Clinical trial NCT02950480
Conditions: Breast Cancer
Keywords: Mastectomy
Sponsor: University of California, San Francisco
Start date: 2017-03-13; Completion date: 2018-12-20
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A 2 arm, 90 patient (45 per cohort) trial in patients with breast cancer who will be undergoing mastectomy with immediate tissue-expander reconstruction to determine whether treatment with zafirlukast (20mg PO BID) can reduce or prevent the development of capsular contracture.

Detailed description:
A 2 arm, 90 patient (45 per cohort) trial in patients with breast cancer who will be undergoing mastectomy with immediate tissue-expander reconstruction to determine whether treatment with zafirlukast (20mg PO BID) can reduce or prevent the development of capsular contracture.

Patients will be block randomized 1:1 into two cohorts: treatment with zafirlukast and the standard of care, or standard of care alone. Patients will begin treatment with zafirlukast on post-operative day one following placement of tissue expander(s) once determined safe from a surgical recovery standpoint. They will be continued on the standard dosing (20mg PO twice per day) of zafirlukast through expander fill (6-12 weeks, up to 18 weeks for women receiving radiation). Treatment will be stopped 48 hours prior to expander-implant exchange, which is equivalent to 5 half-lives of the drug. Patients will be seen every 1-2 weeks for expander fill, and will be assessed clinically based on the Baker classification system of capsular contracture at every appointment. The day of surgery for their expander-implant exchange, their Baker classification will also be noted.

During expander-implant exchange, three representative sections of the expander capsule will be collected: medial, lateral and anterior capsule specimens. These specimens will be bisected; half will be sent to pathology and half will be collected by the Munster lab. Gross and microscopic determination of capsule thickness will be performed by the pathology department. The Munster lab will fix and stain the tissues to look for the presence of collagen, level of fibrosis and number of myofibroblasts. Fibrosis level and collagen presence will be determined by performing immunohistochemistry with a Trichrome stain of the tissues, as well as Western blot analysis with Collagen-1. Myofibroblasts will be detected using immunohistochemistry with commercially available antibodies.

Arms: arm 1: Zafirlukast arm 2: Standard of Care (no intervention)
Interventions: intervention 1: zafirlukast intervention 2: Standard of Care (no intervention)
Intervention descriptions: intervention 1: Patients will begin treatment with zafirlukast on post-operative day one following placement of tissue expander(s) once determined safe from a surgical recovery standpoint. They will be continued on the standard dosing (20mg PO twice per day) of zafirlukast through expander fill (6-12 weeks, up to 18 weeks for women receiving radiation). Treatment will be stopped 48 hours prior to expander-implant exchange, which is equivalent to five half-lives of the drug. Patients will be seen every 1 to 2 weeks for expander fill, and will be assessed clinically based on the Baker classification system of capsular contracture every two weeks. intervention 2: Standard of Care (no intervention)

Protocol documents:
Prot_SAP_001.pdf: 
Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws.  Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed. 
Breast capsular contracture following post-mastectomy 
reconstruction in women treated with the leukotriene 
inhibitor zafirlukast: A Phase II Trial  
Protocol Number:  CC #15754 
Study Drugs: Zafirlukast 
Version Number:  5.3 
Version Date:  06/13/2018 
IND Number: Exempt 
Principal Investigator (Sponsor-Investigator)   
Pamela Munster, MD 
University of California, San Francisco 
 
 
 
 
 
  
   
Revision History 
Version 5.3 
06/13/18 
Version 5.2 
Version 5.1 
02/12/18 
12/15/17 
Version 5.0 
Version 4.0 
06/28/17 
01/24/17 
Version 3.2 
11/15/16 
Version 3.1 
Version 3.0 
Version 2.0 
Version 1.4 
09/28/16 
08/11/16 
07/08/16 
2/23/16 
Version 1.3 
Version 1.2 
Version 1.1 
Version 1.0 
6/08/15 
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3/09/15 
2/17/15 
NCT# 02950480


 
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Page 2 of 33 
Protocol Signature Page 
Protocol No.:  15754       
Version Date: 06/13/2018        
1. I agree to follow this protocol version as approved by the UCSF Protocol Review 
Committee (PRC), Committee on Human Research (CHR), and Data Safety Monitoring 
Committee (DSMC).  
2. I will conduct the study in accordance with applicable CHR requirements, Federal 
regulations, and state and local laws to maintain the protection of the rights and welfare 
of study participants.  
3. I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol.  
4. I have read and understand the information in the Investigators’ Brochure (or 
Manufacturer’s Brochure) regarding the risks and potential benefits. I agree to conduct the 
protocol in accordance with Good Clinical Practices (ICH-GCP), the applicable ethical 
principles, the Statement of Investigator (Form FDA 1572), and with local regulatory 
requirements. In accordance with the FDA Modernization Act, I will ensure the registration 
of the trial on the www.clinicaltrials.gov website.  
5. I agree to maintain adequate and accurate records in accordance with CHR policies, 
Federal, state and local laws and regulations. 
UCSF Principal Investigator / Study Chair 
Printed Name 
Signature 
Date 
 
 
 
Principal Investigator 
Site 
Printed Name 
Signature 
Date 
 


 
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Abstract 
 
Title: Breast capsular contracture following post-mastectomy reconstruction in women treated 
with the leukotriene inhibitor zafirlukast 
Patient population: Patients who will be undergoing mastectomy with immediate tissue-
expander reconstruction 
Background 
 
Primary objective:  
a) Compare capsular thickness by gross and microscopic measurement at the time of 
expander-implant exchange in those treated with zafirlukast (20 mg PO BID) compared 
with standard of care 
 
Secondary objectives: 
a) Perform histologic analysis of the capsule specimens to compare overall fibrosis and 
collagen deposition between the zafirlukast and standard of care groups 
Exploratory objectives: 
a) The capsule tissue that is removed at the time of expander-implant exchange will be 
fixed and histologically assessed for the presence of fibroblasts and myofibroblasts. 
Study design: 
We propose a 2-arm, 90 patient (45 per cohort) trial in patients who will be undergoing 
mastectomy with immediate tissue-expander reconstruction to determine whether treatment 
with zafirlukast (20 mg PO BID) can reduce or prevent the development of capsular 
contracture. All patients undergoing mastectomy with immediate tissue-expander placement 
will be approached in clinic at the time of their initial consultation with the plastic surgeon 
and enrolled in the trial at this point. Approximately 60 women undergo mastectomy with 
tissue-expander reconstruction at our institution per year, thus enrollment will occur over a 
two-year period.  
Number of patients:  
90 total: 45 per cohort factoring in a 10% attrition rate 
 
Duration of therapy: 
In the absence of treatment delays due to adverse events, treatment may continue until 
tissue expansion is complete or until: 
 
Illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Patients decides to withdraw from the study 
 
Significant patient non-compliance with protocol 
 
General or specific changes in the patients’ condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 


 
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Duration of follow up: 
Patients are routinely followed for two years after undergoing implant-based reconstruction. In 
this study, we will initially see patients periodically for research visits until tissue expansion has 
been completed.  After implant exchange, we will see patients every 2 weeks for the first month, 
and every month for the subsequent 4 months. We will then see them every 6 months for the 
remainder of the two years. Those patients who are removed from treatment will be followed as 
per our standard of care, which is monthly for the first six months and then every six months for 
two years.  Serious adverse events will be collected for 30 days after the end of treatment, or until 
death, whichever occurs first.  Patients removed from the study for unacceptable treatment-
related adverse event(s) will be followed until resolution or stabilization of all treatment-related 
adverse events to Grade 1 or baseline. 
Study drugs: 
Zafirlukast 20mg PO BID 
Safety assessments: 
Safety will be assessed by reviewing adverse events (AEs), laboratory evaluations, physical 
examination, and spontaneous report. Each patient will be assessed periodically for the 
development of any toxicity. All AEs and serious AEs (SAEs) will be documented and reported. 
We will also pay particular attention to adverse events of clinical interest specific to zafirlukast.  
Unique aspects of this study: 
This is the first study to prospectively investigate the potential of zafirlukast to slow or prevent 
capsular contracture from occurring. 
 
 


 
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List of Abbreviations 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CBC 
complete blood cell (count) 
CHR 
Committee on Human Research (UCSF IRB) 
CR 
complete response 
CRC 
Clinical Research Coordinator 
CRF 
case report form 
CSF 
cerebral spinal fluid 
CT 
computerized tomography 
CTCEA 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trial Management System 
DFS 
disease-free survival 
DLT 
dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HDFCCC Helen Diller Family Comprehensive Cancer Center 
HGB 
Hemoglobin 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IND 
investigational new drug application 
IP 
investigational product 
IRB 
Institutional Review Board 
iwCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IV 
Intravenous 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 


 
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List of Abbreviations 
NHL 
non-Hodgkin’s lymphoma 
ORR 
overall response rate 
PD 
disease progression 
PK 
Pharmacokinetics 
PO 
Per os (by mouth, orally) 
PR 
partial response 
PRC 
Protocol Review Committee (UCSF) 
QOL 
Quality of Life 
RBC 
red blood cell (count) 
SD 
stable disease 
SD 
standard deviation 
ULN 
upper limit of normal 
WBC 
white blood cell (count) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table of Contents 
Protocol Signature Page ........................................................................................................................ 2 
List of Abbreviations ............................................................................................................................... 5 
1 
Introduction .......................................................................................................................................... 8 
1.1 
Background on Indication ..................................................................................................... 8 
1.2 
Background on the Compounds .......................................................................................... 9 
1.3 
Rationale for the Proposed Study ....................................................................................... 9 
2 
Objectives of the Study ................................................................................................................... 10 
2.1 
Primary objective ................................................................................................................... 10 
2.2  
Secondary objectives............................................................................................................ 10 
2.3 
Exploratory objectives.............................................................................................................. 10 
3 
Study Design ..................................................................................................................................... 10 
3.1 
Characteristics ........................................................................................................................ 10 
3.2 
Number of Subjects ............................................................................................................... 11 
3.3 
Eligibility Criteria .................................................................................................................... 11 
3.3.1 
Inclusion Criteria ............................................................................................................ 11 
3.3.2 
Exclusion Criteria ........................................................................................................... 12 
4 
Study Drugs....................................................................................................................................... 12 
4.1 
Description, Supply and Storage of Investigational Drugs ........................................ 12 
4.1.1 
Investigational Drug Zafirlukast ................................................................................. 13 
4.2 
Drug Accountability ............................................................................................................... 13 
4.3 
Drug Ordering ......................................................................................................................... 13 
4.4 
Packaging and Labeling of Study Drugs ......................................................................... 13 
5 
Treatment Plan ................................................................................................................................. 13 
5.1 
Dose Modifications and Dosing Delays ....................................................................... 13 
5.2 
Monitoring and Toxicity Management .............................................................................. 13 
6 
Study Procedures and Assessments ............................................................................................ 13 
6.1 
Screening Assessments .......................................................................................................... 14 
6.2 
Assessments and procedures during treatment .................................................................. 14 
Table 6. 
Schedule of Study Procedures and Assessments ...................................................... 16 
6.3 
Randomization Procedures ................................................................................................. 17 
6.4 
Duration of Therapy ................................................................................................................. 17 
6.5 
Long Term/Survival Follow-up Procedures .......................................................................... 17 
6.6 
Survival Follow-up .................................................................................................................... 18 
6.6.1 
Discontinuation of Therapy ......................................................................................... 18 
6.7 
Usage of Concurrent/Concomitant Medications .................................................................. 18 
6.8 
Dietary Restrictions .................................................................................................................. 18 
6.9 
Prohibited Concomitant Medications ..................................................................................... 18 


