Clinical trial NCT02595372
Conditions: Cancer of the Breast
Sponsor: Kathy Miller
Start date: 2015-11-12; Completion date: 2021-03-01
Enrollment: 42 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In preliminary laboratory science studies, the investigators show that proton pump inhibitors (PPIs) effectively inhibit human fatty acid synthase (FASN) and breast cancer cell survival. A preliminary retrospective study shows that PPI usage in breast cancer patients during chemotherapy significantly improved overall survival. The impact was most striking in patients with triple negative breast cancer (TNBC). Thus, PPIs may be repositioned as safe and effective breast cancer drugs to enhance the effect of chemotherapy.

Many of the hurdles that slow progress from target, to lead compound, to investigational agent, to standard therapy are not barriers for the PPIs. The PPIs are FDA-approved, chronically used, and well tolerated so the investigators can move quickly from the laboratory to a proof of concept clinical trial. Incorporating the PPIs into standard care will require more than the investigators propose here, but the investigators have already plotted the additional steps needed to truly impact patient care. If successful, the data gathered in this proposal will lend support to and guide development of a definitive randomized trial.

Detailed description:
Primary Objective

• Estimate the rate of pathologic complete response (pCR) in patients with triple negative breast cancer and FASN expression treated with standard neoadjuvant chemotherapy (NAC) in combination with high dose omeprazole.

Secondary Objectives

* Quantify the number of patients with newly diagnosed TNBC with tumors that express FASN.
* Estimate the rate of pCR in patients with triple negative breast cancer (irrespective of FASN status) treated with standard NAC in combination with high dose omeprazole.
* Describe the safety of incorporating high dose omeprazole with standard NAC.
* Estimate the biologic activity of high dose omeprazole in modulating FASN expression and activity.

This is a single arm Phase II study. Patients should begin therapy within 7 working days of study entry. Patients will be treated with omeprazole 80 mg orally twice a day (BID) beginning 4-7 days prior to chemotherapy and continuing until surgery. After the brief period of omeprazole monotherapy, patients will begin standard neoadjuvant chemotherapy with doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) for 4 cycles followed by paclitaxel (80 mg/m2) weekly x 12. Doxorubicin and cyclophosphamide (AC) may be administered on a classical every 3 week or dose dense every 2 week (with growth factor support) schedule at the treating physician's discretion. Routine incorporation of carboplatin is not recommended, however use of carboplatin (AUC 6 on week 1, 4, 7, and 10) with paclitaxel is allowed at the treating investigator's discretion. Chemotherapy will be adjusted based on toxicity according to standard treatment guidelines. Patients with overt disease progression during AC should move immediately to paclitaxel therapy. Patients with disease progression during paclitaxel should proceed immediately to surgery.

Arms: arm 1: Patients will be treated with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing until surgery.
Interventions: intervention 1: Omeprazole
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
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Inhibiting fatty acid synthase to improve efficacy of neoadjuvant chemotherapy 
Protocol Number: 
IUSCC-0555 
Principal Investigator: 
Kathy D. Miller, M.D. 
IU Simon Cancer Center 
535 Barnhill Drive, RT-473 
Indianapolis, IN 46202 
(317) 948-3855
kathmill@iupui.edu 
Co-Investigators: 
Brian Schneider, M.D. 
Anna Maria Storniolo, M.D. 
Lida Mina, M.D. 
Sara Grethlein, M.D. 
Erin Newton, M.D. 
Linda Han, M.D. 
Gary Dunnington, M.D. 
Kandice Ludwig, M.D. 
Jian-Ting Zhang, Ph.D. 
Lang Li, Ph.D. 
Research Nurse: 
LaTrice Vaughn, R.N. 
Study Statistician: 
Susan Perkins, Ph.D. 
Support Provided By: 
Breast Cancer Research Foundation 
Protocol Version Date: 
 April 03, 2020 
IND#: EXEMPT 
NCT02595372


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PROTOCOL SIGNATURE PAGE 
Inhibiting fatty acid synthase to improve efficacy of neoadjuvant chemotherapy. 
VERSION DATE: 04/03/2020 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and to the 
ethical principles stated in the latest version of the Declaration of Helsinki, the applicable guidelines for 
good clinical practices, or the applicable laws and regulations of the country of the study site for which I am 
responsible, whichever provides the greater protection of the individual. I will accept the monitor’s 
overseeing of the study. I will promptly submit the protocol to applicable ethical review board(s).  
 
 
 
 
 
 
 
 
 
 
 
 
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Signature of Investigator  
 
 
 
 
Date  
 
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Investigator Name (printed)  
 
 
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Investigator Title  
 
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Name of Facility  
 
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 Not Submitting to IRB 
Expected IRB Submission Date  
 
COMPLETE AND EMAIL COPY TO INDIANA UNIVERSITY SIMON CANCER CENTER CLINICAL TRIALS OFFICE 
Instructions to the investigator: Please SIGN and DATE this signature 
page. PRINT your name and title, the name and location of the facility in 
which the study will be conducted, and the expected IRB approval date. 
Scan and email the completed form to Indiana University Simon Cancer 
Center and keep a record for your files. 
 


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TABLE OF CONTENTS 
1. 
SCHEMA ............................................................................................................................................................. 6 
2. 
BACKGROUND & RATIONALE ............................................................................................................................. 6 
2.1 
OVERVIEW ............................................................................................................................................................... 6 
2.2 
THE ROLE OF FASN FUNCTION IN DRUG RESISTANCE ....................................................................................................... 7 
2.3 
TARGETING FASN TO REVERSE CHEMOTHERAPY RESISTANCE ............................................................................................ 9 
2.4 
PHARMACO-EPIDEMIOLOGIC SUPPORT FOR USE OF PPIS ................................................................................................ 11 
2.5 
NEOADJUVANT THERAPY IN BREAST CANCER ................................................................................................................ 12 
3. 
OBJECTIVES ...................................................................................................................................................... 12 
3.1 
PRIMARY OBJECTIVE ................................................................................................................................................ 12 
3.2 
SECONDARY OBJECTIVES ........................................................................................................................................... 12 
3.3 
TERTIARY/ EXPLORATORY/ CORRELATIVE OBJECTIVES ..................................................................................................... 12 
3.4 
PRIMARY OUTCOME MEASURE .................................................................................................................................. 13 
3.5 
SECONDARY OUTCOME MEASURES............................................................................................................................. 13 
3.6 
TERTIARY/ EXPLORATORY/ CORRELATIVE OUTCOME MEASURES ...................................................................................... 13 
4. 
ELIGIBILITY CRITERIA ........................................................................................................................................ 13 
4.1 
INCLUSION CRITERIA ................................................................................................................................................ 13 
4.2 
EXCLUSION CRITERIA ................................................................................................................................................ 14 
5. 
STUDY DESIGN .................................................................................................................................................. 14 
6. 
PATIENT REGISTRATION ................................................................................................................................... 14 
7. 
TREATMENT PLAN ............................................................................................................................................ 15 
7.1 
OVERVIEW ............................................................................................................................................................. 15 
7.2 
OMEPRAZOLE ......................................................................................................................................................... 16 
7.3 
DOXORUBICIN AND CYCLOPHOSPHAMIDE (AC)† ........................................................................................................... 17 
7.4 
PACLITAXEL (T)† ..................................................................................................................................................... 17 
7.5 
MANAGEMENT OF DISEASE PROGRESSION ................................................................................................................... 18 
7.6 
BREAST SURGERY AND MANAGEMENT OF THE AXILLA .................................................................................................... 18 
8. 
TOXICITIES TO BE MONITORED/DOSAGE MODIFICATIONS ............................................................................... 18 
8.1 
OMEPRAZOLE ......................................................................................................................................................... 18 
8.2 
AC† ..................................................................................................................................................................... 19 
8.3 
PACLITAXEL (+/- CARBOPLATIN)† ............................................................................................................................... 20 
8.4 
SUPPORTIVE CARE ................................................................................................................................................... 23 
8.5 
DURATION OF FOLLOW-UP ........................................................................................................................................ 23 
9. 
STUDY PARAMETERS/CALENDAR ..................................................................................................................... 24 
10. 
CRITERIA FOR EVALUATION/REMOVAL FROM STUDY ...................................................................................... 26 
10.1 DEFINITIONS ASSOCIATED WITH RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) VERSION 1.1 ........................... 26 
10.2 EVALUATION OF TARGET LESIONS ............................................................................................................................... 27 
10.3 EVALUATION OF NON-TARGET LESIONS ....................................................................................................................... 29 
10.4 NEW LESIONS ......................................................................................................................................................... 30 
10.5 EVALUATION OF BEST OVERALL RESPONSE .................................................................................................................... 31 
10.6 CRITERIA FOR REMOVAL FROM STUDY ......................................................................................................................... 31 


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11. 
DRUG INFORMATION ....................................................................................................................................... 32 
11.1 DRUG NAME .......................................................................................................................................................... 32 
11.2 OTHER NAMES ....................................................................................................................................................... 32 
11.3 CLASSIFICATION ...................................................................................................................................................... 32 
11.4 MODE OF ACTION ................................................................................................................................................... 32 
11.5 STORAGE AND STABILITY ........................................................................................................................................... 32 
11.6 METABOLISM ......................................................................................................................................................... 32 
11.7 DOSAGE FORMS AND STRENGTHS ............................................................................................................................... 32 
11.8 ADMINISTRATION .................................................................................................................................................... 32 
11.9 AVAILABILITY .......................................................................................................................................................... 32 
11.10 SIDE EFFECTS .......................................................................................................................................................... 33 
11.11 NURSING IMPLICATIONS ........................................................................................................................................... 34 
12. 
STATISTICAL METHODS .................................................................................................................................... 34 
12.1 GENERAL CONSIDERATIONS ....................................................................................................................................... 34 
12.2 STUDY DESIGN ........................................................................................................................................................ 34 
12.3 ANALYSIS DATASETS ................................................................................................................................................ 34 
12.4 SAMPLE SIZE .......................................................................................................................................................... 34 
12.5 PATIENT CHARACTERISTICS ........................................................................................................................................ 35 
12.6 DISPOSITION .......................................................................................................................................................... 35 
12.7 ANALYSIS OF PRIMARY OBJECTIVES ............................................................................................................................. 35 
12.8 ANALYSIS OF SECONDARY OBJECTIVES ......................................................................................................................... 35 
12.9 ANALYSIS OF TERTIARY OBJECTIVES ............................................................................................................................. 35 
12.10 INTERIM ANALYSIS ................................................................................................................................................... 36 
12.11 SUBGROUP ANALYSIS ............................................................................................................................................... 36 
13. 
SPECIAL INSTRUCTIONS .................................................................................................................................... 36 
13.1 TUMOR BIOPSY REQUIREMENTS ................................................................................................................................. 36 
13.2 SERUM LIPID PROFILE .............................................................................................................................................. 37 
13.3 SERUM NEFA ........................................................................................................................................................ 38 
13.4 OMEPRAZOLE EXPOSURE .......................................................................................................................................... 38 
13.5 PLASMA FOR CELL-FREE DNA ................................................................................................................................... 38 
14. 
PATIENT CONSENT AND PEER JUDGMENT ........................................................................................................ 38 
15. 
DATA AND SAFETY MONITORING ..................................................................................................................... 39 
15.1 DATA SAFETY MONITORING COMMITTEE....................................................................................................................... 39 
15.2 DATA SAFETY MONITORING PLAN ................................................................................................................................ 39 
15.3 DATA SAFETY MONITORING BOARD ............................................................................................................................. 40 
15.4 DATA ACQUISITION ................................................................................................................................................... 41 
16. 
REPORTING ADVERSE EVENTS .......................................................................................................................... 41 
16.1 DEFINITIONS OF ADVERSE EVENTS .............................................................................................................................. 41 
16.2 REPORTING OF ADVERSE EVENTS: ................................................................................................................................ 44 
17. 
MULTICENTER GUIDELINES ............................................................................................................................... 46 
17.1 STUDY DOCUMENTS .................................................................................................................................................. 46 
17.2 STUDY INITIATION ..................................................................................................................................................... 46 
17.3 PATIENT ENROLLMENT ............................................................................................................................................... 46 
17.5 DATA MONITORING .................................................................................................................................................. 46 
17.6 RECORD RETENTION .................................................................................................................................................. 47 
18. 
REFERENCES ..................................................................................................................................................... 48 


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19. 
APPENDICES ..................................................................................................................................................... 51 
19.1 APPENDIX I: NCI COMMON TOXICITY CRITERIA VERSION 4.0 .......................................................................................... 51 
19.2 APPENDIX II: PERFORMANCE STATUS SCALES/SCORES .................................................................................................... 52 
19.3 APPENDIX III: DSMC CHECK SHEET ............................................................................................................................ 53 
19.4 APPENDIX IV: POTENTIAL DRUG INTERACTIONS ............................................................................................................ 54 
 
 
 


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1. SCHEMA 
 
 
2.  BACKGROUND & RATIONALE 
 
2.1 Overview 
Human fatty acid synthase (FASN) is the sole cytosolic enzyme responsible for de novo 
synthesis of palmitate (1-3). It has seven catalytic domains (β-ketoacyl synthase, 
malonyl/acetyltransferase, dehydrogenase, enoyl reductase, β-ketoacyl reductase, acyl 
carrier protein, and thioesterase) and synthesizes palmitate by condensing acetyl-CoA and 
malonyl-CoA (1). Breast cancers with high levels of FASN are much more likely to recur 
and metastasize with significantly shorter disease free and overall survival (2-5). FASN 
induces resistance to multiple anticancer drugs including doxorubicin and cisplatin (6-8). 
The typical Western diet contains sufficient free fatty acids so that FASN is not required for 
normal cell function and, thus, its expression is very low in normal cells except lactating 
breast, cycling endometrium, and fatty tissues. In contrast, breast cancer cells require de 
novo fatty acid synthesis for survival. Inhibition of FASN induces apoptosis selectively in 
cancer cells both in vitro and in vivo (9-12) with minimal effect on normal cells (6, 13, 14). 
Thus, FASN drives breast cancer survival and is an ideal therapeutic target. In this 
application, we will target FASN to stop breast cancer growth. 
 
