A Phase IIB Study of Neoadjuvant ZT Regimen (Enzalutamide Therapy in Combination With Weekly Paclitaxel) for Androgen Receptor (AR)-Positive Triple-Negative Breast Cancer
Phase: PHASE2
Conditions: Invasive Breast Carcinoma, Stage I Breast Cancer AJCC v7, Stage IA Breast Cancer AJCC v7, Stage IB Breast Cancer AJCC v7, Stage II Breast Cancer AJCC v6 and v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7, Stage III Breast Cancer AJCC v7, Stage IIIA Breast Cancer AJCC v7, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7, Triple-Negative Breast Carcinoma
Sponsor: M.D. Anderson Cancer Center

Ver. 13; 12/16/2022 
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A phase IIB study of neoadjuvant ZT regimen (Enzalutamide therapy in combination with 
weekly paclitaxel) for androgen receptor (AR)-positive triple-negative breast cancer 
Principal Investigator: Clinton Yam, M.D. 
Co-principal Investigator: Takeo Fujii, MD,  
Collaborating Statistician: Roland Bassett Jr.  
Clinical Collaborators: Debu Tripathy, MD; Jennifer Litton, MD; Savitri Krishnamurthy, MD; 
Wei Yang, MD 
Laboratory Collaborators: James Reuben; W. Fraser Symmans, MD 
Department: 
Breast M edical Oncology 
Phone: 
713-792-2817
Fax: 
713-794-4385
Research Nurse: 
Alyson Clayborn
Protocol Type: 
Standard Protocol 
Protocol Phase: 
Phase IIB 
Version Status:              13 
Table of Contents: 
Title page ......................................................................................................................................... 1 
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Study schema .................................................................................................................................. 3 
1. Introduction ................................................................................................................................. 4 
2. Objectives .............................................................................................................................. 8 
3. Selection of patients ................................................................................................................... 9 
3.1 Inclusion criteria ...................................................................................................................... 9 
3.2 Exclusion criteria ................................................................................................................... 10 
4. Registration procedures .......................................................................................................... 10 
5. Treatment plan .......................................................................................................................... 11 
5.1 Treatment ........................................................................................................................ 11 
5.2 Study Calendar ................................................................................................................ 12 
5.3 Scheduled Evaluations ..................................................................................................... 13 
5.4 Correlative Studies ................................................................................................................ 13 
6. Drug Information………………………………………………………………………………………14 
 
6.1 Enzalutamide………………………………………………………………………………………14 
6.2 Paclitaxel…………………………………………………………………………………………...17 
7. Therapy Administration and Dose Reductions ……………………………………………….20 
7.1 Supportive Care ................................................................................................................... 22 
7.2 Duration of Therapy ............................................................................................................. 22 
7.3 Duration of Follow-up……………………………………………………………………………22 
7.4 Protection of Human 
Subjects………………………………………………………………….22 
8. Measurement of effects  ........................................................................................................... 22 
8.1 Pathological response  .......................................................................................................... 22 
8.2 Radiographic imaging  .......................................................................................................... 23 
9. Adverse Event Reporting  ........................................................................................................ 24 
9.1 Definition of Adverse Events (AEs)  ...................................................................................... 21 
9.2 Definition of Serious Adverse Events (SAEs)  ...................................................................... 21 
9.2.1 
Serious Adverse Event Reporting  ................................................................................. 24 
9.2.2 
Procedure in Case of Pregnancy  .................................................................................. 25 
10. Statistical Considerations……………………………………………………………………….…26 
References  ................................................................................................................................... 27 
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Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. 
Introduction 
 
Patients with localized TNBC are preferably treated with systemic chemotherapy in the 
neoadjuvant setting (NACT) as this allows for close monitoring of response in the intact primary 
tumor and often results in ‘down staging’ of tumors, which increases the feasibility of breast 
conserving surgery. The response to NACT at the time of surgical resection can be determined 
by measuring the amount of residual cancer remaining in the breast and draining lymph nodes 
during routine pathologic evaluation and is such a powerful indicator of prognosis that the Food 
and Drug Administration (FDA) has recognized significant improvement in complete response to 
neoadjuvant therapy as a pathway to drug approval. Investigators at MDACC have developed 
and validated a scoring system known as the Residual Cancer Burden (RCB) to quantify the 
extent of residual disease remaining after NACT and surgical resection.[2] Approximately 50% of 
patients with localized TNBC treated with standard taxane/anthracycline-based NACT will have 
either pathologic compete response (pCR/RCB-0) or minimal residual disease (RCB-I) at the time 
of surgical resection and those patients have identical and exceptionally good long-term prognosis 
with less than 10% risk of developing distant metastatic disease within 5 years. Unfortunately, 
those with more extensive residual disease (RCB-II or RCB-III) have a much worse prognosis, with 
50%-80% of patients developing distant metastatic disease within 3 years of initial diagnosis.[3] 
Additionally, clinical trials of NACT in breast cancer have demonstrated that patients without 
response to their first chemotherapeutic regimen have very low chance (5%) of achieving pCR after 
their second neoadjuvant chemotherapy regimen.[4] However, this has not been the case with 
targeted regimens such as trastuzumab in HER2+ tumors, suggesting that intrinsic resistance 
to chemotherapy can be overcome with appropriate  targeted therapy.[5] Though several targeted 
agents have been tested for treatment in TNBC, so far none have been successful. The underlying 
causes of this failure are commonly attributed to the molecular heterogeneity of tumors classified 
within the ‘catch all’ category of TNBC as well as the dilution effects of chemotherapy sensitive 
disease which requires clinical trials to enroll larger number of patients to show benefit of 
combined targeted therapy/chemotherapy regimens over standard chemotherapy. Additionally, 
clonal selection of resistant cells with escape mechanisms also likely develops. Recent advances 
in gene expression profiling have identified  subgroups of triple- negative breast cancer (TNBC) 
with distinct molecular features that, if appropriately selected, may be more responsive to targeted 
therapy with existing FDA-approved drugs, leading to rapid improvement of outcomes in this high-
risk breast cancer population[1, 6-8]. 
 
Prediction of chemosensitivity and  molecular aberrations associated with TNBC subtypes: Our 
collaborator, Dr. Symmans, and his team have developed microarray-based predictive signatures 
of chemotherapy response using fresh primary tumor tissue 
obtained from a routine biopsy of breast cancer at the time of 
diagnosis or surgery. This approach has been retrospectively 
validated and tested for feasibility using a prospective registry 
study (MDACC clinical trial 2011-0007).[9] The proposed 
predictor  was  tested  on  an  independent  cohort  of  breast 
cancers irrespective of receptor status (N=198, 99% with clinical 
Stage II-III) who received neoadjuvant (N=180) or adjuvant 
(N=18) taxane-anthracycline chemotherapy. Predictions were 
accurate if  ER+/HER2- (30% predicted sensitive, Distant 
relapse-free survival (DRFS) 97%, CI 91-100; Absolute risk 
reduction (ARR) 11%, CI 0.1-21) or ER-/HER2- (26% predicted 
sensitive, DRFS 83%, CI 68-100; ARR 26%, CI 4-48) (Fig 1).[9] 
Predicted treatment sensitivity was significantly associated with 
lower relapse risk (HR 0.19, CI 0.07-0.55) in a multivariate 
model including ER status, tumor and nodal stage, grade, age, 
and type of taxane treatment (paclitaxel or docetaxel). 
 
