Clinical trial NCT01847001
Conditions: Locally Advanced Malignant Neoplasm Breast Cancer
Keywords: Breast Cancer Neoadjuvant Experimental Biomarker Breast imaging
Sponsor: Columbia University
Start date: 2012-10-01; Completion date: 2019-10-16
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

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.

Arms: arm 1: 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.
Interventions: intervention 1: Propranolol intervention 2: DOT imaging intervention 3: Paclitaxel intervention 4: Nab-paclitaxel intervention 5: Trastuzumab intervention 6: Pertuzumab intervention 7: Doxorubicin intervention 8: Cyclophosphamide intervention 9: Surgery intervention 10: Premedication intervention 11: Anti-nausea therapy intervention 12: Pegfilgrastim
Intervention descriptions: intervention 1: 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 2: (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 3: (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 4: (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 5: (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 6: (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 7: (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 8: (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 9: 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 10: 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 11: In addition to doxorubicin, you will receive an anti-nausea therapy and dexamethasone about 3060 minutes before AC chemotherapy. intervention 12: 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).

Protocol documents:
Prot_SAP_000.pdf: 
 
Title:  
Phase II Study of the Beta-Blocker Propranolol With 
Chemotherapy in Patients Receiving Neoadjuvant 
Treatment for Newly Diagnosed Breast Cancer 
 
NCT Number:  
NCT01847001 
 
Protocol Version Date:  
March 03, 2014 
 


Page 1 
Protocol dated 03/03/2014 
Columbia University Medical Center 
IRB # AAAI9158 
 
Phase II Study of the Beta-Blocker Propranolol With Chemotherapy in Patients 
Receiving Neoadjuvant Treatment for Newly Diagnosed Breast Cancer 
 
Principal Investigator: Kevin Kalinsky, M.D. 
Co-Investigators: Dawn Hershman, M.D. 
Katherine Crew, M.D. 
Matthew Maurer, M.D. 
Andreas Hielscher, Ph.D. 
Hyun Keol Kim, MD 
 
While a number of therapeutic options exist for patients with breast cancer (BC), breast tumor biology is 
heterogeneous 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 BC1.  While this targeted therapy may benefit some patients, no appropriate 
predictive marker has been identified in the drug development process1.  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. 
 
We are conducting a neoadjuvant single-institution trial with the non-selective, inexpensive β –blocker 
propranolol alone and with chemotherapy in locally advanced BC.  β-blockade regulates angiogenesis 
in primary breast tumors2,3.  In these trials, we 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 agents4.  DOT changes occur as early as 1 week after starting pre-
operative therapy5.  The dynamic DOT system incorporated in these trials is unique to CUMC, as it has 
been designed by Columbia biomedical engineers.  Our laboratory collaborators have measured this 
DOT system with anti-angiogenesis agents in animal models6, demonstrating the translational nature of 
this project.  While non-dynamic DOT has been assessed in other neoadjuvant trials with small cohorts 
receiving heterogeneous chemotherapy agents5,7-10, none have evaluated DOT response to anti-
angiogenic agents.   
 
Design: We are performing a phase II study investigating neoadjuvant propranolol alone, followed by 
propranolol with cytotoxic chemotherapy (taxane, followed by adriamycin/cytoxan) in 20 patients with 
locally advanced breast cancer.  Once enrolled, patients will start propranolol in combination with 
weekly treatments of taxane therapy (+ every 3 week Herceptin and every 3 week Pertuzumab, if 
HER2+) followed by adriamycin/cytoxan + propranolol. Patients will continue to take propranolol 
through the day before surgery (last dose of propranolol: night before surgery).  
 
Primary Endpoint:  
1. To assess the feasibility of giving neoadjuvant propranolol alone and in combination with 
chemotherapy.  Our hypothesis is that it will be feasible for patients to take propranolol with 
chemotherapy in the neoadjuvant setting. 


Page 2 
Protocol dated 03/03/2014 
 
Secondary Endpoints: 
 
1. To evaluate deoxyhemoglobin reduction as a non-invasive, image-based biomarker of angiogenic 
response after 2 weeks of neoadjuvant propranolol administration in combination with paclitaxel, as 
measured by DOT.  These images will be compared to DOT collected for the ongoing prospective IRB-
AAAI0480 trial. 
 
 
2.  To explore the modulation of DOT markers at 5 time-points with propranolol: a)baseline,; b) before 
starting taxane week #3; c) before starting AC cycle #1; d) before starting AC cycle #2; and e) before 
surgery.  These images will be compared to DOT collected for the ongoing prospective IRB-AAAI0480 
trial.   
 
3. To evaluate the association between changes in optical images and markers of angiogenesis [tumor 
(VEGF, CD31, CD105, microvessel density and area), serum (VEGF, V-cam, and PIGF expression)], 
proliferation (tumor KI-67 levels), and tumor macrophage infiltration (CD163 expression) compared to 
baseline levels. 
 
4.  To explore whether acute stress levels, as measured by urinary cortisol and responses to the 
Questionnaire on Stress in Cancer Patients - revised version (QSC-R23), associate with image- or 
blood-based biomarker changes after propranolol.   
 
5.  To assess the safety and tolerability of neoadjuvant propranolol along with chemotherapy  
A.Background: 
A.1. Angiogenesis in BC: A number of studies have demonstrated that angiogenesis, the process of 
blood vessel formation, is essential in the role in the growth, progression and metastatic potential of BC 
cells11,12. The most clinical experience with anti-angiogenic agents in BC has been with bevacizumab 
(Avastin), the humanized recombinant monoclonal antibody that specifically blocks the binding of 
vascular endothelial growth factor (VEGF) to high-affinity receptors.  Three randomized control trials 
have demonstrated an improvement in progression free-survival and response rates with the addition of 
bevacizumab to front-line chemotherapy13-15.  However, while significant, the improvement in these 
outcomes in the AVADO14 and Ribbon-115trials has not been clinically compelling, given the median 
progression-free survival of 1-2 months when adding bevacizumab to chemotherapy.  Combined with 
the potential side effects and lack of overall survival advantage in these trials and subsequent meta-
analyses16, there remains uncertainty about how to use bevacizumab in advanced BC. In July 2011, 
The ODAC Committee of the FDA revoked approval for patients with metastatic BC1.  In addition, 
bevacizumab is an expensive drug.  An economic analysis in 2009, based on efficacy data from ECOG 
E210013 and European cost-estimates, suggests an incremental cost-effectiveness ratio of 189,427 
euros per quality-adjusted life-year17.  While some women benefit from bevacizumab, it seems that 
neither prior adjuvant therapy nor tumor subtype serve as selection factors for bevacizumab-based 
treatment.  A remaining major issue is that bevacizumab lacks a robust, predictive, biologic, or clinical 
marker of activity. This experience has highlighted the need for developing clear predictive biomarkers 
for anti-angiogenic agents in BC. 
 
