blocker and switch to propranolol for the duration of the study * Pregnant or nursing female participants * Unwilling or unable to follow protocol requirements * Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events | Up to 5 weeks post-surgery | Will evaluate safety and tolerability of adding propranolol to standard radiation therapy for soft tissue sarcoma. Will determine the occurrence of a grade 3 or higher treatment related adverse events. Will summarize using frequencies and relative frequencies, with the grade 3 or higher toxicity rate estimated using a 90% credible region obtained by Jeffrey's prior method. Will summarize toxicities and adverse events (as per Common Terminology Criteria for Adverse Events version 5.0) by attribution and grade using frequencies and relative frequencies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ribonucleic acid sequencing | Up to 12 weeks | Will evaluate with biopsy specimens. Will summarize using the mean and standard deviation, and graphically using line and mean plots. Will be modeled as a function of time and a random patient effect using linear mixed models. Tests about the appropriate contrast of model estimates will be used to evaluate changes over time. All model assumptions will be verified graphically and transformations applied as appropriate. |
| Changes in immune markers | Up to 12 weeks | Changes in immune markers of CD8+ and CD4+ T cells and polymorphonuclear-myeloid-derived suppressor cells will be determined by flow cytometry in peripheral blood. Will summarize using the mean and standard deviation, and graphically using line and mean plots. Will be modeled as a function of time and a random patient effect using linear mixed models. Tests about the appropriate contrast of model estimates will be used to evaluate changes over time. All model assumptions will be verified graphically and transformations applied as appropriate. |
| Catecholamines | Up to 12 weeks | Will correlate the levels of catecholamines and metabolites in peripheral blood. Will summarize using the mean and standard deviation, and graphically using line and mean plots. Will be modeled as a function of time and a random patient effect using linear mixed models. Tests about the appropriate contrast of model estimates will be used to evaluate changes over time. All model assumptions will be verified graphically and transformations applied as appropriate. |
| Metabolites | Up to 12 weeks | Will correlate the levels of catecholamines and metabolites in peripheral blood. Will summarize using the mean and standard deviation, and graphically using line and mean plots. Will be modeled as a function of time and a random patient effect using linear mixed models. Tests about the appropriate contrast of model estimates will be used to evaluate changes over time. All model assumptions will be verified graphically and transformations applied as appropriate. |
Countries
United States
Outcome results
None listed