Fig 1: Distant RFS by genomic 
prediction of chemosensitivity in 
ER-/HER2- breast cancer 
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As important as predicting chemosensitivity may be, outcomes for TNBC patients will not be 
improved unless targeted therapy is developed for patients with 
chemoresistant disease. Recent advances in molecular profiling 
have identified subsets of TNBC (Fig. 2) with distinct molecular 
features targetable with existing FDA approved drugs.[1, 7, 10, 11] 
Basal-like TNBCs (BL1 and BL2) are heavily enriched in cell cycle 
and cell division pathways. Gene expression profiling has revealed 
that these tumors have high expression of proliferation genes such 
as aurora kinases, MYC, NRAS and PLK1 as well as elevated DNA 
damage response (BL1 subtype). These tumors may have higher 
Figure 2: Classification of 75 
TNBC samples at MDACC 
using signatures published by 
Pietenpol et al.[1] 
rates of pCR to standard chemotherapy compared to other TNBC 
subtypes. The BL2 subset displays gene ontologies involving 
growth factor signaling such as EGFR and IGF1R pathways. Cell 
lines classified as basal-like had high rates of sensitivity to cisplatin 
and relative resistance to PI3K directed therapy in both cell culture 
and xenograft models. Though most triple-negative breast cancers are classified as basal-like 
(BL1  and  BL2)  by  microarray  analysis,  approximately  30%  of  triple  negative  tumors  are 
molecularly  distinct  from  basal-like  breast  cancers  as  they  display  mesenchymal  features, 
including   enrichment   in   epithelial-to-mesenchymal   transition   (EMT)   and   stem-cell   like 
characteristics. Subgroups with these features have been identified by independent investigators 
and have been termed mesenchymal (M), mesenchymal-stem cell like (MSL) and claudin-low. 
Mesenchymal-like  TNBCs  carry  a  high  rate  of  molecular  aberrations  that  activate  the 
PI3K/Akt/mTOR axis suggesting that this subgroup may be responsive to therapeutic regimens 
targeting  this  pathway.  Approximately  10-15%  of  TNBC  are  associated  with  expression  of 
androgen  receptor  (AR+ or  LAR) and approximately  20-25%  are immune modulatory  (IM), 
expressing genes associated with immune activation. Approximately 10-20% of patients with 
TNBC are carriers of germline BRCA1/2 mutations. When treated with NACT, pCR rates similar 
to  slightly  higher  than  non-carriers.[12]  BRCA1  and  BRCA2  are  required  for  homologous 
recombination repair of DNA strand breaks leading to a defect in DNA repair in cancers harboring 
such mutations. As such, these tumors may be more sensitive to chemotherapy inducing DNA 
breaks or poly ADP-ribose polymerase (PARP) inhibitors. 
 
Notably, investigators at MDACC also determined that rates of pCR/RCB-I to standard NACT 
were not statistically different amongst the subtypes, though the lowest rates of pCR were seen in 
the BL-2 subtype and the highest rates of RCB-III disease was within the mesenchymal subtypes, 
further validating the need for both predictors of chemotherapy sensitivity as well as molecular 
characterization of predicted chemotherapy-insensitive disease to determine appropriate therapy 
for patients with localized TNBC.[13] 
 
Given the disparity of treatment outcomes from NACT for TNBC, a molecular triaging protocol 
(MDACC 2014-0185) has been developed and IRB approved as a diagnostic platform to identify 
patients whose tumors are likely or 
unlikely to achieve pCR or RCB-I, in 
order to direct predicted responders 
toward standard chemotherapy and to 
direct 
predicted 
chemotherapy 
insensitive patients toward potentially 
more effective experimental therapies 
within    clinical    trials    (Figure    3). 
Previously 
untreated 
patients with 
localized TNBC who are candidates for 
standard       NACT       (anthracycline 
taxane 
based 
therapy) 
will 
be 
enrolled    into    2014-0185,    a    non- 
therapeutic, randomized trial where they 
will undergo biopsy of the primary 
 
 
Fig. 3 Clinical Trial Schema for 2014-0185 
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tumor for molecular characterization within the MDACC CLIA certified diagnostic lab, including 
predicted sensitivity to chemotherapy using gene signatures described above. Patients will be 
randomized 2:1 to know the results of the molecular characterization (given within 4-6 weeks after 
biopsy) or not know the results (treating physician blinded as well). All patients will be treated the 
same except for this randomization (Figure 3). 
 
All patients will then initiate a planned 4 cycles of standard neoadjuvant anthracycline based 
chemotherapy based upon physician’s choice (AC, dose-dense AC, FAC, EC or FEC are all 
allowed) with assessment of response by diagnostic imaging after 4 cycles of therapy (or at the 
time  of  progression  in  patients  who  develop  clinical  evidence  of  disease  progression  on 
chemotherapy). 
In 
our 
retrospective 
analysis 
of 
molecularly 
characterized 
patients 
with 
available 
diagnostic 
imaging, 
approximately 
10-15% 
of 
patients will have obvious, 
extreme discordance between 
volumetric measurement 
of 
tumor response by ultrasound 
after 4 cycles of NACT and 
response prediction by gene 
signature with the diagnostic 
Figure 4: BMO Neoadjuvant Portfolio for Treatment of Chemotherapy 
Insensitive TNBC 
    imaging 
best 
predicting      
outcome   in   these   extreme 
cases of response or lack thereof (parameters outlined in Fig. 3). As such, patients with discordant 
imaging/molecular predictor results will be advised of these results and counseled to proceed 
based upon imaging. After response assessment, all patients will be offered the option of continuing 
forward with standard taxane (paclitaxel or docetaxel) or participation in clinical trials (Figure 4). 
Molecular characterization of the tumor (if known) can also be used by the treating physician to 
select for clinical trials within the BMO neoadjuvant clinical trials portfolio (Figure 4). 
 
Additionally, because of the 2:1 randomization in 2014-0185 (Figure 3), a subgroup of patients 
molecularly profiled will not know the results for decision making (control arm). Like the 
experimental arm, patients on the control arm will be allowed to choose between study 
participation or to receive standard chemotherapy with paclitaxel based regimen for 12 addition al 
weeks. Essentially, those who do not know the results of the molecular profiling are offered the 
same options as those who do, they simply will not have the molecular analysis to guide their 
decision making. Since all patients enrolled in 2014-0185 have biopsies for molecular 
characterization and diagnostic imaging, for research purposes all patients can be characterized 
as chemosensitive or chemoresistant and further subtyped into the TNBC molecular subtypes 
mentioned above. As such, those patients characterized with chemoresistant, subtype specific 
disease who receive standard NACT with taxane-based regimens can be compared with matched 
patients treated on clinical trials with targeted agents, such as Enzalutamide. Though this 
comparison will not be a randomized comparison, it will provide evidence as to whether patients 
treated on a single arm phase II trial of targeted therapy derive additional clinical benefit and the 
comparison can be used to provide more robust data for confirmatory phase III clinical trial 
design. Likewise, patients whose tumors do not have luminal androgen receptor (LAR) features 
can be enrolled on this protocol and receive Enzalutamide, which will allow a control group of 
non-LAR TNBCs to serve as a control to determine the predictive value of potential biomarkers to 
define the mesenchymal population. 
 