A.2. Propranolol in Breast Cancer: Anti-angiogenic Effects: There is emerging pre-clinical and 
observational data that neuro-endocrine signaling influences BC metastatic potential.  Used to treat 
cardiovascular disease, β -blockade associates with a reduction in distant BC metastases in 
observational studies18-21. β-blocker use independently predicts metastatic risk (HR=0.43; p=0.031) and 
BC-specific mortality at 10 years (HR=0.29; p=0.007)19.   Compared to other anti-hypertensives, β-
blocker use significant reduces BC recurrence (p=0.026).  In a retrospective study of patients receiving 
neoadjuvant therapy, β-blocker use is an independent predictor of improved relapse free survival (HR: 
0.52; p=0.015), with a trend in overall survival (HR 0.64; p=0.09)21.  In another study, BC-specific 


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Protocol dated 03/03/2014 
Figure 1: Tumor samples from mice treated with a placebo (HeyA): isoproterenol (nonspecific β 
agonist), terbutaline (β2 agonist), xamoterol (β1 agonist), or isoproterenol plus propranolol. Stained for 
CD31 and VEGF (IHC and ISH). Tumor VEGF protein levels (ELISA). Microvessel Density is higher in 
the isoproterenol and terbutaline groups than in controls or in the combination group. 
mortality is significantly lower for propranolol users (median: 80 mg daily) as compared to nonusers 
(HR: 0.19)22. Non-BC mortality is similar. No effect is seen with atenolol (β1 antagonist), suggesting that 
the β2 adrenergic receptor is the likely mediator.  These studies provide evidence that propranolol 
should be evaluated prospectively. 
 
There is strong pre-clinical data in accordance with these observations, suggesting that β-blockers offer 
this advantage in BC by impacting the primary BC microenvironment2,3.  Activation of cellular β-
adrenergic receptors by norepinephrine triggers transcription factor activation, regulating tumor cell 
proliferation23 and apoptosis inhibition24. Norepinephrine stimulates the migration and chemotaxis of 
MDA-MB-468 (triple negative: TN) BC cells23.   This effect is completely inhibited by β2-specific 
blockade and only partially reduced by the β1-specific blocker atenolol.  The functionality of the β-
adrenergic receptor is also observed in CG-5 BC (ER+) cells25.  In BALB/c mice syngeneic to 66cl4 BC 
cells (TN), the β-agonist isoproterenol increases distant metastasis by 22-fold vs. control (p=0.03), and 
the β-blocker propranolol completely blocks stress-enhanced metastasis (p<0.0001). While primary BC 
size does not change with propranolol, propranolol largely abrogates primary tumor macrophage 
infiltration (F4/80+), as well as stress-induced vascularization of primary mammary tumors (CD31) (p 
<0.001). In SKOV3ip1 ovarian and MDA-MB-231 (TN) BC orthotropic models, less visceral metastases 
are seen in mice treated with propranolol (0%) vs. placebo (50%) (p = 0.01)3.  While the β-agonist 
isoproterenol and β2-agonist terbutaline increase tumor weight and metastatic number, the β1 agonist 
xamoterol does not (Figure 1), which, similar to observational data3, implicates the role of β2. In 
SKOV3ip1 cells, VEGF mRNA expression increases by 842% after norepinephrine and promoter 
activity increases by 1,240%. This effect is blocked by propranolol.  This supports the evaluating 
propranolol as an angiogenic modulator in BC.  β-adrenergic receptor functionality is observed in ER+25 
and HER2+ cells26.  Given these consistent findings, we plan to investigate propranolol in a 
prospective, translational clinical trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A.3. Diffuse Optical Tomography (DOT) as an Image-based Marker of Tumor Angiogenic 
Response:  As DOT provides information on tissue vascularity, it can monitor response to anti-
angiogenic agents4. DOT utilizes optical transmission measurements with low-intensity light (i.e. non-
ionizing radiation) to provide 3-dimensional information on tissue vascularity. The optical property 
contrast from endogenous chromophores [oxyhemoglobin (Hb02), deoxyhemoglobin (Hb), water, and 


Page 4 
Protocol dated 03/03/2014 
Figure 2: Change in DOT Parameters - Oxygenated Hemoglobin (Hb02) and Deoxyhemoglobin (Hb): 
Baseline vs. 2 weeks of Paclitaxel in Patient #1 (A1) and Patient #2 (B1) 
lipid] can distinguish malignant from normal tissue4,27. Total hemoglobin levels, which directly relate to 
blood vessel density in tumors, are double those in benign breast lesions28. Vascular changes precede 
measurable structural changes in mouse models29. A limited number of small series (n=7-16 patients) 
report DOT changes in patients undergoing neoadjuvant chemotherapy5,7-10.  None incorporate targeted 
therapy beyond trastuzumab.  Total hemoglobin levels significantly decreases with pathologic complete 
response (p=0.001)5,10.  Changes occur as early as 1 week after starting pre-operative chemotherapy, 
with tumor Hb levels dropping 33% +/-7% in responders vs. non-responders (18% +/- 10%: z=0.008)5.  
In addition, pre-treatment total hemoglobin levels correlate with pre-treatment mean vessel density of 
CD105-expressing vessels, a neoangiogenesis marker (p<0.001)9. We will evaluate DOT as an early 
marker of angiogenic response in this neoadjuvant trial with propranolol. 
 
In an ongoing pilot (IRB-AAAD7133), 50 subjects with BCs are being recruited, with 10 subjects with 
healthy breasts as controls.  The primary objective is to evaluate if DOT can differentiate between BC-
bearing and healthy breasts.  In the first 29 patients, there is a significant difference between 
deoxyhemoglobin levels in BC-bearing vs. healthy (p=0.017).  The current data suggests a sensitivity of 
91% and a specificity of 83%.  In our ongoing study of 20 women receiving neoadjuvant taxane 
followed by adriamycin plus cytoxan (IRB-AAAI0480), we are assessing the percentage change in DOT 
parameters and pCR.  This study has enrolled 15 patients (open: 8/2011). Figure 2 demonstrates DOT 
change in the first 2 analyzable patients after 2 weeks of paclitaxel.  In the first 4 patients, the mean 
Hb02 and Hb decrease is 70% and 50%, respectively. 
 
