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

• ClinicalTrials.gov Identifier: NCT01847001
• Recruitment Status: Completed
• First Posted: May 6, 2013
• Results First Posted: January 10, 2020
• Last Update Posted: September 10, 2021
• Sponsor: Columbia University
• Information provided by (Responsible Party): Columbia University

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:

1. Determine the effect of propranolol plus chemotherapy on breast cancer cells as well as the growth of blood vessels surrounding breast cancer cells.
2. 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.

Condition or disease	Intervention/treatment	Phase
Locally Advanced Malignant Neoplasm; Breast Cancer	Drug: Propranolol; Other: DOT imaging; Drug: Paclitaxel; Drug: Nab-paclitaxel; Drug: Trastuzumab; Drug: Pertuzumab; Drug: Doxorubicin; Drug: Cyclophosphamide; Procedure: Surgery; Drug: Premedication; Drug: Anti-nausea therapy; Drug: Pegfilgrastim	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Study of the Beta-blocker Propranolol Alone and With Chemotherapy in Patients Receiving Neoadjuvant Treatment for Newly Diagnosed Breast Cancer
• Study Start Date: October 2012
• Actual Primary Completion Date: December 31, 2018
• Actual Study Completion Date: October 16, 2019

Arms and Interventions

Arm

Intervention/treatment

Experimental: Propranolol + Neoadjuvant Chemotherapy; 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.

Drug: Propranolol; 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.; Other Names: Inderal; Inderal LA ®; InnoPran XL ®; Other: DOT imaging; (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.; Other Name: Breast imaging - Diffuse Optical Tomography (DOT); Drug: Paclitaxel; (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).; Other Name: Abraxane; Drug: Nab-paclitaxel; (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.; Other Name: Abraxane; Drug: Trastuzumab; (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.; Other Name: Herceptin; Drug: Pertuzumab; (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.; Other Name: Perjeta; Drug: Doxorubicin; (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.; Other Name: Adriamycin; Drug: Cyclophosphamide; (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.; Other Name: AC; Procedure: Surgery; 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.; Other Name: No other name; Drug: Premedication; 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).; Other Name: No other name; Drug: Anti-nausea therapy; In addition to doxorubicin, you will receive an anti-nausea therapy and dexamethasone about 3060 minutes before AC chemotherapy.; Other Name: No other name; Drug: Pegfilgrastim; 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).; Other Name: Neulasta

Outcome Measures

Primary Outcome Measures :

1. Mean Adherence to Propranolol [ Time Frame: Approximately 6 months ]
   Propranolol adherence was documented biweekly by pill counts and drug diary checks.
2. Total Number of Participants Who Reached The Target Propranolol Dosing [ Time Frame: Approximately 6 months ]
   The target Propranolol dosing was 80mg ER daily.

Secondary Outcome Measures :

1. Number of Patients With Pathologic Complete Response [ Time Frame: Approximately 6 months ]
   Response was confirmed with pathology.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, New York

Columbia University Irving Medical Center

New York, New York, United States, 10032

Sponsors and Collaborators

Columbia University

Investigators

• Principal Investigator: Kevin M. Kalinsky, MD, MS; Columbia University

  Study Documents (Full-Text)

Documents provided by Columbia University:

Study Protocol and Statistical Analysis Plan  [PDF] March 3, 2014

More Information

• Responsible Party: Columbia University
• ClinicalTrials.gov Identifier: NCT01847001
• Other Study ID Numbers: AAAI9158; UL1TR000040 ( U.S. NIH Grant/Contract )
• First Posted: May 6, 2013
• Results First Posted: January 10, 2020
• Last Update Posted: September 10, 2021
• Last Verified: August 2021

• 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

Keywords provided by Columbia University:

Breast Cancer; Neoadjuvant; Experimental; Biomarker; Breast imaging

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Paclitaxel; Albumin-Bound Paclitaxel; Cyclophosphamide; Doxorubicin; Trastuzumab; Pertuzumab; Propranolol; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antibiotics, Antineoplastic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Antineoplastic Agents, Immunological