A Phase 2 Study of Zafirlukast for the Treatment of Tumor-marker Only Relapsed Ovarian Cancer
Phase: PHASE2
Conditions: Ovarian Cancer
Sponsor: Beth Israel Deaconess Medical Center

1
DF/HCC Protocol #: 19-814
TITLE: A phase 2 study of zafirlukast for the treatment of tumor-marker only relapsed ovarian
cancer
Coordinating Center:
Beth Israel Deaconess Medical Center
*Principal Investigator (PI):
Rushad Patell, M.D.
Beth Israel Deaconess Medical Center
rpatell@bidmc.harvard.edu
Other Investigators:
Brian Carney, M.D.
Beth Israel Deaconess Medical Center
bjcarney@bidmc.harvard.edu
Meghan Shea, M.D.
Beth Israel Deaconess Medical Center
mshea4@bidmc.harvard.edu
Rushad Patell, M.D.
Beth Israel Deaconess Medical Center
rpatell@bidmc.harvard.edu
Mary Buss, M.D.
Beth Israel Deaconess Medical Center
mbuss@bidmc.harvard.edu
Statistician:
Study Coordinator:
Donna Neuberg
Amanda Pinson
Dana Farber Cancer Institute
Beth Israel Deaconess Medical Center
neuberg@jimmy.harvard.edu
apinson@bidmc.harvard.edu
Responsible Research Nurse:
Caitlin Smith, RN1
Beth Israel Deaconess Medical Center
Csmith38@bidmc.harvard.edu
Other Agent(s): Zafirlukast [commercial]

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IND #: Exempt
IND Sponsor: Rushad Patell, M.D.
Protocol Type / Version # / Version Date:
Amendment/Version#6/Date: 12/21/22
SCHEMA

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TABLE OF CONTENTS
SCHEMA
......................................................................................................................2
1.
OBJECTIVES5
1.1
Study Design............................................................................................................5
1.1
Primary Objective....................................................................................................5
1.2
Key Secondary Objective ........................................................................................5
1.3
Exploratory Objectives ............................................................................................5
2.
BACKGROUND .................................................................................................................5
2.1
Study Disease(s).......................................................................................................5
2.2
IND Agent................................................................................................................8
2.3
Rationale ..................................................................................................................9
3.
PARTICIPANT SELECTION.............................................................................................9
3.1
Eligibility Criteria....................................................................................................9
3.2
Exclusion Criteria ..................................................................................................10
3.3
Inclusion of Women and Minorities ......................................................................12
4.
registration procedures.......................................................................................................12
4.1
General Guidelines for DF/HCC Institutions ........................................................12
1.1
Registration Process for DF/HCC Institutions.......................................................12
1.
TREATMENT PLAN........................................................................................................12
1.1
Treatment Regimen................................................................................................12
1.2
Pre-Treatment Criteria ...........................................................................................13
1.3
Agent Administration.............................................................................................13
1.4
General Concomitant Medication and Supportive Care Guidelines......................13
1.5
Criteria for Taking a Participant Off Protocol Therapy.........................................14
1.6
Duration of Follow Up...........................................................................................14
1.7
Criteria for Taking a Participant Off Study ...........................................................14
2.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................15
3.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ............................15
3.1
Expected Toxicities................................................................................................16
3.2
Adverse Event Characteristics...............................................................................16
3.3
Adverse Event Reporting.......................................................................................17
3.4
Reporting to Hospital Risk Management...............................................................17
3.5
Routine Adverse Event Reporting .........................................................................17
4.
PHARMACEUTICAL INFORMATION..........................................................................17
4.1
Zafirlukast..............................................................................................................17
5.
CORRELATIVE STUDIES ..............................................................................................19

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5.1
Laboratory Correlative Studies..............................................................................19
6.
STUDY CALENDAR .......................................................................................................20
7.
MEASUREMENT OF EFFECT .......................................................................................23
7.1
Antitumor Effect....................................................................................................23
7.2
Other Response Parameters ...................................................................................23
8.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................23
8.1
Data Reporting.......................................................................................................23
8.2
Data Safety Monitoring..........................................................................................23
9.
STATISTICAL CONSIDERATIONS...............................................................................24
9.1
Study Design/Endpoints ........................................................................................24
9.2
Sample Size, Accrual Rate and Study Duration ....................................................24
9.3
Interim Monitoring Plan ........................................................................................25
9.4
Analysis of Primary Endpoints..............................................................................25
9.5
Analysis of Key Secondary Endpoint....................................................................25
9.6
Analysis of Exploratory Objectives.......................................................................25
9.7
Reporting and Exclusions ......................................................................................25
10.
PUBLICATION PLAN .....................................................................................................25
REFERENCES
....................................................................................................................27
APPENDIX A
PERFORMANCE STATUS CRITERIA ..................................................32
APPENDIX B
INFORMATION ON POSSIBLE DRUG
INTERACTIONS ..............................................................................................................33

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1.
OBJECTIVES
1.1
Study Design
This is a single-arm Simon two-stage phase 2 clinical trial to evaluate the dual antithrombotic
and antineoplastic activity of zafirlukast in tumor marker-only relapsed ovarian cancer.
1.1
Primary Objective
The primary objective is to determine efficacy of zafirlukast in terms of CA-125 response rate
per Gynecologic Cancer Intergroup (GCIG) criteria.
1.2
Key Secondary Objective
Assess changes in CA-125 doubling time in the 3 months prior to enrollment and
following initiation of zafirlukast
1.3
Exploratory Objectives

Measure changes PDI and ERp57 inhibitory activity in plasma

Measure changes in platelet-dependent thrombin generation

Determine progression free survival (PFS)

