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Study of Propranolol in Newly Diagnosed Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy

Primary Purpose

Locally Advanced Malignant Neoplasm, Breast Cancer

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Propranolol
DOT imaging
Paclitaxel
Nab-paclitaxel
Trastuzumab
Pertuzumab
Doxorubicin
Cyclophosphamide
Surgery
Premedication
Anti-nausea therapy
Pegfilgrastim
Sponsored by
Columbia University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Locally Advanced Malignant Neoplasm focused on measuring Breast Cancer, Neoadjuvant, Experimental, Biomarker, Breast imaging

Eligibility Criteria

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

Inclusion Criteria:

  • English or Spanish speaking women age ≥18
  • Heart Rate > 60 bpm
  • Systolic Blood Pressure > 100 mm/Hg
  • Deemed eligible to receive neoadjuvant chemotherapy with 12 cycles of weekly taxane therapy (paclitaxel 80mg/m2 or Abraxane 100 mg/m2 if there is a shortage of paclitaxel) followed by 4 cycles of Adriamycin (60mg/m2) and cyclophosphamide (600 mg/m2) given every 2 weeks with growth-factor support.
  • Echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) with ejection fraction > 50%.
  • Patients with hormone receptor +/- and human epidermal growth factor receptor 2 protein (HER2) +/- breast cancer are eligible
  • If a patient has HER2-positive breast cancer, Herceptin and Perjeta will be given along with taxane therapy
  • Any stage invasive breast cancer provided the primary breast tumor size is ≥ 1 cm
  • Agree to participate in research blood collection at 4 different time periods (20 ml = 4 teaspoons)
  • Agree to the evaluation of already collected core biopsy, as well as surgical resection tissue, for predictive biomarkers. The biopsy prior to Taxol #1 is optional.

Exclusion Criteria:

  • Patients failing to meet the inclusion criteria
  • Corrected QT interval (QTc) prolongation as defined by > 470 milliseconds on electrocardiogram (ECG)
  • First-degree Atrioventricular (AV) block on ECG in which P-R interval lengthened > 200 milliseconds; Second Degree; or Third Degree
  • On beta-blocker treatment. If discontinued, patients must have been off beta-blockers for at least 3 months.
  • History of asthma, given concern for β-blockade in this population

Sites / Locations

  • Columbia University Irving Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Propranolol + Neoadjuvant Chemotherapy

Arm Description

Subjects will receive 2 types of chemotherapy regimens plus propranolol treatment. Regimen I, involves paclitaxel (may be substituted with nab-paclitaxel; maybe given with premedication), and Regimen II involves doxorubicin (maybe given with anti-nausea therapy) and cyclophosphamide (maybe given with Pegfilgrastim). If your tumor is HER2 positive, you will also receive trastuzumab and pertuzumab. After you complete all chemotherapy plus propranolol treatment, you will then have surgery to remove the breast tumor. DOT imaging will be done at 4 additional time points, including beo.

Outcomes

Primary Outcome Measures

Mean Adherence to Propranolol
Propranolol adherence was documented biweekly by pill counts and drug diary checks.
Total Number of Participants Who Reached The Target Propranolol Dosing
The target Propranolol dosing was 80mg ER daily.

Secondary Outcome Measures

Number of Patients With Pathologic Complete Response
Response was confirmed with pathology.

Full Information

First Posted
April 23, 2013
Last Updated
August 19, 2021
Sponsor
Columbia University
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1. Study Identification

