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Propranolol Hydrochloride in Treating Patients With Locally Recurrent or Metastatic Solid Tumors That Cannot Be Removed By Surgery

Primary Purpose

Male Breast Cancer, Recurrent Melanoma, Stage IV Breast Cancer

Status
Completed
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
propranolol hydrochloride
Correlative Studies
Sponsored by
William Carson
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Male Breast Cancer focused on measuring Beta-Blocker, metastatic melanoma, hepatocellular carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients must have histologically-proven locally-recurrent or metastatic solid tumor; the first 10 patients may have cancer of any histology; preference will be given to patients with metastatic ovarian cancer, breast cancer, and malignant melanoma, as these malignancies have been shown to be sensitive to manipulation of the beta-adrenergic receptor; the final twenty-five patients to be accrued must have locally-recurrent or metastatic malignant melanoma that is not surgically resectable. An additional cohort of 10 patients with BCLC stages A to C locally advanced or metastatic hepatocellular carcinoma (HCC) that is not surgically resectable will also be enrolled (See appendix for BCLC staging system). Patients with liver transplantation will not be eligible.
  • The diagnosis of hepatocellular carcinoma may be made by one of the following methods:

    1. Pathologically (histologically or cytologically) proven diagnosis of HCC.
    2. At least one solid liver lesion or vascular tumor thrombosis (involving portal vein, IVC and/or hepatic vein) > 1 cm with arterial enhancement and delayed washout on multiphasic computerized tomography (CT) or magnetic resonance imaging (MRI) in the setting of cirrhosis or chronic hepatitis B or C without cirrhosis.
    3. For patients whose CURRENT disease is vascular only: Enhancing vascular thrombosis (involving portal vein, IVC and/or hepatic vein) demonstrating early arterial enhancement and delayed washout on multi-phasic CT or MRI, in a patient with known HCC (diagnosed according to criteria in (a) or (b).
  • Patients may have had any number of prior systemic therapies; patients need not have exhausted standard therapy for their disease, but must be stable and must not have actively progressing
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Karnofsky >= 60%
  • Life expectancy of greater than 6 months
  • Patients (except for the HCC cohort) must have normal organ and marrow function as defined below:
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
  • Creatinine within normal institutional limits OR
  • Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Parameters for the HCC cohort:
  • leukocytes > or = 3000/mcl
  • absolute neutrophil count > or =1000/mcl
  • platelets > or = 70,000
  • total bilirubin < or = 2mg/dL
  • AST/ALT <6 times ULN
  • creatinine within normal institutional limits OR
  • creatinine clearance > or = 60mL/min/1.73m2 for patients with creatinine levels above institutional normal level
  • INR < or = 1.7
  • The effects of propranolol on the developing human fetus may be detrimental. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document
  • Patients with brain metastases may participate in this clinical study provided that symptoms have been controlled with standard therapies and/or appropriate medications; the principal investigator (P.I.) will carefully evaluate the suitability of patient participation when brain metastases are present

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Patients may not be receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to propranolol
  • Uncontrolled hypertension
  • 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
  • Patients with significant lung disease, an ejection fraction less than 40%, or a resting heart rate less than 60/min will not be enrolled
  • Pregnant women are excluded from this study because propranolol is an agent with the potential for teratogenic or abortifacient effects
  • Patients who are currently receiving a beta-blocker for another medical condition will be excluded from this study; patients with extremes of blood pressure (e.g., systolic blood pressure [SBP] > 150 or < 100) may be excluded from participation if the treating physician feels that this medical condition has not been adequately addressed by the patient's primary care physician
  • Patients with worsening depression that has not been addressed clinically will be excluded from this study

Sites / Locations

  • Ohio State University Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (propranolol hydrochloride)

Arm Description

Patients receive propranolol hydrochloride PO BID for 4 months in the absence of disease progression or unacceptable toxicity. Propranolol will be administered on an out-patient basis. Blood for correlative studies (30 ml - green top tube) will be drawn at baseline and at each clinic visit. Tumor tissue for analysis will be obtained via core needle biopsy (or other appropriate modality) pre-study and at approximately the two month time point.