 
Rationale for Enzalutamide in lum inal androgen receptor TNBC: Androgen receptor (AR) is a 
steroid hormone and is positive in 10-50% of TNBC patients by IHC. [14-16] Based on  the 
molecular features, 20 out of 130 TNBC patients (15%) are classified to LAR. Among the seven 
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molecular subtypes, based on their gene profiles, LAR is the most distinct in the sense that 
its gene ontologies are heavily enriched in hormonally regulated pathways including 
androgen/estrogen metabolism regardless of a negative IHC for estrogen receptor.[1, 13] LAR 
has o t h e r  distinguishing clinical characteristics as well. Our previous data shows that the pCR 
rate differed according to molecular subtype within TNBC and that the LAR subtype is associated 
with a low pCR rate (0.1%; 95% CI: 0.003-0.23) but with a high RCB-I rate, however, the survival 
outcome is relatively better compared to the other subtypes such as IM, MSL, or BL2.[13] This 
characteristic of low pCR rate and yet better survival outcome is similar to that of hormone 
receptor positive breast cancer. As a supporting data, genome-wide transcript analysis using 
DNA microarrays shows that a subset of ER/PR-negative cancer resembles ER-positive breast 
cancer, and this subtype contains AR-responsive genes. Thus, therapies targeting AR could be 
utilized to treat ER/PR-negative breast cancer with such characteristics.[17] In vitro experiment 
using MDA-MB-453 cell line, which molecularly resembles to ER positive breast cancer based on 
the clustering results, it is demonstrated that cell line incubation with only antiestrogens had no 
effect on overall cell viability. In the experiment using the same cell line, incubation with  a 
synthetic androgen (R-1881) stimulated growth and this proliferative effect was abrogated by the 
addition of the AR antagonist flutamide, confirming that the response was AR dependent and ER 
independent. [17] These data suggest that therapeutic AR blockade warranted consideration as a 
potential endocrine therapy for the subset of patients with ER negative breast cancer.[18] 
 
In the previous Phase II study investigating the efficacy of Bicalutamide in patients’ estrogen 
receptor and progesterone receptor negative, androgen positive (IHC >10% nuclear staining) 
metastatic breast cancer, the 6-month clinical benefit rate was 19% (95% CI, 7-39%), and the 
median PFS was 12 weeks (95% CI, 11-22 weeks).[19] Enzalutamide is an androgen-receptor– 
signaling inhibitor and is distinct from the currently available antiandrogen agents in that it inhibits 
nuclear translocation of the androgen receptor, DNA binding, and coactivator recruitment. It also 
has a greater affinity for the receptor, induces tumor shrinkage in xenograft models (in which 
conventional agents only retard growth), and has no known agonistic effects. [20, 21] 
 
Of note, preclinical data in prostate cancer cell lines have shown that enzalutamide has a 
synergic effect with taxane via the AR pathway, and the prostate cancer cell lines may have a 
cross-resistance between 
taxanes 
and 
enzalutamide when 
these 
drugs were 
used 
sequentially.[22, 23] A phase I study of prostate cancer patients showed that enzalutamide does 
not have a clinically significant effect on docetaxel PK when these drugs were used 
concurrently.[24] 
 
 
Study Rationale: 
Based on the above mentioned data, it is hypothesized that among patients with AR-positive 
TNBC who were non-responders to initial anthracycline and cyclophosphamide chemotherapy, ZT 
regimen (the combination of enzalutamide and weekly paclitaxel) administered in the neoadjuvant 
setting increases pCR and RCB-I rates compared with conventional taxane-based chemotherapy. 
 
Rationale for Correlative Studies: 
Optional tumor tissue will be collected prior to beginning enzalutamide therapy and at the time of 
surgery. Peripheral blood will be collected prior to beginning enzalutamide, after six cycles of 
paclitaxel, and at the time of surgery (see above “Study Schema” on page3). These samples will 
be used to perform  correlative  studies  aimed  at  identifying  predictive  markers  and  to  
enhance  our understanding of the biology of AR positive TNBC. All studies will be performed at 
MD Anderson. 
 
Gene profiles and reverse phase protein assay (RPPA)/RNA sequences: The 
experiments using breast cancer cells are limited since the mechanism and cross talk of 
androgen receptor signaling is still unclear in breast cancer. However, both in vitro and in 
vivo experiments using prostate cancer cells have been performed to investigate the roles 
of androgen receptor signaling pathway. In prostate cancer, it is thought that there are 
two signaling pathways; androgen-dependent and androgen-independent signaling [25, 
26] PI3K/Akt pathway has been shown to promote prostate cancer cell survival and
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growth via enhancing AR-mediated transcription. Both PTEN and the PI3K inhibitor 
negatively regulate this process. It is shown that the cross talk between the androgen and 
PI3K/Akt pathways is mediated through the modulation of the PI3K/Akt downstream 
effector GSK3 β. Its inactivation by phosphorylation results in increased nuclear levels of 
β-catenin, which augment AR activity. These findings delineate a novel mechanism by 
which PI3K/Akt and PTEN regulate the androgen pathway during prostate cell growth   
and survival. [27] AR, the progesterone receptor (PR), and the estrogen receptor (ER) are 
able to activate the MAPK/ERK through a mechanism independent of their transcriptional 
activity. AR has been found to interact with the intracellular tyrosine kinase Src. One of 
the targets of Src is the adapter protein Shc, an upstream regulator of the MAPK   
pathway. [26] 
 
Given there are some related proteins in AR signaling in prostate cancer, reverse phase 
protein assay (RPPA) and RNA sequences of relevant signaling pathways including ERK, 
PI3K, SRC, PTEN, Akt, p53, EGFR,GSK3, β-catenin , IGF-IR, Raf, and MAPK will be 
performed on all biopsies to better understand the molecular mechanism related to AR 
signaling and their changes by enzalutamide. The expression level of those AR related 
genes will be also evaluated using an Affymetrix GeneChip. 
 
Circulating tumor cells (CTCs): CTCs are found in human blood when cancers undergo 
metastatic dissemination and spread to distant organs.[28, 29] CTCs have been reported 
as a surrogate marker for tumor response and linked to shorter survival in metastatic 
breast, prostate and colorectal lung cancer patients.[28, 30-34] CTCs also carry highly 
specific oncogenic mutations.[35] In prostate cancer cell lines, it has been known that 
androgen receptor signaling is activated by translocation of AR from the cytoplasm to the 
nucleus where AR activates AR-target genes. In vivo experiment using castrate resistant 
prostate cancer patients, taxane inhibits AR nuclear localization and AR cytoplasmic 
localizations correlated with clinical response to taxane. This may suggest that monitoring 
AR subcellular localization in the CTCs might predict clinical response to treatment 
blocking AR translocation such as enzalutamide. [36] 
 
 
2.0 Objectives 
 
2.1 Primary Objective: 
 
2.1.1 To evaluate the pCR and RCB-I rates of patients with TNBC who were non- 
responders to initial anthracycline and cyclophosphamide chemotherapy and who were 
treated with Enzalutamide in combination with weekly paclitaxel in the neoadjuvant 
setting. 
 
 
2.2 Secondary Objectives: 
 
2.2.1 To estimate progression free survival (PFS) distribution of AR-positive TNBC patients 
who were non-responders to initial anthracycline and cyclophosphamide chemotherapy, 
treated with Enzalutamide in combination with weekly paclitaxel in the neoadjuvant setting. 
 
2.2.2 To determine the safety of administering Enzalutamide in combination with weekly 
paclitaxel in the neoadjuvant setting. 
 
 
2.3 Exploratory Objectives: 
 
2.3.1 To investigate the association between biomarkers in the peripheral blood and 
tumor tissue with safety and efficacy for TNBC patients who were treated with 
Enzalutamide and treatment in combination with weekly paclitaxel in the neoadjuvant 
setting. 
 
 
 
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2.3.2 
To investigate the correlation between CTC characteristics and/or gene profiles 
and treatment response of enzalutamide and taxane. 
 
 
 
 
3.0 Selection of Patients 
 
To be included in the study, the subject must have: 
 
3.1 Inclusion Criteria: 
 
1) Signed written informed consent 
 
2) Patients with histologically confirmed intact primary cancer that is confirmed invasive 
carcinoma of the breast, with at least 1.0 cm residual disease as measured by 
mammography, ultrasound, or breast MRI after neoadjuvant anthracycline based 
chemotherapy. 
 
3) Triple-negative breast cancer defined as ER<10%; PR<10% by immunohistochemistry 
(IHC) and HER2 0-1+ by IHC, or 2+ FISH non-amplified. 
 
4)  Androgen Receptor will be quantified using CLIA-compliant assays for AR on a 
biopsy specimen obtained prior to initiation of treatment.. AR-positivity is defined as > 
10% of nuclear staining. 
 
5) AJCC 7th edition stage I-III Breast Cancer 
 
6) Men or women 18 years of age or older. 
 