Unique Protocol Identification Number
NCT01847001
Brief Title
Study of Propranolol in Newly Diagnosed Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy
Official Title
A Study of the Beta-blocker Propranolol Alone and With Chemotherapy in Patients Receiving Neoadjuvant Treatment for Newly Diagnosed Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Completed
Study Start Date
October 2012 (undefined)
Primary Completion Date
December 31, 2018 (Actual)
Study Completion Date
October 16, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Columbia University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study is being conducted in patients with newly diagnosed breast cancer that will be undergoing chemotherapy prior to surgery - neoadjuvant chemotherapy. The study involves treatment with standard chemotherapy and a commonly used, FDA-approved, blood pressure drug called propranolol (Inderal). The purposes of this study are to: Determine the effect of propranolol plus chemotherapy on breast cancer cells as well as the growth of blood vessels surrounding breast cancer cells. Determine the side effect profile of propranolol and chemotherapy in patients with breast cancer receiving neoadjuvant chemotherapy. This research is being done because previous laboratory work has shown that propranolol may decrease the ability for the blood vessels around breast cancer cells to grow, which may be important in helping cancer cells grow. It also may reduce the likelihood for breast cancer cells to spread. If changes are seen in the breast cancer cells and surrounding blood vessels in this study, we will pan to evaluate whether propranolol decreases the likelihood of breast cancer from recurring in future, later studies. All chemotherapy regimens used in this study have been the standard of care for many years; however, the use of propranolol is being researched along with the chemotherapy regimens.
Detailed Description
While a number of therapeutic options exist for patients with breast cancer (BC), breast tumor biology is differs across tumors and not all BCs respond to treatment. Identifying a marker predicting response could spare non-responders unnecessary side effects, cost, and time. A recent example in BC is bevacizumab, an expensive anti-angiogenic monoclonal antibody, for which the FDA revoked approval for patients with metastatic BC. While this targeted therapy may benefit some patients, no appropriate predictive marker has been identified in the drug development process. An ideal biologic marker would be easy to perform, reliable, low-cost and non-invasive. A limitation of assessing tumor-based markers in metastatic BC is the inability to procure tumor tissue at different treatment times. To circumvent this issue, anti-cancer agents can be assessed pre-operatively, where women with newly diagnosed BC receive a study drug, alone or with chemotherapy, between diagnostic breast biopsy and surgical resection. In addition, tumor changes can be directly compared to modulation of non-invasive markers, such as functional radiographs or blood, to identify a non-invasive marker predicting tumor response. The investigators are conducting a neoadjuvant single-institution trial with the non-selective, inexpensive β -blocker propranolol with chemotherapy in locally advanced BC. β-blockade regulates angiogenesis in primary breast tumors. In these trials, the investigators plan to evaluate treatment-related microvascular response via changes in breast Diffuse Optical Tomography (DOT), a non-invasive, fast, safe, and inexpensive breast imaging tool. As the optical property contrast from endogenous chromophores (oxyhemoglobin, deoxyhemoglobin, water, and lipid) provides information on tissue vascularity, it can monitor response to anti-angiogenic agents. DOT changes occur as early as 1 week after starting pre-operative therapy. The dynamic DOT system incorporated in these trials is unique to Columbia University Medical Center (CUMC), as it has been designed by Columbia biomedical engineers. CUMC's laboratory collaborators have measured this DOT system with anti-angiogenesis agents in animal models, demonstrating the translational nature of this project. While non-dynamic DOT has been assessed in other neoadjuvant trials with small cohorts receiving heterogeneous chemotherapy agents, none have evaluated DOT response to anti-angiogenic agents.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Locally Advanced Malignant Neoplasm, Breast Cancer
Keywords
Breast Cancer, Neoadjuvant, Experimental, Biomarker, Breast imaging