Having identified FASN as an important therapeutic target, we began searching for an 
inhibitor. In preliminary studies, we found that the proton pump inhibitors (PPIs) effectively 
inhibit FASN, reduce breast cancer cell survival, and restore sensitivity to chemotherapy 
(15). PPIs are FDA-approved for treatment of a variety of acid-related diseases that plague 
the digestive system, are widely used, and are well tolerated without major adverse effects 
(16-18). Interestingly, a recent retrospective study in head and neck cancer patients reported 
an increased overall survival associated with PPI use (19). Chinese investigators reported 
intriguing results of a phase II trial of intermittent high dose esomeprazole in combination 
with docetaxel and cisplatin in patients with metastatic breast cancer (NCT01069081, 20). 
Median PFS was 7.5 months in the control group compared to 9.5 months in PPI treated 
patients (p=0.030); impact as greatest in the subset of patients with triple negative disease 


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(n=17, 3.3 vs. 9.5 months, p=0.014). Though small, the results of this trial are consistent 
with our hypothesis and support further exploration. Thus, we hypothesize that the PPIs may 
be repositioned as safe and effective drugs to augment the effect of chemotherapy without 
adding significantly to the cost or toxicity of therapy. 
 
2.2 The Role of FASN Function in Drug Resistance 
FASN up-regulation in doxorubicin-resistant breast cancer cells. While comparing protein 
profiles between the parental MCF7 and its doxorubicin-selected and resistant derivative 
MCF7/AdVp3000 (M3K) cells, we found a 270-kDa protein with increased expression in 
the drug resistant M3K cells (Fig. 1A). This protein was identified to be human FASN by 
MALDI-TOF mass spectrometry. Functional analysis showed that FASN activity was 
dramatically (5 fold) up-regulated in M3K cells (Fig. 1B). FASN up-regulation in M3K cells 
was validated using Western blot analysis (Fig. 1C). During the stepwise selection of M3K 
cells, cell lines (e.g., M10 and M100) with low and intermediate doxorubicin resistance 
levels were also generated (21-23). Interestingly, these cells also showed increased FASN 
level but to a less extent than M3K cells (Fig. 1C). 
 
FASN over-expression causes resistance to multiple DNA-damaging agents. To investigate 
whether FASN up-regulation contributes to drug resistance in M3K cells, we first performed 
stable FASN knockdown using shRNA and tested cellular response to doxorubicin and 
mitoxantrone. As shown in Fig. 2A-B, FASN knockdown significantly reduced resistance of 
M3K cells to both doxorubicin and mitoxantrone. We next performed the reverse 
experiment to over-express ectopic FASN in the parental MCF7 cells. A stable MCF7 clone 
with FASN over-expression (FASN) was generated, and as predicted, it was significantly 
more resistant to doxorubicin and 
mitoxantrone than the control Vec 
clone (Fig. 2C-D). The FASN-
mediated doxorubicin resistance 
Figure 2. Effect of FASN over-expression on drug 
resistance. A & C, Western blot analysis of FASN in M3K 
cells stably transfected with FASN shRNA (Sh) or scrambled 
control shRNA (Scr) (A) and in MCF7 cells with stable FASN 
overexpression (FASN) or vector-transfected control (Vec) 
cells (C). B & D, Relative drug resistance of M3K cells with 
FASN knockdown (B) and MCF7 cells with FASN over-
expression (D) as determined using SRB assay. E, Orlistat 
sensitization of FASN-mediated doxorubicin resistance. 
Dose response of SRB assay was analyzed by GraphPad 
Prism to generate IC50. Relative resistance 
factor=IC50(FASN or Sh)/IC50(Vec or Scr). 
DOX=doxorubicin; MXT=mitoxantrone. (* p<0.05; **p<0.01). 
Figure 1. Over-expression of FASN in drug resistant M3K cells. A, 
SDS-PAGE profile of cell lysates from parental MCF7 (MCF) and its 
drug resistant derivative MCF7/AdVp3000 (M3K) cells. The arrowhead 
indicates the protein, which was identified as FASN. B, FASN activity in 
MCF7 and M3K cells as determined using coupled enzyme assay. C, 
Western blot analysis of FASN expression in MCF7 (MCF) and drug 
resistant derivative cell lines, MCF7/AdVp10 (M10), MCF7/AdVp100 
(M100), and MCF7/AdVp3000 (M3K) cells, which were generated by 
stepwise selection of MCF7 in the presence of 10 ng/ml, 100 ng/ml, and 
3000 ng/ml Adriamycin (doxorubicin), respectively. 


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Figure 3. Effect of FASN knockdown on drug response of MDA-MB-468 
and MCF10A1 cells. A, Western blot analysis of FASN expression in MDA-
MB-468 (468) and MCF10A1 cells following transient transfection with FASN 
(Si) or scrambled (Scr) siRNAs. B & C, Survival analysis of MDA-MB-468 (B) 
and MCF10A1 (C) cells following transfection with FASN siRNA (Si) or control 
scrambled (Scr) siRNAs in the absence or presence of doxorubicin (DOX) or 
mitoxantrone (MXT). RRF=relative resistance factor=IC50(Si)/IC50(Scr). 
(**p<0.01). 
was also dramatically reduced using the known FASN inhibitor, orlistat (Fig. 2E). FASN 
over-expression also significantly increased resistance to etopside, cisplatin, and ionizing 
radiation (IR) but had no effect on cellular response to paclitaxel and vinblastine [data not 
shown but see (7)]. Thus, FASN up-regulation likely causes resistance to DNA-damaging 
therapy but not anti-mitotic drugs. To ensure that the impact of FASN was not unique to 
MCF-7 cells, we performed FASN knockdown and survival analysis of another breast 
cancer cell line, MDA-MB-468. Fig. 3A shows effective knockdown of FASN and Fig. 3B 
shows that FASN knockdown is accompanied by significant reduction in cellular resistance 
to both doxorubicin and mitoxantrone. Similar results were observed with MDA-MB-231 
cells (data not shown). 
 
FASN silencing does not increase chemo-sensitivity in non-malignant cells. We had 
hypothesized that non-malignant cells would be less dependent on FASN expression, and 
thus would not be affected by FASN inhibition. To test this hypothesis we performed a 
similar knockdown experiment using human mammary epithelia cell line MCF10A1. Fig. 
3A shows effective FASN knockdown in MCF10A1 cells. However, FASN knockdown had 
no significant effect on cellular response to doxorubicin or mitoxantrone in MCF10A1 cells 
(Fig. 3C).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.3 Targeting FASN to Reverse Chemotherapy Resistance 
Identification of PPIs as FASN TE inhibitors. To identify FDA-approved drugs that target 
FASN TE, we first performed in-silico screening of a library of 2,417 FDA-approved drugs 
using DOCK programs and the 
crystal structure of FASN TE (ID: 
3TJM) (24). The 200 top-scoring 
compounds were clustered based 
on their chemical structure and 25 
representative drugs from 
different clusters were tested 
using the 4-MUH fluorogenic 
assay. We found that one of these 
drugs, pantoprazole, dose-
dependently inhibited FASN TE 
activity (Fig. 4A) with a Ki of 4.1 
μM (Table 1). Interestingly, the 
remaining drugs in the cluster 
containing pantoprazole were 
other PPIs including omeprazole, 
lansoprazole and rabeprazole. As 
shown in Fig. 4A and Table 1, all 
these PPIs similarly inhibited TE in a dose-dependent manner with Ki values of 3.4-5.9 μM 
and an activity ranking of omeprazole>pantoprazole>lansoprazole>rabeprazole. Hence, PPIs 
are effective FASN TE inhibitors. Analysis of the structure and activity of PPIs suggests that 
the size of either 2- pyridylmethyl or the benzimidazole moiety in PPIs may affect the ability 
of PPIs to inhibit FASN TE. 
 
We also performed molecular dynamics (MD) 
simulations of each PPI docked in the active site 
of TE and calculated the binding free energy 
(ΔGbind) using Poisson Boltzman surface area 
(PBSA) analyses. Table 1 shows that the ΔGbind 
is favorable and that omeprazole has the highest 
while rabeprazole has the lowest ΔGbind, similar 
to the ranking of their experimental Ki’s. Fig. 4B 
shows the simulated average structure of each PPI 
in FASN TE. Omeprazole, with the most favorable ΔGbind and Ki, shows potential 
formation of a strong hydrogen bond between serine residue (Ser2308) of the catalytic triad 
of TE and the sulfoxide moiety of omeprazole, which may prevent Ser2308 from 
nucleophilically attacking a substrate with an ester moiety. The hydrophobic benzamidazole 
moiety of PPIs may interact with residues of the “specificity channel,” which is predicted to 
accommodate the growing carbon chain during fatty acid synthesis (30), and may block 
access of the carbon chain to the channel. These findings provide theoretical support for PPI 
inhibition of TE. 
 


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PPIs inhibit and bind to cellular FASN. To determine if PPIs inhibit cellular FASN, we 
performed FASN activity assay in the absence or presence of PPIs using MCF7 cell lysate as 
we previously described (6, 7). Fig. 5A shows that 10 μM PPIs reduce >75% while 50 μM 
reduces >95% FASN activity. To investigate if PPI inhibits cellular FASN by binding to 
FASN, we performed a probe binding displacement experiment using the ActivX 
Desthiobiotin-fluorophosphonate (FP) serine hydrolase probe, which covalently binds to the 
Ser residue in the catalytic triad of serine hydrolases such as FASN TE (25). For this 
experiment, we tested lansoprazole. Briefly, cell lysate was incubated with the FP probe in 
the absence or 
presence of 
different 
concentrations of 
lansoprazole and 
subjected to 
Western blot 
analysis probed 
with streptavidin 
conjugated HRP. 
As shown in Fig. 
5B, lansoprazole 
inhibited FP probe 
labeling of FASN 
in a dose-
dependent manner. However, it had no effect on the binding of the FP probe to other Ser 
hydrolases, suggesting that lansoprazole selectively inhibits FASN TE. Lansoprazole also 
had no effect on the total FASN level (Fig. 5C).  
 
PPIs inhibit breast cancer cell proliferation and 
sensitize doxorubicin resistance. To determine if PPIs 
have any anti-breast cancer activity, we performed a 
colony formation assay using the TNBC cell line 
MDA-MB-231 in the absence or presence of PPIs. All 
PPIs effectively inhibited proliferation of MDA-MB-
231 cells with IC50 of 5.6-12.2 μM (Fig. 6). 
Omeprazole appears to be the most effective with an 
IC50 of 5.6 μM, consistent with the observation that 
it is most effective in inhibiting FASN TE activity 
(Table 1). Importantly the IC50 is near the plasma 
concentration (Cmax=4.2 µM and AUC=9.7 µM·h) 
achieved in patients (40 mg dose). Furthermore, PPI 
treatments induced apoptosis in a dose dependent manner (data not shown). Next, we tested 
the drug-resistant M3K cells using lansoprazole, which has the highest IC50 at 12.2 μM for 
MDA-MB-231 cells with the idea that if lansoprazole is effective, the other PPIs may be 
better. We found that M3K cells are more resistant to lansoprazole with a higher IC50 of 
~37 μM (Fig. 7A) than its IC50 of 12.2 μM in MDA-MB-231 cells, presumably due to high 
FASN level in M3K cells. However, lansoprazole at 5 μM, which causes <10% cell death 
Figure 6. Effect of PPIs on survival 
of breast cancer MDA-MB-231 cells 
as determined by colony formation 
assay. 


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(Fig. 7A), was able to reduce the doxorubicin IC50 from 46 to 28 nM in M3K cells (Fig. 
7B). Further study of lansoprazole-doxorubicin combination using the combination assay as 
described previously (26) showed that lansoprazole and doxorubicin have a synergistic 
effect on M3K cells with combination index around 0.3-0.7 (Fig. 7C). These findings 
suggest that PPIs not only have independent anticancer activity but also sensitize resistant 
breast cancer cells to doxorubicin.  
 