 
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6.10 
Contraception ..................................................................................................................... 19 
7.0 Correlative Studies ............................................................................................................................ 20 
8 
Adverse Events ................................................................................................................................. 20 
8.1 
Adverse Event (AE) Monitoring .............................................................................................. 20 
8.2 
Definition of Adverse Event ............................................................................................ 20 
8.3 
Adverse reaction ....................................................................................................................... 20 
8.4 
Evaluation of an Adverse Event ............................................................................................. 22 
8.5 
Follow-up of Adverse Events .............................................................................................. 22 
8.6 
Adverse Events Reporting ................................................................................................... 23 
8.7 
Expedited Reporting.............................................................................................................. 23 
9.0 
Statistical Considerations and Evaluation of Results ............................................................. 23 
9.1 
Analyses Plans ......................................................................................................................... 24 
10.0 
Study Management ...................................................................................................................... 25 
10.1 
Pre-study Documentation........................................................................................................ 25 
10.2 
Institutional Review Board Approval ...................................................................................... 25 
10.3 
Informed Consent ..................................................................................................................... 25 
10.4 
Changes in the Protocol .......................................................................................................... 25 
10.5 
Handling and Documentation of Clinical Supplies .............................................................. 25 
10.6 
Case Report Forms (CRFs) .................................................................................................... 26 
10.7 
Oversight and Monitoring Plan ............................................................................................... 26 
10.8 
Record Keeping and Record Retention ................................................................................ 26 
11.0 
Protection of Human Subjects .................................................................................................... 27 
11.1 
Protection from Unnecessary Harm ...................................................................................... 27 
11.2 
Protection of Privacy ................................................................................................................ 27 
References ............................................................................................................................................... 28 
Appendix 1: Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study .................... 31 
APPENDIX 2: UCSF POLICY/PROCEDURE FOR REQUIRED REGULATORY DOCUMENTS 
FOR UCSF INVESTIGATOR-INITIATED ONCOLOGY CLINICAL TRIALS WITH AN 
INVESTIGATOR HELD INVESTIGATIONAL NEW DRUG (IND) 
 
 
 
 
 
 
 
 
 
1 
INTRODUCTION 
1.1 
Background on Indication 
The majority of women who undergo mastectomy for breast cancer will choose expander-implant 
reconstruction. Unfortunately, breast implants are frequently complicated by the development of 


 
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capsular contracture1. Contracture formation is an excessive foreign body reaction that results in 
a tight and hard fibrous capsule around the implant. This causes distortion of the breast, 
displacement of the implant, and in more severe cases, pain and limited range of 
motion.  Reported rates in the literature of women affected by this condition range from 3 to 50%2-
4. However, these percentages likely under-represent the actual number of women affected as 
this complication may develop long after a patient is regularly evaluated by the plastic surgeon.  
Radiation therapy increases the likelihood of capsular contracture1-3,5,6. Women who have been 
irradiated face contracture rates upwards of 20%7-9. Unfortunately, many women who require 
mastectomy and implant reconstruction for breast cancer had radiation in the past or will require 
radiation therapy in the future, thus putting them at greater risk for this complication.  
The treatment of capsular contracture is primarily surgical, requiring removal of the implant, 
excision of the capsule, and replacement of the implant. However, excision of the capsule and 
implant replacement does not guarantee contracture will not recur, and many women face 
repeated operations. 
Recent research has focused on methods to decrease capsule formation10-13. These include: 
altering the properties of implants14-16, coating the implants17, fat grafting the capsule18, inserting 
acellular dermal matrix19,20, treating with anti-estrogens21 and treating with leukotriene receptor 
antagonists (LTAs)22,23. The goal of many of these interventions is to actually prevent capsular 
contracture from even occurring.  
1.2 
Background on the Compounds 
1.2.1  Zafirlukast 
 
Zafirlukast is a synthetic, selective peptide leukotriene receptor antagonist (LTRA), with the 
chemical name 4-(5-cyclopentyloxycarbonylamino-1-methyl-indol-3-ylmethyl)-3-methoxy-N-o-
tolylsulfonylbenzamide. It is a selective and competitive receptor antagonist of leukotriene D4 and 
E4 (LTD4 and LTE4), components of slow-reacting substance of anaphylaxis (SRSA). Cysteinyl 
leukotriene production and receptor occupation have been correlated with the pathophysiology of 
asthma, including airway edema, smooth muscle constriction, and altered cellular activity 
associated with the inflammatory process, which contribute to the signs and symptoms of asthma. 
Patients with asthma were found in one study to be 25-100 times more sensitive to the 
bronchoconstricting activity of inhaled LTD4 than non-asthmatic subjects. In vitro studies 
demonstrated that zafirlukast antagonized the contractile activity of three leukotrienes (LTC4, 
LTD4 and LTE4) in conducting airway smooth muscle from laboratory animals and humans. 
Zafirlukast prevented intradermal LTD4-induced increases in cutaneous vascular permeability 
and inhibited inhaled LTD4-induced influx of eosinophils into animal lungs. Inhalational challenge 
studies in sensitized sheep showed that zafirlukast suppressed the airway responses to antigen; 
this included both the early-and late-phase response and the nonspecific hyper-responsiveness. 
In humans, zafirlukast inhibited bronchoconstriction caused by several kinds of inhalational 
challenges. Pretreatment with single oral doses of zafirlukast inhibited the bronchoconstriction 
caused by sulfur dioxide and cold air in patients with asthma. Pretreatment with single doses of 
zafirlukast attenuated the early-and late-phase reaction caused by inhalation of various antigens 
such as grass, cat dander, ragweed, and mixed antigens in patients with asthma. Zafirlukast also 
attenuated the increase in bronchial hyper-responsiveness to inhaled histamine that followed 
inhaled allergen challenge. 
1.3 
Rationale for the Proposed Study 
The development of capsular contracture is multifactorial24-26with histologic studies demonstrating 
the primary role of inflammatory cells in this process. Peptide growth factors and inflammatory 
cytokines are reactivated by the presence of an implant, leading to a persistent sub-acute 


 
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inflammatory response ultimately resulting in capsular contracture27-29. As inflammation is induced 
as part of normal healing, as well as by the ongoing presence of an implant, pharmacologic 
inhibition of inflammation is an appealing target in preventing capsular contracture from 
developing. The control of inflammation has been an underlying factor in successful treatment26,30.  
Cysteinyl leukotrienes play a role in the activation and up-regulation of capsular contracture 
mechanisms31-33. Grella et al. demonstrated that in women with severe capsular contracture 
(Baker grade III/IV) there was marked up-regulation of cysLTR mRNA and protein compared to 
women with implants who did not develop capsular contracture32. Treatment with leukotriene 
receptor antagonists thereby presents a novel mechanism in the potential prevention of capsular 
contracture. Zafirlukast specifically inhibits LTC4, LTD4 and LTE4 and has a presumed 
suppressive effect on myofibroblasts. Several studies have looked at the effects of leukotriene 
inhibitor administration on capsular contracture in animal models, and found decreased capsule 
formation following treatment22,34. Histologic analysis of capsules in rats treated with zafirlukast 
demonstrated thinner capsules with decreased collagen fibers34,35 .  
There are descriptive studies of patients treated with LTAs as an off-label use for capsular 
contracture36-40. Women who have developed capsular contracture who are subsequently treated 
with standard dosing of LTAs show decreased capsule contracture based on clinical 
assessment36,38,40. However, there have been no studies to date evaluating the biology behind 
this observation in humans. Based on an evidence-based analysis by Cheng et al., further 
prospective randomized studies are needed to determine the efficacy and safety of leukotriene 
inhibitors as a potential treatment of capsular contracture19. No studies are prospectively 
investigating the potential of zafirlukast to slow or prevent capsular contracture from occurring. 
 
2 
OBJECTIVES OF THE STUDY 
2.1 
Primary objective  
 
Compare capsular thickness by gross and microscopic measurement at the time of 
expander-implant exchange in those treated with zafirlukast (20 mg PO BID) compared 
with standard of care 
   
2.2  
Secondary objectives 
 
Perform histologic analysis of the capsule specimens to compare overall fibrosis and 
collagen deposition between the zafirlukast and standard of care groups 
2.3 
Exploratory objectives 
 
 
The capsule tissue that is removed at the time of expander-implant exchange will be 
fixed and histologically assessed for the presence of fibroblasts and myofibroblasts. 
 
3 STUDY DESIGN 
3.1 
Characteristics 
We propose a 2-arm, 90 patient (45 per cohort) trial in patients who will be undergoing 
mastectomy with immediate tissue-expander reconstruction to determine whether treatment with 
zafirlukast (20mg PO BID) can reduce or prevent the development of capsular contracture. All 
patients undergoing mastectomy with immediate tissue-expander placement will be approached 


 
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Page 11 of 33 
in clinic at the time of their initial consultation with the plastic surgeon and enrolled in the trial at 
this point. Approximately 60 women undergo mastectomy with tissue-expander reconstruction at 
our institution per year, thus enrollment will occur over a two-year period.  
Patients will be block randomized 1:1 into two cohorts: treatment with zafirlukast and the standard 
of care, or standard of care alone. Patients will begin treatment with zafirlukast on post-operative 
day one (+/- 5 days) following placement of tissue expander(s) after the participant is determined 
safe from a surgical recovery standpoint. They will be continued on the standard dosing (20mg 
PO twice per day) of zafirlukast through expander fill. Last dose of Zafirlukast will be administered 
the day prior to expander implant exchange procedure. Patients will be seen every 1 to 2 weeks 
for expander fill, and will be assessed clinically (refer to section 6.2 for research visits). The 
treating physician will determine the frequency of visits based on each patient’s expander need.  
 