 
 
 
 
 
 
 
 
 
 
B. Study Design  
 
B.1. Overview: We propose a phase II study investigating the impact of neoadjuvant propranolol alone 
and in combination with cytotoxic chemotherapy (taxane, followed by adriamycin/cytoxan).  Once 
enrolled, patients will start propranolol 20 mg po bid, ultimately increasing the dose of propranolol up to 
a maximum 80 mg po daily ER if tolerating propranolol (Section F.2 for details), when receiving 12 
weeks of taxane therapy + propranolol (+ Herceptin and Pertuzumab, if HER2+) followed by 
adriamycin/cytoxan + propranolol (Figure 3).  This dose of propranolol has been chosen as it is the 
median propranolol dose in the Barron study, in which propranolol is associated with reduced breast 
cancer progression and mortality22.  We chose to start with a lower dose at initiation to make sure that 
patients are tolerating the dose, prior to titrating up.  This was discussed with cardiologists at CUMC 
and agreed to be the safest approach. 
 
B.2. Intervention: We will also be evaluating changes in tumor-, image- and blood- biomarkers.  The 
main inclusion criteria will be English or Spanish speaking women over the age of 18 with recently 
diagnosed invasive breast cancer deemed eligible to receive neoadjuvant propranolol plus cytotoxic 
chemotherapy.  Patients should have a tumor size ≥ 1 cm by clinical measurement and scheduled to 
Baseline 
Two-week 
Hb02 
Hb 
2 weeks after paclitaxel 
Baseline 
2 weeks after 
A1 
Baseline 
Hb02 
Hb 
A1 
B1 


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Protocol dated 03/03/2014 
undergo 12 cycles of weekly paclitaxel (80mg/m2) (T) followed by 4 cycles of adriamycin (60mg/m2) 
and cyclophosphamide (600 mg/m2)(AC) given every 2 weeks with growth-factor support (i.e. 
neulasta).  Full details are in Section D.6.Paclitaxel is administered as an IV infusion over 1 hour.  
Adriamycin is given by slow IV injection over 5-10 minutes. Cyclophosphamide is given by IV infusion 
over 30-60 minutes.  The day following chemotherapy, the patient will receive neulasta, which 
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 AC.  Neulasta may cause bone or joint pain and reactions at the injection sites.   Prior to 
each infusion of paclitaxel, patients are administered diphenhydramine, dexamethasone, and an H2 
blocker.  Prior to each infusion of AC, patients are administered dexamethasone and outpatient anti-
emetics. 
 
If paclitaxel is not available secondary to drug supply issues, weekly nab-paclitaxel (abraxane) can be 
substituted at a dose of 100 mg/m2.  The first cycle of AC should start no more than 3 weeks after the 
last taxane dose unless the physician deems a longer break necessary.  Subjects will be recruited from 
CUMC. 
 
B.3. Measures: In addition to DOT, we will collect tumor tissue and blood for changes in angiogenesis, 
macrophage infiltration, proliferation, and adrenergic signaling.  For angiogenesis, we will explore 
modulation of tumor angiogenesis: CD31 (IHC: Dako), CD 105 (Vector labs), mean vessel density and 
area as described9.  Serum VEGF, V-CAM levels, and PIGF (ELISA) will be assessed in the Irving 
Institute for Clinical and Translational Research Biuomarkers Core.   For tumor macrophage infiltration, 
we will investigate tumor expression of CD163 by immunohistochemistry, as previously described30.  If 
there is an issue with this signal, we will consider CD68 (PGM-1).  Tumor proliferation will be assessed 
by immunohistochemistry, (Ki-67: Dako) In addition to serum norepinephrine levels to assess for 
adrenergic signaling , we will assess serum IL-6, since this cytokine is implicated in tumor progression 
and metastasis and increases with β -adrenergic receptor activation (all: Columbia Biomarker Core: 
ELISA)31.Because stressed animals demonstrate the most significant benefit to propranolol in pre-
clinical models, we plan to explore measures of stress and their association with other biomarker 
changes.  This will be measured at a) baseline, b) prior to week #3 taxane, c) prior to cycle #1 AC, and 
d) before surgery.  We will also explore responses to the Questionnaire on Stress in Cancer Patients 
revised version (QSC-R23), a disease-specific questionnaire to assess psychosocial stress in cancer 
patients32.  This questionnaire, which is grouped into 5 five homogeneous scale (psychosomatic 
complaints, fears, information deficits, everyday life restrictions and social strains), has been measured 
at serial time periods (regardless of menopausal status)33.  Future tissue marker considerations will be 
rt-pcr on FFPE for pro-metastatic gene expression [candidates including COX2 (PTGS2), MMP9, 
ARG1, TGFB, VEGF, alpha2 integrin, gelsolin, Vcam1, Csf1]2.   
 
Figure 3: Schema 
 
 
 
 
 
C. Statistical Analysis 
 
C.1: Primary Endpoint: We will evaluate the feasibility of neoadjuvant propranolol, along with cytotoxic 
chemotherapy.  The combination will be deemed feasible if at least 75% of patients (15 patients) are 
compliant with taking > 80% take the drug on a daily basis as prescribed (nonadherence/medication 
possession ratio < 20%)34.This rate is higher than the 52% compliance rate, defined by dose reduction 
or interruption, in other series with oral therapies in the neoadjuvant setting35.    
 
 
Sign 
Consent 
Weekly Paclitaxel 
x 12 + Every 3 
week Herceptin 
and Perjeta (if 
HER2+) + Daily 
Propranolol 
DDACx4+ 
Daily 
Propranolol 
Surgery 


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Protocol dated 03/03/2014 
C.2: Secondary Endpoints: We will evaluate the modulation of DOT deoxyhemoglobin measurements 
between the baseline and 2 weeks after propranolol plus paclitaxel .  Assuming different correlation 
levels (0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8 and 0.9) between the baseline and 2 week measurements, we 
have over 95% power to detect a difference of 0.39 (from 10.82456/+-0.5455374 to 10.43346/+-
0.2017752) at 5% significance level using paired t-tests. These statistical considerations are based on 
recently reviewed data in patients with repeated DOT measures. 
We will use the Spearman rank correlation coefficient to analyze relationships between angiogenic 
markers, tumor proliferation, and adrenergic signaling.  The Wilcoxon signed-rank (matched-pairs) test 
will be used to compare expression levels between matched pre-and post-samples treated with 
propranolol alone. We will explore modulation of biomarkers collected at different time periods (Table 
1).  SAS Version 9.2 and STATA Version 9.0 will be used.  This trial is feasible to conduct, as we treat 
4-6 patients/month with neoadjuvant chemotherapy at Columbia. We expect half to enroll in this study.  
We plan to compare this data to the 20 patients treated with neoadjuvant chemotherapy (ongoing - no 
propranolol: IRB-AAAI0480) as a non-randomized concurrent control.   
 