 
 
2.4 Pharmaco-epidemiologic Support for Use of PPIs 
Many breast cancer patients use PPIs for management of concurrent gastrointestinal reflux 
or ulcer disease. Thus, we performed a preliminary retrospective analysis of de-identified 
electronic medical records (EMR) of 6,323 breast cancer patients from Indiana Network for 
Patient Care (INPC). The average age at diagnosis was 58.9 years (range 19-102) and 
average age at death or last visit is 61.5 (range 21-104). Of this cohort, the EMR 
documented PPI use after diagnosis in 534 patients. There are 488 triple negative breast 
cancer (TNBC) patients, among them 35 used PPIs. Using the Cox proportional hazard 
regression model, overall survival was analyzed against PPI usage. Breast cancer patients 
who took PPIs had significantly increased overall survival than patients who did not (Fig. 
8A). Analysis of the TNBC subgroup showed that PPI usage also had significant but perhaps 
more protective effect (Fig. 8B). The protective effect of PPIs on patient survival was 
adjusted for age, tumor stage, and time of first diagnosis.  
Figure 8. Retrospective survival analysis of 
breast cancer patients with or without use of 
PPIs. De-identified EMR of 6,323 breast cancer 
patients were retrieved from the database of INPC 
and subjected to Kaplan-Meier survival analysis in 
association with PPI usage in all patients (A) or in 
TNBC subgroup (B). The p-value and hazard ratio 
(HR) were calculated from Cox proportional hazard 
models, which were adjusted for age, tumor stage, 
and time of first diagnosis.   
Figure 7. Effect of PPI on breast cancer cell 
drug resistance. A, Lansoprazole IC50 in drug 
resistant M3K cells by MTT assay. B, Effect of 
5 μM lansoprazole on doxorubicin IC50 in M3K 
cells by MTT assay. C, Combination index of 
lansoprazole and doxorubicin in M3K cells. 


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2.5 
Neoadjuvant Therapy in Breast Cancer 
Neoadjuvant chemotherapy has a well-established role in the management of both early-
stage and locally advanced breast cancer. Providing treatment prior to definitive surgery not 
only improves the ability to achieve breast conservation, but also allows determination of in 
vivo sensitivity to therapy and offers an ideal platform for clinical research. Although many 
will experience shrinkage in tumor volume with neoadjuvant therapy, at the time of surgery 
only about ~35% of patients with triple negative disease will experience a pathologic 
complete response (pCR), indicating the absence of invasive tumor tissue in the surgical 
specimen. Long-term follow-up of neoadjuvant studies consistently demonstrates 
significantly improved survival in individuals with pCR, with comparatively inferior 
outcomes in those with residual disease at surgery (27-29).  
 
We propose a single arm phase II trial of omeprazole + standard neoadjuvant chemotherapy 
as an obligate first step toward the definitive trial we envision. This study will provide 
safety, pharmacokinetic, biologic, and preliminary efficacy data that is needed for marshal 
support of an adequately designed, definitive randomized trial. 
3. OBJECTIVES 
 
3.1 Primary Objective 
• Estimate the rate of pCR in patients with triple negative breast cancer and FASN 
expression treated with standard neoadjuvant chemotherapy in combination with 
high dose omeprazole. 
 
3.2 Secondary Objectives 
• Quantify the number of patients with newly diagnosed TNBC with tumors that 
express FASN. 
• Estimate the rate of pCR in patients with triple negative breast cancer (irrespective of 
FASN status) treated with standard neoadjuvant chemotherapy in combination with 
high dose omeprazole. 
• Describe the safety of incorporating high dose omeprazole with standard 
neoadjuvant chemotherapy. 
• Estimate the biologic activity of high dose omeprazole in modulating FASN 
expression and activity. 
 
3.3 Tertiary/ Exploratory/ Correlative Objectives 
• Describe omeprazole exposure 
• Compare peak omeprazole concentration to level associated activity based on 
preclinical testing (~5.6 μM based on IC50) 
• Using PK-PD models, use omeprazole concentration and change in lipid levels to 
predict clinical outcome 
• Explore changes in lipid profile over time 


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3.4 Primary Outcome Measure 
• pCR is defined as no invasive disease in the breast or axilla at the time of definitive 
surgery 
 
3.5 Secondary Outcome Measures 
• FASN expression at baseline 
• Toxicity based on NCI CTC v 4.0 
• Change in FASN expression from baseline to after omeprazole monotherapy (Day 4-
7 biopsy) and after all therapy (surgery sample). 
• Change in FASN activity from baseline to after omeprazole monotherapy (Day 4-7 
biopsy) and after all therapy (surgery sample). 
• Change in FASN downstream target gene expression from baseline to after 
omeprazole monotherapy (Day 4-7 biopsy) and after all therapy (surgery sample). 
 
3.6 Tertiary/ Exploratory/ Correlative Outcome Measures 
• Population PK analyses based on a limited sampling strategy 
• Lipid profile including total cholesterol, triglycerides, high-density lipoprotein, low-
density lipoprotein, and non-esterified free fatty acids (NEFA) at baseline, after 
omeprazole monotherapy (NEFA only), the mid-point of chemotherapy and prior to 
surgery. 
4. ELIGIBILITY CRITERIA 
 
4.1 Inclusion Criteria 
1. Newly diagnosed triple negative breast cancer (TNBC) clinical stage I (must be T1c), II, 
or III 
• ER and PR < 10% 
• HER2 negative based on one of the following:    
o IHC 0 or 1+ 
o IHC 2+ and FISH negative  
o IHC 2+ and FISH equivocal and no indication for HER2 targeted 
therapy based on the treating investigators discretion (i.e., HER2: 
CEP17 ratio < 2.0 or HER2 total copy number <6) 
2. Planned neoadjuvant treatment with anthracycline and taxane containing chemotherapy 
3. ≥ 18 years old at the time of informed consent 
4. ECOG Performance Status 0-1 
5. Ability to provide written informed consent and HIPAA authorization 
6. Women of childbearing potential definition must have a negative pregnancy test within 
14 days of registration. All women (regardless of sexual orientation, having undergone a 
tubal ligation, or remaining celibate by choice) are considered to have childbearing 
potential unless they meet one of the following criteria: 
• Prior hysterectomy or bilateral oophorectomy;  
• Has not had menses at any time in the preceding 24 consecutive months 
7. Adequate organ function for anthracycline and taxane based therapy 


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• LVEF > LLN based on cardiac ECHO or MUGA 
• Hgb > 8.5 
• ANC > 1,000 
• Platelets > 100,000 
• Creatinine < 1.5 
• T. bili < 1.3 
• AST < 2.5 x ULN 
 
4.2 Exclusion Criteria 
1. Use of prescription PPIs within 12 months prior to study entry 
• Dexlansoprazole (Dexilant) 
• Pantoprazole (Protonix) 
• Rabeprazole (Aciphex) 
• Esomeprazole (Nexium) 
• Lansoprazole (Prevacid) 
• Omeprazole (Prilosec, Zegerid) 
2. Use of OTC PPIs within 6 months prior to study entry 
• Esomeprazole (Nexium) 
• Lansoprazole (Prevacid) 
• Omeprazole (Prilosec, Zegerid) 
3. Use of Orlistat or any other known FASN inhibitor within 6 months prior to study entry 
4. Nursing mothers are excluded. 
5. Known hypersensitivity to any component of the formulation or substituted 
benzimidazoles. 
6. Prior osteoporotic fracture 
5. STUDY DESIGN 
Single arm Phase II 
6. PATIENT REGISTRATION 
All patients will be registered with the Indiana University Cancer Center Clinical 
TrialsOffice, Registration must occur prior to the initiation of therapy. 
 
For participating sites to register a patient, the following documents should be completed by 
the study team and sent to the Coordinating Center Multicenter Network Administrator, 
(MNA), or designee. 
• Signed patient consent form 
• Completed and signed eligibility checklist 
 
• Copies of source documentation verifying eligibility 
 
The Coordinating Center will then review the documents to confirm eligibility. To complete 
the registration process, the MNA, or designee, will: 


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• Assign a patient study number 
• E-mail the patient study number to the participating site 
 
• The participating site will register the patient into OnCore 
 
Regulatory files will be maintained by the Clinical Trials Office. Applicable regulatory 
documents must be completed and on file prior to registration of any patients. Potential 
patients will be identified in the Oncology outpatient clinics or by referrals from outside 
physicians. Patients who appear to be eligible for this trial will undergo the Informed 
Consent Process and be screened for eligibility utilizing the Eligibility Criteria. The original 
signed IRB approved Informed Consent Document and completed eligibility checklist will 
be forwarded to the Clinical Trials Office designee for eligibility verification and 
registration in the OnCore® database. Notification will be sent to the principal investigator, 
treating physician and research nurse when registration is complete to confirm registration 
and inform them of patient ID number. 
 
Study data will be collected and stored in OnCore®, developed by Forte Research Systems, 
Inc. (www.forteresearch.com). OnCore® Enterprise Research is a comprehensive, web-
based, Clinical Trial Management System (CTMS) which utilizes an Oracle database.  It has 
been licensed by Indiana University (IU) to support the operations and data capture of 
clinical research trials. 
 
The system has been installed and configured within a HIPAA-aligned, Information 
Technology (IT), operations center supported by IU’s IT organization, University 
Information Technology Services (UITS). 
 
OnCore® provides users secure access with unique IDs/passwords and restricts access by 
assigned roles, from any location, to record, manage, and report on data associated with the 
operation and conduct of clinical trials. The system is comprised of three specific 
applications—Clinical Research Management (CRM), Biospecimen Management (BSM), 
and Unified Registries Management (URM). Indiana University leverages OnCore® to 
support clinical research operations specifically as it relates to the following 
functions/processes:  electronic Scientific Review Committee (SRC), regulatory 
management, protocol and subject life cycle management, coverage analysis, study 
financials management, subject registration and visit management, subject safety 
monitoring, protocol deviation monitoring, study auditing and monitoring, electronic data 
management, correlative study sample management, specimen banking and management, 
registries management, effort tracking, and reporting. 
7. TREATMENT PLAN 
 
7.1 Overview 
Patients should begin therapy within 7 working days of study entry. Patients will be treated 
with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and 
continuing until surgery. After the brief period of omeprazole monotherapy, patients will 


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begin standard neoadjuvant chemotherapy with doxorubicin (60 mg/m2) and 
cyclophosphamide (600 mg/m2) for 4 cycles followed by paclitaxel (80 mg/m2) weekly x 12.  
 
Doxorubicin and cyclophosphamide (AC) may be administered on a classical every 3 week 
or dose dense every 2 week (with growth factor support) schedule at the treating physician’s 
discretion. Routine incorporation of carboplatin is not recommended, however use of 
carboplatin (AUC 6 on week 1, 4, 7, and 10) with paclitaxel is allowed at the treating 
investigator’s discretion. Chemotherapy will be adjusted based on toxicity according to 
standard treatment guidelines. Additional details regarding neoadjuvant chemotherapy can 
be found in Sections 7.3 and 7.4. Information contained in these sections is intended to be 
used as a guideline for administering standard of care neoadjuvant chemotherapy, and 
modifications to these dosing guidelines  can be made based upon institutional standard 
practice or physician discretion. These modifications will not be recorded as deviations for 
this protocol.  
 
Patients with overt disease progression during AC should move immediately to paclitaxel 
therapy. Patients with disease progression during paclitaxel should proceed immediately to 
surgery. Additional details regarding disease progression can be found in Section 7.5.  
 
Doses should be based upon actual body weight. If subject’s weight changes by  
> 10% during the course of the study, the body surface area and drug dose should be 
recalculated.
 
7.2 Omeprazole 
Omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing 
throughout chemotherapy until surgery. Omeprazole should be discontinued the night prior to 
surgery. 
 
NOTE: Omeprazole inhibits CYP2C19. Patients taking drugs known to be substrates of 
CYP2C19 (Appendix IV) may enroll but the treating investigator should be aware of the 
potential drug interaction. When possible, changing to an alternative agent that is not 
metabolized by CYP2C19 is advised. 
 
 
 
 


 
 
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7.3 Doxorubicin and Cyclophosphamide (AC)† 
Agent 
Time 
Dose 
Route 
Day 
Fosaprepitant 
30 minutes 
prior to AC 
150 mg 
IV infusion in 145 mL NS 
over 20-30 minutes 
1 
Doxorubicin 
NA 
60 mg/m2 
IV push through running 
IV of NS 
1 
Cyclophosphamide 
NA 
600 mg/m2 
IV infusion in 150 mL NS 
over 20-30 minutes 
1 
Pegfilgrastim*  
OR 
Filgrastim* 
NA 
6 mg (regardless 
of BSA) 
 
SQ 
 
2 
NA 
5 µg/kg** 
2-11 
* Pegfilgrastim or filgrastim are recommended after each AC treatment (cycle 1-4) for patients receiving 
dose dense AC. Otherwise, hematologic growth factors are not recommended but may be used in 
accordance with the ASCO guidelines.  
** Rounded to the nearer of 300 or 480 μg.  
† Information contained in this table is intended to be used as a guideline for administering standard of 
care neoadjuvant AC chemotherapy, and modifications to this table can be made based upon institutional 
guidelines or physician discretion. These modifications will not be recorded as deviations for this 
protocol. 
 