7) Patients must have a performance status of (0-1) on the ECOG performance scale 
 
8) Negative serum or urine pregnancy test must be done within 72 hours before the first 
dose of the study medication for women of childbearing potential as per institutional 
guidelines. Post-menopausal women (defined as no menses for at least 1 year) and 
surgically sterilized women are not required to undergo pregnancy test. 
 
9) Men on study must use a condom if having sex with a pregnant woman. 
 
10) Male patient and his female partner who is of childbearing potential must use 2 
acceptable methods of birth control (one of which must include a condom as a barrier 
method of contraception) starting at screening and continuing throughout the study 
period and for 3 months after final study drug administration 
 
11) Patient must have adequate organ function as determined by the following laboratory 
values: 
□ 
Absolute neutrophil count ≥ 1,500 /μL 
□ 
Platelets ≥ 100,000 / μL 
□ 
Hemoglobin ≥ 9 g/dL 
□ 
Creatinine Clearance > 50 ml/min 
□ 
Total Bilirubin < 1.5 x ULN 
□ 
ALT/AST < 2.5 x ULN 
 
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3.2 Exclusion Criteria: 
 
1) Patients who have received any previous antitumor therapies (other than anthracycline-
based neoadjuvant chemotherapy for the current cancer event). 
 
2) Female patients must not be breast-feeding at screening or planning to become 
pregnant during the course of therapy. 
 
3) Patients having major surgery within 21 days before Cycle 1, Day 1. 
 
4) Patients with known history of hypersensitivity to paclitaxel that did not 
resolve with pre- medication. 
 
 
5) Patients with left ventricular ejection fraction <50% or 10% decrease 
from baseline on echocardiogram after anthracycline based 
chemotherapy. 
 
6) Patients with gastrointestinal impairment that would affect the absorption of Enzalutamide; 
or previous history of colitis. 
 
7) Subjects requiring daily corticosteroids, other than those given as premedication for 
the anthracycline-based chemotherapy. 
 
8) Patients with known or suspected brain metastasis or active leptomeningeal disease. 
 
9) History of seizure or any condition that may predispose to seizure (e.g., prior cortical 
stroke, significant brain trauma) at any time in the past. Also, history of loss of 
consciousness or transient ischemic attack within 12 months of Day 1 visit. 
 
10) Myocardial infarction within 6 months before starting therapy, symptomatic 
congestive heart failure (New York Heart Association > class II), unstable angina, or 
unstable cardiac arrhythmia requiring medication. 
 
 
 
4.0 Registration Procedures 
 
 
Patients must not start protocol treatment prior to registration. 
 
 
 
The following information will be requested: 
 
 
Protocol Number 
 
 
Investigator Identification 
 
• 
Investigator’s name 
 
 
Patient Demographics 
 
• 
Patient’s initials 
• 
Sex 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
 
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         Eligibility Verification 
 
Patients must meet all of the eligibility requirements listed in section 4. 
Baseline measurements and evaluations must be obtained within 4 weeks of 
registration to the study. All areas of disease should be recorded in order to 
assess response and uniformity of response to therapy. 
 
 
         Additional Requirements: 
All patients must be provided with a signed and dated copy of the informed consent.  
 
 
        Instructions for Patients who do Not Start Assigned Protocol Treatment 
 
If a patient is found ineligible, baseline and follow-up data will still be collected and submitted 
into the electronic database. Documentation of the reason for not starting protocol treatment 
will also be recorded. 
 
 
 
5.0 Treatment Plan 
 
5.1 Treatment 
 
Patients will initiate therapy with enzalutamide and p a c l i t a x e l  at the doses and 
schedules listed in study schema (page 3) and as defined in Table 3. Each cycle will be defined 
as 7 days of therapy with oral enzalutamide taken daily. Patients will undergo a planned 12 
cycles of therapy prior to surgical resection.  
Patients who are unable to receive combination therapy due to toxicity will be considered non- 
responders. Patients withdrawing prior to the c ompletion of 4 cyc les for any reasons 
other than (1) toxicity or (2) for progression of disease will be replaced. For drug administration 
guidelines and dose reductions, see Therapy Adm inistration and Dose Reductions. 
 
All patients will undergo surgical resection of their primary tumor unless they are deemed not fit 
for surgery after 12 weeks of therapy. Patients may undergo either lymph node sampling or 
complete axillary dissection as considered standard of care by their surgeon. 
 
Review of adverse events will be done within 28 days before start of study drug, every week 
during treatment, at the time of surgery or progression, and 30 days after the discontinuation of 
study drug. 
 
 
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5.2 Study Calendar 
 
Trial Period 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post Treatment 
 
Screening 
1-6 
7 
8-12 
Discontinuation 
Safety Follow-up 
Scheduling Window (Days) 
-28 to -1 
-10 to -1 
+/- 3 
+/-3 
+/-3 
At Time of 
Surgery or 
Progression 
30 Post 
Discontinuation 
(+/-3 Days) 
Administrative Procedures 
Informed Consent 
x 
 
 
 
 
 
 
Eligibility 
x 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
Clinical Procedures / Assessments 
Review Adverse Events 
x 
 
x 
 
x 
x 
x 
Physical Exam / Weight / VitalsG 
x 
 
x 
 
x 
x 
x 
ECOG / Performance Status 
x 
 
x 
 
x 
x 
x 
Enzalutamide, Oral Daily 
 
 
x 
x 
x 
 
 
Paclitaxel, IV weekly 
 
 
x 
x 
x 
 
 
Laboratory Procedures 
Serum or Urine Pregnancy Test F 
 
x 
 
 
 
 
 
CBC with Differentials B 
 
x 
x 
x 
x 
 
x 
Chemistry Panel A,B 
 
x 
x 
x 
x 
 
x 
CTCs, Plasma, PBMCs E 
 
x 
 
x 
 
x 
 
Tumor Tissue Biopsy / Analysis 
 
 
 
 
 
 
 
Optional Tissue Biopsy 
x 
 
 
 
 
x C 
 
RPPA / RNA seq 
x 
 
 
 
 
x 
 
Response Measurements 
 
 
 
 
 
 
 
Tumor Imaging D 
 
x 
 
 
 
x 
 
A. Total Bilirubin, ALT, AST, Alkaline Phosphatase, Albumin, BUN, Creatinine, Sodium, Potassium, Bicarbonate, Chloride, Calcium, 
Magnesium, Glucose 
B. Blood Tests must be performed within 48 hours prior to starting each cycle of paclitaxel. 
C. For patients having surgery, biopsy will not be performed, instead a surgical specimen will be collected. 
D. Tumor Imaging ideally should be as close to start of treatment as possible, however baseline imaging within 28 days of start is acceptable. 
Imaging can also be performed at the time of suspected Clinical Progression. Acceptable Imaging includes: Mammogram, Ultrasound 
and/or MRI. 
E. CTCs, Plasma, PBMCs will be collected at Baseline, Post Cycle 6 just Prior to Cycle 7, End of Treatment or Discontinuation. 
F. Women of Child-Bearing Potential only. (WCBP) 
G. Physical Exams will be done prior to start of cycles 1, 5, & 9; or if clinically indicated. 

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13 
 
 
5.3     Scheduled Evaluations: 
 
5.3.1    Pretreatment Evaluation 
 
 
History and physical examination. 
 
 
Laboratory studies: CBC with differential, sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, calcium, magnesium, albumin, alkaline phosphatase, total bilirubin, AST, ALT, serum 
pregnancy test (women of child bearing potential only). 
 
 
Radiologic evaluation of measurable disease within 4 weeks of starting treatment. 
 
 
Patient must sign IRB-approved informed consent prior to any study-specific procedures unless such 
procedures are part of the standard of care. 
 
5.3.2 
Evaluation During Study 
 
 
Physical examination (including vital signs, weight, performance status): on day 1 (or up to 3 days 
prior) of cycles 1, 5 and 9. Clinic visits are also to be scheduled if indicated, i.e. toxicities, progression of 
disease, or if treatment has been held for greater than 7 days.  
 