During expander-implant exchange, three representative sections of the expander capsule will be 
collected: medial, lateral and anterior capsule specimens. These specimens will be bisected; half 
will be sent to pathology and half will be collected by the Munster lab. Gross and microscopic 
determination of capsule thickness will be performed by the pathology department. The Munster 
lab will fix and stain the tissues to look for the presence of collagen, level of fibrosis, and number 
of myofibroblasts. Fibrosis level and collagen presence will be determined by performing 
immunohistochemistry with a Trichrome stain of the tissues, as well as Western blot analysis with 
Collagen-1. Myofibroblasts will be detected using immunohistochemistry with commercially 
available antibodies. 
3.2 
Number of Subjects 
90 total: 45 per cohort factoring in a 10% attrition rate 
3.3 
Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria.  In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent.  The written informed consent must be obtained 
from the patient prior to enrollment.  The following criteria apply to all patients enrolled onto the 
study unless otherwise specified. 
3.3.1 Inclusion Criteria 
1. Patients who are scheduled to undergo therapeutic or prophylactic mastectomy with 
immediate placement of tissue expanders and have a strong family history or hereditary 
cancer  
2. Age ≥ 18 years 
3. Zafirlukast is pregnancy category B. There are no adequate and well-controlled trials in 
pregnant women. Therefore, the effects of zafirlukast on the developing human fetus are 
unknown.  For this reason, women of child-bearing potential must agree to use adequate 
contraception: 2 methods of birth control, prior to study entry and for the duration of 
study participation.  Should a woman become pregnant or suspect she is pregnant while 
she is participating in this study, she should inform her treating physician immediately. 
4. Ability to understand a written informed consent document, and the willingness to sign it 
5. At least 4 weeks post-completion of chemotherapy 
6. Adequate organ function within 14 days start of study start: 
a. Absolute neutrophil count (ANC) ≥ 1.5 X 109/L 
b. Hemoglobin (Hgb) ≥9g/dL  
c. Platelets (plt) ≥ 100 x 109/L 
d. Potassium within normal range, or correctable with supplements; 


 
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e. AST and ALT ≤2.5 x Upper Limit Normal (ULN) or ≤5.0 x ULN if liver tumor is 
present 
f. 
Serum total bilirubin ≤ 1.5 x ULN 
g. Serum creatinine ≤ 1.5 x ULN, or 24-hr clearance ≥ 60ml/min 
3.3.2 Exclusion Criteria 
1. Any significant medical condition, laboratory abnormalities, which places the subject at 
unacceptable risk if he/she were to participate in the study 
2. Currently on a leukotriene inhibitor or used within the past 6 months 
3. Prior chest wall radiation  
4. Pregnant or breastfeeding  
5. Hepatic impairment as defined by: 
 
AST(SGOT) > 2.5X institutional ULN and ALT(SGPT) > 2.5X institutional ULN 
6. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
4 STUDY DRUGS 
4.1 
Description, Supply and Storage of Investigational Drugs 
Classification 
Zafirlukast is a synthetic, selective peptide leukotriene receptor antagonist (LTRA). 
Mechanism of Action 
Zafirlukast is a selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD4 and 
LTE4), components of slow-reacting substance of anaphylaxis (SRSA). Cysteinyl leukotriene 
production and receptor occupation have been correlated with the pathophysiology of asthma, 
including airway edema, smooth muscle constriction, and altered cellular activity associated with 
the inflammatory process, which contribute to the signs and symptoms of asthma. Patients with 
asthma were found in one study to be 25- 100 times more sensitive to the bronchoconstricting 
activity of inhaled LTD4 than non-asthmatic subjects. 
In vitro studies demonstrated that zafirlukast antagonized the contractile activity of three 
leukotrienes (LTC4, LTD4 and LTE4) in conducting airway smooth muscle from laboratory 
animals and humans. Zafirlukast prevented intradermal LTD4-induced increases in cutaneous 
vascular permeability and inhibited inhaled LTD4-induced influx of eosinophils into animal lungs. 
Inhalational challenge studies in sensitized sheep showed that zafirlukast suppressed the airway 
responses to antigen; this included both the early- and late-phase response and the nonspecific 
hyper-responsiveness. 
In humans, zafirlukast inhibited bronchoconstriction caused by several kinds of inhalational 
challenges. Pretreatment with single oral doses of zafirlukast inhibited the bronchoconstriction 
caused by sulfur dioxide and cold air in patients with asthma. Pretreatment with single doses of 
zafirlukast attenuated the early- and late-phase reaction caused by inhalation of various antigens 
such as grass, cat dander, ragweed, and mixed antigens in patients with asthma. Zafirlukast also 
attenuated the increase in bronchial hyper-responsiveness to inhaled histamine that followed 
inhaled allergen challenge. 
Storage 
Store at controlled room temperature, 20-25°C (68-77°F). See Investigator Brochure. Protect 
from light and moisture. Dispense in the original airtight container. 


 
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Method of Administration 
Because food can reduce the bioavailability of zafirlukast, it should be taken at least 1 hour 
before or 2 hours after meals. 
Patient Care Implications: 
Patients should be told that a rare side effect of zafirlukast is hepatic dysfunction, and to contact 
their physician immediately if they experience symptoms of hepatic dysfunction (e.g. right upper 
quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, and 
anorexia). Liver failure resulting in liver transplantation and death has occurred in patients taking 
zafirlukast. 
4.1.1 Investigational Drug Zafirlukast  
Zafirlukast is available in the following doses for oral administration. 
20mg PO twice per day 
Complete and updated adverse event information is available in the Investigational Drug Brochure 
and product package insert.  
4.2 
Drug Accountability 
The Investigational Pharmacist will manage drug accountability records. 
4.3 
Drug Ordering 
UCSF will provide the study drug directly to the patient 
4.4 
Packaging and Labeling of Study Drugs 
Drugs will be packaged and labeled per UCSF institutional standards, adhering to applicable local 
and federal laws. 
 
5 TREATMENT PLAN 
5.1 
Dose Modifications and Dosing Delays  
Zafirlukast will be administered in 20mg tablets as a single dose. Although zafirlukast is available 
as a 10mg tablet as well, there will be no dose modification. Should a patient be unable to tolerate 
the standard dose of 20mg, she will be removed from this study. Zafirlukast should be stopped 
prior to expander implant exchange 
5.2 
Monitoring and Toxicity Management 
Each patient receiving zafirlukast will be evaluable for safety.  The safety parameters include all 
laboratory tests and hematological abnormalities, physical findings, and spontaneous reports of 
adverse events reported to the investigator by patients. 
 
6 
STUDY PROCEDURES AND ASSESSMENTS 
The study-specific assessments are detailed in this section and outlined in Table 6 Schedule of 
Study Procedures and Assessments.  Screening assessments must be performed from day -28 
to day 1, prior to the scheduled mastectomy and tissue-expander placement. Treatment or visit 
delays for public holidays or weather conditions, patient’s personal reasons or per PI discretion 


 
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that do not compromise safety do not constitute a protocol violation. Treatment delays may not 
exceed 3 weeks, unless discussed with the study team for patients with documented benefit. 
6.1 
Screening Assessments 
Must be performed  from day -28 to day 1, prior to the scheduled mastectomy and tissue-expander 
placement: 
 
Medical history  
 
Physical examination (including height and weight)  
 
Vital signs (blood pressure, pulse rate, respiratory rate, temperature) 
 
Con-Med review 
 
CBC with differential  
 
Serum biochemical panel including creatinine, fasting glucose, potassium, sodium, 
chloride, bicarbonate, ALT/AST, total bilirubin 
 
Blood or urine pregnancy test 
 
6.2 
Assessments and procedures during treatment 
Once the patient is confirmed to be eligible based on screening assessments, the following study 
assessments will be performed. See Table 6 for summary. Cohort A participants will begin 
treatment with zafirlukast on post-operative day one (+/- 5 days) following placement of tissue 
expander(s) after the participant is determined safe from a surgical recovery standpoint. Cohort 
A participants will take zafirlukast twice per day until the patient has completed expansion of the 
tissue expander.  Zafirlukast should be stopped prior to expander implant exchange. Patients will 
be randomized on the day of surgery by a study personnel other than the surgeon.  The surgeon 
and patient will be informed of the assigned cohort immediately post-surgery. 
 
Research Visits (+/- 1 week) 
 
Physical examination (including height and weight)  
 
Vital signs (blood pressure, pulse rate, respiratory rate, temperature) 
 
Con-Med and AE review 
 
CBC with differential and platelet count  
 
Serum biochemical panel including creatinine, fasting glucose, potassium, sodium, 
chloride, bicarbonate 
 
Liver function tests: alkaline phosphatase, ALT/AST, total bilirubin (only for Cohort A) 
 
Expander-Implant Exchange 
 
 
Tissue specimen collection 
 


 
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End of Treatment (14 days (+/- 3 days) of expander-implant exchange) 
 
 
Medical history, physical examination (including height and weight), vital signs (blood 
pressure, pulse rate, respiratory rate, temperature) 
 
CBC with differential and platelet count 
 
Serum biochemical panel including creatinine, fasting glucose, potassium, sodium, 
chloride, bicarbonate 
 
Liver funtion tests: alkaline phosphatase, ALT/AST, total bilirubin (only for Cohort A) 
 
Con-Med and AE review 
Follow up  
 
Patients are followed for two years after implant reconstruction. After implant exchange we will 
see patients every 2 weeks for the first month, every month for the subsequent 4 months, and, 
every 6 months for the remainder of the two years. For those patients are removed from the 
treatment, they will be followed as per our standard of care which is monthly for the first six months 
and then every six months for a total of two years. 
 