Assess the incidence of venous thromboembolism

Assess incidence of major hemorrhage and clinically relevant non-major bleeding
2.
BACKGROUND
2.1
Study Disease(s)
Ovarian Cancer
Epithelial ovarian cancer is the seventh most common malignancy among women with 230,000
women diagnosed annually. The rate of survival is poor, with an approximately 50% survival at 5
years following diagnosis [1]. Debulking surgery is considered front-line treatment for women
with ovarian cancer with neoadjuvant and/or adjuvant chemotherapy administered for more
advanced disease. Intravenous administration of carboplatin and paclitaxel is the standard first-
line chemotherapy for advanced ovarian cancer. Two randomized trials demonstrated improved
progression free survival with the addition of maintenance bevacizumab in high-risk stage III
disease without improved overall survival [2, 3], although more recent work has called these
findings into question [4]. More recently, poly ADP ribose polymerase (PARP) inhibitors have
shown improved progression free survival as maintenance therapy in the first line setting for all
patients, though patients with BRCA-mutated ovarian cancer gained the most benefit[5, 6]. PARP
inhibitors are approved for all patients after platinum-based chemotherapy with a platinum
sensitive relapse [7-9], and those patients with BRCA-mutated ovarian cancer have improved
overall survival with this approach[10],

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Monitoring for recurrence of ovarian cancer following initial therapy includes serial measurement
of the tumor marker CA-125. Tumor marker-only relapse is defined as the absence of recurrent
disease by imaging or symptoms along with a rising CA-125, i.e. CA-125 more than twice the
upper limit of normal (35 U/mL) in the setting of a normal baseline CA-125 levels or CA-125
greater than twice the nadir count on two successive measurements for CA-125 values that remain
above baseline. A randomized study evaluated the benefit of early versus delayed chemotherapy
in patients with tumor marker-only relapse of ovarian cancer [11]. Early treatment was started
within 28 days of CA-125 increase while delayed treatment was started in response to clinical or
symptomatic relapse. There was no difference in overall survival between the arms. In light of
these results, observation is currently standard-of-care for tumor marker-only relapsed ovarian
cancer. For patients desiring systemic treatment, endocrine therapy is typically preferred given
reduced toxicity compared to cytotoxic chemotherapy. This approach has been observed to result
in a 17% response rate in CA-125 per GCIG criteria in patients with estrogen receptor-positive
ovarian cancer [12]. However, it has not been shown to improve progression-free or overall
survival compared to observation in this population.
Venous Thromboembolism and Ovarian Cancer
Venous thromboembolism (VTE) is commonly observed in cancer patients. It is a leading cause
of morbidity and is associated with increased mortality in this population [13, 14]. In high-risk
cancer patients especially where protocol-driven radiographic monitoring for deep vein thrombosis
is implemented, the incidence of VTE within the initial few months of chemotherapy often exceeds
15% [15-17]. Ovarian cancer is among the most prothrombotic malignancies. According to
Medicare discharge data, ovarian cancer was associated with the highest incidence of cancer-
associated VTE [18]. Similarly, in large registries from California (528,693 adults) and the
Netherlands (66,329 adults), the incidence of VTE in ovarian cancer patients exceeded essentially
that of all other malignancies including pancreatic cancer and malignant glioma [19, 20]. Patients
with advanced malignancies are also at an increased risk of bleeding [21]. Notably, apixaban, a
direct oral anticoagulant, was recently shown to be efficacious in reducing VTE in cancer patients
but were also associated with a doubling in rate of major hemorrhage [22]. Developing
antithrombotics that reduce the incidence of VTE without increasing the risk of major hemorrhage
would broadly impact the care of patients with advanced malignancy.
Protein Disulfide Isomerase
PDI is a member of a large family of thiol isomerase/disulfide oxidoreductases exist in humans
[23]. These thiol isomerases are generally capable of oxidation reduction and isomerization
reactions. Recent studies have determined that a subset of thiol isomerases, including PDI, ERp5,
ERp57, and ERp72 have extracellular activity, which play important roles in both arterial and
venous thrombosis as well as in a variety of cancers. PDI, ERp5, ERp57, and ERp72 are secreted

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by platelets and reattach to the plasma membrane, where they function as extracellular
oxidoreductases [24-27]. They are required for thrombus formation and fibrin formation [26, 28-
31], as well as for platelet aggregation, dense granule secretion, fibrinogen binding, and calcium
mobilization [25].
Thiol isomerases are also upregulated in many distinct cancer types, including ovarian, prostate,
lung, melanoma, lymphoma, and glioma, while inhibition of PDI is cytotoxic in ovarian cancer
and multiple myeloma cell lines [29, 32]. Increased levels of thiol isomerases have been positively
correlated increased oncogenic transformation [33], gene transcription [34], metastasis [35], and
even promoting resistance to chemotherapy [36] and radiation [37]. Similar to its role in platelets,
thiol isomerases can also be secreted from tumor cells and perform functions on the cell surface
[38].
In the context of thromboembolic disease, PDI is released from activated platelets and endothelial
cells and is thought to modulate through oxidation, reduction, or isomerization a number of
extracellular substrates, the best characterized being vitronectin [29, 39-43]. Targeting PDI activity
with blocking antibodies or small molecules prevents both platelet accumulation and fibrin
generation at the site of vascular injury in several distinct animal models of thrombosis [28, 30,
39, 44, 45].
Several
small
molecule
inhibitors
of
PDI
have
been
identified.
In
a
pharmacokinetic/pharmacodynamics study conducted in healthy volunteers, isoquercetin inhibited
PDI activity in plasma and reduced platelet-dependent thrombin generation in a dose and time-
dependent manner [41]. In a recently completed a phase II clinical trial in advanced cancer patients
demonstrating that daily isoquercetin significantly reduced coagulation markers of the thrombosis
(i.e. D-Dimer and thrombin generation) and prevented the development of VTE (Figure 1).
Isoquercetin was well tolerated without any attributable significant adverse events reported and no
major hemorrhages observed [46].
Figure 1. The PDI inhibitor, isoquercetin, reduces the hypercoagulability of advanced malignancy. Patients with advanced lung, colorectal,
and pancreatic cancer were treated with isoquercetin 1000 mg daily for 2 months. Shown in figure are the waterfall plots for comparison
with baseline measurements. A) D-dimer plasma concentrations decreased by a median of 20% equating to a median decrease of 206
ng/ml fibrinogen equivalent units (P<0.001). B) Median decrease of circulating soluble P-selectin was 58% (P<0.001) and C) platelet-
dependent thrombin generation decreased by 55% (P=0.006).