Outcomes

Primary Outcome Measures

Incidence of toxicity graded according to Common Terminology Criteria for Adverse Events (CTCAE) V. 4.0
A dose-limiting toxicity (DLT) will be considered as any grade 3 or higher hematologic or non- hematologic toxicity that is probably or definitely related to treatment.
Change in vascular endothelial growth factor (VEGF)
Effect of beta-adrenergic blockade on the tumor microenvironment
Measured via a series of correlative laboratory studies using cancer tumor tissue and peripheral blood mononuclear cells.
Effect of beta-adrenergic blockade on the host immune system
Measured via a series of correlative laboratory studies using cancer tumor tissue and peripheral blood mononuclear cells.

Secondary Outcome Measures

Progression-free survival
Overall survival

Full Information

First Posted
December 11, 2013
Last Updated
December 4, 2022
Sponsor
William Carson
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1. Study Identification

Unique Protocol Identification Number
NCT02013492
Brief Title
Propranolol Hydrochloride in Treating Patients With Locally Recurrent or Metastatic Solid Tumors That Cannot Be Removed By Surgery
Official Title
A Pilot Study of Beta-Blockers in Patients With Advanced Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Completed
Study Start Date
January 21, 2014 (Actual)
Primary Completion Date
June 12, 2015 (Actual)
Study Completion Date
June 12, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
William Carson