Physical examination (including height and weight), vital signs (blood pressure, pulse rate, 
respiratory rate, temperature) 
 
 


 
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Table 6. 
Schedule of Study Procedures and Assessments 
Period/ 
Procedure 
Screening9 
 
Treatment period (+/- 1 week) 
Expander-
implant 
exchange 
End of 
Treatment 
Follow up 
visits5 
Study Day/Visit 
Day 
Days -28 to 
 Day 1 
Mastectomy 
and Tissue- 
expander 
placement 
(week 0) 
Day 
15-21 
(wk 2) 
Day 
29-35 
(wk 5) 
Day 
71-77 
(wk 11) 
Day 
113-119 
(wk 17)8 
 
 
 
 
Informed 
Consent 
x 
 
 
 
 
 
 
 
 
Baseline 
Conditions1 
x 
 
 
 
 
 
 
 
 
Tissue Specimen 
Collection 
 
 
 
 
 
 
x 
 
 
Zafirlukast6 
 
x 
 
 
 
Medical History 
x 
 
 
 
 
 
 
x 
 
Vital Signs 
x 
 
x 
x 
x 
x 
 
x 
x 
Physical Exam 
x 
 
x 
x 
x 
x 
 
x 
x 
Con-med and AE 
review7 
x 
 
x 
 
CBC w/diff2 
x 
 
x 
x 
x 
x 
 
x 
 
Chemistry3 
x 
 
x 
x 
x 
x 
 
x 
 
Liver Function 
Tests4 
x 
 
 
x 
 
 
 
x 
 
Pregnancy Test 
(HCG) 
x 
 
 
 
 
 
 
 
 
1. 
Baseline conditions assessment per DSMC policy. 
2. 
Including CBC with differential and platelet count. 
3. 
Including creatinine, fasting glucose, potassium, sodium, chloride, bicarbonate. 
4. 
Including alkaline phosphatase, ALT/AST, total bilirubin. For Cohort A only on week 5 and EOT. Alkaline phosphatase is not required for 
screening. 
5. 
Patients are followed for two years after implant reconstruction. After implant exchange we will see patients every 2 weeks for the first month, 
every month for the subsequent 4 months, and, every 6 months for the remainder of the two years. For those patients are removed from 
treatment, they will be followed as per our standard of care which is monthly for the first six months and then every six months for a total of two 
years. 
6. 
20mg PO twice per day from Day 1 to Treatment Termination for Cohort A only.  Treatment may continue until tissue expansion is complete.  
Zafirlukast should be stopped prior to expander implant exchange. 
7. 
Con-med and AE review begins 28 days prior to treatment and continues 30 days after treatment termination. 
8. 
As needed . 
9.  
Screening procedures must be completed prior to mastectomy and tissue-expander placement.


 
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6.3 
Randomization Procedures 
This study is an open-label randomized trial; therefore the investigator and subject will know the 
treatment administered. Patients will be randomized by a study personnel other than the 
surgeon.  The surgeon and patient will be notified of the patient’s cohort immediately post-
surgery.  Two arms will be tested, with each independent assessment. Patients will be block 
randomized to either treatment with zafirlukast or the standard of care. Enrollment will continue 
until 90 patients (45 per cohort) have been enrolled. 
 
6.4 
Duration of Therapy  
In the absence of treatment delays due to adverse events, treatment may continue until tissue 
expansion is complete or until: 
 
Illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Patients decides to withdraw from the study 
 
Significant patient non-compliance with protocol 
 
General or specific changes in the patients’ condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
Patients are routinely followed for two years after undergoing implant based reconstruction. In this 
study we will initially see patients periodically for research visits until tissue expansion has been 
completed.  After implant exchange we will see patients every 2 weeks for the first month, and 
every month for the subsequent 4 months. We will then see them every 6 months for the 
remainder of the two years. Those patients who are removed from treatment will be followed as 
per our standard of care, which is monthly for the first six months and then every six months for 
two years.  Serious adverse events will be collected for 30 days after the end of treatment, or until 
death, whichever occurs first.  Patients removed from treatment for unacceptable treatment 
related adverse event(s) will be followed until resolution or stabilization of all treatment related 
adverse events to Grade 1 or baseline. 
Subjects may withdraw consent at any time for any reason, or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is violated, 
or for administrative and/or other safety reasons.   
 
6.5 
Long Term/Survival Follow-up Procedures 
Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment. All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 2 will be followed until the resolution of the AE to Grade 1 or 
baseline. 


 
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6.6 Survival Follow-up 
6.6.1 Discontinuation of Therapy 
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interests.  Reasons for withdrawing a patient include, but are not limited to, disease 
progression, the occurrence of an adverse event or a concurrent illness, a patient’s request to 
end participation, or simply significant uncertainty on the part of the Investigator that continued 
participation is prudent.  There may also be administrative reasons to terminate participation, such 
as concern about a patient’s compliance with the prescribed treatment regimen. 
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled 
for the final trial visit should be performed at the time of discontinuation.  Any adverse events 
which are present at the time of discontinuation/withdrawal should be followed in accordance with 
the safety requirements outlined in Section 8.   
6.7 
Usage of Concurrent/Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids. If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF.  
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
Events of Clinical Interest (ECI) as defined in Section 8.  
6.8 
Dietary Restrictions 
There are no dietary restrictions within this trial.  
6.9 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial:  
 
Anti-cancer systemic chemotherapy or biological therapy  
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. Subjects 
may receive other medications that the investigator deems to be medically necessary.  
Potential Drug Interactions: 
The following drug interaction studies have been conducted with zafirlukast  
 
Co-administration of multiple doses of zafirlukast (160 mg/day) to steady-state with a single 
25 mg dose of warfarin (a substrate of CYP2C9) resulted in a significant increase in the mean 
AUC (+63%) and half-life (+36%) of S-warfarin. The mean prothrombin time increased by 
approximately 35%. The pharmacokinetics of zafirlukast were unaffected by co-administration 
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 
Co-administration of zafirlukast (80 mg/day) at steady-state with a single dose of a liquid 
theophylline preparation (6 mg/kg) in 13 asthmatic patients, 18 to 44 years of age, resulted in 
decreased mean plasma concentrations of zafirlukast by approximately 30%, but no effect on 
plasma theophylline concentrations was observed. 
 
Co-administration of zafirlukast (20 mg/day) or placebo at steady-state with a single dose of 
sustained release theophylline preparation (16 mg/kg) in 16 healthy boys and girls (6 through 
11 years of age) resulted in no significant differences in the pharmacokinetic parameters of 
theophylline. 
 
Co-administration of zafirlukast dosed at 40 mg twice daily in a single-blind, parallel-group, 3-
week study in 39 healthy female subjects taking oral contraceptives, resulted in no significant 
effect on ethinyl estradiol plasma concentrations or contraceptive efficacy. 
 
Co-administration of zafirlukast (40 mg/day) with aspirin (650 mg four times daily) resulted in 
mean increased plasma concentrations of zafirlukast by approximately 45%. 
 
Co-administration of a single dose of zafirlukast (40 mg) with erythromycin (500 mg three 
times daily for 5 days) to steady-state in 11 asthmatic patients resulted in decreased mean 
plasma concentrations of zafirlukast by approximately 40% due to a decrease in zafirlukast 
bioavailability. 
 
Co-administration of zafirlukast with fluconazole, a moderate CYP2C9 inhibitor, resulted in 
increased plasma levels of zafirlukast, by approximately 58% (90% CI:28, 95). The clinical 
significance of this interaction is unknown. Zafirlukast exposure is likely to be increased by 
other moderate and strong CYP2C9 inhibitors. Co-administration of zafirlukast with 
itraconazole, a strong CYP3A4 inhibitor, caused no change in plasma levels of zafirlukast. 
6.10 
Contraception 
Zafirlukast may have adverse effects on a fetus in utero.  Furthermore, it is not known if zafirlukast 
has transient adverse effects on the composition of sperm.  Non-pregnant, non-breast-feeding 
women may be enrolled if they are willing to use 2 methods of birth control or are considered 
highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) 
postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 1 
year will be considered postmenopausal), or 3) not heterosexually active for the duration of the 
study.  The two birth control methods can be either two barrier methods or a barrier method plus 
a hormonal method to prevent pregnancy. Subjects should start using birth control from study 
Visit 1 throughout the study period up to 120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), intrauterine device, sponge, or spermicide.  Appropriate hormonal contraceptives will 
include any registered and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  
 


 
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7.0 CORRELATIVE STUDIES 
Collection of tissue specimen 
At the time expander-implant exchange, a portion of the capsule is normally excised as part of 
the standard of care. For research purposes, we will collect and study several small pieces of 
capsular tissue excised at the time of surgery. The tissue collected will be used to determine if 
zafirlukast can reduce the thickness and scarring of the capsule tissue compared to standard of 
care.  
Handling of specimen 
Tissue samples will be fixed in 10% neutral-buffered formalin and embedded in paraffin for further 
analysis. 
Shipping of specimen 
Specimen will be processed by the surgical pathology department laboratory affiliated with UCSF. 
 
8 ADVERSE EVENTS 
8.1 
Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs and more frequently if clinically indicated.  Adverse experiences will be assessed, 
graded and recorded throughout the study and during the follow-up period by the treating 
physician.  Toxicities will be characterized in terms regarding seriousness, causality, toxicity 
grading, and action taken with regard to trial treatment.  
8.2 
Definition of Adverse Event 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related.  
More specifically, an adverse event can be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, 
without any judgment about causality.  An adverse event can arise from any use of the drug (e.g., 
off-label use, use in combination with another drug) and from any route of administration, 
formulation, or dose, including an overdose.  
8.3 
Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
 
8.3.1 Suspected  
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship between 
the drug and the adverse event.  A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction. 