We will evaluate the safety and tolerability of propranolol plus chemotherapy.  The addition of 
propranolol to taxane therapy does not significantly alter biologic response, as measured by cellular 
apoptosis36.  In the literature, there is various reporting on the cardiac safety of propranolol with 
adriamycin, ranging from protective37-39 to harmful40,41.  However, the majority of the data suggests a 
cardioprotective effect, leading to its prospective investigation as a beneficial agent in cancer.  In 
patients with lymphoma treated with adriamycin, β-blockade has demonstrated cardioprotective effects 
in a randomized controlled trial42.  There are ongoing studies investigating β-blockade in the breast 
cancer adjuvant setting to determine if β-blockers reduce the risk of cardiomyopathy, including those 
receiving trastuzumab43.  In this trial, we plan to closely monitor side effects, per the CTCAE v 4.0, as 
well as closely monitoring for cardiac dysfunction with echocardiogram or MUGA (Table 1).   
 
Stopping Rule: We will stop the trial if 20% of the patients (i.e. 4/20) need to be removed from the 
study due to toxicities. 
 
D. Study Procedure 
 
D.1. Anthropometric Measures: Upon or prior to enrollment, each study participant will have a 
targeted physical exam: height, weight, blood pressure, pulse, and breast exam including bra cup size 
as reported by the patient.  Measurement of the breast tumor size will be documented using 
standardized calipers in metric notation with the patient lying in the supine position with the ipsilateral 
arm placed behind the head (or in the same position on all subsequent exams).   
 
D.2. Imaging: During the baseline visit, each participant will undergo static and dynamic DOT 
evaluation of their tumor for determination of oxyhemoglobin, deoxyhemoglobin, water, and fat content 
in the affected breast.  Static and dynamic DOT readings will be obtained at 5 time points: at baseline, 
before starting taxane week #3, before starting AC cycle #1, before starting AC cycle #2, and before 
surgery.  During treatment, patients will be followed every two weeks with clinic visits and breast exam 
measuring tumor size with calipers. 
 
D.3. Tissue-Based Biomarker Collection: For patients that provide consent at the time of enrollment, 
there is an optional breast biopsy for research purposes only. This biopsy will be a core needle biopsy 
of the known breast mass. The procedure will be performed by a member of the study team, surgical 
unit or radiology unit at CUMC. Breast core biopsy is optional prior to the third week of taxane therapy. 
A core biopsy gun will be used and four to six passes will be made to obtain tissue from the mass. 
Tissue will be placed in cold formalin prior to paraffin embedding and processing. Once the tissue is 
processed, it will be reviewed by the CUMC Department of Pathology and stored.   
 
 


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Protocol dated 03/03/2014 
D.4. Blood-Based Biomarker collection: We plan to collect blood at 4 different time periods. At each 
time period, we will collect one 10 ml SST tube, one 3 ml green-top tube, and one 7 ml EDTA tube.  We 
plan on evaluating plasma norepinephrine.  Blood will be collected and stored at -80.  We will evaluate 
the blood in collaboration with Serge Cremers (CTSA).  Currently, we plan on evaluating 
norepinephrine (plasma: HPLC/ECD), epinephrine (plasma: LCMSMS), and IL-6 (plasma: ELISA).  We 
will consider future evaluation of other blood markers, such as CRP (serum: turbidimetric)  
 
D.5. Safety: Safety will be monitored with toxicity interviews performed every 2 weeks while a patient is 
on study (except if a patient has a 3-week delay between taxane therapy and AC, per the investigator’s 
discretion).  Steps should be taken as per Tables2-6.   
 
D.6. Toxicity Monitoring: All unresolved adverse events greater than grade 1 should be followed by 
the investigator until the event has returned to baseline or grade 1, or the adverse event is otherwise 
explained.  Patients will complete a pill diary during the study.  This diary will be collected at the post-
treatment follow-up.  The purpose of the diary is to document that the patient appropriately takes 
propranolol and ensure an accurate toxicity assessment. Toxicities will be graded per CTCAE v. 4.0.  
The study will be monitored by the HICCC DSMB. 
 
D.7. Treatment Plan 
Agent Administration and Study Design 
Treatment will be administered on an outpatient basis. No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the patient's 
malignancy. 
 
Propranolol.  
Each dose of propranolol should taken within 30 minutes of food. The dosing of propranolol is 
described in Section F. 
 
Paclitaxel: 80 mg/m2 IV infusion over 60 min (or institutional guidelines) weekly x 12 consecutive 
weeks. Paclitaxel premedication: administer dexamethasone 20 mg PO BID approximately 12 and 6 
hours prior the first dose of paclitaxel only; or 10 mg IV prior to the first paclitaxel dose. If there is no 
taxane-induced reaction after the first dose, administer dexamethasone 6-10 mg IV (or lower doses if 
the taxane is well tolerated without reaction), diphenhydramine 25-50 mg IV, and an H2 blocker 
(cimetidine 300 mg, ranitidine 20 mg, or an equivalent) approximately 30-60 minutes prior to each 
subsequent paclitaxel dose. 
 
Nab-paclitaxel (Abraxane): 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. 
 
Trastuzumab (only if HER2-positve): 8 mg/kg IV loading dose over 90 minutes, then 6 mg/kg weekly 
over 30-60 minutes x 3 doses (covering 12 weeks, including loading dose). To be administered after 
paclitaxel.  
 
Pertuzumab (only if HER2-positive): 840 mg IV loading dose over 60 minutes, then 420 mg every 3 
weeks x 3 doses (covering 12 weeks, including loading dose).  To be administered before paclitaxel. 
 
Granulocyte colony stimulating factor (G-CSF; filgrastim): G-CSF should not be used during 
paclitaxel +/- trastuzumab/pertuzumab unless: (1) treatment with paclitaxel is delayed due to 
neutropenia, (2) the patient has a serious or life-threatening documented or suspected infection 
associated with neutropenia (absolute neutrophil count [ANC]< 1000/mm3), or (3) or another 
complication that in the judgment of the treating physician could derive potential benefit from G-CSF. 
The drug should be used at a dose/schedule specified in the package insert. Pegfilgrastim should not 


Page 8 
Protocol dated 03/03/2014 
be used.  
 