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This pilot trial studies propranolol hydrochloride in treating patients with locally recurrent or metastatic solid tumors that cannot be removed by surgery. Propranolol hydrochloride may slow the growth of tumor cells by blocking the use of hormones by the tumor cells.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the feasibility and tolerability of beta-adrenergic blockade in patients with metastatic or locally advanced cancer. II. To determine the effects of beta-adrenergic blockade on the tumor microenvironment and host immune system via a series of correlative laboratory studies using cancer tumor tissue and peripheral blood mononuclear cells from the study patients. SECONDARY OBJECTIVES: I. Evaluate the effects of beta-adrenergic blockade on progression-free survival and overall survival. OUTLINE: Patients receive propranolol hydrochloride orally (PO) twice daily (BID) for 4 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for up to 1 year.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Male Breast Cancer, Recurrent Melanoma, Stage IV Breast Cancer, Stage IV Melanoma, Stage IV Ovarian Epithelial Cancer, Stage IV Ovarian Germ Cell Tumor, Unspecified Adult Solid Tumor, Protocol Specific, Hepatocellular Carcinoma
Keywords
Beta-Blocker, metastatic melanoma, hepatocellular carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
1 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (propranolol hydrochloride)
Arm Type
Experimental
Arm Description
Patients receive propranolol hydrochloride PO BID for 4 months in the absence of disease progression or unacceptable toxicity. Propranolol will be administered on an out-patient basis. Blood for correlative studies (30 ml - green top tube) will be drawn at baseline and at each clinic visit. Tumor tissue for analysis will be obtained via core needle biopsy (or other appropriate modality) pre-study and at approximately the two month time point.
Intervention Type
Drug
Intervention Name(s)
propranolol hydrochloride
Other Intervention Name(s)
Inderal
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Correlative Studies
Intervention Description
Correlative studies will be conducted using the following materials: Plasma derived from peripheral blood. Peripheral blood mononuclear cells (PBMC) derived from patient blood Tumor tissue obtained at the time of core needle biopsy at the 2 month time point. Paraffin-embedded tumor tissue obtained pre-therapy to make the diagnosis of metastatic disease.
Primary Outcome Measure Information:
Title
Incidence of toxicity graded according to Common Terminology Criteria for Adverse Events (CTCAE) V. 4.0
Description
A dose-limiting toxicity (DLT) will be considered as any grade 3 or higher hematologic or non- hematologic toxicity that is probably or definitely related to treatment.
Time Frame
Up to 4 months
Title
Change in vascular endothelial growth factor (VEGF)
Time Frame
Baseline to 4 months
Title
Effect of beta-adrenergic blockade on the tumor microenvironment
Description
Measured via a series of correlative laboratory studies using cancer tumor tissue and peripheral blood mononuclear cells.
Time Frame
Up to 4 months
Title
Effect of beta-adrenergic blockade on the host immune system
Description
Measured via a series of correlative laboratory studies using cancer tumor tissue and peripheral blood mononuclear cells.
Time Frame
Up to 4 months
Secondary Outcome Measure Information:
Title
Progression-free survival
Time Frame
Up to 1 year
Title
Overall survival
Time Frame
Up to 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have histologically-proven locally-recurrent or metastatic solid tumor; the first 10 patients may have cancer of any histology; preference will be given to patients with metastatic ovarian cancer, breast cancer, and malignant melanoma, as these malignancies have been shown to be sensitive to manipulation of the beta-adrenergic receptor; the final twenty-five patients to be accrued must have locally-recurrent or metastatic malignant melanoma that is not surgically resectable. An additional cohort of 10 patients with BCLC stages A to C locally advanced or metastatic hepatocellular carcinoma (HCC) that is not surgically resectable will also be enrolled (See appendix for BCLC staging system). Patients with liver transplantation will not be eligible. The diagnosis of hepatocellular carcinoma may be made by one of the following methods: Pathologically (histologically or cytologically) proven diagnosis of HCC. At least one solid liver lesion or vascular tumor thrombosis (involving portal vein, IVC and/or hepatic vein) > 1 cm with arterial enhancement and delayed washout on multiphasic computerized tomography (CT) or magnetic resonance imaging (MRI) in the setting of cirrhosis or chronic hepatitis B or C without cirrhosis. For patients whose CURRENT disease is vascular only: Enhancing vascular thrombosis (involving portal vein, IVC and/or hepatic vein) demonstrating early arterial enhancement and delayed washout on multi-phasic CT or MRI, in a patient with known HCC (diagnosed according to criteria in (a) or (b). Patients may have had any number of prior systemic therapies; patients need not have exhausted standard therapy for their disease, but must be stable and must not have actively progressing Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Karnofsky >= 60% Life expectancy of greater than 6 months Patients (except for the HCC cohort) must have normal organ and marrow function as defined below: Leukocytes >= 3,000/mcL Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Total bilirubin within normal institutional limits Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal Creatinine within normal institutional limits OR Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Parameters for the HCC cohort: leukocytes > or = 3000/mcl absolute neutrophil count > or =1000/mcl platelets > or = 70,000 total bilirubin < or = 2mg/dL AST/ALT <6 times ULN creatinine within normal institutional limits OR creatinine clearance > or = 60mL/min/1.73m2 for patients with creatinine levels above institutional normal level INR < or = 1.7 The effects of propranolol on the developing human fetus may be detrimental. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to understand and the willingness to sign a written informed consent document Patients with brain metastases may participate in this clinical study provided that symptoms have been controlled with standard therapies and/or appropriate medications; the principal investigator (P.I.) will carefully evaluate the suitability of patient participation when brain metastases are present Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier Patients may not be receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to propranolol Uncontrolled hypertension 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 Patients with significant lung disease, an ejection fraction less than 40%, or a resting heart rate less than 60/min will not be enrolled Pregnant women are excluded from this study because propranolol is an agent with the potential for teratogenic or abortifacient effects Patients who are currently receiving a beta-blocker for another medical condition will be excluded from this study; patients with extremes of blood pressure (e.g., systolic blood pressure [SBP] > 150 or < 100) may be excluded from participation if the treating physician feels that this medical condition has not been adequately addressed by the patient's primary care physician Patients with worsening depression that has not been addressed clinically will be excluded from this study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
William Carson, MD
Organizational Affiliation
Ohio State University Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://cancer.osu.edu
Description
The Jamesline

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Propranolol Hydrochloride in Treating Patients With Locally Recurrent or Metastatic Solid Tumors That Cannot Be Removed By Surgery

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