 
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P a g e 2 1  of 3 3  
8. 3. 2  U n e x p e ct e d  
A n a d v er s e e v e nt or s u s p e ct e d a d v er s e r e a cti o n i s c o n si d er e d u n e x p e ct e d if it i s n ot li st e d i n t h e 
i n v e sti g at or br o c h ur e or p a c k a g e i n s ert( s), or i s n ot li st e d at t h e s p e cifi cit y or s e v erit y t h at h a s 
b e e n o b s er v e d, or, if a n i n v e sti g at or br o c h ur e i s n ot r e q uir e d or a v ail a bl e, i s n ot c o n si st e nt wit h 
t h e ri s k i nf or m ati o n d e s cri b e d i n t h e g e n er al i n v e sti g ati o n al pl a n or el s e w h er e i n t h e c urr e nt 
a p pli c ati o n.  
“ U n e x p e ct e d,” a s u s e d i n t hi s d efi niti o n, al s o r ef er s t o a d v er s e e v e nt s or s u s p e ct e d a d v er s e 
r e a cti o n s t h at ar e m e nti o n e d i n t h e i n v e sti g at or br o c h ur e a s o c c urri n g wit h a cl a s s of dr u g s or a s 
a nti ci p at e d fr o m t h e p h ar m a c ol o gi c al pr o p erti e s of t h e dr u g, b ut ar e n ot s p e cifi c all y m e nti o n e d a s 
o c c urri n g wit h t h e p arti c ul ar dr u g u n d er i n v e sti g ati o n.  
A d v er s e e v e n t s t h at w o ul d b e a nti ci p at e d t o o c c ur a s p art of t h e di s e a s e pr o c e s s ar e c o n si d er e d 
u n e x p e ct e d f or t h e p ur p o s e s of r e p orti n g b e c a u s e t h e y w o ul d n ot b e li st e d i n t h e i n v e sti g at or 
br o c h ur e.  F or e x a m pl e, a c ert ai n n u m b er of n o n -a c ut e d e at h s i n a c a n c er tri al  w o ul d b e 
a nti ci p at e d a s a n o ut c o m e of t h e u n d erl yi n g di s e a s e, b ut s u c h d e at h s w o ul d g e n er all y n ot b e 
li st e d a s a s u s p e ct e d a d v er s e r e a cti o n i n t h e i n v e sti g at or br o c h ur e. 
S o m e a d v er s e e v e nt s ar e li st e d i n t h e I n v e sti g at or Br o c h ur e a s o c c urri n g wit h t h e s a m e cl a s s of 
dr u g s, or a s a nti ci p at e d fr o m t h e p h ar m a c ol o gi c al pr o p erti e s of t h e dr u g, e v e n t h o u g h t h e y h a v e 
n ot b e e n o b s er v e d wit h t h e dr u g u n d er i n v e sti g ati o n.  S u c h e v e nt s w o ul d b e c o n si d er e d 
u n e x p e ct e d u ntil t h e y h a v e b e e n o b s er v e d wit h t h e dr u g u n d er  i n v e sti g ati o n. F or e x a m pl e, 
alt h o u g h a n gi o e d e m a i s a nti ci p at e d t o o c c ur i n s o m e p ati e nt s e x p o s e d t o dr u g s i n t h e A C E 
i n hi bit or cl a s s a n d a n gi o e d e m a w o ul d b e d e s cri b e d i n t h e i n v e sti g at or br o c h ur e a s a cl a s s eff e ct, 
t h e fir st c a s e of a n gi o e d e m a o b s er v e d wit h t h e dr u g u n d er i n v e sti g ati o n s h o ul d b e c o n si d er e d 
u n e x p e ct e d f or r e p orti n g p ur p o s e s.  
8. 3. 3  S eri o u s  
A n a d v er s e e v e nt or s u s p e ct e d a d v er s e r e a cti o n i s c o n si d er e d s eri o u s if, i n t h e vi e w of t h e st u d y 
PI , it r e s ult s i n a n y of t h e f oll o wi n g o ut c o m e s:  
 D e at h  
 Lif e -thr e at e ni n g a d v er s e e v e nt  
 I n p ati e nt h o s pit ali z ati o n or pr ol o n g ati o n of e xi sti n g h o s pit ali z ati o n 
 A p er si st e nt or si g nifi c a nt i n c a p a cit y or s u b st a nti al di sr u pti o n of t h e a bilit y t o c o n d u ct 
n or m al lif e f u n cti o n  
 C o n g e nit al a n o m al y/ birt h d ef e ct  
I m p ort a nt 
m e di c al e v e nt s t h at 
m a y n ot r e s ult i n d e at h, ar e lif e -t hr e at e ni n g, or r e q uir e 
h o s pit ali z ati o n m a y b e c o n si d er e d s eri o u s w h e n, b a s e d u p o n a p pr o pri at e m e di c al j u d g m e nt, t h e y 
m a y j e o p ar di z e t h e p ati e nt or s u bj e ct a n d m a y r e q uir e m e di c al or s ur gi c al i nt er v e nti o n t o p r e v e nt 
o n e of t h e o ut c o m e s li st e d i n t hi s d efi niti o n.  E x a m pl e s of s u c h m e di c al e v e nt s i n cl u d e all er gi c 
br o n c h o s p a s m r e q uiri n g i nt e n si v e tr e at m e nt i n a n e m er g e n c y r o o m or at h o m e, bl o o d d y s cr a si a s 
or c o n v ul si o n s t h at d o n ot r e s ult i n i n p ati e nt h o s pit ali z at i o n, or t h e d e v el o p m e nt of dr u g 
d e p e n d e n c y or dr u g a b u s e.  
8. 3. 4  Lif e -t hr e at e ni n g 
A n a d v er s e e v e nt or s u s p e ct e d a d v er s e r e a cti o n i s c o n si d er e d lif e -t hr e at e ni n g if, i n t h e vi e w of 
eit h er t h e st u d y P ri n ci p al I n v e sti g at or, it s o c c urr e n c e pl a c e s t h e p ati e nt or s u bj e ct at i m m e di at e 
ri s k of d e at h. It d o e s n ot i n cl u d e a n a d v er s e e v e nt or s u s p e ct e d a d v er s e r e a cti o n t h at, h a d it 
o c c urr e d i n a m or e s e v er e f or m, mi g ht h a v e c a u s e d d e at h.  


 
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8.4 
Evaluation of an Adverse Event 
All grade 3 and above adverse events will be entered into OnCore®, whether or not the event is 
believed to be associated with use of the study drug.   
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below:  
Relationship  
Attribution  
Description  
Unrelated to investigational 
drug/intervention 
Unrelated 
The AE is clearly NOT related to the intervention 
Unlikely 
The AE is doubtfully related to the intervention  
Related 
to 
investigational 
drug/intervention 
Possible 
The AE may be related to the intervention  
Probable 
The AE is likely related to the intervention  
Definite 
The AE is clearly related to the intervention  
 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions: 
Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL) 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL 
Grade 4: Life-threatening consequences; urgent intervention indicated 
Grade 5: Death related to AE 
8.4.1 NCI Common Terminology for Adverse Events (CTCAE)  
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
8.5 
Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management until resolved.  Patients 
removed from study for unacceptable adverse events will be followed for 30 days or until 
resolution or stabilization of the adverse event.  For selected adverse events for which 
administration of the investigational drug was stopped, a re-challenge of the subject with the 
investigational drug may be conducted if considered both safe and ethical by the Investigator. 


 
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8.6 
Adverse Events Reporting  
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®, as noted above. 
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board, 
the Committee on Human Research (CHR); and, when the study is conducted under an 
Investigational New Drug Application (IND), to the Food and Drug Administration (FDA) if it meets 
the FDA reporting criteria. 
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis.  The Site Committee will 
review and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s). 
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
Site Committee meetings. The Site Committee will review and discuss the selected toxicity, the 
toxicity grade, and the attribution of relationship of the adverse event to the administration of the 
study drug(s). 
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and 
discussed at DSMC meetings, which take place every six weeks. 
8.7 
Expedited Reporting  
Reporting to the Data and Safety Monitoring Committee 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) or 
to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or qualified 
alternate) within 1 business day of knowledge of the event.  The contact may be by phone or e-
mail. 
Reporting to UCSF Committee on Human Research (Institutional Review Board) 
The Principal Investigator must report events meeting the UCSF CHR definition of “Unanticipated 
Problem” (UP) within 10 business days of his/her awareness of the event. 
 
9.0 STATISTICAL CONSIDERATIONS AND EVALUATION OF RESULTS 
Determination of sample size and accrual rate 
Sample size calculated to be 82 (41 per arm) based on a two-tailed alpha of 0.05, with a beta of 
0.18. With a possible 10% attrition rate, the sample size is increased to 90 (45 per arm). As 
approximately 60 patients undergo mastectomy with immediate tissue expander placement per 
year at Mt. Zion, it is expected that roughly 80% of these women will be enrolled in the study. 
The determination of sample size is based on the assumption that treatment with the leukotriene 
inhibitor zafirlukast will decrease capsule thickness in women with tissue expanders at the time 
of implant exchange. Based on the reported results from literature review, a capsule thickness of 
>2.4mm would be considered undesirable and <1.2mm would be considered desirable. We 
assume the capsule thickness is <1.2mm under zafirlukast as the target efficacy of clinical 
importance for the study population and an efficacy of 50% reduction in capsule contracture 
between two cohorts would be considered clinically meaningful. Under the t-test with a 2-sided 
alpha of 5%, we will need 45 evaluable patients in each cohort to have >80% power to detect an 


 
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improvement in capsule thickness from average 2.4mm (sd 2mm) to average 1.2mm (sd 2mm), 
Specifically, the study hypothesis is defined as: 
H0: µ1 ≥ µ0 (The capsule thickness of the cohort A is greater than capsule thickness of the 
cohort B versus 
H1: µ1 < µ 0 (The capsule thickness of the cohort A is greater than capsule thickness of the 
cohort B.  
9.1 Analyses Plans 
This is an intention to treat analysis. All patients who were randomized will be evaluated. 
Data will be summarized using descriptive statistics by study cohorts. For continuous variables, 
descriptive statistics will include the number of non-missing values, mean, standard deviation, 
median, minimum and maximum. For categorical variables, descriptive statistics will include 
counts and percentages per category by study cohorts.  
Primary analysis: 
The primary objective of the trial is to determine the capsule contracture between the two study 
cohorts and the primary efficacy outcome in this trial is capsule thickness at the time of 
expander-implant exchange. Capsule thickness will be determined by averaging thickness from 
three separate specimens per patient. The capsule thickness will be analyzed by study cohorts, 
and t-tests and descriptive statistics with mean, standard deviation and 95% confidence 
intervals will be used for significance. Missing data will not be imputed. An alpha level of 0.05 
will be considered significant for the primary endpoint. For exploratory analysis, the primary 
endpoint of capsule thickness will be presented as mean ± SEM and evaluated using analysis of 
variance (ANOVA) with factors including study cohort, radiotherapy and length of drug 
treatment. 
 
Secondary Analysis: 
For secondary objectives of the trial, we will determine the level of fibrosis and presence of 
collagen from the biopsy specimens. The level of fibrosis and the presence of collagen will be 
analyzed descriptively as continuous levels and as ordinal levels with mean, standard deviation 
and 95% confidence intervals. The difference in the level of fibrosis and relative presence of 
collagen between study cohorts will be compared using t-tests for significance.  
Similar statistical methods will also be employed to analyze the capsule tissue that is removed 
at the time of expander-implant exchange to determine the level and presence of collagen, 
fibroblasts and myofibroblasts. 
 