AC may be administered every 21 days (classical schedule) OR every 14 days with growth 
factor support (dose dense schedule). Choice of AC schedule is at the treating investigator’s 
discretion. 
 
 
 
7.4 Paclitaxel (T)† 
Agent 
Time 
Dose 
Route 
Day 
Dexamethasone* 
30-60 minutes 
prior to 
paclitaxel 
12 mg 
IV or po 
Every 7 days 
Diphenhydramine* 
50 mg 
IV or po 
Cimetadine** 
300 mg 
IV 
Paclitaxel 
NA 
80 
mg/m2 
IV infusion in 250 
mL NS or D5W over 
1 hour 
Every 7 days 
Carboplatin*** 
NA 
AUC 6 
IV infusion 
Every 21 days 
(weeks 1, 4,7, and 
10 with paclitaxel) 
* The doses of diphenhydramine and dexamethasone may be adjusted after the first dose, based on 
tolerability. 
** Ranitidine (50 mg IV) or famotidine (20 mg IV) may be substituted for cimetidine; however, 
famotidine is preferred.  
*** Incorporation of carboplatin is not recommended, however the use of carboplatin with paclitaxel is 
allowed at the treating investigator’s discretion. Magnesium wasting may be more common in patients 
receiving concurrent carboplatin. More frequent monitoring of magnesium should be considered in those 
patients. 
† Information contained in this table is intended to be used as a guideline for administering standard of 
care neoadjuvant paclitaxel chemotherapy, and modifications to this table can be made based upon 
institutional guidelines or physician discretion. These modifications will not be recorded as deviations for 
this protocol. 


 
 
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7.5 Management of Disease Progression 
Frank disease progression during neoadjuvant chemotherapy is unusual. In the event of disease 
progression, the treatment plan should be modified as follows: 
• Locally progressive disease at any point during AC - defer remaining cycles of AC and 
begin treatment with paclitaxel (+ carboplatin if desired) according to the original treatment 
plan. 
• Locally progressive disease at any point during paclitaxel - defer remaining cycles of 
paclitaxel, perform required completion of chemotherapy evaluation and refer for definitive 
surgery. 
• Systemic disease progression - any patient who develops evidence of metastatic disease will 
be removed from study. 
 
7.6 Breast Surgery and Management of the Axilla 
At the completion of neoadjuvant chemotherapy, patients will undergo definitive surgical 
resection. Decisions regarding the type of surgery (breast conserving surgery, unilateral or 
bilateral mastectomy), management of the axillary lymph nodes, and incorporation of 
reconstruction will be according to the patient’s preference and treating surgeon’s 
recommendation. Similarly, the use of post-surgery radiation therapy and additional adjuvant 
systemic therapy are at the treating investigator’s discretion and are not specified by this 
protocol.  
 
When appropriate and desired, patients may enroll in other studies addressing important 
local therapy and post-neoadjuvant systemic therapy questions.  
 
8. TOXICITIES TO BE MONITORED/DOSAGE MODIFICATIONS 
All toxicities should be graded according to the Common Terminology Criteria for Adverse Events 
(version 4.0). 
If a patient develops multiple toxicities, delay treatment or modify dose based on the greatest indicated 
dose reduction or delay. Dose re-escalations are not allowed. 
 
8.1 Omeprazole  
No dose modification of omeprazole is planned during this study. If patients are unable to take 
omeprazole for more than 14 consecutive days, they should come off the study. 
 
Omeprazole should be discontinued for any of the following: 
• Acute interstitial nephritis  
• Osteoporosis-related fractures of the hip, wrist, or spine  
• Vitamin B-12 deficiency 
• Clostridium difficile associated diarrhea 
• Grade 3 hypomagnesemia 
• Any other grade 3 or greater toxicity thought to be related to omeprazole 


 
 
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8.2 AC† 
 
Event  
Dose Modification 
Neutropenia (on Day 1 of any cycle) 
> 1000/mm3 
No change 
 
< 1000/mm3  
Hold until ANC >1000, resume based on timing of recovery:  
< 1 week – no change or add growth factor support (if not already used) 
>1 but < 3 weeks - reduce dose 20% for subsequent cycles or add 
growth factor support (if not already used) 
> 3 weeks – stop AC, proceed to paclitaxel 
Neutropenic Fever (at any point) 
ANC< 1000, fever 
> 38.5 
Interrupt until resolved (ANC >1000, fever <38.5), resume according to 
number of episodes:  
1st  = no change or add growth factor support (if not already used) 
2nd = 20% dose reduction or add growth factor support (if not already 
used) 
3rd = stop AC, proceed with paclitaxel 
Thrombocytopenia (on Day 1 of any cycle) 
>100,000/mm3 
No change 
75-99,999/mm3 
Hold until > 100,000, resume based on timing of recovery:  
< 1 week – no change` 
>1 but < 3 weeks - reduce dose 20% for subsequent cycles 
> 3 weeks – stop AC, proceed to paclitaxel 
<75,000 
Hold until >100,000, Resume with 20% dose reduction for subsequent 
cycles. If > 3 weeks delay  
is required, stop AC and proceed with paclitaxel. 
Anemia 
All grades 
No change – erythropoietin or darbepoietin therapy may be initiated at 
the investigator’s discretion. Transfusion support is allowed 
Hepatic (on Day 1 of any cycle) 
Grade 0 or 1  
No change 
> Grade 2 
Interrupt until < Grade 1, then resume previous dose. If > 3 weeks delay 
is required, stop AC and proceed with paclitaxel. 
Nausea/Vomiting (at any point) 
Grade 0 - 2 
No change 
> Grade 3 
 
Hold until resolved to < Grade 1, reduce dose 20% in subsequent cycles. 
Mucositis (at any point) 
Grade 0 - 2 
 
No change 
> Grade 3 
Hold until resolved to < Grade 1, reduce dose 20% in subsequent cycles. 


 
 
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Event  
Dose Modification 
Cardiac (at any point) 
Grade 0 - 2 
No change 
> Grade 3 
 
Discontinue AC if: 
o a patient has symptoms of CHF and a diagnosis of CHF is 
confirmed  
o a patient has a myocardial infarction 
o >15% absolute decline in LVEF from baseline, or >10% decline in 
LVEF from baseline to below LLN  
Patients who discontinue AC due to cardiac toxicity may receive 
paclitaxel at the investigator’s discretion  
Other clinically significant toxicity excluding fatigue, alopecia and leukopenia 
Grade 0 or 1 
No change 
Grade 2 
Hold until resolved to < Grade 1, resume at previous dose. Increase 
supportive care measures if possible. 
> Grade 3 
Hold until resolved to < Grade 1, resume with 20% dose reduction for 
subsequent cycles. If Grade 3 or greater toxicity recurs, stop AC and 
proceed with paclitaxel. 
† Information contained in this table is intended to be used as a guideline for AC dose modifications, and 
variation from this table can be made based upon institutional guidelines or physician discretion. These 
modifications will not be recorded as deviations for this protocol. 
 
8.3 Paclitaxel (+/- Carboplatin)† 
AC dose modification or delay will not impact paclitaxel therapy. 
If toxicity requires carboplatin to be held, paclitaxel should be held as well to maintain the same 
treatment schedule. However patients who discontinue carboplatin may complete the planned 
paclitaxel. 
Infusions that are ‘held’ will be ‘made up’ when recovery allows treatment to resume. 
However the total time for paclitaxel (+carboplatin) therapy may not exceed 16 weeks. 
Event 
Paclitaxel  
Carboplatin 
Neutropenia (On day of planned treatment) 
> 1000/mm3 
No change 
 
No change 
< 1000/mm3  
Hold until ANC >1000, resume 
based on timing of recovery:  
< 1 week – no change 
>1 but < 3 weeks - reduce dose 
20% for subsequent cycles 
> 3 weeks – stop paclitaxel 
Hold until ANC >1000, resume 
based on timing of recovery:  
< 1 week – no change 
>1 but < 3 weeks - reduce dose 1 
AUC for subsequent cycles 
> 3 weeks – stop carboplatin 
Neutropenic Fever (at any point) 


 
 
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Event 
Paclitaxel  
Carboplatin 
ANC < 1000, fever > 
38.5 
Interrupt until resolved (ANC 
>1000, fever <38.5), resume 
according to number of episodes:  
1st  = no change 
2nd = 20% dose reduction 
3rd = stop paclitaxel 
Interrupt until resolved (ANC 
>1000, fever <38.5), resume 
according to number of episodes:  
1st  = no change 
2nd = 1 AUC dose reduction 
3rd = stop carboplatin 
Thrombocytopenia (on day of planned treatment) 
> 100,000/mm3
 
 
No change 
No change 
75-99,999/mm3 
Hold until > 100,000, resume 
based on timing of recovery:  
< 1 week – no change 
>1 but < 3 weeks - reduce dose 
20% for subsequent cycles 
>3 weeks – stop paclitaxel 
Hold until > 100,000, resume 
based on timing of recovery:  
< 1 week – no change 
>1 but < 3 weeks - reduce 1 
AUC for subsequent cycles 
>3 weeks – stop carboplatin  
<75,000 
Hold until > 100,000, Resume 
with 20% dose reduction for 
subsequent cycles. If > 3 weeks 
delay is required, stop paclitaxel 
Hold until > 100,000, Resume 
with 1 AUC dose reduction for 
subsequent cycles. If > 3 weeks 
delay is required, stop 
carboplatin 
Anemia 
All grades 
No change – erythropoietin or darbepoietin therapy may be initiated 
at the investigator’s discretion. Transfusion support is allowed.  
Hepatic 
Grade 0 or 1  
No change 
No change 
> Grade 2 
Interrupt until < Grade 1, then 
resume previous dose. If > 3 
weeks delay is required, stop 
paclitaxel  
No change 
Renal 
Grade 0-1 
No change 
No change 
> Grade 2 
No change 
Discontinue carboplatin 
Nausea/Vomiting ( any point) 
Grade 0 - 2 
No change 
No Change 
> Grade 3 
 
Hold until resolved to < Grade 1, 
reduce dose 20% in subsequent 
cycles. 
Hold until resolved to < Grade 1, 
reduce dose 1 AUC in 
subsequent cycles. 
Mucositis (at any point) 
Grade 0 - 2 
 
No change 
No change 


 
 
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Event 
Paclitaxel  
Carboplatin 
> Grade 3 
Hold until resolved to < Grade 1, 
reduce dose 20% in subsequent 
cycles. 
Hold until resolved to < Grade 1, 
reduce dose 1 AUC in 
subsequent cycles. 
Neurotoxicity (at any point) 
Grade 0 - 1 
No change 
No change 
Grade 2 
If interval Grade 2 toxicity has 
resolved to < Grade 1 on the day 
of treatment, proceed with 
treatment at the previous dose. 
If Grade 2 toxicity is present on 
the day of treatment, reduce dose 
20% for all subsequent cycles. 
If interval Grade 2 toxicity has 
resolved to < Grade 1 on the day 
of treatment, proceed with 
treatment at the previous dose. 
If Grade 2 toxicity is present on 
the day of treatment, reduce dose 
1 AUC for all subsequent cycles. 
Grade 3 
Hold until resolved to < Grade 1, 
reduce dose 20% in all 
subsequent cycles. If > 3 weeks 
delay is required, stop 
carboplatin 
Hold until resolved to < Grade 1, 
reduce dose 1 AUC in all 
subsequent cycles. If > 3 weeks 
delay is required, stop 
carboplatin 
Grade 4 
Discontinue paclitaxel  
Discontinue carboplatin 
Anaphylaxis/Hypersensitivity 
Mild (e.g., mild 
flushing, rash, 
pruritis) 
No treatment needed. Supervise 
at bedside and complete 
paclitaxel infusion. 
No treatment needed. Supervise 
at bedside and complete 
carboplatin infusion. 
Moderate (e.g., 
moderate flushing, 
rash, mild dyspnea, 
chest discomfort) 
Stop paclitaxel. Administer 
diphenhydramine 25 mg and 
dexamethasone 10 mg IV. After 
recovery, resume infusion at half 
the previous rate for 15 minutes. 
If no further symptoms occur, 
complete the infusion at the full 
dose rate. If symptoms recur, 
stop paclitaxel.  
Stop carboplatin. Administer 
diphenhydramine 25 mg and 
dexamethasone 10 mg IV. After 
recovery, resume infusion at half 
the previous rate for 15 minutes. 
If no further symptoms occur, 
complete the infusion at the full 
dose rate. If symptoms recur, 
stop carboplatin. 
Severe (e.g., 
hypotension requiring 
pressors, angioedema, 
respiratory distress 
requiring 
bronchodilators) 
Stop paclitaxel. Administer 
diphenhydramine 25 mg and 
dexamethasone 10 mg IV. Add 
epinephrine or bronchodilators as 
needed. Do not restart paclitaxel. 
Stop carboplatin. Administer 
diphenhydramine 25 mg and 
dexamethasone 10 mg IV. Add 
epinephrine or bronchodilators as 
needed. Do not restart 
carboplatin. 
Other clinically significant toxicity excluding fatigue, alopecia and leukopenia 
Grade 0 or 1 
No change 
No change 
Grade 2 
Hold until resolved to < Grade 1, 
resume at previous dose. 
Increase supportive care 
measures if possible. 
Hold until resolved to < Grade 1, 
resume at previous dose. Increase 
supportive care measures if 
possible. 