7. Study Design

Primary Purpose
Other
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Propranolol + Neoadjuvant Chemotherapy
Arm Type
Experimental
Arm Description
Subjects will receive 2 types of chemotherapy regimens plus propranolol treatment. Regimen I, involves paclitaxel (may be substituted with nab-paclitaxel; maybe given with premedication), and Regimen II involves doxorubicin (maybe given with anti-nausea therapy) and cyclophosphamide (maybe given with Pegfilgrastim). If your tumor is HER2 positive, you will also receive trastuzumab and pertuzumab. After you complete all chemotherapy plus propranolol treatment, you will then have surgery to remove the breast tumor. DOT imaging will be done at 4 additional time points, including beo.
Intervention Type
Drug
Intervention Name(s)
Propranolol
Other Intervention Name(s)
Inderal, Inderal LA ®, InnoPran XL ®
Intervention Description
Propranolol starting dose is 20mg b.i.d.; propranolol dose is up-titrated to 40mg b.i.d. to 80 mg daily with chemotherapy depending on tolerability. Tolerability is assessed every 2 weeks.
Intervention Type
Other
Intervention Name(s)
DOT imaging
Other Intervention Name(s)
Breast imaging - Diffuse Optical Tomography (DOT)
Intervention Description
(Non-experimental) During the baseline visit, you will undergo DOT evaluation of your tumor for determination of blood, fat, and water content in the affected and unaffected breast. DOT readings will be obtained at 4 additional time points: after paclitaxel week #3, before AC week #1, before AC week #3, and prior to surgery.
Intervention Type
Drug
Intervention Name(s)
Paclitaxel
Other Intervention Name(s)
Abraxane
Intervention Description
(Non-experimental) given as a one-hour intravenous infusion (IV) every week for a total of 12 weeks; the first dose of paclitaxel may be given over 90 minutes, per the discretion of your treating doctor. The dose will be given in 80 mg/m2 based on individual body surface area (BSA). This drug is given through a vein in the arm or a catheter (eg. Infusaport, Portacath).
Intervention Type
Drug
Intervention Name(s)
Nab-paclitaxel
Other Intervention Name(s)
Abraxane
Intervention Description
(Non-experimental) In the event paclitaxel is not available due to manufacturing and supply shortages, nab-paclitaxel will be substituted for paclitaxel. The dose is 100 mg/m2 IV infusion over 30 minutes weekly (or institutional standard). No premedications are given with nab-paclitaxel.
Intervention Type
Drug
Intervention Name(s)
Trastuzumab
Other Intervention Name(s)
Herceptin
Intervention Description
(Non-experimental) (only if HER2-positive): Trastuzumab is given as an IV infusion initially over 90 minutes for the first dose, then 30-60 minutes every 3 weeks in subsequent doses if well tolerated. To be given every 3 weeks with paclitaxel/propranolol.
Intervention Type
Drug
Intervention Name(s)
Pertuzumab
Other Intervention Name(s)
Perjeta
Intervention Description
(Non-experimental) (only if HER2-positive): Pertuzumab is given as an IV infusion over 60 minutes on the first dose, then 30-60 minutes every 3 weeks if well tolerated. To be given every 3 weeks with paclitaxel/propranolol.
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Other Intervention Name(s)
Adriamycin
Intervention Description
(Non-experimental) Doxorubicin will be given as a 510 minute intravenous infusion (IV) in a dose of 60 mg/m2; cyclophosphamide will be given as a 3060 minutes intravenous infusion (IV) in a dose of 600 mg/m2 based on BSA. This chemotherapy regimen will be given every 2 weeks for total of 8 weeks or 2 months.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
AC
Intervention Description
(Non-experimental) Doxorubicin 60 mg/m2 IV over 5-10 minutes, Cyclophosphamide 600 mg/m2 IV infusion over 30-60 minutes. The first cycle should be initiated with 3 weeks after the last paclitaxel and/or trastuzumab/pertuzumab dose.
Intervention Type
Procedure
Intervention Name(s)
Surgery
Other Intervention Name(s)
No other name
Intervention Description
After you complete all chemotherapy plus propranolol treatment, you will then have surgery to remove the breast tumor if your doctor feels that it is medically appropriate (if you have had a good response to the treatment) - lumpectomy/mastectomy.
Intervention Type
Drug
Intervention Name(s)
Premedication
Other Intervention Name(s)
No other name
Intervention Description
As premedication to prevent some of the side effects associated with paclitaxel, you will also receive dexamethasone (Decadron) in a dose of 10 mg, diphenhydramine (Benadryl) in doses of 2550 mg, and an H2 blocker (eg. ranitidine 50 mg or equivalent) 3060 minutes before each paclitaxel infusion. If no hypersensitivity reactions are experienced, dexamethasone may be reduced in increments of 2 mg per week per dose (until a minimum of 2 mg has been reached).
Intervention Type
Drug
Intervention Name(s)
Anti-nausea therapy
Other Intervention Name(s)
No other name
Intervention Description
In addition to doxorubicin, you will receive an anti-nausea therapy and dexamethasone about 3060 minutes before AC chemotherapy.
Intervention Type
Drug
Intervention Name(s)
Pegfilgrastim
Other Intervention Name(s)
Neulasta
Intervention Description
When you receive the AC chemotherapy, you will also receive treatment with a drug called pegfilgrastim (Neulasta). Neulasta is a commercially available drug. It stimulates the production of white blood cells and reduces the likelihood of developing a low white blood cell count and fever after chemotherapy. It will be given as an injection under the skin on the day after each chemotherapy treatment (day 2).
Primary Outcome Measure Information:
Title
Mean Adherence to Propranolol
Description
Propranolol adherence was documented biweekly by pill counts and drug diary checks.
Time Frame
Approximately 6 months
Title
Total Number of Participants Who Reached The Target Propranolol Dosing
Description
The target Propranolol dosing was 80mg ER daily.
Time Frame
Approximately 6 months
Secondary Outcome Measure Information:
Title
Number of Patients With Pathologic Complete Response
Description
Response was confirmed with pathology.
Time Frame
Approximately 6 months

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: English or Spanish speaking women age ≥18 Heart Rate > 60 bpm Systolic Blood Pressure > 100 mm/Hg Deemed eligible to receive neoadjuvant chemotherapy with 12 cycles of weekly taxane therapy (paclitaxel 80mg/m2 or Abraxane 100 mg/m2 if there is a shortage of paclitaxel) followed by 4 cycles of Adriamycin (60mg/m2) and cyclophosphamide (600 mg/m2) given every 2 weeks with growth-factor support. Echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) with ejection fraction > 50%. Patients with hormone receptor +/- and human epidermal growth factor receptor 2 protein (HER2) +/- breast cancer are eligible If a patient has HER2-positive breast cancer, Herceptin and Perjeta will be given along with taxane therapy Any stage invasive breast cancer provided the primary breast tumor size is ≥ 1 cm Agree to participate in research blood collection at 4 different time periods (20 ml = 4 teaspoons) Agree to the evaluation of already collected core biopsy, as well as surgical resection tissue, for predictive biomarkers. The biopsy prior to Taxol #1 is optional. Exclusion Criteria: Patients failing to meet the inclusion criteria Corrected QT interval (QTc) prolongation as defined by > 470 milliseconds on electrocardiogram (ECG) First-degree Atrioventricular (AV) block on ECG in which P-R interval lengthened > 200 milliseconds; Second Degree; or Third Degree On beta-blocker treatment. If discontinued, patients must have been off beta-blockers for at least 3 months. History of asthma, given concern for β-blockade in this population
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kevin M. Kalinsky, MD, MS
Organizational Affiliation
Columbia University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Columbia University Irving Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Study of Propranolol in Newly Diagnosed Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy

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