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Zafirlukast was recently identified through a small molecule screen as an inhibitor of PDI along
with other thiol isomerases including ERp5, ERp57, ERp72. Similar to isoquercetin, zafirlukast
reduces platelet aggregation and fibrin generation in a dose-dependent manner as shown in Figure
2.
Figure 2 – (A) Washed human platelets were incubated with ZFL or vehicle for 5 minutes prior to stimulation with
collagen for 180 seconds in an optical aggregometer. (B) Data were normalized to vehicle and % inhibition of
aggregation (mean + SEM) calculated, n=12. (C) Fibrinogen binding was measured by flow cytometry. Platelets were
incubated with vehicle or ZFL (0.6- 20µM) for 5 minutes prior to stimulation with 0.25µg/mL CRP-XL n=6. Graphs
represent mean ± SEM. Data was analyzed by one-way ANOVA *p<0.05, **p<0.01, ***p<0.005.
The expression of PDI and other thiol isomerases are increased in ovarian cancer and increased
PDI expression has been associated with disease progression and shortened survival [47]. Small
molecule inhibitors of PDI such as propynoic acid carbomyl methyl amides (PACMA) have been
shown to reduce tumor growth in human ovarian cancer mouse xenografts [48]. Zafirlukast inhibits
ovarian cancer cell growth as shown in Figure 3 in a dose-dependent manner.
Updated results of trial in women with tumor-marker only relapsed ovarian cancer:
We enrolled a total of four women who received zafirlukast 40 mg twice daily and performed
serial CA-125 measurements to assess for tumor response. None of the women demonstrated a
decrease in CA-125 following the initiation of zafirlukast. However, in all 4 women the rate of
rise of CA-125 was reduced following treatment with zafirulast (Figure 4). Accordingly, the mean
change in CA-125 was 0.036 U/mL per day prior to treatment compared with 0.015 U/mL per day
following zafirlukast (paired t-test p=0.026). This equated to a mean CA-125 doubling time of
29.8 days in the weeks prior to treatment compared with a mean doubling time of 85.69 days
following treatment. There were no grade 3 or higher toxicities observed on study. As shown in
Figure 4B, there was only modest inhibition of PDI activity in plasma as measured by Di-eosin-
Figure 3 – The effect of Zafirlukast on cancer
cell viability was determined by the Prestoblue
assay. Cells were seeded at 3,000 cells/well in
a 96 well plate and drug treated 24 hours later.
After a 24 hour incubation, cell viability was
determined per the manufacturer’s instructions.

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GSSG assay. In the study subject who demonstrated the greatest PDI inhibition there was the CA-
125 doubling was most pronounced. These data suggest that higher doses of zafirlukast may
provide additional PDI inhibitory activity and further inhibit ovarian cancer cell growth.
2.2
IND Agent
2.2.1
Zafirlukast
Zafirlukast (Accolate) is FDA approved for the treatment of asthma in children and adults. Its
effectiveness in asthma is attributed to its activity as a competitive receptor antagonist to
leukotriene D4 and E4[49].
Zafirlukast is rapidly absorbed following oral administration and 99% is bound to plasma protein
in circulation. Zafirlukast is extensively metabolized in the liver. Hydroxylated metabolites are
excreted in the feces and formed through cytochrome P450 2C9 pathway. In patients with biopsy-
proven cirrhosis, the clearance of zafirlukast is 50-60% slower compared to healthy subjects. There
is no apparent effect on pharmacokinetic profile in renal insufficiency.
While the FDA approved dose of zafirlukast is 20 mg twice daily, doses up to 80 mg twice daily
appear well tolerated. In a randomized clinical study with over 360 patients to assess asthma
response, observed side effects were similar in cohort receiving zafirlukast 80 mg twice daily
compared to placebo for 6 weeks [50]. Serious adverse events were reported in two patients
receiving zafirlukast (e.g. detached retina and exacerbation of asthma). Two patients developed
transient increase in liver transaminases which resolved in one patient despite continuing therapy
and another after withdrawal of treatment.
Following oral ingestion of zafirlukast 40 mg the peak plasma concentration is ~3 M which
approximates the IC50 for both inhibition of cell viability, ex vivo platelet inhibition and PDI
inhibitory activity [51].
2.3
Rationale
Pre
Post
0
50
100
150
200
Zafirlukast
Doubling Time (Days)
Day 0
Day 28
Day 0
Day 28
Day 0
Day 28
Day 0
Day 28
0.0
0.5
1.0
1.5
Di-eosin-GSSG
(RFU, normalized)
Patient 1
Patient 2
Patient 3
Patient 4
Figure 4. CA-125 doubling time following zafirlukast in women with ovarian cancer. A)
Comparison of CA-125 doubling time before and after start of zafirlukast. B) Inhibition of
plasma PDI activity before and 28 days following initiation of zafirlukast.