 
 
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Event 
Paclitaxel  
Carboplatin 
> Grade 3 
Hold until resolved to < Grade 1, 
resume with 20% dose reduction 
for subsequent cycles. If Grade 3 
or greater toxicity recurs, stop 
paclitaxel. 
Hold until resolved to < Grade 1, 
resume with 1AUC dose 
reduction for subsequent cycles. 
If Grade 3 or greater toxicity 
recurs, stop carboplatin. 
† Information contained in this table is intended to be used as a guideline for AC dose modifications, and 
variation from this table can be made based upon institutional guidelines or physician discretion. These 
modifications will not be recorded as deviations for this protocol. 
 
8.4 
Supportive Care 
• It is anticipated that nausea and vomiting may be a significant side effect of the treatment 
regimen. Therefore, the following combination regimen is recommended: Dexamethasone, 
10 mg IV or PO, plus a 5-HT3 receptor antagonist prior to AC chemotherapy. 
Prochlorperazine or another antiemetic at the physician’s discretion may be used before 
paclitaxel treatment. 
• All supportive measures consistent with optimal patient care will be given throughout the 
study. 
• Pegfilgrastim or filgrastim are recommended after each AC treatment (cycle 1-4) for patients 
receiving dose dense AC. Otherwise, hematologic growth factors are not required but may be 
used in accordance with the ASCO guidelines. 
 
8.5 Duration of Follow-up 
The primary endpoint of this trial is pCR, therefore study treatment will end at surgery. Patients 
who developed omeprazole related toxicities will be followed until the toxicity has resolved, 
returned to baseline, or have been determined to be irreversible. Data regarding therapies 
administered after surgery, disease recurrence, and overall survival will not be collected. 


 
 
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9. STUDY PARAMETERS/CALENDAR 
 
 
Omeprazole 
monotherapy 
AC 
 
BaselineA 
Day 1 of 
omeprazole 
treatment 
After 4-7 
days of 
omeprazole 
treatment 
C1 
D1 
C2 
D1 
C3 
D1 
C4 
D1 
REQUIRED 
ASSESSMENTS 
 
 
 
 
+/-7 
days 
+/-7 
days 
+/-7 
days 
Informed consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical 
exam/ECOG PS 
X 
 
 
X 
X 
X 
X 
Urine pregnancyB 
X 
 
 
 
 
 
 
CBC 
X 
 
 
X 
X 
X 
X 
CMP 
X 
 
 
X 
 
X 
 
Serum B-12 
X 
 
 
 
 
 
 
Serum magnesium 
X 
 
 
 
 
 
 
LVEFC 
X 
 
 
 
 
 
 
AE assessment 
X 
 
Continuous 
DISEASE 
ASSESSMENT 
 
 
 
 
 
 
 
Breast ImagingD 
XE 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
Omeprazole 
 
X 
X 
Continuous 
ACF 
 
 
 
X 
X 
X 
X 
Paclitaxel 
 
 
 
 
 
 
 
Carboplatin 
 
 
 
 
 
 
 
CORRELATIVE 
STUDIES 
 
 
 
 
 
 
 
Tumor biopsyG 
X 
 
X 
 
 
 
 
Cell-free DNA 
X 
 
XJ 
 
 
 
 
Serum lipid 
profileH,K 
X 
 
XJ 
 
 
 
 
Serum NEFAH 
X 
 
XJ 
 
 
 
 
Omeprazole Level 
 
XI 
 
 
X 
 
X 
Footnotes:  
ABaseline assessment should be completed within 21 days of study registration. 
BPregnancy testing should be completed with 14 days of study registration in all patients with childbearing potential. 
CLVEF may be assessed by either ECHO or MUGA. 
DBreast imaging should include mammogram and ultrasound. Breast MRI is not required and will not be repeated 
solely for the purposes of this study.  
EBreast imaging should be completed within 28 days of study registration. 
FAC may be administered every 3 weeks or every 2 weeks with growth factor support. Cycle 1 should begin within 
4-7 days after starting omeprazole monotherapy. 
GA core biopsy will be obtained after study registration but prior to starting omeprazole treatment (baseline), and 
after 4-7 days of omeprazole treatment but prior to initiation of AC. IU subjects are required to have a fresh biopsy 
at baseline. Non-IU subjects may donate archived tissue in lieu of a fresh biopsy at baseline if adequate tissue is 
available. See Section 13.1 for additional details. 
HFasting for 12-14 hours prior to blood collection is required. 
IPlasma for measurement of omeprazole will be obtained prior to dosing and 2 hours after the first dose of 
omeprazole only. All other time points will collect a single plasma sample without regard to time from last dose.  
JThese labs can be done on C1D1 of AC instead of the after 4-7 days of omeprazole visit if needed. 
Calendar 
continued 
on page 22 


 
 
Version 04/03/2020 
Page 25 
KThis test should be run by the hospital as it is a routine laboratory test. Separate tubes for serum lipid will not be 
included in the correlative blood collection kits. 
 
 
Paclitaxel (+Carboplatin if desired) 
 
 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
Pre-
Surgery 
REQUIRED 
ASSESSMENTS 
+/-7 
days 
+/-7 
days 
+/-7 
days 
+/-7 
days 
+/-7 
days 
+/-7 
days 
+/-7 
days 
+/-7 
days 
+/-7 
days 
+/-7 
days 
+/-7 
days 
+/-7 
days 
 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
exam/ECOG PS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CMP 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Serum B-12 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum 
magnesium 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
LVEF 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE assessment 
Continuous 
 
DISEASE 
ASSESSMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breast ImagingA 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
Omeprazole 
Continuous 
 
AC 
 
 
 
 
 
 
 
 
 
 
 
 
 
PaclitaxelB 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CarboplatinC 
(X) 
 
 
(X) 
 
 
(X) 
 
 
(X) 
 
 
 
CORRELATIVE 
STUDIES 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
(X)D 
Cell-free DNA 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum lipid 
profileE,G 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum NEFAE 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Omeprazole 
LevelF 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
ABreast imaging should include mammogram and ultrasound. Breast MRI is not required and will not be repeated 
solely for this study. 
BInfusions that are ‘held’ will be ‘made up’ when recovery allows treatment to resume. However the total time for 
paclitaxel (+carboplatin) therapy may not exceed 16 weeks. 
CCarboplatin is not recommended but is allowed at the treating investigator’s discretion. 
DOnly in patients with clinically apparent residual abnormality. May be obtained intraoperatively.  
EFasting for 12-14 hours prior to blood collection is required. 
FA single plasma sample for measurement of omeprazole will be obtained at each time point without regard to time 
from last dose. 
GThis test should be run by the hospital, as it is a routine laboratory test. Separate tubes for serum lipid will not be 
included in the correlative blood collection kits.


 
 
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10. CRITERIA FOR EVALUATION/REMOVAL FROM STUDY 
 
10.1 
Definitions Associated with Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 
10.1.1 Measurable disease - At baseline, tumor lesions/lymph nodes will be categorized 
measurable or non-measurable as follows: 
 
10.1.2 Measurable  
Tumor lesions –will be measured using any of the following methods of measurement: 
 
• Chest X-ray: Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung. However, CT scans are 
preferable. 
 
• Clinical Lesions: For superficial non-nodal lesions, physical examination is 
acceptable, but imaging is preferable, if both can be done. Clinical lesions will only 
be considered measurable when they are superficial (e.g., skin nodules and palpable 
lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using calipers (e.g., skin 
nodules). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced 
in their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will 
be taken from one assessment to the next. If new lesions are identified by ultrasound 
in the course of the study, confirmation by CT or MRI is advised. If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected 
instances. 
 
Malignant lymph nodes: 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be 
no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.   
 
10.1.3 Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions.  
Lesions considered truly non-measurable include:  leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, abdominal masses/ abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
 
10.1.4 Baseline documentation of “Target” and “Non-Target” lesions  
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 


 
 
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of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means if a patient has only one or two organ sites involved, a 
maximum of two and four lesions, respectively, will be recorded.  
 
 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs and should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be selected.  
 
10.1.4.1 Lymph nodes 
Pathological nodes which are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the short axis 
of these nodes will contribute to the baseline sum.  The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor. 
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short 
axis. For example, an abdominal node which is reported as being 20mm·x 30mm has a 
short axis of 20mm and qualifies as a malignant, measurable node. In this example, 
20mm should be recorded as the node measurement. All other pathological nodes (those 
with short axis ≥ 10 but < 15 mm) should be considered non-target lesions. Nodes that 
have a short axis <10 mm are considered non-pathological and should not be recorded or 
followed.  
 
10.4.1.2 Sum of Diameters 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  As noted 
above, if lymph nodes are to be included in the sum, only the short axis is added into the 
sum.  The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease.   
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as ‘present’, ‘absent’, or in rare 
cases ‘unequivocal progression’.  In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case report form (e.g., ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
10.2 
Evaluation of Target Lesions 
 
Response 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm) 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters 


 
 
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Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). 
In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  
NOTE: the appearance of one or more new lesions is also 
considered progression. 
 
 
 


 
 
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10.2.1 Special notes on assessment of target lesions 
 
10.2.1.1  Lymph nodes: 
Target lesion lymph nodes should always have the short axis measurement recorded 
(measured in the same anatomical plane as the baseline exam), even if the nodes regress 
to below 10 mm.  Thus, when lymph nodes are included as target lesions, the ‘sum’ of 
lesions may not be zero even if complete response criteria are met, since a normal lymph 
node is defined as having a short axis < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate 
section where, in order to qualify for CR, each node must achieve a short axis <10mm. 
For PR, SD and PD, the actual short axis measurement of the nodes is to be included in 
the sum of target lesions. 
 
10.2.1.2 Target lesions that become ‘too small to measure’: 
All lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g., 2 
mm). However, sometimes lesions or lymph nodes become so faint on scan that the 
radiologist may report them as ‘too small to measure’. 
When this occurs it is important that a value be recorded on the case report form. If it is 
the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present and is faintly seen but 
too small to measure, a default value of 5 mm should be assigned (derived from 5 mm 
slice thickness).  Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such 
as in the retroperitoneum; however, if a lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5mm should be assigned in this 
circumstance as well. However, if the radiologist is able to provide an actual 
measurement, it should be recorded even if it is below 5 mm.  
 
10.2.1.2 Lesions that split or coalesce on treatment: 
When non-nodal lesion ‘fragment’, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum.  Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion.  If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance 
should be the maximal longest diameter for the ‘coalesced lesion’.  
 
10.3 
Evaluation of Non-Target Lesions 
Response 
Evaluation of Non-Target Lesions 
Complete Response 
(CR) 
Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in 
size (< 10 mm short axis) 
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
Progressive Disease 
(PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
 


 
 
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10.3.1 Special notes on assessment of progression of non-target disease 
 
10.3.1.1 When the patient also has measurable disease 
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target 
disease, there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the size 
of one or more non-target lesions is usually not sufficient to quality for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
 
10.3.1.2 When the patient has only non-measurable disease 
This circumstance arises in some phase III trials when it is not a criterion of study entry 
to have measurable disease. The same general concepts apply here as noted above, 
however, in this instance there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden. Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly non-
measurable) a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e., an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include an increase in a pleural 
effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from localised to 
widespread, or may be described in protocols as ‘sufficient to require a change in 
therapy’. If ‘unequivocal progression’ is seen, the patient should be considered to have 
had overall PD at that point. While it would be ideal to have objective criteria to apply to 
non-measurable disease, the very nature of that disease makes it impossible to do so, 
therefore the increase must be substantial. 
 
10.4 
New Lesions 
There are no specific criteria for the identification of new radiographic lesions; however, 
the finding of a new lesion should be unequivocal: i.e., not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent 
something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s 
baseline lesions show partial or complete response. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not. 
 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of 
this is the patient who has visceral disease at baseline and while on study has a CT or 
MRI brain ordered which reveals metastases. The patient’s brain metastases are 
considered to be evidence of PD even if he/she did not have brain imaging at baseline.  
 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 


 
 
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there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 
 
10.5 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for PD the smallest 
measurements recorded since the treatment started). The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also 
take into consideration the appearance of new lesions.  
 
Target Lesions 
Non-Target 
Lesions 
New Lesion? Best Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non CR/  
Non PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 
having “symptomatic deterioration”.  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status. 
 