Confounding Factors: 
In addition to primary and secondary analysis, we will also determine if there are other 
confounding factors such as variables in time and length treated with zafirlukast and radiation 
therapy by using ANOVA models on capsule thickness. Univariate analysis will be done on 
capsule thickness with all potential factors and selected variables of interest deemed significant 
will be further analyzed for interaction effect. Capsule thickness will be reported per subgroup of 
patients to account for time and radiation variables.   
 
Other analysis:  
An interim analysis is planned at 1 year to assess treatment efficacy in the treatment group 
compared to standard of care group.   
 
 


 
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10.0 STUDY MANAGEMENT 
10.1 
Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable 
regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the Institutional 
Review Board for the protocol, written informed consent form, subject recruitment materials, and 
any other written information to be provided to subjects before any protocol related procedures 
are performed on any subjects.   
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements.  
10.2 
Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) will be reviewed and approved by 
the UCSF CHR (UCSF Institutional Review Board).  Prior to obtaining CHR approval, the protocol 
must be approved by the Helen Diller Family Comprehensive Cancer Center Site Committee and 
by the Protocol Review Committee (PRC).  The initial protocol and all protocol amendments must 
be approved by the IRB prior to implementation.   
10.3 
Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants must 
sign the CHR-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  The 
original signed copy of the consent document must be retained in the medical record or research 
file.  
10.4 
Changes in the Protocol 
Once the protocol has been approved by the UCSF CHR, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by PRC and the CHR prior to implementation.   
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to CHR approval.  In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after implementation.  
The Study Chair and the UCSF study team will be responsible for updating any participating sites. 
10.5 
Handling and Documentation of Clinical Supplies 
The UCSF Principal Investigator will maintain complete records showing the receipt, dispensation, 
return, or other disposition of all investigational drugs.  The date, quantity and batch or code 
number of the drug, and the identification of patients to whom study drug has been dispensed by 
patient number and initials will be included.  The sponsor-investigator will maintain written records 
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The Principal Investigator shall not make the investigational drug available to any individuals other 
than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol. 
10.6 
Case Report Forms (CRFs) 
The Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into OnCore® via standardized CRFs 
in accordance with the CTMS study calendar, using single data entry with a secure access 
account.  The Clinical Research Coordinator (CRC) will complete the CRFs as soon as possible 
upon completion of the study visit; the Investigator will review and approve the completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by UCSF 
personnel.  All source documentation should be kept in separate research folders for each patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate.  
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the database 
will be locked.  Any changes to the data entered into the CRFs after that time can only be made 
by joint written agreement among the Study Chair, the Trial Statistician, and the Protocol Project 
Manager. 
10.7 
Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring entity 
for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-approved Data 
and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all adverse events and 
suspected adverse reactions considered “serious.”  The DSMC will audit study-related activities 
to ensure that the study is conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant results of the DSMC 
audit will be communicated to the IRB and the appropriate regulatory authorities at the time of 
continuing review, or in an expedited fashion, as applicable.   
10.8 
Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by subjects, as well as written records of the disposition of the 
drug when the study ends.   
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. Case 
histories include the case report forms and supporting data (e.g., signed and dated consent forms 
and medical records, such as progress notes of the physician, the individual's hospital chart(s), 
and the nurses' notes. The case history for each individual shall document that informed consent 
was obtained prior to participation in the study. 


 
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Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it is 
being investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and FDA is notified. 
 
11.0 PROTECTION OF HUMAN SUBJECTS 
11.1 
Protection from Unnecessary Harm  
Each clinical site is responsible for protecting all subjects involved in human experimentation. This 
is accomplished through the CHR mechanism and the process of informed consent. The CHR 
reviews all proposed studies involving human experimentation and ensures that the subject’s 
rights and welfare are protected and that the potential benefits and/or the importance of the 
knowledge to be gained outweigh the risks to the individual. The CHR also reviews the informed 
consent document associated with each study in order to ensure that the consent document 
accurately and clearly communicates the nature of the research to be done and its associated 
risks and benefits.  
11.2 Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the individuals 
described in the informed consent document. 
 
 


 
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References 
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causes, biocompatibility, and prophylactic strategies. Med Devices (Auckl). 2013;6:211-218. 
2. Benediktsson K, Perbeck L. Capsular contracture around saline-filled and textured 
subcutaneously-placed implants in irradiated and non-irradiated breast cancer patients: Five 
years of monitoring of a prospective trial. J Plast Reconstr Aesthet Surg. 2006;59(1):27-34. 
3. Rosato RM, Dowden RV. Radiation therapy as a cause of capsular contracture. Ann Plast 
Surg. 1994;32(4):342-345. 
4. Embrey M, Adams EE, Cunningham B, Peters W, Young VL, Carlo GL. A review of the 
literature on the etiology of capsular contracture and a pilot study to determine the outcome of 
capsular contracture interventions. Aesthetic Plast Surg. 1999;23(3):197-206. 
5. Hirsch EM, Seth AK, Fine NA. Capsular contracture after breast reconstruction: A modified 
classification system incorporating the effects of radiation. Plast Reconstr Surg. 
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6. Hvilsom GB, Holmich LR, Steding-Jessen M, et al. Delayed breast implant reconstruction: Is 
radiation therapy associated with capsular contracture or reoperations? Ann Plast Surg. 
2012;68(3):246-252. 
7. Cordeiro PG, Pusic AL, Disa JJ, McCormick B, VanZee K. Irradiation after immediate tissue 
expander/implant breast reconstruction: Outcomes, complications, aesthetic results, and 
satisfaction among 156 patients. Plast Reconstr Surg. 2004;113(3):877-881. 
8. Lam TC, Hsieh F, Boyages J. The effects of postmastectomy adjuvant radiotherapy on 
immediate two-stage prosthetic breast reconstruction: A systematic review. Plast Reconstr 
Surg. 2013;132(3):511-518. 
9. Kronowitz SJ, Robb GL. Radiation therapy and breast reconstruction: A critical review of the 
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10. Wu YC, Jao JC, Yang YT, Wang HS, Wu CH, Chen PC. Preliminary study of non-invasive 
shock wave treatment of capsular contracture after breast implant: Animal model. Conf Proc 
IEEE Eng Med Biol Soc. 2013;2013:1108-1111. 
11. Reichenberger MA, Heimer S, Lass U, et al. Pulsed acoustic cellular expression (PACE) 
reduces capsule formation around silicone implants. Aesthetic Plast Surg. 2014;38(1):244-251. 
12. Fernandes JR, Salinas HM, Broelsch GF, et al. Prevention of capsular contracture with 
photochemical tissue passivation. Plast Reconstr Surg. 2014;133(3):571-577. 
13. Costagliola M, Atiyeh BS, Rampillon F. An innovative procedure for the treatment of primary 
and recurrent capsular contracture (CC) following breast augmentation. Aesthet Surg J. 
2013;33(7):1008-1017. 
14. Bergmann PA, Tamouridis G, Lohmeyer JA, et al. The effect of a bacterial contamination on 
the formation of capsular contracture with polyurethane breast implants in comparison with 
textured silicone implants: An animal study. J Plast Reconstr Aesthet Surg. 2014. 
15. Spear SL, Murphy DK, Allergan Silicone Breast Implant U.S. Core Clinical Study Group. 
Natrelle round silicone breast implants: Core study results at 10 years. Plast Reconstr Surg. 
2014;133(6):1354-1361. 
16. Stevens WG, Nahabedian MY, Calobrace MB, et al. Risk factor analysis for capsular 
contracture: A 5-year sientra study analysis using round, smooth, and textured implants for 
breast augmentation. Plast Reconstr Surg. 2013;132(5):1115-1123. 
17. Park JU, Ham J, Kim S, et al. Alleviation of capsular formations on silicone implants in rats 
using biomembrane-mimicking coatings. Acta Biomater. 2014. 


 
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18. Roca GB, Graf R, da Silva Freitas R, et al. Autologous fat grafting for treatment of breast 
implant capsular contracture: A study in pigs. Aesthet Surg J. 2014;34(5):769-775. 
19. Cheng A, Lakhiani C, Saint-Cyr M. Treatment of capsular contracture using complete 
implant coverage by acellular dermal matrix: A novel technique. Plast Reconstr Surg. 
2013;132(3):519-529. 
20. Moyer HR, Pinell-White X, Losken A. The effect of radiation on acellular dermal matrix and 
capsule formation in breast reconstruction: Clinical outcomes and histologic analysis. Plast 
Reconstr Surg. 2014;133(2):214-221. 
21. Persichetti P, Segreto F, Carotti S, Marangi GF, Tosi D, Morini S. Oestrogen receptor-alpha 
and -beta expression in breast implant capsules: Experimental findings and clinical correlates. J 
Plast Reconstr Aesthet Surg. 2014;67(3):308-315. 
22. Sapountzis S, Kim JH, Francescato Veiga D, Masako Ferreira L. The effect of zafirlukast on 
capsule formation in post-radiation silicone implants. Med Hypotheses. 2012;78(6):787-789. 
23. Yang JD, Kwon OH, Lee JW, et al. The effect of montelukast and antiadhesion barrier 
solution on the capsule formation after insertion of silicone implants in a white rat model. Eur 
Surg Res. 2013;51(3-4):146-155. 
24. Becker H, Springer R. Prevention of capsular contracture. Plast Reconstr Surg. 
1999;103(6):1766-8; discussion 1769-74. 
25. Burkhardt BR. Comparing contracture rates: Probability theory and the unilateral 
contracture. Plast Reconstr Surg. 1984;74(4):527-529. 
26. Schlesinger SL, Desvigne MN, Ellenbogen R, Svehlak S, Heck R. Results of using 
zafirlukast (accolate) and montelukast (singulair) for treatment of capsular contracture. Aesthet 
Surg J. 2003;23(2):101-102. 
27. Henriksen TF, Fryzek JP, Holmich LR, et al. Surgical intervention and capsular contracture 
after breast augmentation: A prospective study of risk factors. Ann Plast Surg. 2005;54(4):343-
351. 
28. Kjoller K, Holmich LR, Jacobsen PH, et al. Epidemiological investigation of local 
complications after cosmetic breast implant surgery in denmark. Ann Plast Surg. 
2002;48(3):229-237. 
29. Macadam SA, Clugston PA, Germann ET. Retrospective case review of capsular 
contracture after two-stage breast reconstruction: Is colonization of the tissue expander pocket 
associated with subsequent implant capsular contracture? Ann Plast Surg. 2004;53(5):420-424. 
30. Schlesinger SL, Ellenbogen R, Desvigne MN, Svehlak S, Heck R. Zafirlukast (accolate): A 
new treatment for capsular contracture. Aesthet Surg J. 2002;22(4):329-336. 
31. D'Andrea F, Nicoletti GF, Grella E, et al. Modification of cysteinyl leukotriene receptor 
expression in capsular contracture: Preliminary results. Ann Plast Surg. 2007;58(2):212-214. 
32. Grella E, Grella R, Siniscalco D, et al. Modification of cysteinyl leukotriene receptors 
expression in capsular contracture: Follow-up study and definitive results. Ann Plast Surg. 
2009;63(2):206-208. 
33. Riccioni G, Bucciarelli T, Mancini B, Di Ilio C, D'Orazio N. Antileukotriene drugs: Clinical 
application, effectiveness and safety. Curr Med Chem. 2007;14(18):1966-1977. 
34. Bastos EM, Neto MS, Alves MT, et al. Histologic analysis of zafirlukast's effect on capsule 
formation around silicone implants. Aesthetic Plast Surg. 2007;31(5):559-565. 
35. Spano A, Palmieri B, Taidelli TP, Nava MB. Reduction of capsular thickness around silicone 
breast implants by zafirlukast in rats. Eur Surg Res. 2008;41(1):8-14. 