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The rationale to evaluate zafirluast as a dual phase 2 study in this population are several-fold. First,
zafirlukast and other PDI inhibitors have demonstrated anti-tumor activity in preclinical ovarian
cancer models [48]. PDI and ERp57 are both upregulated in ovarian cancer and correlate with
tumor progression [47]. Women with ovarian cancer following surgery and adjuvant
chemotherapy often relapse with tumor marker only (i.e. elevation of CA-125) in the absence of
measurable disease by radiographic imaging. Patients are typically monitored without therapy in
this setting and are a stated unmet need for a chemotherapeutic with favorable toxicity profile [52].
Finally, ovarian cancer is one of the most prothrombotic malignancies [19] and PDI inhibition has
been shown to reduce the hypercoagulability associated with advanced cancer.
3.
PARTICIPANT SELECTION
Laboratory tests required for eligibility must be completed within 14 days prior to the date of
registration. Baseline measurements must be documented from tests within 14 days of the date of
registration for protocols requiring measurable disease. Diagnostic tests, such as CT scans, must
be performed within 4 weeks of the date of registration.
3.1
Eligibility Criteria
3.1.1
Participants must have histologically confirmed epithelial ovarian, fallopian tube, or
primary peritoneal cancer.
3.1.2
Participants must have completed at least first-line platinum based chemotherapy and
surgery with a response, in the opinion of the investigator, defined as no evidence of
disease progression or rising CA-125 at any time during front-line treatment.
3.1.3
Participants must meet criteria for tumor marker-only relapse, defined as CA-125 more
than twice the upper limit of normal (35 U/mL) in the setting of a normal baseline CA-
125 levels or CA-125 greater than twice the nadir count on two successive measurements
for CA-125 values that remain above baseline without measurable radiographic disease.
3.1.4
Minimum age ≥18 years. Because no dosing or adverse event data are currently available
on the use of zafirlukast in participants under 18 years of age with ovarian cancer,
children are excluded from this study but will be eligible for future pediatric trials.
3.1.5
Life expectancy of greater than 4 months.
3.1.6
ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).
3.1.7
Participants must be able to swallow tablets.
3.1.8
Participants must have adequate organ and marrow function as defined below:

Absolute neutrophil count
≥1,000/mcL

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
Platelets
≥90,000/mcL

Total bilirubin
≤1.3 × institutional upper limit of normal (ULN)

AST(SGOT)/ALT(SGPT)
≤2 × institutional ULN

Creatinine
≤institutional ULN
OR

Glomerular filtration rate (GFR) ≥45 mL/min/1.73 m2
3.1.9
The effects of zafirlukast on the developing human fetus are incompletely characterized.
For this reason, women of child-bearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she should
inform her treating physician immediately. Men are not eligible for this study.
3.1.10 Ability to understand and the willingness to sign a written informed consent document.
3.2
Exclusion Criteria
Participants who exhibit any of the following conditions at screening will not be eligible for
admission into the study.
3.2.1
Non-epithelial tumors (pure sarcomas) or ovarian tumors with low malignant potential (ie
borderline tumors) or mucinous tumors. Mixed mullerian tumors or carcinosarcomas are
allowed.
3.2.2
Participants who have had cytotoxic chemotherapy including bevacizumab or
radiotherapy within 4 weeks prior to entering the study. This does not include
maintenance therapy with a PARP inhibitor, such as olaparib or niraparib. (PARP
inhibitor, rucaparib is not allowed to be co-administed with CYP2C9 substrates as
maintenance therapy as it could increase exposure to zafirlukast).
3.2.3
Participants who have ongoing adverse effects from prior anti-cancer therapy greater than
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE, v5.0) Grade 1, with the exception of Grade 2 non-hematologic toxicity such as
alopecia and peripheral neuropathy.
3.2.4
Participants who are receiving any other investigational agents.
3.2.5
Participants with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.
3.2.6
History of allergic reactions attributed to compounds of similar chemical or biologic
composition to zafirlukast.

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3.2.7
Currently receiving anticoagulant therapy.
3.2.8
Current daily use of aspirin (> 81 mg daily), clopidogrel (Plavix), cilostazol (Pletal),
aspirin-dipyridamole (Aggrenox) (within 10 days) or considered to use regular use of
higher doses of non-steroidal anti-inflammatory agents as determined by the treating
physician (e.g. ibuprofen > 800 mg daily or equivalent).
3.2.9
Participants receiving any medications or substances that are inhibitors or inducers of
CYP2C9 are ineligible. Because the lists of these agents are constantly changing, it is
important to regularly consult a frequently updated medical reference. As part of the
enrollment/informed consent procedures, the participant will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be prescribed or
if the participant is considering a new over-the-counter medicine or herbal product.
3.2.10 Participants with uncontrolled intercurrent illness.
3.2.11 Participants with psychiatric illness/social situations that would limit compliance with
study requirements.
3.2.12 Pregnant women are excluded from this study because zafirlukast is a class B agent with
the potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the mother
with zafirlukast, breastfeeding should be discontinued if the mother is treated with
zafirlukast.
3.3
Inclusion of Women and Minorities
The study is open to any individual who meets above eligibility criteria without discrimination
based on race or gender. We do not anticipate that inclusion or exclusion criteria will negatively
affect recruitment or retention of underrepresented minorities.
4.
REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS)
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or
intervention. Any participant not registered to the protocol before protocol-specific therapy or
intervention begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the
protocol-specific eligibility checklist.
Following registration, participants may begin protocol-specific therapy and/or intervention.
Issues that would cause treatment delays should be discussed with the Overall Principal

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Investigator (PI). If the subject does not receive protocol therapy following registration, the
subject must be taken off study in the CTMS (OnCore) with an appropriate date and reason
entered.
1.1
Registration Process for DF/HCC Institutions
Applicable DF/HCC policy (REGIST-101) must be followed.
1.
TREATMENT PLAN
1.1
Treatment Regimen
Treatment will be administered on an outpatient basis every 4 weeks, with 28 consecutive days
defined as a treatment cycle. Expected toxicities and potential risks as well as dose modifications
for zafirlukast are described in Section 6 (Expected Toxicities and Dosing Delays/Dose
Modification).
Regimen Description
Agent
Premedications;
Precautions
Dose
Route
Schedule
Cycle
Length
Zafirlukast
None
40 mg
Oral tablets
Twice daily
28 days
The first cohort of 4 participants will receive zafirlukast 40 mg (two 20 mg tablets) twice daily.
In the absence of drug related serious adverse events (grade 3 or 4 possibly or probably related),
an additional cohort of 4 patients will be enrolled at 80 mg twice daily.
Participants will be requested to maintain a medication diary of each dose of medication. The
medication diary will be returned to clinic staff at the end of each cycle.
1.2
Pre-Treatment Criteria
5.1.1.
Cycle 1, Day 1