10.6 
Criteria for Removal from Study 
Patients will be removed from study under any of the following conditions: 
• When removal from study is thought to be in the best interest of the patient by the 
patient or the patient’s treating physician. 
• Unacceptable toxicity in the judgement of the patient or patient’s treating physician. 
• Pregnancy or failure to practice appropriate contraception. 
• Patient’s request. 
• Evidence of systemic metastatic disease. 
• Inability to take omeprazole for 14 continuous days. 
 


 
 
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11. DRUG INFORMATION 
 
11.1 
Drug Name 
Omeprazole 
 
11.2 
Other Names 
 
PRILOSEC 
 
11.3 
Classification 
Proton pump inhibitor 
 
11.4 
Mode of Action 
Omeprazole belongs to a class of antisecretory compounds, the substituted 
benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ 
ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this 
enzyme system is regarded as the acid (proton) pump within the gastric mucosa, 
omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the 
final step of acid production. This effect is dose-related and leads to inhibition of both 
basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate 
that after rapid disappearance from plasma, omeprazole can be found within the gastric 
mucosa for a day or more. 
 
11.5 
Storage and Stability 
Store omeprazole (PRILOSEC) Delayed-Release Capsules in a tight container protected 
from light and moisture. Store between 15°C and 30°C (59°F and 86°F). 
 
11.6 
Metabolism 
Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system. 
 
11.7 
Dosage Forms and Strengths 
Delayed-Release Capsules: 10 mg, 20 mg and 40 mg 
Delayed-Release Oral Suspension: 2.5 mg or 10 mg 
 
11.8 
Administration 
Patients will be instructed to take two 40 mg capsules (80 mg) twice daily. Capsules 
should not be chewed or crushed. Missed doses should not be made up.  
 
Patients will begin taking the omeprazole 4-7 days before chemotherapy, and will 
continue taking the medication throughout chemotherapy until surgery (up to 8 months).  
 
11.9 
Availability  
This study will be conducted in compliance with 21 CFR 312.7 (promotion and charging 
for investigational drugs). Omeprazole will be obtained, stored, and dispensed by the 
IUSCC Investigational Drug Service (IDS). Patients will be instructed to bring their 
bottles with unused omeprazole back to the clinic. After pill counts to document 


 
 
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compliance and drug exposure, remaining omeprazole will be returned to IDS for proper 
disposal.  
 
11.10 Side Effects  
The most common adverse reactions reported in adults (incidence > 2%) are 
headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence. 
 
The following adverse reactions have been identified during post- approval use of 
PRILOSEC Delayed-Release Capsules. Because these reactions are voluntarily 
reported from a population of uncertain size, it is not always possible to reliably 
estimate their actual frequency or establish a causal relationship to drug exposure. 
• Body As a Whole: Hypersensitivity reactions including anaphylaxis, anaphylactic 
shock, angioedema, bronchospasm, interstitial nephritis, uticaria, (see also Skin 
below); fever; pain; fatigue; malaise   
• Cardiovascular: Chest pain or angina, tachycardia, bradycardia,  palpitations, 
elevated blood pressure, peripheral edema 
• Endocrine: Gynecomastia 
• Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal 
discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, 
abdominal swelling, dry mouth, microscopic colitis.  During treatment with 
omeprazole, gastric fundic gland polyps have been noted rarely.  These polyps are 
benign and appear to be reversible when treatment is discontinued.  
• Gastroduodenal carcinoids have been reported in patients with ZE syndrome on 
long-term treatment with PRILOSEC.  This finding is believed to be a 
manifestation of the underlying condition, which is known to be associated with 
such tumors.  
• Hepatic: Liver disease including hepatic failure (some fatal), liver necrosis (some 
fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed 
hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, 
alkaline phosphatase, and bilirubin] Infections and Infestations:  Clostridium 
difficile associated diarrhea  
• Metabolism and Nutritional disorders: Hypoglycemia, hypomagnesemia, 
hyponatremia, weight gain  
• Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain, 
bone fracture  
• Nervous System/Psychiatric: Psychiatric and sleep disturbances including 
depression, agitation, aggression, hallucinations, confusion, insomnia, 
nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, 
paresthesia; vertigo  
• Respiratory: Epistaxis, pharyngeal pain  
• Skin: Severe generalized skin reactions including toxic epidermal necrolysis 
(some fatal), Stevens-Johnson syndrome, and erythema multiforme; 
photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; 
alopecia; dry skin; hyperhidrosis  
• Special Senses: Tinnitus, taste perversion  
• Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye 
syndrome, ocular irritation, blurred vision, double vision  


 
 
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• Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated serum 
creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary 
frequency, testicular pain 
• Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, 
neutropenia, anemia, thrombocytopenia, leukopenia, leukocytosis 
 
11.11 Nursing Implications 
Omeprazole concentrations have been measured in breast milk of a woman following oral 
administration of 20 mg. The peak concentration of omeprazole in breast milk was less 
than 7% of the peak serum concentration. This concentration would correspond to 0.004 
mg of omeprazole in 200 mL of milk. Because omeprazole is excreted in human milk, 
because of the potential for serious adverse reactions in nursing infants from omeprazole, 
and because of the potential for tumorigenicity shown for omeprazole in rat 
carcinogenicity studies, patients who are nursing are not eligible for this trial. 
 
Omeprazole inhibits CYP2C19. Patients taking drugs known to be substrates of 
CYP2C19 (Appendix IV) may enroll but the treating investigator and nursing staff should 
be aware of the potential drug interaction.  
12. STATISTICAL METHODS 
 
12.1 
General Considerations 
Statistical analysis of this study will be the responsibility of the Biostatistics and Data 
Management Core at the Indiana University Melvin and Bren Simon Cancer Center 
(IUSCC). Parameter estimates and relevant summary statistics will be reported where 
appropriate. For continuous variables, summary statistics will include number of subjects, 
mean, median, standard deviation, minimum and maximum. Categorical endpoints will 
be summarized using number of subjects, frequency, and percentages. Missing data will 
not be imputed. Data analysis will be performed in SAS Version 9.4.  Additional 
exploratory analyses of the data will be conducted as deemed appropriate. Changes from 
this analysis plan will not require an amendment to the protocol unless it changes a 
significant feature of the protocol. 
The statistical analysis methods are outline below. 
 
12.2 
Study Design  
This is a single arm Phase II study of omeprazole + standard neoadjuvant chemotherapy 
as an obligate first step toward a definitive trial. 
 
12.3 
Analysis Datasets 
The enrolled population comprises all patients who meet the eligibility criteria and are 
registered onto the study. 
 
12.4 
Sample Size 
The key clinical endpoint is pCR and the primary subgroup of interest is in patients who 
have the target at baseline.  Based on previously reported trials with standard 
anthracycline/taxane therapy, we estimate a pCR rate of ~40%. Assuming that 70% of 


 
 
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patients with newly diagnosed TNBC have FASN expression, a single stage phase II trial 
to detect a pCR rate of 60% with power = 80% and alpha=0.10  requires 30 FASN 
patients (or 42 patients total). This sample size also provides approximately 80% power 
to identify a change in FASN expression and/or activity of 0.5 SDs using a paired t-test 
and significance level of 0.05. Patients who are inevaluable for the primary endpoint will 
be considered non-responders and will not be replaced.  
 
12.5 
Patient Characteristics 
Demographics, medical history, and physical examination characteristics will be 
summarized using descriptive statistics. 
 
12.6 
Disposition 
Frequencies and percentages of all patients enrolled, discontinuing the study, and 
completing the study will be presented. The reasons for discontinuation will also be 
summarized. 
 
12.7 
Analysis of Primary Objectives 
For estimating pCR rate, a 95% exact confidence interval will be calculated. 
 
12.8 
Analysis of Secondary Objectives 
For number of patients expressing FASN in tumor, a proportion and 95% confidence 
interval will be reported.    
 
For estimating pCR rate in all patients, 95% exact confidence intervals will be calculated. 
 
For safety, NCI CTC Version 4.0 will be used to summarize adverse events in the 
assessment of safety for incorporating high dose omeprazole with standard neoadjuvant 
chemotherapy.  Summaries of treatment related adverse events in the population will be 
tabulated. All adverse events (AEs) will be presented in incidence tables coded by CTC 
term. An adverse event will be considered treatment related if it occurred on or after date 
of first dose of omeprazole, and was possibly, probably, or definitely related to treatment. 
All adverse events will be recorded until off study date. All deaths recoded in this study 
will be listed and summarized, and the cause documented. 
 
For FASN expressors, mean, standard deviation, median, minimum, and maximum 
FASN expression and activity in tumor will be calculated. To see how high dose 
omeprazole impacts biologic activity, changes in FASN expression and activity, FASN 
downstream target gene expression (e.g., PARP1 and SP1), and lipid levels from baseline 
to after 4-7 days on omeprazole treatment and at time of surgery will be assessed by 
linear mixed models.  In addition, linear mixed models will be used to assess the 
association of FASN expression with BMI. 
 
12.9 
Analysis of Tertiary Objectives 
Descriptive statistics (mean, standard deviation, median, minimum, maximum, 95% 
confidence intervals) will be use to summarize omeprazole exposure. 
 


 
 
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Peak omeprazole concentration will be compared to peak based on pre-clinical testing in 
a purely qualitative manner. 
 
Pharmacokinetics-Pharmacodynamic (PK-PD) modeling of omeprazole drug exposure, 
FASN target activity (represented by lipid profiling), and clinical outcome will be 
conducted. A system of PK-PD models will be developed to quantify and predict the 
clinical outcome, i.e., pCR, based on drug exposure and target levels. The omeprazole 
pharmacokinetic model will be constructed using the sparse sampling nonlinear mixed 
effect model, which account for the last dosing time information. The omeprazole-
FASN/lipid PK-PD will be constructed using the nonlinear mixed effect with time-
dependent covariates model (30). Finally, the correlations between PK (omeprazole) 
and/or PD (lipid/FASN) and pCR will be evaluated through Cox proportional hazard 
model with covariates measured in error. The PK and PK-PD modeling will be conducted 
in NONMEM, while the Cox model will be conducted in SAS. 
 
Change in lipid levels from baseline to after 4-7 days on omeprazole treatment and at 
time of surgery will also be assessed separately by linear mixed models. 
 
12.10 Interim Analysis 
No interim analyses are planned for this study. 
 
12.11 Subgroup Analysis 
Additional subgroup analysis may be performed as deemed appropriated. 
13. SPECIAL INSTRUCTIONS 
 
13.1 
Tumor Biopsy Requirements 
Core biopsy samples will be obtained at baseline, after 4-7 days of omeprazole treatment, 
and in residual disease at surgery. At each time point, 3 core samples should be obtained. 
Please refer to the Study Procedure Manual for detailed processing instructions for each 
core.   
 
IU Site: Subjects are required to have a fresh biopsy at baseline to obtain the 3 core 
samples below. 
 
Non-IU Sites: Archived tissue from a previously performed diagnostic biopsy may be 
used to obtain the 3 cores listed below at baseline. If adequate tissue from an archived 
sample is unavailable, subjects will be required to undergo a biopsy at baseline. 
 
• Core 1 – To be tested for FASN and downstream target gene expression 
• Core 2 – To be tested for FASN activity 
• Core 3 – To be tested for NEFA analyses  
 
13.1.1 FASN expression  
We will evaluate FASN expression using immunohistochemistry (IHC) in core biopsy 
samples obtained at baseline, after 4-7 days of omeprazole treatment, and in residual 
disease at surgery. Evaluation of the post-treatment samples will determine the potential 


 
 
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impact of omeprazole on FASN expression and upregulation during chemotherapy. 
Based on our preliminary data, we expect omeprazole to have the greatest potential 
benefit in those patients with baseline FASN expression. However if FASN is 
upregulated in response to chemotherapy, omeprazole may prevent or delay emergence of 
resistance in those without FASN expression at diagnosis. Testing will be coordinated by 
Dr. JT Zhang using an IHC method as described (2).  
 
13.1.2 Expression of FASN downstream target genes  
We will evaluate expression of FASN downstream target genes including PARP1 and 
SP1 in core biopsy samples obtained at baseline, after 4-7 days of omeprazole treatment, 
and in residual disease at surgery as described above for IHC of FASN. Analysis of 
downstream targets will provide verification that inhibition of FASN with omeprazole 
has functional significance. Downstream target genes will be evaluated in the same 
sample as used to assess FASN expression. Testing will be coordinated by Dr. JT Zhang 
using an IHC method as described (2). 
 
13.1.3 FASN activity  
We will evaluate FASN activity in core biopsy samples obtained at baseline, after 4-7 
days of omeprazole treatment, and in residual disease at surgery. FASN activity will be 
determined using coupled enzymatic NDAPH oxidation assay as we previously described 
(3, 4). Based on our preliminary data we expect omeprazole will inhibit FASN activity 
and we will see a difference in FASN activity between pre- and post-treatment samples. 
Testing will be coordinated by Dr. JT Zhang using an IHC method as described (2).  
 