Doxorubicin 
and 
Cyclophosphamide: 
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. 
 
Premedication: Administer antiemetic therapy including a 5-HT3 antagonist and dexamethasone (12 
mg) IVSS 30-60 minutes before AC chemotherapy plus aprepitant (125 mg PO before AC) in 
accordance with NCCN guidelines (www.nccn.org); dexamethasone (8 mg BID) and aprepitant (80 mg 
QD) is recommended on days 2-3 to reduce delayed emesis. 
 
Pegfilgrastim 6 mg SC on day 2 of each cycle of AC. 


Page 9 
Protocol dated 03/03/2014 
 
E. Study Calendar 
 
Table 1 
  
Base-
line1 
Taxane ± Herceptin and Perjeta2 
Adriamycin & 
Cyclophosphamide 
Pre-
Surgery
3 
Surgery 
  
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
AC1 
AC2 
AC3 
AC4 
Physical Exam4: 
- vital signs  
- clinical breast 
exam with 
caliper 
measurements 
- adverse event 
assessment 
x 
x 
  
x 
  
x 
  
x 
  
x 
  
x 
  
x 
x 
x 
x 
x 
  
Systemic Imaging5 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
Echocardiogram 
and/or MUGA6 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
  
ECG7 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
  
Diffuse Optical 
Tomography 
(DOT)8 
x 
 
  
x 
  
  
  
  
  
  
  
  
  
x 
x 
  
  
x 
  
CBC with 
differential9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
Serum βHCG10 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Propranolol11 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
Pill count and diary 
check 
  
x 
  
x 
  
x 
  
x 
  
x 
  
x 
  
x 
x 
x 
x 
x 
  
Serum & Plasma12 
x 
 
  
X  
  
  
  
  
  
  
  
  
  
x 
  
  
  
x 
  
Questionnaire13 
x 
 
  
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
x 
  
Tumor tissue 
collection14 
x 
  
  
 X 
(optional) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x 
Thank you Gift card 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x 
  
 
1. 
Baseline parameters should be completed within 8 weeks prior to the first dose of propranolol. Baseline parameters may be completed the same 
day as the patient initiated propranolol, as long as they are completed prior to the patient starting the medication. Bra cup size per patient report 


Page 10 
Protocol dated 03/03/2014 
should also be captured at baseline.  The only exception is that patients of childbearing potential must have a negative serum or urine pregnancy 
test β-hCG within 72 hours prior to receiving the first dose of study medication. 
2. 
When starting taxane, the propranolol dose is 20 mg po BID (40 mg daily). If tolerating propranolol, increase up to a maximum of propranolol 80 
mg ER (80 mg daily).  If the breast cancer is HER2 positive, patients will receive every 3 week Herceptin and every 3 week Pertuzumab along with 
taxane therapy 
3. 
The pre-surgery parameters may be completed any time between the completion of AC and surgery. Breast exam with clinical measurement and 
DOT imaging will ideally be completed the same day 
4. 
Physical examination, including clinical breast exam with tumor measurement via calipers, vital signs, and adverse event assessment should be 
checked every 2 weeks. Patients should be examined prior to infusion. For all applicable visits, DOT imaging and tumor measurements should be 
completed within 2 days of each other 
5. 
Per the discretion of the treating investigator, the patient may undergo CT scanning of the chest, abdomen and pelvis and bone scan (or FDG 
PET/CT scan) to document extent of disease prior to registration 
6. 
Echocardiogram or MUGA scans to be done at baseline, after taxane ± Herceptin/Pertuzumab and prior to AC, and after AC. These scans may be 
repeated as clinically indicated, per protocol. 
7. 
ECG to be done at baseline, after taxane ± Herceptin/Pertuzumab prior to AC, and after AC. ECGs may be repeated as clinically indicated, per 
protocol. 
8. 
For all applicable study visits, DOT and clinical breast exam with tumor measurement should be completed within 2 days of each other 
9. 
CBC with differential will be checked prior to every infusion per standard practice  
10. Patients of childbearing potential must have a negative serum or urine pregnancy test β-hCG within 72 hours prior to receiving the first dose of 
study medication. 
11. Propranolol taken daily from the point of taxol initiation through the day before surgery (last dose of propranolol: night before surgery). Follow the 
propranolol dosage increase and decrease algorithms as indicated in the protocol and patient’s clinical presentation 
12. Blood serum and plasma biomarkers completed for all patients; biomarkers include norepinephrine, epinephrine, and IL-6.  One 10 ml SST tube, 
one 3 ml green-top tube, and one 7 ml EDTA tube will be collected.  It is mandatory to participate in the blood marker analysis. 
13. Stress questionnaire is only validated in English speaking subjects; for non-English speaking subjects, this questionnaire is optional  
14. Core biopsy at diagnosis and surgical resection are both standard of care procedures; there is an optional tumor biopsy prior to the third week of 
paclitaxel for which the patient will have provided consent  
 
 
 


Page 11 
Protocol dated 03/03/2014 
 
F.  Dose Adjustment secondary to Toxicity 
Dose modifications will be made using the schema outlined in Tables 2-6. 
 
 
F.1. Propranolol Dose Modifications  
The initial dose level of propranolol and chemotherapy is detailed in Table 4. 
 
Table 2: Propranolol + Chemotherapy  
Dose Level 
Propranolol Dose 
Reduced Dose 
4 (Maximum 
dose) 
80 mg ER po daily 
60 mg po daily (in divided dosing) 
3 
60 mg po daily (in divided dosing) 
40 mg po daily (in divided dosing) 
2 (starting dose) 
40 mg po daily (in divided dosing) 
20 mg po daily (in divided dosing) 
1 
20 mg po daily (in divided dosing)  
Off-study 
 
 
A) “Cardiac” toxicities 
 
Grade I 
 
 
The patient will start at 40 mg po daily upon starting chemotherapy (Table 2: dose level 
2). 
 
 
Every 2 weeks, the patient can be re-assessed and, if the patient is tolerating this dose 
(i.e. with no grade I “cardiac toxicities”), the dose can be increased by 1 dose level, with 
a max of 80 mg po ER daily (Table 2: dose level 4).   
 
 
If the patient experiences grade I “cardiac” toxicity, the dose will be held at that level for 2 
weeks.  If, after 2 weeks, this “cardiac” toxicity has resolved, the dose can be up-titrated, 
per physician discretion.  
 