Laboratory assessments recorded within 14 days of signing consent may be used to
determine eligibility and does not have to be repeated (except complete blood count)

Absolute neutrophil count > 1,000/mcL

Platelet count > 90,000/mcL

Participants must be able to tolerate PO tablets
5.1.2.
Subsequent Cycles

Toxicities possibly related to zafirlukast must return to grade 2 or less

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1.3
Agent Administration
Zafirlukast will be supplied as oral tablets.
Cohort 1: Two tablets (total of 40 mg) will be consumed twice daily.
Cohort 2: Four tablets (total of 80 mg) will be consumed twice daily.
Dose modifications will not be made. Tablets will be dispensed from the research pharmacy on
day 1 of each cycle. The tablets will be packaged as a 30-day supply (to allow for unexpected
occurrences such as dropped tablet).
Tablets should be taken without food. Food decreases the bioavailability of zafirlukast by 40%.
Therefore, participants will be instructed to take zafirlukast on an empty stomach, 1 hour before
and 2 hours after meals. Missed doses must be taken within four hours of scheduled dose. If
longer than four hours, or if dose vomited, skip dose. Subjects will keep a drug diary that will be
provided to them by the study team. Subjects will be instructed to return any unused drug. The
unused returns will be counted by pharmacy and destroyed on-site per policy.
1.4
General Concomitant Medication and Supportive Care Guidelines
Because there is a potential for interaction of zafirlukast with other concomitantly administered
drugs through the cytochrome P450 system, the case report form must capture the concurrent use
of all other drugs, over-the-counter medications, or alternative therapies. The Overall PI should
be alerted if the participant is taking any agent known to affect or with the potential to affect
selected CYP450 isoenzymes. Appendix B presents guidelines for identifying
medications/substances that could potentially interact with the study agent(s).
1.5
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will be ongoing (+/- 7 days inclusion of windows) for up to 12 cycles or
until one of the following criteria apply:

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the oral medication
regimen and/or documentation requirements

Participant decides to withdraw from the study, or general or specific changes in the
participant's condition render the participant unacceptable for further treatment in the
opinion of the treating investigator

Clinical or radiographic progression of ovarian cancer

Doubling the pre-treatment CA-125 value (confirmed at least 1 week apart)

Grade 3 or 4 hemorrhage and/or symptomatic bleeding in a critical area or organ such as
intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or
intramuscular with compartment syndrome, and/or bleeding causing a fall in hemoglobin
level > 2 g/dL or bleeding leading to a transfusion of > 2 units of packed red blood cells

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Participants will be removed from the protocol therapy when any of the criteria listed above
applies. The reason for removal from protocol therapy, and the date the participant was removed,
must be documented in the study-specific case report form (CRF). Alternative care options will
be discussed with the participant.
In the event of unusual or life-threatening complications, participating investigators must
immediately notify the Principal Investigator, Rushad Patell at 617-667-9920.
1.6
Duration of Follow Up
Following completion of treatment participants will be followed for a final 30 days post last dose
visit. All AEs and SAEs will be collected during this time. After the completion of the 30 day
post last dose follow up, participants may come off study. Participants removed from study
treatment for unacceptable adverse events will be followed until resolution or stabilization of the
adverse event. Participants who have related unresolved AEs should be followed until resolution
of the adverse event or up to 30 days post last dose, whichever occurs later. Participants removed
from active treatment for reasons listed in section 1.5, will be followed for 30 days post last dose,
prior to coming off study.
1.7
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Completed protocol defined procedures and follow-up

Lost to follow-up

Withdrawal of consent for data submission
Death
The reason for taking a participant off study, and the date the participant was removed, must be
documented in the case report form (CRF). In addition, the study team will ensure the
participant’s status is updated in OnCore in accordance with REGIST-OP-1
2.
DOSING DELAYS/DOSE MODIFICATIONS
Dose delays will be made as indicated in the following table(s). The descriptions and grading
scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE)
version 5.0 will be utilized for dose delays and dose modifications. A copy of the CTCAE
version 5.0can be downloaded from the CTEP website
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
Thrombocytopenia
Management/Next Dose for
Zafirlukast
≤Grade 1
No change in dose
Grade 2
No change in dose
Grade 3
Hold until ≤Grade 1. Resume at
same dose level.
Grade 4
Do not restart

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ALT/AST
Management/Next Dose for
Zafirlukast
≤Grade 1
No change in dose
Grade 2
Hold until within normal range.
Resume at same dose level.
Grade 3
Do not restart
Grade 4
Do not restart
Bilirubin
Management/Next Dose for
Zafirlukast
≤Grade 1
No change in dose
Grade 2
Hold until within normal range.
Resume at same dose level.
Grade 3
Do not restart.
Grade 4
Do not restart
3.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an
observed AE (Section 7.2) will determine whether the event requires expedited reporting in
addition to routine reporting.
3.1
Expected Toxicities
3.1.1
Adverse Event List(s) for Zafirlukast
Headache 12.9%
Infection 3.5%
Nausea 3.1%
Diarrhea 2.8%
Pain (generalized) 1.9%
Asthenia 1.8% 1.6%
Abdominal Pain 1.8%
Dizziness 1.6%
Myalgia 1.6%
Fever 1.6%
Back Pain 1.5%
Vomiting 1.5%
Liver function testing elevation 1.5%
Dyspepsia 1.3%
Rarely, elevations of one or more liver enzymes have occurred in patients receiving
zafirlukast in controlled clinical trials. In clinical trials, most of these have been observed

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at doses four times higher than the recommended dose. The following hepatic events
(which have occurred predominantly in females) have been reported from post-marketing
adverse event surveillance of cases of symptomatic hepatitis (with or without
hyperbilirubinemia) without other attributable cause; and rarely, hyperbilirubinemia
without other elevated liver function tests. In most, but not all post-marketing reports, the
patient’s symptoms abated and the liver enzymes returned to normal or near normal after
stopping zafirlukast. In rare cases, patients have presented with fulminant hepatitis or
progressed to hepatic failure, liver transplantation and death
3.2
Adverse Event Characteristics