CBC with differential, sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, 
magnesium, albumin, alkaline phosphatase, total bilirubin, AST, ALT within 48 hours prior to starting 
each cycle of weekly paclitaxel. 
 
 
Patients will undergo repeat imaging (mammogram, ultrasound and/or MRI, as clinically indicated) of 
the involved breast and axillary nodal basin as standard of care prior to surgical resection (after 12 
weeks of therapy) or at the time of clinically suspected disease progression. 
 
5.4  Correlative Studies :  
All molecular correlative studies except for CTC analysis, RPPA, and RNA sequencing will involve molecular 
profiling data generated through biopsy of the primary breast tumor and profiled within the existing BMO 
molecular triaging protocol that is currently IRB approved (MDACC 2014- 0185). Potential biomarkers of response 
will be correlated with pathologic response to enzalutamide and taxane treatment using appropriate statistical 
analyses for the biomarker of interest. 
 
 
Tissue biopsy 
 
RNA sequences and reverse phase protein assay (RPPA) 
Up to three core biopsies may be obtained prior to initiation of enzalutamide and paclitaxel therapy. Tissue 
collected from participating subjects will be de-linked from all personal identifiers per institutional tissue banking 
procedures. 
The following tissue analyses will be completed if sufficient tissue can be obtained: 
• 
Immunohistochemistry of AR and reverse phase protein assay (RPPA) of relevant signaling pathways 
including ERK, PI3K, SRC, PTEN, Akt, p53, EGFR, and MAPK will be performed. 
• 
The expression level of genes related to the response to enzalutamide will be evaluated using a 
molecular method such as Affymetrix. 
 
 
Peripheral Blood 
These samples will be used to perform correlative studies aimed at identifying predictive markers and to enhance 
the understanding of androgen receptor inhibition in the neoadjuvant setting. 
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CTC 
7.5 mL of peripheral blood will be collected at three time points: prior to first dose of paclitaxel (baseline), between 
end of cycle 6 and prior to 7 cycle (mid-treatment), and prior to surgery. 
 
Plasma and PBMCs 
20 mL of peripheral blood will be collected at three time-points: baseline, mid-treatment and before surgery. 
Baseline plasma and PBMC samples will be used to isolate circulating tumor DNA (cfDNA) and RNAseq for 
future analysis if needed. These samples will be bio-banked for future analysis. 
 
 
 
 
6.0 Drug Information: 
 
6.1 Enzalutamide (Xtandi®) [38] 
 
Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor-signaling 
pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors and 
inhibit androgen receptor nuclear translocation and interaction with DNA. 
 
The most common adverse reactions (≥ 5%) observed with Enzalutamide are asthenia/fatigue, back pain, 
diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, 
muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina 
syndrome, hematuria, paresthesia, anxiety, and hypertension. The most clinically important adverse effects are 
discussed below: 
 
Seizure 
 
In the randomized phase 3 study of patients with CRPC previously treated with docetaxel (CRPC2), 0.9% of 
patients receiving enzalutamide (160 mg/daily) experienced a seizure. Seizure events occurred from 31 to 603 
days after initiation of enzalutamide. No seizures occurred in patients treated with placebo. In the randomized 
phase 3 study of chemotherapy naive patients treated with enzalutamide (MDV3100-03), 1 enzalutamide-treated 
patient experienced a seizure and 1 placebo-treated patient experienced a seizure, leading to an incidence 
of 0.1% in both treatment groups. Patients experiencing seizure were permanently discontinued from therapy 
and all seizure events resolved. There is no clinical trial experience re-administering enzalutamide to patients 
who experienced seizure. Limited safety data are available in patients with predisposing factors for seizure 
because these patients were generally excluded from the trials. These exclusion criteria included a history of 
seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, 
cerebrovascular accident, brain metastases, and brain arteriovenous malformation. CRPC2 excluded the use of 
concomitant medications that may lower the seizure threshold, whereas MDV3100-03 permitted the use of these 
medications. Because of the risk of seizure associated with enzalutamide use, patients should be advised of 
the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to 
themselves or others. 
 
Laboratory Abnormalities 
 
In the randomized clinical trial, Grade 1-4 neutropenia occurred in 15% of patients on XTANDI (1% Grade3-4) 
and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in 
both arms; 0.5% of patients on XTANDI and 1% on placebo experienced Grade 3-4 thrombocytopenia. 
Grade 1-4 elevations in ALT occurred in 10% of patients on XTANDI (0.3% Grade 3-4) and 18% of patients 
on placebo (0.5% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of 
patients on placebo. 
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Infections 
 
In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on 
placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 
6% of the patients on both treatment arms. 
 
Falls and Fall-related Injuries 
 
In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI 
compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. 
Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, 
joint injuries, and hematomas. 
 
Hallucinations 
 
In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 
2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority 
was on opioid-containing medications at the time of the event. Hallucinations were visual, tactile, or undefined. 
 
Posterior Reversible encephalopathy Syndrome (PRES) 
 
Two post marketing cases of confirmed PRES were identified from the global safety database (estimated 
cumulative post marketing exposure of 17,704 patient treatment years as of 30August2014). In the first case, 
reported symptoms (confusional syndrome and aphasia; symptom onset on treatment day 27). The patient 
received acute treatment with intravenous corticosteroids. After discontinuing enzalutamide, reported 
symptoms resolved and a follow-up cerebral MRI revealed regression of abnormalities, indicative of positive 
de-challenge. In the second case, reported symptoms (altered mental status, confusion, and word-finding 
difficulties; with a blood pressure of 188/97 mm Hg; symptom onset on treatment day 98) and MRI findings 
were consistent with a diagnosis of PRES. The patient was treated with dexamethasone and an 
antihypertensive regimen of hydralazine and carvedilol. After discontinuing enzalutamide, reported symptoms 
resolved and follow-up cerebral MRI finding showed significant improvement, indicative of positive de-challenge. 
Discontinuation of enzalutamide in patients who develop PRES is recommended. Patients should be informed 
to contact the study physician as soon as possible if they experience rapidly worsening symptoms possibly 
indicative of PRES such as seizure, headache, and confusion, reduced eyesight, or blurred vision. 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1. Adverse Reactions in the Phase III Trials [39, 40] 
 
 
  
PREVAIL Trial 
 
 
AFFIRM Trial  
                            Enzalutamide 
  (n=871)  
 
Placebo (n=844) 
Enzalutamide 
  
 
  (n=800)  
 
Placebo (n=399) 
All 
Grade 
All 
Grade 
All 
Grade 
All 
Grade 
  Grades 
≥ 3 
grades 
≥ 3 
 
grades 
≥ 3 
 
grades 
≥ 3  
 
Number of patients (percent)  
 
Number of patients (percent) 
Fatigue 
310 (36) 
16 (2) 
218 (26) 
16 (2) 
269 (34) 
50 (6) 
116 (29) 
29 (7) 
 
Constipation 
193 (22) 
4 (<1) 
145 (17) 
3 (<1) 
 
Musculoskeletal 
pain 
109 (14) 
8 (1) 
40 (10) 
1 (<1) 
Back pain 
235 (27) 
22 (3) 
187 (2) 
 