 
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36. Mazzocchi M, Dessy LA, Alfano C, Scuderi N. Effects of zafirlukast on capsular contracture: 
Long-term results. Int J Immunopathol Pharmacol. 2012;25(4):935-944. 
37. Huang CK, Handel N. Effects of singulair (montelukast) treatment for capsular contracture. 
Aesthet Surg J. 2010;30(3):404-408. 
38. Scuderi N, Mazzocchi M, Rubino C. Effects of zafirlukast on capsular contracture: Controlled 
study measuring the mammary compliance. Int J Immunopathol Pharmacol. 2007;20(3):577-
584. 
39. Scuderi N, Mazzocchi M, Fioramonti P, Bistoni G. The effects of zafirlukast on capsular 
contracture: Preliminary report. Aesthetic Plast Surg. 2006;30(5):513-520. 
40. Reid RR, Greve SD, Casas LA. The effect of zafirlukast (accolate) on early capsular 
contracture in the primary augmentation patient: A pilot study. Aesthet Surg J. 2005;25(1):26- 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX 1: DATA AND SAFETY MONITORING PLAN FOR A PHASE 2 OR 3 
INSTITUTIONAL STUDY 
1.         Oversight and Monitoring Plan 
 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and 
Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and 
subject safety for all HDFCCC institutional clinical studies.  A summary of DSMC 
activities for this study includes:  
 
 Review of patient data.  
 Review of serious adverse events. 
 Auditing every six months (depending on study accrual). 
 Minimum of a yearly regulatory audit. 
 
2. 
Monitoring and Reporting Guidelines 
 
Investigators will conduct continuous review of data and patient safety and discuss each 
patient’s treatment at monthly site committee meetings.  These discussions are 
documented in the site committee meeting minutes.  The discussion will include the 
number of patients, significant toxicities in accordance with the protocol, and observed 
responses.   
 
All institutional Phase II and III studies are designated with a moderate risk assessment 
(see Appendix H).   The data is audited twice per year with twenty percent of the 
patients monitored (or at least three patients if the calculated value is less than three).   
 
3. 
Review and Oversight Requirements 
 
 
3.1 
Adverse Event Monitoring  
 
All Grade 3-5 Adverse Events (AEs), whether or not considered to be expected 
or unexpected and whether or not considered to be associated with the use of 
the study drug, will be entered into OnCore®, UCSF’s Clinical Trial Management 
System.   
 
Adverse Events are graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) (version 4.03) as developed and revised by the 
Common Therapy Evaluation Program (CTEP) of the National Cancer Institute.  
Adverse events are further given an assignment of attribution or relationship to 
treatment or medical procedure.  Attribution categories are: 
 
• 
Definite – The adverse event is clearly related to the investigational 
agent(s) or medical procedure. 
• 
Probable – The adverse event is likely related to the investigational 
agent(s) or medical procedure. 
• 
Possible – The adverse event may be related to the investigational 
agent(s) or medical procedure. 


 
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• 
Unlikely – The adverse event is doubtfully related to the investigational 
agent(s) or medical procedure. 
• 
Unrelated – the adverse event is clearly not related to the investigational 
agent(s) or medical procedure. 
 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a 
monthly basis at the Site Committee meetings.  The Site Committee will review 
and discuss the selected toxicity, the toxicity grade, and the attribution of 
relationship of the adverse event to the administration of the study drug(s). 
 
3.2 
Serious Adverse Event Reporting  
 
By definition, an adverse event is defined as a serious adverse event (SAE) 
according to the following criteria: 
 
• 
Death. 
• 
Life-threatening (i.e. results in an immediate risk of death). 
• 
Requires inpatient hospitalization or prolongation of existing 
hospitalization, 
• 
Permanent or significant disability/incapacity 
• 
Gives rise to a congenital anomaly/birth defect, or cancer, or any 
experience that suggests a significant hazard, contraindication, side effect, 
or precaution that may require medical or surgical intervention to prevent 
one of the outcomes listed above.  
• 
Event occurring in a gene therapy study. 
• 
Event that changes the risk/benefit ratio of a study. 
• 
Any other event the Principal Investigator judges to be serious or which 
would suggest a significant hazard, contraindication, side effect, or 
precaution. 
 
Serious Adverse Event reporting will be in accordance with the UCSF IRB 
Regulations and Code of Federal Regulation Title 21 Part 312.32.  The SAE will 
be reported on a Med Watch form.   
 
UCSF IRB website for guidance in reporting serious adverse events: 
 
https://irb.ucsf.edu/adverse-event  
FDA website for guidance in reporting serious adverse events: 
 
www.fda.gov/Safety/MedWatch/HowToReport/default.htm 
 
Med Watch forms and information: 
 
www.fda.gov/medwatch/getforms.htm 
 
All serious adverse events are entered into OnCore®, as well as submitted to the 
IRB (per IRB guidelines) via iMedRIS®.  The SAEs are reviewed and monitored 
by the Data and Safety Monitoring Committee on an ongoing basis and 


 
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discussed at DSMC meetings, which take place every six weeks.  The date the 
SAE is sent to all required reporting agencies will be documented in OnCore®.  
 
If the SAE involves a subject death, and is determined to be possibly, probably or 
definitely related to the investigational drug or any research related procedure, 
the event must be reported to the DSMC Chair or Vice Chair within 1 business 
day.   
 
The reporting procedure is by communication via phone or in person with written 
documentation of the one-on-one communication via e-mail, with a copy of the e-
mail to the DSMC Manager. 
 
3.3 
Review of Adverse Event Rates 
 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate 
reported in the Investigator Brochure or package insert) is noted in the study, the 
Principal Investigator will notify the DSMC at the time the increased rate is 
identified.  The report will indicate if the incidence of adverse events observed in 
the study is above the range stated in the Investigator Brochure or package 
insert. 
 
If at any time the Investigator stops enrollment or stops the study due to safety 
issues, the DSMC Chair and DSMC Manager must be notified within 1 business 
day via e-mail.  and the IRB must be notified within 10 business days via an iRIS 
Reporting Form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

ICF_000.pdf: 
IRB NUMBER: 15-18324
IRB APPROVAL DATE: 07/18/2018
IRB EXPIRATION DATE: 02/12/2019
Main ICF 06-13-2018
Page 1 of 9
CC# 15754
Pamela Munster, MD
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
CC#15754: Breast capsular contracture following post-mastectomy reconstruction 
in women treated with the leukotriene inhibitor zafirlukast: A Phase II Trial 
This is a clinical trial, a type of research study. Your study doctors, 
or one of their associates from the UCSF Helen Diller Family 
Comprehensive Cancer Center, will explain the clinical trial to you. 
Clinical trials include only people who choose to take part. Please take your time to make your 
decision about participating. You may discuss your decision with your family and friends and 
with your health care team. If you have any questions, you may ask your study doctor. 
You are being asked to take part in this study because you will be undergoing mastectomy with 
immediate tissue-expander reconstruction. 
Why is this study being done? 
The purpose of this study is to find out if the drug zafirlukast (Accolate™) is safe to use in post- 
mastectomy patients and if it has beneficial effects in reducing capsular contracture. A capsule 
around a breast implant is a naturally occurring tissue that often causes no problems. However, if 
that capsule contracts or thickens, it can squeeze your implant. This contracture is what will 
cause pain, shifting, distortion, and hardening of the reconstructed breast. 
Zafirlukast is in a class of medications called leukotriene receptor antagonists. It works by 
blocking the action of certain natural substances that cause swelling and tightening of the 
airways. It is currently FDA approved to prevent asthma symptoms. However, it has not been 
approved by the US Food and Drug Administration (FDA) for the treatment of people with 
breast capsular contracture. 
UCSF’s Center for BRCA Research and the National Center of Excellence in Women’s Health 
(NCOEWH) are providing funding to the investigator and UCSF to conduct the study. 
How many people will take part in this study? 
About 90 people who will be undergoing mastectomy with immediate tissue-expander 
reconstruction will take part in this study at UCSF. There will be two study groups. There will be 
45 people in each group; one group will be followed with standard of care, and the other group 
will be given zafirlukast in addition to their regular care. 
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What will happen if I take part and how long will I be in this research study? 
If you give your consent to be in this study by signing this form, you will have tests and 
procedures (called “screening”) done. These are done to reduce the risks of taking part in this 
study and to make sure it is okay for you to be in the study. 
It is possible that after these tests are reviewed, you will not be able to be in the study. There may 
be other reasons why you cannot be in this study. These reasons will be discussed with you by 
your study doctor or the clinic staff. 
 
Before you begin the main part of the study: 
You will need to have the following exams, tests or procedures within 28 days prior to the day of 
your surgery to find out if you can be in the main part of the study. These exams, tests or 
procedures are part of regular cancer care and may be done even if you do not join the study. If 
you have had some of them recently, they may not need to be repeated. This will be up to your 
study doctor. This clinic visit may take approximately 2 hours. 
 