Grade II or higher: 
 
 
If grade II or higher “cardiac toxicities” occur at any point during the study, the patient will 
be removed from the study. 
 
 
B) “Non-cardiac” toxicities 
 
Grade I or lower 
 
 
The patient can be re-assessed every 2 weeks and, if the patient is tolerating this dose 
(i.e.no propranolol-related toxicities exceeding grade I), the dose can be increased to up 
to 80 mg ER po daily (Table 3).   
 
Grade II or higher 


Page 12 
Protocol dated 03/03/2014 
 
If grade II toxicity occurs, no change in dose is required, per physician discretion. 
 
 
If grade III or IV toxicity and thought to be related to propranolol, reduce by 1 dose level.  
This toxicity should be monitored every 2 weeks, with a dose reduction by 1 dose level 
every 2 weeks until <grade II. 
 
 
Every 2 weeks, the patient can be re-assessed.  If all “non-cardiac” toxicities thought to 
be related to propranolol are reduced to< grade I, the dose can be increased by one 
dose level, per physician discretion.  The maximum dose is 80 mg ER po daily.   
 
Table 3: Dose Modification for Propranolol based upon Toxicity Grade 
Toxicity 
Grade 
“Cardiac” 
“Non-cardiac” 
I 
No change in dose while grade I; 
If resolved after 2 weeks (i.e. grade 
0), the dose can be increased by 1 
dose level (max: 80 mg daily) 
Dose can be increased by 1 dose 
level every 2 weeks (max: 80 mg 
daily)  
 
II 
Off-study 
No change in dose required; Upon 
toxicity reduction to < grade I, can 
increase by 1 dose level every 2 
weeks (max: 80 mg daily) 
III 
Off-study 
Reduce dose by 1 level every 2 
weeks until < grade II; Upon 
reduction to < grade I, can increase 
by 1 dose level every 2 weeks (max: 
80 mg daily) 
IV 
Off-study 
Same as grade III 
 
F.2. Chemotherapy Dose Modifications 
Patients remain at starting dose (Table 4: 3b), unless a dose reduction is required for the following 
toxicities below.  Each dose reduction is defined as one dose level reduction (Table 4): 
 
 
Grade III or IV febrile neutropenia (fever > 38.5C and ANC < 1,000/mm3) between 
courses.   Filgrastim may also be used with weekly paclitaxel 
 
Platelet nadir < 50,000 
 
Grade III or IV neuropathy (hold paclitaxel until < grade 2 neuropathy, reduce paclitaxel 
dose one dose level, keep propranolol dose stable)   
 
Patients with grade III or IV non-hematologic toxicity (excluding neuropathy and 
“cardiac”).NOTE:  For patients with overlapping toxicities (i.e. possibly related to 
propranolol and chemotherapy, such as fatigue or dizziness), the timing, nature, and 
degree of toxicity must be considered.  Patients may have modification of propranolol 
alone, chemotherapy alone, or both depending upon these factors, per physician 
discretion. 
 
Patients who require a > 4 week delay in therapy due to toxicity should be removed from the 
protocol. 
 


Page 13 
Protocol dated 03/03/2014 
Table 5: Chemotherapy Dose Modifications 
Dose Level 
Paclitaxel 
Adriamycin/Cytoxan 
3b (starting 
dose) 
80 mg/m2: day 1 
60 mg/m2 & 600 mg/m2: day 1 
2b 
60 mg/m2: day 1 
45 mg/m2 & 450 mg/m2: day 1 
1b 
Off-study 
Off-study 
 
F.3.  QTc Prolongation and Echocardiogram (Echo)/MUGA assessment 
ECGs and Echo/MUGA will be conducted throughout the trial.   
 
 
 
ECGs 
 
QTc toxicities should follow the CTCAE v. 4 (“Investigations”).  If > grade II toxicities are 
seen (i.e. QTc > 480 msec), the dose of propranolol will be decreased by 1 dose level, 
with a repeat ECG 4 weeks later.   
 
 
If the repeat ECG demonstrates >grade II toxicity, the dose will be decreased by an 
additional dose level, with a repeat ECG 4 weeks later – until this toxicity is noted to be 
<grade I.   
 
 
Once a stable dose is reached, it is per the discretion of the investigator, whether the 
propranolol dose will be up-titrated.  If up-titrated, the ECG should be repeated within 4 
weeks. 
 
 
Echo/MUGA 
 
If an echo demonstrates an asymptomatic decrease of ejection fraction to less than 50% 
or a decrease more than 15% from baseline, this test should be re-evaluated with 
MUGA.   
 
 
If similar results are seen on MUGA, propranolol should be held for 4 weeks, after which 
time the echo and/or MUGA can be repeated.  If the cardiac imaging demonstrates 
resolution of this issue (i.e. ejection fraction > 50% and the decrease of > 15% from 
baseline is no longer present), propranolol can be resumed at 1 dose level lower, per the 
discretion of the investigator, and remain at this dose.  If the ejection fraction does not 
recover to >50% or to <15% of baseline, propranolol should not be resumed.  The 
ejection fraction must be > 50% prior to initiating adriamycin/cytoxan. 
 
 
If propranolol is resumed, the cardiac imaging should be repeated within 8 weeks to 
demonstrate stability.  At this point, propranolol should not be up-titrated further. 
 
G. Study Drugs 
Propranolol 
 
H. Medical Device 
DOT: 
For this study we will use an optical imaging system developed by Dr. Andreas Hielscher's 
Biophotonics and Optical Radiology Lab at Columbia University. This device is used for investigational 
purposes only. A similar device has previously been used for clinical studies on approximately 70 
subjects at the State University of New York Downstate Medical Center (SUNYDMC), Brooklyn, NY. 


Page 14 
Protocol dated 03/03/2014 
Another system has been used with approximately 40 volunteers here at the Columbia University 
Medical Center. Measurements were performed on breast, limbs, human heads, and finger joints. 
These studies were approved by the IRB boards at SUNYDMC and Columbia University Medical 
Center (current protocol IRB-AAAB0510), respectively. The light intensities and exposure times are 
within required limits as set by the American National Standard Institute (ANSI) and recommended by 
the Occupational and Safety & Health Administration (OSHA) of the US Department of Labor. 
According to these standards (see ANSI Z136.12000, page 48, Table 7, entry for Visible and Near-
Infrared light) the maximum permissible exposure (MPE) before any tissue damage occurs is given by 
MPE = 200x10^[0.002(x700)] mW/cm^2, where x is the wavelength of the light. For example, at x = 800 
nm the MPE = 316 mW/cm^2, which is at least 10 times higher than intensities used in this study. 
Therefore, no adverse effects on the exposed tissues are expected. 
 