 
1Atrial fibrillation 
2Acute Coronary Syndrome 
*Myocardial Infarction 
In phase I trial of combination of enzalutamide and docetaxel, 9% experienced febrile neutropenia 
and 36% did neutropenia in any grades. (Data not shown) 
Arthralgia 
177 (20) 
12 (1) 
135 (16) 
9 (1) 
Decreased 
appetite 
158 (18) 
2 (<1) 
136 (16) 
6 (1) 
Hot flash 
157 (18) 
1 (<1) 
65 (8) 
0 
162 (20) 
0 
41 (10) 
0 
Diarrhea 
142 (16) 
2 (<1) 
119 (14) 
3 (<1) 
171 (21) 
9 (1) 
70 (18) 
1 (<1) 
Hypertension 
117 (13) 
59 (7) 
35 (4) 
19 (2) 
(6.6) 
(3.3) 
Asthenia 
113 (13) 
11 (1) 
67 (8) 
8 (1) 
Fall 
101 (12) 
12 (1) 
45 (5) 
6 (1) 
Weight loss 
100 (11) 
5 (1) 
71 (8) 
2 (<1) 
Peripheral edema 
92 (11) 
2 (<1) 
69 (8) 
3 (<1) 
Headache 
91 (10) 
2 (<1) 
35 (4) 
3 (<1) 
93 (12) 
6 (<1) 
22 (6) 
0 
Any cardiac event 
88 (10) 
24 (3) 
66 (8) 
18 (2) 
49 (6) 
7 (1) 
30 (8) 
8 (2) 
Afib1 
16 (2) 
3 (<1) 
12 (1) 
5 (1) 
ACS2 
7 (1) 
7 (1) 
4 (<1) 
2 (<1) 
2 (<1)* 
2 (<1)* 
2 (<1)* 
2 (<1)* 
Acute renal failure 
32 (4) 
12 (1) 
38 (5) 
12 (1) 
Cerebrovascular 
12 (1) 
6 (1) 
9 (1) 
3 (<1) 
event 
Abnormality on 
8(1) 
2 (<1) 
5 (1) 
1 (<1) 
8 (1) 
3 (<1) 
6 (2) 
3 (<1) 
liver function test 
Seizure 
1 (<1) 
1 (<1) 
1 (<1) 
0 
5 (<1) 
5 (<1) 
0 
0 
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Drug Interactions 
 
Given previously reported CYP hepatic enzyme mediated interaction with other drugs – drugs that 
are known to have strong interaction through either CYP3A4 or CYP 2C9 should be avoided. 
 
Drugs that are confirmed to have strong interactions are: midazolam, gemfibrozil, omeprazole, 
warfarin (attachment: IB page 41 for list of drugs). Other drugs will be evaluated by PI upon 
individual cases. 
 
 
 
 
 
6.2 Paclitaxel (Taxol®) 
 
Contraindications 
 
Taxol is contraindicated in patients who have a history of hypersensitivity reactions to Taxol or other 
drugs formulated in Cremophor® EL (polyoxyethylated castor oil). 
Taxol should not be used in patients with solid tumors who have baseline neutrophil counts of 
<1500 cells/mm3 or in patients with AIDS-related Kaposi’s sarcoma with baseline neutrophil counts 
of <1000 cells/mm3. 
However for the purposes of this trial, once patients have begun active treatment, patients must 
maintain an Absolute Neutrophil Count > 1,000 cells/mm3. 
 
Warnings 
 
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension 
requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients 
receiving Taxol in clinical trials. Fatal reactions have occurred in patients despite premedication. All 
patients should be pretreated with corticosteroids, diphenhydramine, and H2 antagonists 
Patients who experience severe hypersensitivity reactions to Taxol should not be rechallenged with 
the drug. 
 
Bone marrow suppression (primarily neutropenia) 
 
Dose-dependent and is the dose-limiting toxicity. Neutrophil nadirs occurred at a median of 11 days. 
Taxol should not be administered to patients with baseline neutrophil counts of less than 1,500 
cells/mm3 (<1000 cells/mm3 for patients with KS). Frequent monitoring of blood counts should be 
instituted during Taxol treatment. Patients should not be re-treated with subsequent cycles of Taxol 
until neutrophils recover to a level >1,000 cells/mm3 (>1000 cells/mm3 for patients with KS) and 
platelets recover to a level >100,000 cells/mm3. 
Severe conduction abnormalities have been documented in <1% of patients during Taxol therapy 
and in some cases requiring pacemaker placement. If patients develop significant conduction 
abnormalities during Taxol infusion, appropriate therapy should be administered and continuous 
cardiac monitoring should be performed during subsequent therapy with Taxol. 
 
Pregnancy 
 
Taxol can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel 
during the period of organogenesis to rabbits at doses of 3.0 mg/kg/day (about 0.2 the daily 
maximum recommended human dose on an mg/m2 basis) caused embryo- and fetotoxicity, as 
indicated by intrauterine mortality, increased resorptions, and increased fetal deaths. Maternal 
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toxicity was also observed at this dose. No teratogenic effects were observed at 1.0 mg/kg/day 
(about 1/15 the daily maximum recommended human dose on an mg/m2 basis); teratogenic 
potential could not be assessed at higher doses due to extensive fetal mortality. 
There are no adequate and well-controlled studies in pregnant women. If Taxol is used during 
pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised 
of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid 
becoming pregnant. 
 
Precautions 
 
Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or devices 
used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to 
the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or 
sets, diluted Taxol solutions should preferably be stored in bottles (glass, polypropylene) or plastic 
bags (polypropylene, polyolefin) and administered through polyethylene- lined administration sets. 
Taxol should be administered through an in-line filter with a microporous membrane not greater than 
0.22 microns. Use of filter devices such as IVEX-2® filters which incorporate short inlet and outlet 
PVC-coated tubing has not resulted in significant leaching of DEHP. IVEX-2® is the registered 
trademark of the Millipore Corporation. 
 
Drug Interactions 
 
In a Phase 1 trial using escalating doses of Taxol (110–200 mg/m2) and cisplatin (50 or 75 mg/m2) 
given as sequential infusions, myelosuppression was more profound when Taxol was given after 
cisplatin than with the alternate sequence (i.e. Taxol before cisplatin). Pharmacokinetic data from 
these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when Taxol 
was administered following cisplatin. 
 
The metabolism of Taxol is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. 
Caution should be exercised when Taxol is concomitantly administered with known substrates 
(e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), 
inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, 
nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine) 
of CYP3A4. Caution should also be exercised when Taxol is concomitantly administered with known 
substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., 
rifampin) of CYP2C8. Potential interactions between Taxol, a substrate of CYP3A4, and protease 
inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of 
CYP3A4, have not been evaluated in clinical trials. Reports in the literature suggest that plasma 
levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when paclitaxel 
and doxorubicin are used in combination. 
 
 
Hematology 
 
Taxol therapy should not be administered to patients with baseline neutrophil counts of less than 
1500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent 
peripheral blood cell counts be performed on all patients receiving Taxol. Patients should not be re-
treated with subsequent cycles of Taxol until neutrophils recover to a level >1,000 cells/mm3 and 
platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 
for 7 days or more) during a course of Taxol therapy, a 20% reduction in dose for subsequent 
courses of therapy is recommended. 
For patients with advanced HIV disease and poor-risk AIDS-related Kaposi’s sarcoma, Taxol, at the 
recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 
1000 cells/mm3. 
 
 
 
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Hypersensitivity Reactions 
 
Patients with a history of severe hypersensitivity reactions to products containing Cremophor® EL 
(e.g., cyclosporine for injection concentrate and teniposide for injection concentrate) should not be 
treated with Taxol. In order to avoid the occurrence of severe hypersensitivity reactions, all patients 
treated with Taxol should be premedicated with corticosteroids (such as dexamethasone), 
diphenhydramine and H2 antagonists (such as cimetidine or ranitidine). Minor symptoms such as 
flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. 
However, severe reactions, such as hypotension requiring treatment, dyspnea requiring 
bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of Taxol 
and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity 
reactions should not be rechallenged with Taxol. 
 
Cardiovascular 
 
Hypotension, bradycardia, and hypertension have been observed during administration of Taxol, but 
generally do not require treatment. Occasionally Taxol infusions must be interrupted or discontinued 
because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the 
first hour of Taxol infusion, is recommended. Continuous cardiac monitoring is not required except 
for patients with serious conduction abnormalities. When Taxol is used in combination with 
doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is 
recommended. 
 