<0000> Medical history 
<0000> Physical exam: Including your height and weight, and vital signs 
<0000> Blood draw: Approximately 1 tablespoon of blood will be drawn for: 
o Routine safety tests 
<0000> Pregnancy test: A blood or urine pregnancy test will be performed if you are of child- 
bearing age. 
<0000> Review of your medications (both prescription and over-the-counter) and side effects 
 
 
During the main part of the study: 
 
You will be randomized into one of two groups: 
 
Group 1: Treatment with zafirlukast and standard of care 
Group 2: Standard of care alone 
 
Participants assigned to Group 1 will begin treatment with zafirlukast on post-operative day one 
(up to day 4) following placement of tissue expander(s), after you are determined safe from a 
surgical recovery standpoint. If you are in Group 1, you will take zafirlukast twice per day 
until you have completed expansion of the tissue expander. Your last dose of zafirlukast will be 
administered the day prior to expander implant exchange. 
 
You should only take the study treatment as instructed and do nothing else with it. Each dose 
should be taken 1 hour before a meal or 2 hours after a meal with a large glass of water. 
 
 
 
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If the screening exams, tests and procedures show that you can be in the main part of the study, 
and you choose to take part, then you will need the following tests and procedures. The clinic 
visits may take about 1 hour. 
 
Day 8-21 (week 2) 
<0000> Physical exam including your height and weight, and vital signs 
<0000> Blood draw: Approximately 1 tablespoon of blood will be drawn for: 
o Routine safety tests 
<0000> Review of your medications (both prescription and over-the-counter) and side effects 
 
Day 28-42 (week 5) 
<0000> Physical exam including your height and weight, and vital signs 
<0000> Blood draw: Approximately 2 to 3 tablespoons of blood will be drawn for: 
o Routine safety tests 
o Liver function tests (if you are in Group 1) 
<0000> Review of your medications (both prescription and over-the-counter) and side effects 
 
Day 70-84 (week 11) 
<0000> Physical exam including your height and weight, and vital signs 
<0000> Blood draw: Approximately 1 tablespoon of blood will be drawn for: 
o Routine safety tests 
<0000> Review of your medications (both prescription and over-the-counter) and side effects 
 
Day 112-126 (week 17) (If needed) 
<0000> Physical exam including your height and weight, and vital signs 
<0000> Blood draw: Approximately 1 tablespoon of blood will be drawn for: 
o Routine safety tests 
<0000> Review of your medications (both prescription and over-the-counter) and side effects 
 
Expander Implant Exchange 
<0000> Tissue collection of capsule (performed at the time of expander-implant exchange): As 
part of this study, we will obtain a small piece of tissue from the capsule during your 
surgery. This will be done during implant exchange. The tissue collected is used to us 
determine if zafirlukast can reduce the thickness and scarring of the capsule tissue 
compared to standard of care. 
 
End of Treatment 
<0000> Medical history 
<0000> Physical exam including your height and weight, and vital signs 
<0000> Blood draw: Approximately 2 to 3 tablespoons of blood will be drawn for: 
o Routine safety tests 
o Liver function tests (if you are in Group 1) 
<0000> Review of your medications (both prescription and over-the-counter) and side effects 
 
 
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Follow-up Visits 
<0000> Physical exam including your height and weight, and vital signs 
 
You will be followed for two years after reconstruction. After implant exchange, we would like 
to see you every 2 weeks for the first month, then every month for the next 4 months, and then 
every 6 months for the remainder of the two years. If you stop receiving treatment early, then we 
would like to follow you as per routine care, which is monthly for the first six months and then 
every six months for a total of two years. 
 
Study location: All study procedures will be done at the UCSF Cancer Center. 
 
How long will I be in the study? 
For participants in group 1 receiving zafirlukast, you will begin treatment with zafirlukast on 
post-operative day one (up to day 4) following placement of the tissue expander(s), until you 
have completed expansion. For both groups, after you have had your expander fill, the study 
doctor will ask you to visit the office for an End of Treatment visit approximately 14 days after 
surgery. In addition, your study doctor or staff will follow-up with you for 2 years after your 
reconstruction. If you do not want the study doctor or staff to contact you, you will need to 
withdraw your consent from this follow-up. 
 
Can I stop being in the study? 
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop. He or she will tell you how to stop your participation safely. 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
zafirlukast can be evaluated by your doctor. Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you. 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped. 
 
What side effects or risks can I expect from being in the study? 
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don't know all the side effects that may happen. 
Side effects may be mild or very serious. Your health care team may give you medicines to help 
lessen side effects. Many side effects go away soon after you stop taking zafirlukast. In some 
cases, side effects can be serious, long lasting, or may never go away. There also is a risk of 
death. You should talk to your study doctor about any side effects you experience while taking 
part in the study. 
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Risks and side effects related to zafirlukast include those which are: 
Common (>10%) 
<0000> Headache 
 
Less common (1-10%) 
<0000> Infection 
<0000> Nausea 
<0000> Diarrhea 
<0000> Pain – general pain, abdominal pain, back pain 
<0000> Physical weakness or lack of energy (Asthenia) 
<0000> Dizziness 
<0000> Muscle pain (Myalgia) 
<0000> Fever 
<0000> Vomiting 
<0000> Increased enzymes (ALT) in the liver, which may indicate the liver is not working properly 
<0000> Indigestion (Dyspepsia) 
 
In rare cases, the following side-effects have also been seen in patients on zafirlukast: 
<0000> High levels of white blood cells in the blood and lungs 
<0000> Inflammation of the blood vessels  
<0000> Difficulty sleeping 
<0000> Depression 
<0000> Rash and/or swelling of the skin 
<0000> Bleeding 
<0000> Bruising 
<0000> Swelling of the arms and/or legs 
<0000> Painful joints 
<0000> Itchy skin 
 
Risks related to study procedures 
 
<0000> Blood drawing (venipuncture) risks: Drawing blood may cause temporary discomfort 
from the needle stick, bruising, infection, and fainting. 
 
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<0000> Tissue collection of capsule risks: The capsule around the tissue expander is usually removed 
at the time of expander-implant exchange, so there are no separate risks to this portion of 
the study. However, the surgery for expander-implant exchange does have the general 
surgical risks, including pain, bleeding, and infection. We check your laboratory values 
before surgery to make sure that the procedure is as safe as possible and to minimize your 
chance of having a complication. Other potential risks will be described to you and 
discussed with your surgeons who conduct these operations. 
<0000> Reproductive risks: You should not become pregnant while on this study because the drugs 
in this study may affect an unborn baby.  Women should not breastfeed a baby while on this 
study. It is important to understand that you may need to use birth control while on this study. 
Check with you study doctor about what kind of birth control methods to use and how long to 
use them. Some methods might not be approved for use in this study. If you become pregnant 
while on this study, you should inform the study doctor immediately. 
<0000> Randomization risks: You will be assigned to a treatment program by chance, and the 
treatment you receive may prove to be less effective or to have more side effects than the 
other study treatment(s) or other available treatments. 
 
<0000> Unknown Risks: The experimental treatments may have side effects that no one knows 
about yet. The researchers will let you know if they learn anything that might make you 
change your mind about participating in the study. 
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
Taking part in this study may or may not make your health better. While doctors hope zafirlukast 
will reduce capsular contracture compared to the usual treatment, there is no proof of this. We do 
know that the information from this study will help doctors learn more about zafirlukast as a 
treatment for capsular contracture. This information could help future cancer patients. 
 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 
• 
Getting treatment or care for your cancer without being in a study. 
• 
Taking part in another study. 
• 
Getting no treatment. 
 
Please talk to your doctor about your choices before deciding if you will take part in this study. 
 
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How will information about me be kept confidential? 
 
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total privacy. Some 
information from your medical records will be collected and used for this study. If you do not 
have a UCSF medical record, one will be created for you. Your signed consent form and some 
of your research tests will be added to your UCSF medical record. Therefore, people involved 
with your future care and insurance may become aware of your participation and of any 
information added to your medical record as a result of your participation. Study tests that are 
performed by research labs, and information gathered directly from you by the researchers will 
be part of your research records but will not be added to your medical record. Your personal 
information may be given out if required by law. If information from this study is published or 
presented at scientific meetings, your name and other personal information will not be used. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
<0000> The University of California 
<0000> The National Cancer Institute (NCI) and other government agencies, e.g., the Food and 
Drug Administration (FDA), involved in keeping research safe for people. 
 
 
What are the costs of taking part in this study? 
UCSF is supplying zafirlukast at no cost to you. 
 
Two types of procedures will be done during this study. Some are part of your standard medical 
care and others are only for research. You or your insurer will be billed for the standard medical 
care. You will be responsible for your co-pays, deductibles, and any other charges that your 
insurer will not pay. Any procedures done only for research will not be charged to you or your 
insurer. There is a possibility that your insurer may not cover standard medical care costs 
because you are in a research study or because you are receiving medical services out of 
network. 
Before you agree to be in this study, you may want to contact your healthcare payer/insurer to see 
if your plan will cover the costs required as part of your participation. You may request more 
information about the costs of participating in this study and discuss this with the study team. If 
you have any questions, your doctor and the study team will be able to provide you with answers. 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site. 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
Will I be paid for taking part in this study? 
You will not be paid for taking part in this study. 
 
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What happens if I am injured because I took part in this study? 
It is important that you tell your study doctors, 
. or Pamela Munster, M.D., if 
you feel that you have been injured because of taking part in this study. You can tell the doctor in 
person or call them
. 
Treatment and Compensation for Injury: If you are injured as a result of being in this 
study, the University of California will provide necessary medical treatment. The costs 
of the treatment may be billed to you or your insurer just like any other medical costs, or 
covered by the University of California or the study sponsor, depending on a number 
of factors. The University and the study sponsor do not normally provide any other form 
of compensation for injury. For further information about this, you may call the office of 
the Committee on Human Research at 
. 
 
What are my rights if I take part in this study? 
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from our institution. 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form. 
 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions, concerns, or complaints you have about 
this study. Contact your study doctor 
 or Pamela Munster, M.D. 
 
. 
 
If you wish to ask questions about the study or your rights as a research participant to someone 
other than the researchers or if you wish to voice any problems or concerns you may have about 
the study, please call the Office of the Committee on Human Research at 
. 
 
ClinicalTrials.gov is a website that provides information about clinical trials. A description of 
this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
 
 
 
 
 
 
 
 
 
 
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CONSENT 
 
You have been given copies of this consent form and the Experimental Subject's Bill of Rights to 
keep. 
 
You will be asked to sign a separate form authorizing access, use, creation, or disclosure of 
health information about you. 
 
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to which 
you are otherwise entitled. 
 
 
If you wish to participate in this study, you should sign below. 
 
 
 
 
 
Date 
Participant's Signature for Consent 
 
 
 
 
 
Date 
Person Obtaining Consent 
 
 
 
 
 
Date 
Witness – Only required if the participant is a non-English speaker
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