CTCAE term (AE description) and grade: The descriptions and grading scales found
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be
downloaded from the CTEP web site
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:
-
AEs for the agent(s) that are listed above should be reported only if the adverse event
varies in nature, intensity or frequency from the expected toxicity information which
is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
3.3
Adverse Event Reporting
3.3.1
In the event of an unanticipated problem or life-threatening complications treating
investigators must immediately notify the Overall PI.
3.3.2
Investigators must report to the Overall PI any adverse event (AE) that occurs after the
initial dose of study treatment, during treatment, or within 30 days of the last dose of
treatment on the local institutional SAE form.
3.3.3
DF/HCC Adverse Event Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human
Research Studies (OHRS) per the DFCI IRB reporting policy.

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3.4
Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant
safety reports, sentinel events or unanticipated problems that require reporting per institutional
policy.
3.5
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the
IRB, FDA, etc.) must also be reported in routine study data submissions.
4.
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational administered in
this study can be found in Section 7.1.
4.1
Zafirlukast
4.1.1
Description
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.
Zafirlukast is rapidly absorbed following oral administration. Peak plasma concentrations are
generally achieved 3 hours after oral administration. The absolute bioavailability of zafirlukast is
unknown. In two separate studies, one using a high fat and the other a high protein meal,
administration of zafirlukast with food reduced the mean bioavailability by approximately 40%.
Zafirlukast is more than 99% bound to plasma proteins, predominantly albumin. The degree of
binding was independent of concentration in the clinically relevant range. The apparent steady-
state volume of distribution is approximately 70 L, suggesting moderate distribution into tissues.
Studies in rats using radiolabeled zafirlukast indicate minimal distribution across the blood-brain
barrier.
Zafirlukast is extensively metabolized. The most common metabolic products are hydroxylated
metabolites which are excreted in the feces. The metabolites of zafirlukast identified in plasma are
at least 90 times less potent as LTD4 receptor antagonists than zafirlukast in a standard in vitro
test of activity. In vitro studies using human liver microsomes showed that the hydroxylated
metabolites of zafirlukast excreted in the feces are formed through the cytochrome P450 2C9
(CYP2C9) pathway. Additional in vitro studies utilizing human liver microsomes show that
zafirlukast inhibits the cytochrome P450 CYP3A4 and CYP2C9 isoenzymes at concentrations
close to the clinically achieved total plasma concentrations.

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The apparent oral clearance (CL/f) of zafirlukast is approximately 20 L/h. Studies in the rat and
dog suggest that biliary excretion is the primary route of excretion. Following oral administration
of radiolabeled zafirlukast to volunteers, urinary excretion accounts for approximately 10% of the
dose and the remainder is excreted in feces. Zafirlukast is not detected in urine.
In the pivotal bioequivalence study, the mean terminal half-life of zafirlukast is approximately 10
hours in both normal adult subjects and patients with asthma. In other studies, the mean plasma
half-life of zafirlukast ranged from approximately 8 to 16 hours in both normal subjects and
patients with asthma. The pharmacokinetics of zafirlukast are approximately linear over the range
from 5 mg to 80 mg. Steady-state plasma concentrations of zafirlukast are proportional to the dose
and predictable from single-dose pharmacokinetic data. Accumulation of zafirlukast in the plasma
following twice-daily dosing is approximately 45%.
4.1.2
Form
Zafirlukast occurs as a fine white to pale yellow amorphous powder. It is supplied in 20 mg
tablets for oral administration. Film-coated tablet consist of croscarmellose sodium, lactose,
magnesium stearate, microcrystalline cellulose, povidone, hypromellose, and titanium dioxide.
4.1.3
Storage and Stability
Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Protect from light and
moisture. Dispense in the original air-tight container.
4.1.4
Compatibility
No specific compatibility issues.
4.1.5
Handling
No specific measures necessary.
4.1.6
Availability
Zafirlukast will be provided by the research pharmacy. A 30-day supply will be distributed on
C1D1 and Day 1 of each cycle moving forward by the local research pharmacy.
4.1.7
Preparation
No specific measures necessary.
4.1.8
Administration
Zafirlukast will be administered orally twice daily.

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4.1.9
Ordering
Zafirlukast will be purchased by research pharmacy from commercial supplier.
4.1.10 Accountability
The investigator, or a responsible party designated by the investigator, must maintain a careful
record of the inventory and disposition of the agent (investigational or free of charge) using the
NCI Drug Accountability Record or another comparable drug accountability form. (See the
CTEP website at http://ctep.cancer.gov/protocolDevelopment for the “Policy and Guidelines for
Accountability and Storage of Investigational Agents” or to obtain a copy of the drug
accountability form.) Participants will record compliance with study treatment in a drug diary
that will be provided to them. The drug diary will be collected and re-dispensed at each study
visit.
4.1.11 Destruction and Return
At the end of the study, unused supplies of Zafirlukast should be destroyed according to
institutional policies. Destruction will be documented in the Drug Accountability Record Form.
5.
CORRELATIVE STUDIES
5.1
Laboratory Correlative Studies
The contents of the serum separator tube will be used for CA-125 level determination by the
clinical laboratory. CA-125 will be performed in a clinical laboratory using a commercially
available assay.
A total of 10 mL of blood will be drawn into blue top tubes (3.2% citrate) in either two 5 mL
tubes or one 15 mL tube for correlative labs.
Plasma will be separated at 2100 x G for 20 minutes. First centrifugation should be performed
within 1 hour of specimen collection. The plasma layer will be centrifuged a second time at
2100 x G x 20 minutes in a single tube. The plasma supernatant will be transferred to a clean
tube leaving the 1 mL at the bottom of the tube undisturbed (to be discarded). The transferred
plasma sample will be aliquoted (500 mcL) into 1.5mL Eppendorf tubes.
Tubes will be stored at -80 °C.
Correlative Studies:

D-dimer will be performed in a research laboratory using a commercially
available ELISA.