Nervous System 
 
Although the occurrence of peripheral neuropathy is frequent, the development of severe 
symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of 
Taxol. Taxol contains dehydrated alcohol USP, 396 mg/mL; consideration should be given to 
possible CNS and other effects of alcohol.  
 
 
Hepatic 
There is limited evidence that the myelotoxicity of Taxol may be exacerbated in patients with serum 
total bilirubin >2 times ULN. Extreme caution should be exercised when administering Taxol to such 
patients. 
 
Injection Site Reaction 
 
Injection site reactions, including reactions secondary to extravasation, were usually mild and 
consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These 
reactions have been observed more frequently with the 24-hour infusion than with the 3-hour 
infusion. Recurrence of skin reactions at a site of previous extravasation following administration of 
Taxol at a different site, i.e., “recall,” has been reported. 
More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have 
been reported. In some cases the onset of the injection site reaction either occurred during a 
prolonged infusion or was delayed by a week to 10 days. 
A specific treatment for extravasation reactions is unknown at this time. Given the possibility of 
extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug 
administration. 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
 
The carcinogenic potential of Taxol (paclitaxel) has not been studied. 
Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human 
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lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames 
test or the CHO/HGPRT gene mutation assay. 
Administration of paclitaxel prior to and during mating produced impairment of fertility in male and 
female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum 
recommended human dose on a mg/m2 basis). At this dose, paclitaxel caused reduced fertility and 
reproductive indices, and increased embryo- and fetotoxicity. 
 
Pregnancy 
 
Pregnancy (Section 9.2.2). Should a participant, or participant’s partner, become pregnant while on study, 
refer to section 9.2.2 for IRB and sponsor notification. 
 
7.0 Therapy Administration and Dose Reductions: 
NOTE: All toxicities should be graded according to the NCI Common Toxicity Criteria (version 
4.0) 
Dose modification for paclitaxel due to drug interaction to enzalutamide is not necessary based on 
the phase I trial, combination therapy of enzalutamide and docetaxel in CRPCa patients. (Data not 
shown) AEs leading to dose reduction of enzalutamide in the two combined controlled population of 
CRPCa patients were infrequent (enzalutamide 2.1% vs placebo 1.5%). Dose adjustments of 
paclitaxel should be considered first with the exception of nervous system disorders, e.g., seizure, 
PRES, syncope. If the AEs persist after dose reduction of paclitaxel, dose reduction of 
enzalutamide should be considered. Treating physician should consult with PI prior to reduction of 
either, or both, drugs. Dose modification schedule was shown in Table 3. 
 In the case of nervous system toxicity, the trial treatment will be discontinued. 
 
Enzalutamide and paclitaxel will be withheld for drug-related ≥ Grade 3 hematologic toxicities 
(excluding Grade 3 neutropenia, anemia, and thrombocytopenia), or Grade 3 or higher non- 
hematological toxicity, including laboratory abnormalities, and severe or life-threatening AEs as per 
Table 2 below. After those toxicities resolve to Grade 0-1 or baseline, treatment could be resumed 
with one level of dose reduction. 
   
Should a delay of >14 days be required, then the patient should be discontinued from study 
treatment. 
 
 
 
 
 
 
 
 
 
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Table 2: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Restart 
Treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject 
 
Hematologic 
 
Toxicity 
1 
2 
No 
N/A 
N/A 
N/A 
3* 
*Excluding 
Grade 3 
neutropenia, 
anemia, and 
thrombocyto-
penia 
Yes 
Toxicity 
resolves 
to Grade 
0-1 or 
baseline 
One level of 
dose reduction 
Toxicity not 
resolving within 
14 days of dose. 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life- threatening 
event 
4 
Yes 
Toxicity 
resolves 
to Grade 
0-1 or 
baseline 
One level of 
dose reduction 
Non- 
Hematologic 
Toxicity 
 
 
 
1 
2 
No 
N/A 
N/A 
N/A 
3 
4 
Yes 
Toxicity 
resolves 
to Grade 
0-1 or 
baseline 
One level of 
dose reduction 
Toxicity not 
resolving within 
14 days of dose 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life- threatening 
event 
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Table3: Drug Dosing and Recommended Reductions for Toxicity [38] 
Enzalutamide 
Paclitaxel 
Dose Level 1 
120 mg PO daily 
80 mg/m2 weekly 
Dose Level -1 
120 mg PO daily 
60 mg/2 weekly 
Dose Level -2 
 80 mg PO daily 
60 mg/2 weekly 
Dose Level -3 
Hold 
Hold 
 
 
7.1    Supportive Care 
 
All supportive measures consistent with optimal patient care should be given throughout the 
study. Exceptions include the use of erythropoietin to treat therapy-induced anemia. 
Investigators who choose to use myeloid growth factors should administer either GCSF or 
pegylated GCSF beginning on either day 2 or 3 of each cycle. The use of growth factor 
support should follow ASCO guidelines. 
 
 
7.2      Duration of Therapy 
 
Patients will receive protocol therapy unless: 
 
• Patient experiences unacceptable drug toxicity. 
• Patient withdraws consent. 
• Patient has progression of disease. 
• The patient completes the required 12 weeks of therapy. 
                           
   7.3       Duration of Follow-up 
For this protocol, all patients, including those who discontinue protocol therapy early, will 
be followed until at least two years after surgical resection of the tumor. 
 
    7.4   Protection of human subjects 
 
All current FDA, NCI, state federal and institutional regulations concerning informed 
consent will be followed. 
 
In order to protect confidential patient information, all study participants will be assigned a 
study ID number. Specimens will be assigned a separate specimen ID number. All study 
information will be stored in locked file cabinets and in password-protected computer 
files. Only authorized study personnel will have access to these files. 
 
 
8.0    Measurement of Effect 
 
8.1    Pathologic response 
The RCB is a continuous variable derived from the primary tumor dimensions, cellularity of the 
tumor bed, and axillary nodal burden. RCB can be divided into four classes (RCB-0 to RCB-III) 
and will be collected as part of the study. 
RCB-0 (pCR), Minimal RCB (RCB-I), Moderate RCB (RCB-II), and Extensive RCB (RCB-III). 
The following parameters are required from pathologic examination in order to calculate 
Residual Cancer Burden (RCB) after neoadjuvant treatment: 
 
 
 
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The largest two dimensions (mm) of the residual tumor bed in the breast (largest tumor bed if 
multicentric disease) 
 
Submission of the entire largest cross-sectional area of the residual tumor bed for histologic 
mapping, with specific identification of those slides in the pathology report (e.g. "the largest cross- 
sectional area of primary tumor bed was submitted in cassettes A5 - A9") 
 
If the residual tumor is large (i.e. largest diameter > 5 cm), then at least 5 representative 
cassettes from the largest cross-sectional area are sufficient, but should be identified in the 
original pathology report (e.g. "representative sections from the largest cross- sectional area of 
primary tumor bed were submitted in cassettes A5 - A9") 
 
Histologic assessment of the percentage of the tumor bed area that contains carcinoma (all 
carcinoma, i.e. invasive and in situ), select one of the following: 
 
0%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% 
 
To assess cellularity it is helpful to scan across the sections of tumor bed and then estimate the 
average cellularity from the different microscopic fields. 
 
When estimating percentage cancer cellularity in any microscopic field, compare the involved 
area with obvious standards, e.g. more or less than half, one quarter, one fifth, one tenth, one 
twentieth, etc. 
 
Expect there to be variable cellularity within the cross section of any tumor bed, but estimate the 
overall cellularity from the average of the estimates in different microscopic fields of the tumor 
bed. e.g. if cellularity in different fields of the tumor bed were estimated as 20%, 10%, 20%, 0%, 
20%, 30%, then an average estimate of overall cellularity would be 20%. 
 