13.1.4 Tumor NEFA  
Inhibition of FASN in also predicted to decrease the level of non-esterified fatty acids in 
the tumor samples. NEFA will be quantified using the coupled enzyme NEFA Assay Kit 
from BIOO Scientific Corp in the laboratory of Dr. JT Zhang. NEFA quantification will 
be performed on the same sample used for assessment of FASN activity. Given the need 
for fresh/immediate tumor processing, this will be obtained only in patients enrolled at 
IU. 
 
13.1.5 Tumor Autophagy Markers 
Cell death is predicted as a response to omeprazole. We predict that FASN and 
autophagy could be a downstream result of FASN, leading to cell death. FASN is also 
predicted to trigger autophagic mediated aptosis or autophagic cell death by itself. 
Testing will be completed on tissue between pre- and post- treatment and Testing will be 
coordinated by Dr. Lacey McNally using an IHC method as described (2). This will be 
conducted after IU has completed their processing.  
 
13.2 
Serum Lipid Profile 
As FASN is important in lipid metabolism, inhibition of FASN by high dose PPIs may 
alter circulating lipids. A fasting serum sample for assessment of lipid profile including 
total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein, will 
be obtained at baseline, after 4-7 days on omeprazole treatment and prior to surgery. 
Samples will be analyzed in the IU Health University Hospital clinical laboratory or the 
clinical laboratory of participating institutions. 


 
 
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13.3 
Serum NEFA 
A fasting serum sample for assessment of NEFA will be obtained at baseline, after 4-7 
days of omeprazole, at the mid-point of chemotherapy (i.e., week 1 of paclitaxel), and 
prior to surgery. Samples will be analyzed in the laboratory of JT Zhang using the 
coupled enzyme NEFA Assay Kit from BIOO Scientific Corp. Detailed information 
regarding collection and processing can be found in the laboratory manual for this study. 
 
13.4 
Omeprazole Exposure  
Plasma for measurement of omeprazole exposure will be obtained serially during therapy. 
Samples will be obtained prior to the first dose and 2 hours after the first dose. Other 
samples will be obtained during planned clinic visits without regard to time from last 
dose at Cycles 2 and 4 of AC and Week 1 and 7 of paclitaxel. The time last dose prior to 
sampling was taken will be recorded to facilitate population PK modeling to estimate 
peak concentration and time above the therapeutic threshold. Samples will be analyzed in 
the CPAC laboratory under the direction of Dr. David Jones. Detailed information 
regarding collection and processing can be found in the laboratory manual for this study.  
 
13.5 
Plasma for Cell-Free DNA 
Plasma will be obtained to facilitate development of assays to measure cancer-derived 
cell-free DNA in the laboratory of Dr. Milan Radovich. Plasma samples will be obtained 
at baseline, after 4-7 days of omeprazole treatment, and at surgery. As these samples will 
be used in the future for assay development, no formal statistical analysis is planned and 
samples will solely be banked at this time. Detailed information regarding collection and 
processing can be found in the laboratory manual for this study. 
14. PATIENT CONSENT AND PEER JUDGMENT 
The protocol and informed consent form for this study must be approved in writing by the 
appropriate Institutional Review Board (IRB) prior to any patient being registered on this 
study.   
 
Changes to the protocol, as well as a change of principal investigator, must also be 
approved by the Board.  Records of the Institutional Review Board review and approval of 
all documents pertaining to this study must be kept on file by the investigator (housed in 
the Clinical Trials Office) and are subject to inspection at any time during the study.  
Periodic status reports must be submitted to the Institutional Review Board at least yearly, 
as well as notification of completion of the study and a final report within 3 months of 
study completion or termination.   
 
The study will be conducted in compliance with ICH guidelines and with all applicable 
federal (including 21 CFR parts 56 & 50), state or local laws. 
 


 
 
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15. DATA AND SAFETY MONITORING 
 
15.1 Data Safety Monitoring Committee 
The Data Safety Monitoring Committee (DSMC) of the Indiana University Simon Cancer 
Center (IUSCC) is responsible for patient safety and privacy protection, compliance with 
required reporting, and study integrity for all trials conducted at IUSCC. Members are 
subject matter experts from multiple disciplines including medical oncology, pediatrics, 
biostatistics, behavioral oncology, radiation oncology, urology, surgery, gynecologic 
oncology, data and project management and research administration who are appointed 
by the DSMC Chair. The DSMC will provide independent oversight of the clinical trial 
so that study integrity is assured. However, the DSMC is not serving as a Data and Safety 
Monitoring Board (DSMB) for this study. The DSMC will meet per the currently 
approved DSMP, led by the DSMC Chair and Coordinator, and will review all adverse 
events, monitoring and auditing reports, unanticipated problems and study non-
compliance events that require expedited reporting.  Meeting minutes will be maintained 
in the IUSCC Clinical Trials Office (CTO). Specifically the DSMC has the following 
responsibilities:  
• Assessment of the adequacy of trial-specific Data Monitoring and Safety Plan 
(DSMP) of  establish risk based monitoring determination of trial specific DSMB. 
• Review safety data for investigator initiated trials including all adverse events, 
unanticipated problems and study non-compliance events requiring expedited 
reporting. 
• Conduct routine study monitoring and auditing in compliance with the IUSCC 
data quality control review process.  
 
 
15.2 Data Safety Monitoring Plan  
This trial will comply with the current requirements of the Data and Safety Monitoring 
Plan (DSMP) of the IUSCC.  The CTO of the IUSCC will be the Coordinating Center for 
this multicenter phase II trial.  
In accordance with the DSMP of the IUSCC, Investigators will conduct continuous 
review of data and patient safety. Monthly review meetings for moderate risk trials are 
required and will include the principal investigator, clinical research specialist and/or 
research nurse (other members per principal investigator’s discretion). Monthly meeting 
summaries should include the number of patients, significant toxicities as described in the 
protocol, dose adjustments, responses observed, eligibility of patients enrolled at each 
site, serious adverse events (SAEs) or unanticipated problems (UPs) (both IUSCC and 
those reported from other institutions), dose adjustments, and protocol deviations.  
Meeting minutes will be submitted and reviewed by the DSMC at dsmc@iupui.edu. 
In addition, conference calls with investigators and staff at participating sites will be 
scheduled at least monthly (and more often as needed) to discuss study progress. If there 
are no patients on treatment or in follow-up, email communication will be used in lieu of a 
teleconference.  
 
16.2.1 Study Auditing and Monitoring  


 
 
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All trials are subject to auditing and/or monitoring per the currently approved DSMC 
Charter. 
 
16.2.2 Reporting Guidelines  
The DSMC has streamlined the reporting process by utilizing reports from OnCore®. 
This has allowed direct view of reports within the Clinical Trials Management System 
(CTMS); thus discontinuing paper reports. SAE reports are entered into OnCore® 
monthly and reviewed by the DSMC chair and/or coordinator monthly. Findings will be 
reported to the full DSMC at the time of study review.  
 
 
16.2.3 Reporting Death  
Death will be reported per local IRB reporting guidelines (Section 5.8 of the 
Unanticipated Problems and Noncompliance SOP). 
 
 
16.2.4 Study Accrual Oversight  
Accrual data will be entered into the IU Simon Cancer Center OnCore® system. The 
Protocol Progress Committee (PPC) reviews study accrual twice per year while the PPC 
coordinator reviews accrual quarterly. 
 
 
16.2.5 Continuing Review 
All Continuing Reviews (CR) will be reviewed annually or as dictated by the Institutional 
Review Board.  Participating sites will submit a copy of the CR with attachments to the 
IUSCC MNA, or designee. 
 
 
15.2.6 Protocol Deviations  
Investigators are required to submit protocol deviations to the DSMC via the OnCore® 
database 
 
15.2.7 Early Study Closure  
At any time during the conduct of the trial, if it is the opinion of the investigators that the 
risks (or benefits) to the patient warrant early closure of the study, this recommendation 
should be made in writing to the Data Safety Monitoring Committee. Alternatively, the 
DSMC may initiate suspension or early closure of the study based on its review of the 
investigator reports.  
 
 
15.3 Data Safety Monitoring Board 
This study will have a Data and Safety Monitoring Board (DSMB) that will review and 
monitor study progress, toxicity, safety and other data from this trial. The board is 
chaired by an independent medical oncologist or another qualified individual external to 
this trial. Questions about participant safety or protocol performance will be addressed 
with the Principal Investigator, statistician and study team members. Should any major 
concerns arise, the DSMB will offer recommendations regarding whether or not to 
suspend the trial.  


 
 
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The DSMB will meet annually to review accrual, toxicity, response and other information 
reported to the IRB. Information to be provided to the DSMB may include: participant 
accrual, treatment regimen information, adverse events and serious adverse events 
reported by category, summary of any deaths on study, audit and/or monitoring results.  
The DSMB will provide a written recommendation to the PI and team after all 
information is reviewed. The report will indicate one or more of the following decisions:  
• Continuation of the trial without change 
• Continuation of protocol/project with modifications as outlined by the Board 
• Immediate suspension of trial for safety reasons with recommended plan of 
follow up to minimize subject harm 
• Study placed on clinical hold  
• Termination of trial 
The IUSCC will submit the DSMB report(s) to the participating sites as well. The DSMB 
report(s) should be provided to the local IRB at the time of continuing review 
 
 
15.4 Data Acquisition 
Case Report Forms and Data Submission: This study will utilize electronic Case 
Report Form completion in the OnCore® database. A calendar of events and required 
forms are available in OnCore® at https://cancer.iu.edu/oncore.  The OnCore® database 
is a comprehensive database used by the IUSCC CTO and supported by the Indiana 
University Cancer Center.  Access to data through OnCore® is restricted by user 
accounts and assigned roles.  Once logged into the OnCore® system with a user ID and 
password, OnCore® defines roles for each user which limits access to appropriate data.   
All source documents are to remain in the patient’s clinic file.  All documents should be 
kept according to applicable federal guidelines.  Clinical trial data in OnCore® are 
periodically monitored by the IU Simon Cancer Center per the DSMC Charter.  
16. REPORTING ADVERSE EVENTS 
Adverse events (AEs) will be recorded from the time of first study drug administration 
and for at least 30 days after treatment discontinuation, regardless of whether or not the 
event(s) are considered related to trial medications.  All AEs considered related to trial 
medication will be followed until resolution, return to baseline, or deemed clinically 
insignificant, even if this occurs post-trial. 
 
16.1 
Definitions of Adverse Events 
16.1.1 Adverse Event (AE) 
Adverse event (AE): An adverse event is an unplanned, unwanted event which occurs to 
a study participant and which is possibly, but not necessarily, related to the use of 
protocol therapy. While some events may not initially appear to be associated with the 
use of the study treatment, a relationship may not emerge until sufficient numbers of 
reports accumulate from participating sites. An AE may also include a newly occurring 
event or a previous condition that has increased in severity or frequency since the 


 
 
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administration of the investigational product. Assessment of the occurrence of an AE will 
be based on changes in the subject’s physical examination, laboratory results and/or signs 
and symptoms. AEs will be monitored until they are resolved or are clearly determined to 
be due to a subject’s stable or chronic condition or intercurrent illness. Medical care will 
be provided, as defined in the informed consent document, for any AE related to 
participation in this clinical trial 
 
16.1.2 Suspected Adverse Reaction (SAR) 
Suspected adverse reaction is 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’ means 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 adverse reaction, which means any adverse event caused by 
a drug. Suspected adverse reactions are the subset of all adverse events for which there is 
a reasonable possibility that the drug caused the event. 
 
Examples of types of evidence that would suggest a causal relationship between the drug 
and the adverse event: 
• A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome). 
• One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., 
tendon rupture). 
• An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other 
events that commonly occur in the study population independent of drug therapy) that 
indicates those events occur more frequently in the drug treatment group than in a 
concurrent or historical control group. 
 
16.1.3 Unanticipated Problem (UP) 
Unanticipated Problem (UP): any incident, experience, or outcome that meets all of the 
following criteria: 
1) unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being study; 
2) related or possibly related to participation in the research; and  
3) suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) related to the 
research than was previously known or recognized. 
Only a small subset of adverse events occurring in human subjects participating in 
research will meet these three criteria for an unanticipated problem. Furthermore, 
there are other types of incidents, experiences, and outcomes that occur during the 


 
 
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conduct of human subjects research that represent unanticipated problems but are not 
considered adverse events. For example, some unanticipated problems involve social 
or economic harm instead of the physical or psychological harm associated with 
adverse events. In other cases, unanticipated problems place subjects or others at 
increased risk of harm, but no harm occurs. 
 
16.1.4 Adverse Reaction (AR) 
An adverse reaction is any adverse event caused by a drug. Adverse reactions are a subset 
of all suspected adverse reactions where there is reason to conclude that the drug caused 
the event. 
 