The Diffuse Optical Tomography machine is located in the Herbert Irving Pavilion, on the same floor as 
the Breast Oncology clinic.  DOT measurements will be made by placing each subject’s breasts into a 
measurement head containing 96 optical fibers.  During the optical measurements, light from four laser 
diodes (wavelengths  765 - 905nm, with light intensity comparable to that emitted by a conventional 
light bulb) will be sequentially coupled into 32 fibers that are contacting the breast.  Transmitted light 
intensities will be collected by 64 detection fibers that are coupled to individual silicon photodiodes, 
which record the light intensities.  The measured data is then processed and produces a cross 
sectional image of the breast’s optical properties from which values for water, oxyhemoglobin, 
deoxyhemoglobin and fat concentrations can be determined.  Levels of each component will be 
quantified by selecting a region of interest (the area surrounding the highest concentration) and 
calculating the mean concentration for that region.  Dynamic measurement of DOT will be made during 
a 30 second breath hold, and the recovery period 5 minutes after breath hold.  Explaining the 
procedure, positioning the breast in the imaging head, setting up and conducting the measurements 
takes about 30 minutes and produces minimal discomfort. 
 
 
I. Study Subjects 
 
Inclusion criteria: 
 
1. English or Spanish speaking women age ≥18 
 
2. Heart Rate > 60 bpm 
3. Systolic Blood Pressure > 100 mm/Hg 
4. 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.   
5. Echo or MUGA with ejection fraction > 50%. 
6. Patients with hormone receptor +/- and HER2 +/- breast cancer are eligible 
7. If a patient has HER2-positive breast cancer, Herceptin and Pertuzumab will be given along with 
taxane therapy 
8. Any stage invasive breast cancer provided the primary breast tumor size is ≥ 1 cm 
10.  Agree to participate in research blood collection at 4 different time periods (20 ml = 4 
teaspoons) 
11.  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: 
 
1. Patients failing to meet the inclusion criteria 


Page 15 
Protocol dated 03/03/2014 
2. QTc prolongation as defined by > 470 milliseconds on ECG 
3. First degree AV block on ECG in which PR interval lengthened > 200 milliseconds; Second 
Degree; or Third Degree 
4. On beta-blocker treatment.  If discontinued, patients must have been off beta-blockers for at 
least 3 months. 
5. History of asthma, given concern for β-blockade in this population 
 
J. Recruitment of Subjects 
Patients will be recruited directly by their surgical or medical oncologists at Columbia University Medical 
Center (CUMC).  In the Breast Oncology Clinic of CUMC, we estimate an accrual rate of 2 patients per 
month over a 12- month period.  Therefore, we anticipate the accrual of 20 patients is feasible and that 
the recruitment period will be completed within 1 year. 
 
K. Confidentiality of Study Data 
The research file that links subject's name to the code number will be kept in a locked file cabinet on 
the 9th floor of the Herbert Irving Pavilion and only the investigator and study staff will have access to 
the file. The study data collected, specimens and questionnaire responses will be assigned a code 
number, and separated from the patient name or any other information that could identify them.  
 
If the results of this research project are published or presented at a scientific or medical meeting, the 
patient will not be identified.  Otherwise, all results will be kept confidential and will not be divulged 
(except as required by law) without permission. 
 
Except when required by law, study information shared with persons and organizations outside of 
Columbia University Medical Center will not identify the patient by name, social security number, 
address, telephone number, or any other direct personal identifier. 
 
L. Potential Conflict of Interest 
None 
 
M. Location of the Study 
The study will be conducted at Columbia University Medical Center (CUMC). 
 
N. Potential Risk 
Potential Side effects include the following: 
 
Propranolol 
Less Likely (5-10%): 
Dizziness 
Joint Ache (Arthralgia) 
Headache 
Chest Discomfort 
Coughing 
Fatigue 
Back Pain 
 
Rare (1-4%): 
Depression 
Belly Pain (Abdominal Pain) 
Shortness of Breath (Dyspnea) 
Muscle Ache (Myalgia) 
Heart Rate Slowing (Bradycardia) 
Nausea 


Page 16 
Protocol dated 03/03/2014 
Vomiting 
Hypersensitivity Reaction (Skin reaction) 
Elevated blood sugars (Elevated glucose) 
 
Doxorubicin (Adriamycin) and Cyclophosphamide (Cytoxan) 
More likely (occurs in at least 10%): 
Lowered white blood count (may make you more likely to get an infection) 
Lowered platelet count (may make you more likely to bruise or bleed) 
Loss of appetite 
Fatigue 
Metallic taste 
Nausea 
Vomiting 
Diarrhea 
Mouth and throat sores 
Temporary hair loss 
Skin and nail discoloration 
Time away from work 
Irregular menstrual cycle 
Infertility 
Red discoloration of the urine 
 
Less likely (occurs in 1% - 10%): 
Blood in the urine or bladder irritation 
Skin damage/severe irritation (including blistering, itching, streaking of the skin) in that area of the vein 
where the drug is injected 
An allergic reaction with fever, chills, facial flushing, itching, swollen eyelids and watery eyes 
Irregular heartbeat 
 
Uncommon (occurs in < 1%): 
Scarring of the lungs 
Acute leukemia 
Congestive heart failure 
 
Taxane (Paclitaxel) 
More likely (occurs in at least 10%): 
Lowering of your blood cell counts that could cause infection, easy bruising and bleeding, or anemia 
Mild to severe allergic reaction (Not seen with Abraxane) 
Numbness and pain of the hands and feet that sometimes worsens with additional treatment and may 
not disappear after the drug is stopped 
Hair loss 
Muscle weakness and muscle loss 
Muscle and joint aches 
 
Less likely (occurs in 1% - 10%): 
Slowing of the heart rate 
Irregular heartbeats 
Nausea and/or vomiting 
Diarrhea 
 
If there is a national drug shortage of paclitaxel, the Regimen I chemotherapy of paclitaxel may be 
substituted for weekly nab-paclitaxel (Abraxane) for a total of 12 weeks.  
 