Histologic estimate of the percentage of the carcinoma in the tumor bed that is in situ, select one 
of the following: 
 
0%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% 
 
The number of positive (metastatic) lymph nodes 
 
The largest diameter (mm) of the largest nodal metastasis 
 
The RBC can be accessed online: www.m danderson.org/breastcancer_RBC 
 
8.2    Radiographic Imaging 
 
Radiographic criteria of response will be based on the on regional ultrasound 
examination (decrease in size of the primary tumor and/or fatty replacement in regional lymph 
nodes) 
 
A decrease in size of the product of the two largest dimensions should =/> 50% will be 
considered a partial response. 
 
Complete disappearance of the primary tumor by physical exam and or ultrasound and 
normalization of the lymph nodes by ultrasound will be considered a complete clinical response. 
 
Progression of disease will be defined as 30% increase in the size of the primary tum or 
and/or lymph nodes on physical exam and/or ultrasound. 
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9.0       Adverse Event Reporting 
 
 
9.1   Definition of Adverse Events (AEs) 
 
An adverse event (AE) is defined as any untoward medical occurrence in a subject administered 
a study drug and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a study drug, whether or not 
related to the study drug. 
 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, 
physical exam) should be defined as an AE only if the abnormality meets one of the following 
criteria: 
• 
Induces clinical signs or symptoms. 
• 
Requires active intervention. 
• 
Requires interruption or discontinuation of study medication. 
• 
The abnormality or investigational value is clinically significant in the opinion of the 
investigator. 
 
All adverse events, whether or not related to the study drug, must be documented in the electronic 
database. 
 
 
9.2   Definition of Serious Adverse Events (SAEs) 
 
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in any 
of the following outcomes: 
 
• 
Results in death, 
• 
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death.), 
• 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions, 
• 
Results in congenital anomaly, or birth defect, 
• 
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious), 
• 
Other medically important events. 
 
9.2.1Serious Adverse Event Reporting 
 
Any serious adverse event will be reported to both sponsor, and institution as per 
guideline outlined below. 
 
Report to Astellas: 
Within 24 hours of awareness of a serious adverse event, whether or not related to the study drug, 
the Investigator will complete and submit a MedWatch 3500A Form to FDA, containing all required 
information (reference 21 CFR 312.32). The Investigator will submit a copy of this MedWatch 
3500A form to Astellas by either e-mail or fax, within the same timeframe. If submission of this 
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SAE to FDA or Astellas or is not possible within 24 hours, the Investigator’s local drug safety 
contact (IRB, etc.) should be informed by phone. 
 
The SAE documentation, including the MedWatch 3500A Form and available source records 
should be emailed or faxed to: 
 
Astellas Pharma Global Development – United States 
Email: Safety-us@us.astellas.com 
Fax number: (847) 317-1241 
 
The following minimum information is required: 
• 
Study number/IIT regulatory identifier 
• 
Subject number, sex and age 
• 
The date of report 
• 
A description of the SAE (event, seriousness of the event) 
• 
Causal relationship to the study drug 
 
Follow-up information for the event should be sent within promptly (within 7 days) as necessary. 
 
Report to M D Anderson IRB 
 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the timeframes and procedures outlined in “University of 
Texas M. D. Anderson Cancer Center Institutional Review Board Policy on Reporting Serious 
Adverse Events”. Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to ORERM, regardless of attribution (within 5 working days of knowledge of the 
event). All life-threatening or fatal events, expected or unexpected, and regardless of attribution to 
the study drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in ORERM. The MDACC “Internal SAE 
Report Form for Prompt Reporting” will be used for reporting to ORERM. Serious adverse events 
will be captured from the time the patient signs consent until 30 days after the last dose of drug. 
Serious adverse events must be followed until clinical recovery is complete and laboratory tests 
have returned to baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. Serious adverse events will be forwarded to FDA by the Safety Project 
Manager ORERM according to 21 CFR 312.32 
 
9.2.2 Procedure in Case of Pregnancy 
 
The effect of enzalutamide in pregnant and lactating women is not known, and the exposure of a 
fetus or nursing infant is considered a potential risk. Enzalutamide can cause fetal harm when 
administered to a pregnant woman based on its mechanism of action. Subjects receiving 
enzalutamide are advised to use 2 acceptable methods of birth control (one of which must include 
a condom as a barrier method of contraception) starting at the time of screening for an 
enzalutamide study and continuing throughout the course of treatment and for at least three 
months after enzalutamide is discontinued. 
 
If during the conduct of the clinical trial, a male subject impregnates his partner, the subject 
should report the pregnancy to the Investigator. The Investigator should report the pregnancy to 
the Sponsor as an SAE within 24 hours of awareness of the event. The expected date of delivery 
or expected date of the end of the pregnancy, last menstruation, estimated fertility date, 
pregnancy result and neonatal data etc., should be included in this information. 
 
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The Investigator should report the outcome of the pregnancy (independent of outcome, e.g. full 
term delivery, pre-term delivery, spontaneous abortion, induced abortion, stillbirth, death of 
newborn, congenital anomaly [including anomaly in a miscarried fetus, etc.] in accordance with 
the same reporting procedure as for SAEs. The date of outcome of the pregnancy, gestational 
age, date of birth and neonatal data etc., should be included in this information. 
 
 
 
10.  Statistical Considerations 
 
Overview 
This is a non-randomized open label phase IIB study. Counting pCR (RCB-0) or RCB-I as 
response, using a Simon optimal two-stage design with alpha = beta = 10%, and then setting the 
threshold for an acceptable pCR or RCB-I rate at 20%. We will enroll 12 patients into the first 
stage. If we see 0 patients with pCR or RCB-I, we will stop the study after the first stage. If we 
see at least one patient with pCR or RCB-I, we will continue to enroll 25 more patients for a total 
of 37 patients. We would declare the treatment worthy of further study if we see at least 4 of the 
37 patients with pCR or RCB-I. This design has a 54% probability of early termination after the 
first stage if the true pCR or RCB-I probability is 5%. 
 
Patients who are unable to complete the combination therapy due to toxicity will be considered 
non- responders. Patients withdrawing early for any reasons other than (1) toxicity or (2) for 
progression of disease will be replaced. Additionally, a secondary efficacy analysis will be based 
on a modified intent-to-treat population receiving at least one dose of experimental therapy such 
that patients withdrawing early for any reason are considered non-responders. We will require 
37 patients enrolled in order to ensure a sufficient number of evaluable patients at the final 
protocol analysis. 
 
 
Secondary Objectives and Correlative Studies: 
Potential biomarkers of response will be correlated with pathologic response to this treatment 
using appropriate statistical analyses for the biomarker of interest. 
 
A secondary objective of this study is to also estimate the PFS distribution. PFS is defined as the 
time from enrollment to progression of disease (>30% increase in tumor size as defined in 
Section 8.2) or death whichever comes first. 
 
We will estimate the proportion of patients with pCR (RCB-0) or RCB-I as the response rate along 
with an appropriate 95% confidence interval. We will estimate the proportion of patients in the 
remaining RCB categories with confidence intervals as well. We will estimate the PFS distribution 
using the Kaplan-Meier method from the date of enrollment onto this study until the date of 
progression or death without evidence of progression. Patients alive and disease-free at the latest 
clinical evaluation will be censored at the date of that evaluation. 
 
Early drop outs (i.e., patients not getting to surgery) should be counted as treatment failures (i.e., 
non-responders with RCB > 1). 
If no RCB-0 or -1 response has been observed prior to enrolling the 13th patient, enrollment will 
stop until all of the 12 patients in the first stage are evaluable and resume only if a response has 
been documented. 
 
 
Inclusion of Minorities 
 
The study will be available to all eligible patients regardless of race, or ethnic origin. There is no 
information currently available regarding differential effects of this regimen in subsets defined by 
race or ethnicity. 
 
 
 
 
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Protocol Monitoring 
The study will be monitored by the PI. Bi-monthly safety review meetings/telephone conferences 
will be held to discuss toxicities, serious adverse events, and study progress. Meeting invitees will 
include the study PI, co-PI, study nurse, and data coordinator. 
 
 
 
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