16.1.4 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if it results in any 
of the following outcomes: 
• 
Results in death  
• 
Is life-threatening. Life-threatening is defined as an adverse event or suspected 
adverse reaction that places the subject at immediate risk of death. It does not 
include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death.  
• 
Requires inpatient hospitalization ≥ 24 hours or prolongation of existing 
hospitalization  
NOTE: Hospitalizations that are not considered SAEs are:  
 Hospitalization planned prior to first administration of study drug 
 Hospitalization for less than 24 hours 
 Hospitalization for elective treatment of a pre-existing condition 
unrelated to the study medication 
 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above).  Examples of such events include, but 
are not limited to, intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions not resulting in 
hospitalization; or the development of drug dependency or drug abuse. 
• 
Pregnancy 
 Pregnancy of a patient or of the female partner of a male patient during the 
study or within 30 days after the last dose of study drug should be reported 
via an SAE report.  Should pregnancy occur in a female participant during 
the treatment period, study drug should be discontinued. Should a 
pregnancy occur in a female companion of a male participant during the 
treatment period, the male participant can continue treatment. Any such 
pregnancy is to be followed until final outcome.   
 
16.1.5 Unexpected Adverse Event 


 
 
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An adverse event, of which the specificity or severity is not listed in the study protocol, 
product inserts, investigator brochure or informed consent document. 
 
 
16.1.6 Determining Attribution to the Investigational Agent(s) 
Attribution: An assessment of the relationship between the AE and the medical 
intervention. CTCAE does not define an AE as necessarily “caused by a therapeutic 
intervention”. After naming and grading the event, the clinical investigator must assign 
an attribution to the AE using the following attribution categories: 
 
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related 
Unlikely 
The AE is doubtfully related 
Related to investigational 
agent/intervention 
Possible 
The AE may be related 
Probable 
The AE is likely related 
Definite 
The AE is clearly related 
 
 
16.1.7 Classification and Grading 
Classification and grading of adverse event will utilize the National Cancer Institute 
Common Terminology Criteria for Adverse events (CTCAE) version 4.0 to determine the 
severity of the reaction for adverse event reporting. A copy of the current CTCAE 
version 4 is available at http://ctep.cancer.gov/reporting/. 
 
 
 
16.2 Reporting of Adverse Events:  
16.2.1 Participating Site Reporting Responsibilities:  
 
Any serious adverse event or unanticipated problem occurring within 30 days of the last 
study treatment or procedure must be reported to the IU Simon Cancer Center within 1 
business day of notification or discovery of the incident, using the SAE reporting Form 
found in the study procedures manual.  SAEs that occur greater than 30 days from last 
dose of study treatment or procedure must be reported to the IU Simon Cancer Center if 
the event is possibly, probably, or definitely related to the study treatment or procedure.  
This form must be accompanied by a cover letter which:  identifies the event, is signed by 
the local principal investigator or treating physician, includes the applicable study 
number and title, and contains the following: 
 
• Site assessment of the event attribution to investigational product or study 
procedure 
• Site assessment of event expectedness (expected vs. unexpected) 
• Assessment of whether or not the research places subjects at a greater risk of harm 
than was previously known or recognized 
• Assessment of the event’s effect on the risk to benefit ratio  
• Statement as to whether the informed consent statement should reflect changes in 
the potential risks involved  


 
 
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• Statement as to whether the event has been reported previously, and if so, whether 
the frequency is considered unusually high 
 
 
Send to: 
 
IUSCC Clinical Trials Office 
ATTN: Multicenter coordinator/ Protocol # IUSCC-0555 
 
 
 
Fax: (317) 274-8022 
E-mail: IUSCCSAE@iu.edu 
 
 
The MNA, or designee, will distribute the reports to all participating sites per section 
10.5.2 below. Copies of all serious adverse event reports or unanticipated problems 
reports will be kept on file in the IU Simon Cancer Center Clinical Trials Office. 
 
16.2.3 Reporting to the IRB:  
 
Each participating site will report adverse events and unanticipated problems to their IRB 
per local guidelines. Any event that requires expedited reporting to the local IRB will 
also be submitted to the IU Simon Cancer Center 
 
16.2.1.4 Coordinating Center Reporting Responsibilities 
 
The Coordinating Center will maintain documentation of all adverse event reports for 
each participating site in the case report forms in OnCore®. AE and SAE reports will be 
reviewed at weekly meetings. If an adverse event or SAE requires modification of the 
informed consent, protocol or other study documents, participating sites will be informed 
by way of an amendment and during monthly teleconferences, or sooner as deemed 
necessary by the Principal Investigator 
 
16.2.1.5 Reporting to the IUSCC Data Safety Monitoring Committee:  
 
Regardless of study sponsorship, the study team must enter all initial and follow-up SAE, 
expedited, and noncompliance reports into OnCore® for review by the DSMC chair 
and/or coordinator. Expedited reports may include IRB Prompt Report Forms, AdEERS 
reports, MedWatch, and additional SAE forms as required by the sponsor. When follow-
up information is received, a follow-up report should also be created in OnCore®. This 
DSMC reporting requirement is in addition to any other regulatory bodies to be notified 
(i.e., IRB, pharmaceutical company, etc.). The DSMC chair and/or coordinator will 
review all SAE, expedited, and noncompliance reports monthly. 
 
• Statement as to whether this adverse event has been reported previously, and if so, 
whether the frequency is considered unusually high 
 


 
 
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17. MULTICENTER GUIDELINES 
 
17.1 Study Documents 
Each participating site must submit regulatory documents (informed consents, 1572s, 
Financial Disclosures, IRB approval documents, Continuing Reviews, Amendments, 
patient brochures or recruitment material etc.) to the Coordinating Center. The 
Coordinating Center will provide each site with a comprehensive list of the required 
documents prior to study start-up, throughout the duration of the study and upon study 
close-out. It is the responsibility of the participating site to maintain copies of all 
documentation sent to the Coordinating Center. 
  
17.2 Study Initiation  
Before activating the clinical trial at each participating site, the IUSCC CTO MNA, or 
designee,  will ensure that: 
• Full Institutional Review Board (IRB) approval has been obtained.  
• Research staff at the participating site has been trained in data entry into OnCore®  
• A start-up meeting with each institution has taken place via telephone conference. 
The start-up meeting will cover protocol details (including eligibility criteria, 
treatment plan, etc.), responsibilities of the participating investigators, and reporting 
procedures.   
• A financial conflict of interest statement from each investigator has been obtained. 
  
17.3 Patient Enrollment 
After eligibility is confirmed by the participating site staff, a completed eligibility 
checklist, supporting source documentation, and signed consent will be sent to IUSCC for 
verification.  The MNA, or designee, will assign the patient a study number and return 
the enrollment information to the site.  The site staff will then register the patient in 
OnCore®. Additional details of this process can be found in the Study Procedure 
Manual.   
  
17.5 Data Monitoring 
All multicenter investigator initiated trials conducted at the IUSCC are subject to data 
monitoring by the MNA, or designee. External sites will be notified of upcoming 
monitoring visits and will be expected to provide the MNA, or designee, with de-
identified source documents for remote monitoring of patients.  Queries will be issued in 
OnCore® and a detailed monitoring report will be provided to the participating site.  The 
IUSCC will also forward any monitoring and/or auditing reports to the DSMC.  
When a patient enrolled on this trial, or the trial itself, is selected for local monitoring or 
auditing, the participating site will forward the results to the MNA, or designee. In 
addition, if a participating site patient is selected for local auditing by the IUSCC DSMC, 
the site will be responsible for sending IUSCC de-identified source documents.  


 
 
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17.6 Record Retention 
All documentation of adverse events, records of study drug receipt, dispensation, 
destruction, and all IRB correspondence will be stored in accordance with all applicable 
federal guidelines. 
Following closure of the study, each participating site will maintain a copy of all site 
study records in a safe and secure location. The Coordinating Center will inform the 
investigator at each site at such time that the records may be destroyed. 
 
 
 


 
 
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19. APPENDICES 
 
19.1 
Appendix I: NCI Common Toxicity Criteria Version 4.0 
 
Due to the size of the latest version of the Common Toxicity Criteria, copies of this appendix are 
not included with this protocol document. 
 
An electronic copy is available on the CTEP web site, http://ctep.cancer.gov/reporting/ctc.html 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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19.2 
Appendix II: Performance Status Scales/Scores 
 
       ECOG or Zubrod                              Karnofsky  
                Lansky 
 
 
 
 
Score        Activity               Score                Activity                      Score               Activity 
0 
Fully active, able 
to carry on all pre-
disease 
performance 
without restriction. 
100 
 
 
90 
Normal, no complaints, no 
evidence of disease. 
 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
 
100 
 
 
90 
Fully active, normal. 
 
 
Minor restrictions in physically 
strenuous activity. 
1 
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. 
80 
 
 
 
 
70 
Normal activity with effort; 
some signs or symptoms of 
disease. 
 
Cares for self, unable to 
carry on normal activity or 
do active work. 
80 
 
 
 
 
70 
Active, but tires more quickly. 
 
 
 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and 
capable of all 
selfcare but unable 
to carry out any 
work activities.  
Up and about more 
than 50% of 
waking hours. 
 
 
60 
 
 
 
50 
Requires occasional 
assistance, but is able to 
care for most of his/her 
needs. 
 
Requires considerable 
assistance and frequent 
medical care. 
 
 
60 
 
 
 
50 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
 
 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only 
limited selfcare, 
confined to bed or 
chair more than 
50% of waking 
hours. 
40 
 
 
 
30 
Disabled, requires special 
care and assistance. 
 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
40 
 
 
 
30 
Mostly in bed; participates in 
quiet activities. 
 
In bed; needs assistance even 
for quiet play. 
4 
Completely 
disabled.  Cannot 
carry on any 
selfcare. Totally 
confined to bed or 
chair. 
20 
 
 
10 
Very sick, hospitalization 
indicated.  Death not 
imminent. 
Moribund, fatal processes 
progressing rapidly. 
20 
 
 
10 
 
Often sleeping; play entirely 
limited to very passive 
activities. 
No play; does not get out of 
bed. 
 


 
 
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19.3 
Appendix III: DSMC Check Sheet 
Y
N
N/A
*Notes
Has accrual been entered into Oncore for all IUSCC programs per the "Data Requirements for Cancer Center 
Reporting"  SOP
Deviation Log reviewed, discussed and signed by ALL team members including PI                                                       
Has patient safety data been discussed/reviewed? Have  all SAE's and deviations been reported in Oncore for 
all IUSCC programs. 
Has all data been entered into Oncore per the "Data Requirements for Cancer Center Reporting"  SOP? 
Weekly and Monthly meetings should include discussion on data, patient safety, dose levels, accrual 
numbers, significan toxicities, dose adjustments and responses observed, deviation summaries and SAE 
reports. (per IUSCC DSMP)
Meeting Date: 
Protocol & Status (open/closed to accrual)
PI:
CRS:
Team/Program: (include meeting sign in sheet)
 


 
 
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19.4 
Appendix IV: Potential Drug Interactions 
Omeprazole inhibits CYP2C19. Patients taking drugs known to be substrates of CYP2C19 may enroll but 
the treating investigator should be aware of the potential drug interaction. When possible, changing to an 
alternative agent that is not metabolized by CYP2C19 is advised. 
 
CYP2C19 substrates include: 
cyclophosphamide 
citalopram  
amitriptyline 
clopidogrel 
voriconazole 
diazepam 
phenytoin 
S-mephenytoin 
imipramine 
thalidomide 
phenobarbitone 
carisoprodol 
chloramphenicol 
clomipramine 
hexobarbital 
indomethacin 
labetalol 
R-mephobarbital 
moclobemide 
nelfinavir 
nilutamide 
primidone 
progesterone 
proguanil 
teniposide 
 
Specific guidance is available for the following potential interactions 
Atazanavir and nelfinavir: omeprazole reduces plasma levels of atazanavir and nelfinavir.  
Saquinavir: omeprazole increases plasma levels of saquinavir. Monitor for toxicity and consider dose 
reduction of saquinavir.  
May interfere with drugs for which gastric pH affects bioavailability (e.g., ketoconazole, iron salts, 
erlotinib, ampicillin, esters, digoxin and mycophenolate mofetil). Patients treated with omeprazole and 
digoxin may need to be monitored for increases in digoxin toxicity.  
Clopidogrel: omeprazole decreases exposure to the active metabolite of clopidogrel.  
Cilostazol: omeprazole increases systemic exposure of cilostazol and one of its active metabolites. 
Consider dose reduction of cilostazol.  
Drugs metabolized by cytochrome P450 (e.g., diazepam, warfarin, phenytoin, cyclosporine, disulfiram, 
benzodiazepines): omeprazole can prolong their elimination. Monitor and determine need for dose 
adjustments. Patients treated with proton pump inhibitors and warfarin may need to be monitored for 
increases in INR and prothrombin time.  
Combined inhibitor of CYP2C19 and 3A4 (e.g., voriconazole) may raise omeprazole levels.  
Tacrolimus: omeprazole may increase serum levels of tacrolimus.  
Methotrexate: omeprazole may increase serum levels of methotrexate.