Page 17 
Protocol dated 03/03/2014 
Abraxane (Nab-Paclitaxel) 
More Likely (at least 10%) 
Lowering of your blood cell counts that could cause infection, easy bruising and bleeding, or  
anemia  
Numbness and pain of the hands and feet that sometimes worsens with additional treatment  
and may not disappear after the drug is stopped   
Hair loss  
Muscle weakness and muscle loss  
Muscle and joint aches  
 
Less Likely (1-10%) 
Slowing of the heart rate  (bradycardia) 
Irregular heartbeats  
Nausea and/or vomiting  
Diarrhea  
Sores in the mouth or throat  
Fatigue  
Lightheadedness  
Headaches  
Sensation of ﬂashing lights or spots  
Changes in kidney function tests  
Increase in triglyceride (blood lipid) levels  
Changes in liver enzymes  
Skin irritation and swelling if the drug leaks from the vein into which it is being  
injected into the surrounding skin  
 
Rare (<1%) 
Liver damage or failure  
Seizure 
 
Herceptin (Trastuzumab: if breast cancer is HER2 positive) 
More Likely  
 
Chills and/or fever with the infusion  
 
Nausea  
 
Vomiting  
 
Chills  
 
Headache  
 
Dizziness  
 
Shortness of breath  
 
Rash  
 
Pain (generalized, abdominal, back and muscle)  
 
Diarrhea  
 
Swelling in the ankles/legs  
 
Weakness  
 
Allergic reactions that include rash, itching and hives/swelling of the skin  
Rare  
 
Hypersensitivity reaction (skin reaction) 
 
Abnormal liver function blood tests, hepatitis (inﬂammation of the liver)  
 
Bone pain  


Page 18 
Protocol dated 03/03/2014 
 
Pain in the tumor  
 
Decreased red blood cells, which can cause anemia  
 
Decreased white blood cells, which can cause increased risk of developing an infection 
 
 
Decreased platelets, which can cause an increased tendency to bleed  
 
Difﬁculty breathing  
 
Fluid leaking into the lungs making it difficult to breathe. In the most severe form, this could 
require oxygen from a ventilator to breathe. This could lead to death 
 
Serious heart failure that may not be reversible.  
Perjeta (Pertuzumab: if breast cancer is HER2 positive) 
More Likely  
 
Diarrhea 
 
Tiredness 
Less Likely 
 
Anemia which may require blood transfusion 
 
Pain 
 
Heartburn, nausea, vomiting 
 
Sores in mouth which may cause difficulty swallowing 
 
Chills, fever 
 
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
 
Swelling of the face or throat 
 
Infection, especially when white blood cell count is low 
 
Change in heart function 
 
Loss of appetite 
 
Headache 
 
Shortness of breath 
 
Itching, rash, hives 
Rare 
 
Heart failure, heart attack which may cause shortness of breath, swelling of ankles, and 
tiredness 
 
Filgrastim (Neupogen) or pegfilgrastim (Neulasta) 
More likely (occurs in at least 10%) 
Bone pain 
Increase in some blood tests (uric acid, alkaline phosphatase, lactate dehydrogenase) 
 
Rare (< 1%) 
Temporarily decreased blood pressure 
 
Other Risks: 
 
Dexamethasone (Decadron) 
More likely (> 20%) 
Decreased or increased appetite 
Difficulty sleeping 
An excess of sugar in the blood 
An exaggerated feeling of well-being 
Headache, dizziness 


Page 19 
Protocol dated 03/03/2014 
 
Less likely (< 20%) 
Hallucinations or delusions  
Depression 
Fluid retention 
An increase in white blood cells 
Increased susceptibility to infection 
Nausea and/or vomiting 
Weight gain 
Aggravation of peptic ulcers 
 
Diphendyramine 
This drug may cause sleepiness and/or restlessness. 
 
H2 Blockers (eg, cimetidine, ranitidine, famotidine) 
These drugs may cause constipation, diarrhea, or dizziness. Mild discomfort and time taken to perform 
diffuse optical tomography. 
 
For patients consenting to the optional biopsy to be performed prior to the start of taxane therapy, there 
are potential risks. Risks and side effects related to the breast biopsy procedure include bruising, 
bleeding, infection, and pain at the biopsy site. 
 
There are some risks associated with blood draws.  Possible risks associated with venipuncture include 
some minor discomfort at the puncture site, failure of proper coagulation resulting in excessive bleeding 
or development of a hematoma at the wound site.  Some individuals may have a vasovagal response to 
the procedure and may faint.  There is also a small risk of infection which is associated with any 
procedure in which the skin is broken.   
 
O. Potential Benefit 
Patients may or may not obtain clinical benefit. Information obtained from this study may be of benefit 
to formulate future breast cancer clinical trials using propranolol. 
 
P. Alternative Therapies 
Patients may choose not to participate in the study. 
 
Q. Compensation to Subjects 
Subjects will be compensated with a $100 gift card at study completion. 
 
R. Cost to Subjects 
The propranolol will be provided at no cost to the patients. DOT measurements will be performed at no 
cost to the patients.  No injury is anticipated, but if participation in this study leads to research-related 
injury (as determined by the medical staff), then the patient or the patient’s insurance company will be 
responsible for the cost of such care. The optional biopsies will be at no charge to the patient as it is for 
research purposes only. 
 
Pathology evaluation of the patient’s tumor tissue will be covered by their insurance.  Other non-
standard tumor tissue evaluations will be covered by the study. 
 
S. Minors as Research Subjects 
Not applicable 
 
T. Radiation or Radioactive Substances 


Page 20 
Protocol dated 03/03/2014 
The patients will be exposed to radiation or radioactive substances only with mammography and MUGA 
scans (if they undergo MUGA).  DOT does not use ionizing radiation.  With DOT the intensity of light 
coupled into each breast is approximately 10-30mW/cm2 for about 10 seconds at each fiber end.  This 
light intensity if comparable to that emitted by a conventional light bulb and is well below the threshold 
for injury as specified by ANSI and OSHA.   
 
U. Plans for Monitoring Data and Safety 
The HICCC NCI approved Data Safety Monitoring Committee (DSMC) will oversee the conduct of this 
trial.  This protocol will adhere to the policies of the HICCC Cancer Center Data and Safety Monitoring 
Plan, version 2 guidelines in accordance with NIC regulations.  The committee is led by Dr. Gregory 
Mears and consists of HICCC members.  The DSMC meets monthly to review adverse event reporting 
and the timeliness of adverse event reporting.  The PI will submit data and safety monitoring reports to 
the DSMC. All unanticipated problems will be reported to the CUMC IRB as per the latest IRB policy 
and according to the FDA 21 CFR 812.46. 
 
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