Plasma PDI-inhibitory activity: The plasma PDI-inhibitory activity will be
measured using a modified DiEGSSG assay[53]. The exposure of the

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DiEGSSG probe to exogenous PDI and plasma results in increased
fluorescence measured spectrophotometrically and can be used to detect the
presence of PDI inhibitor activity.
Plasma samples may be sent for coagulation and PDI-based assays (e.g. platelet-dependent
thrombin generation assay) to Western New England University for analysis after a DUA is
executed. Samples will be de-identified and coded by study number prior to being sent for
analysis.
6.
STUDY CALENDAR
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy. All
assessments must be performed prior to administration of any study medication. All study
assessments and medications should be administered within +/- 7 days of the protocol-specified
date, unless otherwise noted.

22
Baseline
Cycle 1f
Cycle 2f
Cycles
3-12f
Off Treatment
30 Day post
Last Dose
Follow Up/
Off Studycd
EDC Timepoints
Day
1
Day
8
Day
15
Day
22
Day
1
Day
15
Day 1
ZafirlukastB
X
X
X
Day 1 of every Cycle
Informed consent
X
N/A
Demographics
X
Baseline
Medical history
X
Baseline
CT Scan
Xi
Baseline
Concurrent Medications
X-----------------------------------------------------------------------------------------------------X
N/A
Physical exam
X
X
X
X
X
X
Baseline
Vital signs
X
X
X
X
X
X
Baseline
Height
X
Baseline
Weight
X
X
X
X
X
X
X
Baseline
Performance status
X
X
X
X
X
X
X
Baseline, Day 1 of every Cycle, Off
Treatment, Off Study
CBC w/diff,
X
X
X
X
X
X
X
X
X
X
Baseline, Cycle 1 Day 1, 8, 15 & 22, Cycle
2 Day 1 & 15, Cycle 3+ Day 1, Off
Treatment and Off Study
Serum chemistrya
X
Xg
X
X
X
X
X
X
X
X
Baseline, Cycle 1 Day 1, 8, 15 & 22, Cycle
2 Day 1 & 15, Cycle 3+ Day 1, Off
Treatment and Off Study
CA-125 Measurement
X
X
X
X
X
X
Adverse Event Evaluation
X---------------------------------------------------------------------------------X
During all visits
Radiologic Evaluation
X
Radiologic measurements should be performed every 3
cyclese
X
Baseline, Every 3 Cycles during treatment,
Off Treatment, each follow-up visit, Off
Study. If a Radiologic Evaluation is
performed during any other Cycle, it must
be captured in InForm.
B-HCG
Xb
N/A
Drug Diary Review
X
X
X
X
Other correlative studiesh
X
X
X
N/A

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Baseline
Cycle 1f
Cycle 2f
Cycles
3-12f
Off Treatment
30 Day post
Last Dose
Follow Up/
Off Studycd
EDC Timepoints
Survival
X--------------------------------------------------------------------------------------------X
During all visits
B:
Zafirlukast 40 mg twice daily
a:
Total bilirubin, BUN, Creatinine, SGOT [AST], SGPT [ALT].
b:
Serum pregnancy test (women of childbearing potential).
c:
30 Days Post Last Dose: Follow up visits or other contact are required in order to identify SAWs during the 30 days (+/- 7 days) following the end of study treatment.
d:
Follow-Up evaluation. After the completion of the 30 days post last dose study visit, participants may be removed from the study.
e:
Radiologic measurements should be performed every 3 cycles prior to the initiation of the next cycle. Scans may be performed within a +/-7 day window.
f:
Cycles are 28 days in length.
g:
Laboratory assessments recorded within 14 days of signing consent may be used to determine eligibility and does not have to be repeated (except complete blood count) for
C1D1 if within this window
h:
Refer to section 5.1
i.
CT Scan for Baseline within 4 weeks of registration

24
7.
MEASUREMENT OF EFFECT
7.1
Antitumor Effect
Participants will be evaluated for CA-125 response every 4 weeks.
7.1.1
Definitions
Response will be defined according to GCIG criteria which requires a reduction of CA-125 of >
50% relative to pre-treatment CA-125 level, maintained for at least 28 days [54].
CA-125
Non-target lesions
New lesions
Overall serological
response
Response and
normalized
CR
No
CR
Response
Non-PD
No
PR
Normalized but not
response
Non-CR/Non-PD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
7.2
Other Response Parameters
Doubling time of CA-125 in the 3 months prior to enrollment compared to doubling time
following enrollment.
Progression, defined as development of clinical symptoms deemed secondary to ovarian cancer
and/or radiographically visible disease and/or a doubling in the pre-treatment CA-125 value,
confirmed on successive measurements (1-3 weeks after initial measurement).[54] Zafirlukast
should be continued until progression is confirmed.
8.
DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0
(Adverse Events: List and Reporting Requirements).
8.1
Data Reporting
8.1.1
Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data
for this study.

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8.1.2
Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data
forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies.
8.2
Data Safety Monitoring
Each participating site will conduct local data and safety monitoring in accordance with the enrolling
institution’s data safety monitoring plan and policies. A summary DSMC report from each site
should be provided to the Study PI whenever it is generated.
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity
and accrual data from this study. The committee is composed of medical oncologists, research
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research.
Information that raises any questions about participant safety will be addressed with the Overall
PI and study team.
The DSMC will review each protocol up to four times a year with the frequency determined by
the outcome of previous reviews. Information to be provided to the committee may include: up-
to-date participant accrual; current dose level information; DLT information; all grade 2 or
higher unexpected adverse events that have been reported; summary of all deaths occurring
within 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of
all deaths while being treated and during active follow-up; any response information; audit
results, and a summary provided by the study team. Other information (e.g. scans, laboratory
values) will be provided upon request.
9.
STATISTICAL CONSIDERATIONS
The primary objective is to determine the rate of antineoplastic response to zafirlukast as
measured by response in CA-125 concentration.
9.1
Study Design/Endpoints
Primary Endpoint: Response rate in CA-125 per GCIG criteria.
Study Design: Two dose level pilot study.
Accrual: 8 participants
9.2
Sample Size, Accrual Rate and Study Duration

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In the 4 women treated with zafirlukast 40 mg twice daily, there were no responses in terms of
decline of CA-125. However, However, the mean change in CA-125 was 0.036 U/mL per day
prior to treatment compared with 0.015 U/mL per day following zafirlukast (paired t-test
p=0.026). This equated to a mean CA-125 doubling time of 29.8 days in the weeks prior to
treatment compared with a mean doubling time of 85.69 days following treatment.
A second cohort of 4 women at 80 mg twice daily will be enrolled to assess whether CA-125
doubling time is significantly prolonged compared with pre-treatment values and whether we
observe PDI inhibitory activity in plasma using Di-eosin-GSSG assay.
9.3
Analysis of Primary Endpoints
CA-125 response rate will be calculated as a proportion along with a two-stage 95% confidence
interval using the Atkinson and Brown procedure.
9.4
Analysis of Key Secondary Endpoint
Calculation of CA-125 doubling time before and after initiation of zafirlukast will be performed.
9.5
Analysis of Exploratory Objectives

Changes PDI and ERp57 inhibitory activity in plasma, platelet-dependent thrombin will
be performed by paired t-test analyses comparing baseline with C2D1 samples.

Determine progression free survival (PFS)

Assess the incidence of venous thromboembolism

Assess incidence of major hemorrhage and clinically relevant non-major bleeding
9.6
Reporting and Exclusions
9.6.1
Evaluation of Toxicity
All participants who received a dose of study drug will be assessed for toxicity.
9.6.2
Evaluation of the Primary Efficacy Endpoint
All participants included in the study must be assessed for response to treatment, even if there
are major protocol treatment deviations or if they are ineligible.
10. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of
the study is the time point at which the last data items are to be reported, or after the outcome
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate,

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and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that
initial release may be an abstract that meets the requirements of the International Committee of
Medical Journal Editors. A full report of the outcomes should be made public no later than three
(3) years after the end of the study.

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APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence
of disease.
0
Normal activity. Fully active, able
to carry on all pre-disease
performance without restriction.
90
Able to carry on normal activity;
minor signs or symptoms of disease.
80
Normal activity with effort; some
signs or symptoms of disease.
1
Symptoms, but ambulatory.
Restricted in physically strenuous
activity, but ambulatory and able
to carry out work of a light or
sedentary nature (e.g., light
housework, office work).
70
Cares for self, unable to carry on
normal activity or to do active work.
60
Requires occasional assistance, but
is able to care for most of his/her
needs.
2
In bed <50% of the time.
Ambulatory and capable of all
self-care, but unable to carry out
any work activities. Up and about
more than 50% of waking hours.
50
Requires considerable assistance and
frequent medical care.
40
Disabled, requires special care and
assistance.
3
In bed >50% of the time. Capable
of only limited self-care, confined
to bed or chair more than 50% of
waking hours.
30
Severely disabled, hospitalization
indicated. Death not imminent.
20
Very sick, hospitalization indicated.
Death not imminent.
4
100% bedridden. Completely
disabled. Cannot carry on any
self-care. Totally confined to bed
or chair.
10
Moribund, fatal processes
progressing rapidly.
5
Dead.
0
Dead.

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APPENDIX C
INFORMATION ON POSSIBLE DRUG INTERACTIONS
Information on Possible Interactions with Other Agents for Patients and Their Caregivers
and Non-Study Healthcare Team
Zafirlukast interacts with many drugs that are processed by your liver. Because of this, it is very
important to tell your study doctors about all of your medicine before you start this study. It is
also very important to tell them if you stop taking any regular medicine, or if you start taking a
new medicine while you take part in this study. When you talk about your medicine with your
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter
remedy), or herbal supplements such as St. John’s wort.
Many health care prescribers can write prescriptions. You must also tell your other prescribers
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial.
Bring this paper with you and keep the attached information card in your wallet. These are
the things that you and they need to know:
Zafirlukast interacts with (a) certain specific enzyme(s) in your liver.
The enzyme in question is CYP2C9 and zafirlukast is broken down by this enzyme in order
to be cleared by your liver.
Zafirlukast must be used very carefully with other medicines that need these liver enzymes
to be effective or to be cleared from your system.
Other medicines may also affect the activity of the enzyme.
o
Aspirin
o
Erythromycin
o
Theophylline
o
Warfarin
Zafirlukast is considered an inhibitor of the enzyme, meaning that it can affect the levels of
other drugs that are processed by that enzyme. This can lead to harmful side effects
and/or reduce the effectiveness of those medications.
You and healthcare providers who prescribe drugs for you must be careful about adding or
removing any drug in this category.
Before you start the study, your study doctor will work with your regular prescriber to
switch any medicines that are considered “strong inducers/inhibitors or substrates of
CYP2C9”.
Your prescribers should look at this web site
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a medical reference to see
if any medicine they want to prescribe is on a list of drugs to avoid.
Please be very careful! Over-the-counter drugs have a brand name on the label—it’s
usually big and catches your eye. They also have a generic name—it’s usually small and
located above or below the brand name, and printed in the ingredient list. Find the
generic name and determine, with the pharmacist’s help, whether there could be an
adverse interaction.
Other medicines can be a problem with your study drugs.

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
You should check with your doctor or pharmacist whenever you need to
use an over-the-counter medicine or herbal supplement.

Your regular prescriber should check a medical reference or call your
study doctor before prescribing any new medicine for you. Your study
doctor’s name is
_____________________________________
and he or she can be contacted at
_____________________________________

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