Clinical trial NCT02282345
Conditions: Breast Adenocarcinoma Deleterious BRCA1 Gene Mutation Deleterious BRCA2 Gene Mutation HER2/Neu Negative Invasive Breast Carcinoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-04-16; Completion date: 2022-06-07
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies the side effects of talazoparib when given before standard therapy in treating patients with breast cancer that has spread to nearby healthy tissue and has a mutation in a breast cancer, early onset (BRCA) gene. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, and may be especially effective in patients with BRCA mutations. It is not yet known whether adding talazoparib before standard treatment is safe in treating patients with BRCA mutated breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the feasibility of using talazoparib prior to initiating standard neoadjuvant therapies.

II. To evaluate the toxicity profile in women taking talazoparib in the neoadjuvant setting.

SECONDARY OBJECTIVES:

I. To provide first estimate of clinical response to talazoparib in the neoadjuvant setting in a pilot trial setting.

II. To evaluate biomarkers of therapy efficacy as well as initiate patient derived xenograft (PDX) models: targeted or whole exome sequencing for BRCA pathway mutations and other somatic and germline alterations; ribonucleic acid (RNA) sequencing; evaluation of changes in immune response; transcriptional profile to assess triple negative breast cancer (TNBC) subtype, BRCA-ness signature and putative PARP sensitivity predictors; functional proteomics with reverse phase protein array (RPPA); generate PDX models and mammosphere cultures from patient derived tumors; PTEN, gamma-H2A histone family, member x (gamma-H2A.X), Ki-67 and cleaved caspase 3 by immunohistochemistry (IHC).

OUTLINE:

Patients receive talazoparib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then proceed to the standard of care therapy of the treating physician's choice.

After completion of study treatment, patients are followed up until the day after definitive breast surgery.

Arms: arm 1: Patients receive talazoparib PO QD on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then proceed to the standard of care therapy of the treating physician's choice.

This arm was concluded early after 13 patients. An expansion arm of 20 patients was opened in August 2016 to include at least 4 and up to 6 cycles of talazoparib, followed by surgery to estimate residual cancer burden after therapy with single-agent talazoparib.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Talazoparib
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
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A Pilot Study of Talazoparib as a Neoadjuvant Study in Patients with a Diagnosis of Invasive 
Breast Cancer and a Deleterious BRCA Mutation 
 
IND NUMBER: 125080 
 
 
 
Study Chair: Jennifer K. Litton, M.D. 
 
 
Associate Professor, Departments of Breast Medical Oncology  
 
 
The University of Texas MD Anderson Cancer Center 
 
 
1515 Holcombe Boulevard, Unit 1354 
 
 
Houston, TX 77030 
 
 
(713) 792-2817 tel. 
 
 
(713) 794 4385 fax. 
 
 
jlitton@mdanderson.org 
 
 
Co-Chair: 
Banu K. Arun, M.D. 
 
 
Professor, Department of Breast Medical Oncology  
 
 
The University of Texas MD Anderson Cancer Center 
 
 
 
Collaborators: 
 
Gordon Mills, M.D., Ph.D. 
Director, Precision Oncology, Knight Cancer Institute 
Professor, Cell, Developmental and Cancer Biology 
Director, SMMART Trials, Knight Cancer Institute 
Wayne and Julie Drinkward Endowed Chair, Precision Oncology, Knight Cancer Institute 
Oregon Health & Science University (OHSU) 
 
 
Helen Piwnica-Worms, Ph.D. Vice Provost, Science 
The University of Texas MD Anderson Cancer Center 
 
Naoto T Ueno, M.D., Ph.D. 
Professor, Department of Breast Medical Oncology  
The University of Texas MD Anderson Cancer Center 
  
Stacy Moulder, M.D. 
Associate Professor, Department of Breast Medical Oncology  
The University of Texas MD Anderson Cancer Center 
 
 
Funda Meric-Bernstam, M.D. 
Professor and Chair, Investigational Cancer Therapeutics 
 The University of Texas M.D. Anderson Cancer Center 


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Gary Whitman, M.D. 
Professor, Department of Diagnostic Imaging 
The University of Texas M.D. Anderson Cancer Center 
 
Constance Albarracin, M.D., Ph.D. 
Associate Professor, Department of Pathology, Division of Pathology/Lab Medicine  
The University of Texas MD Anderson Cancer Center 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
Table of Contents............................................................................................................................. 3 
1.0 OBJECTIVES AND RESEARCH HYPOTHESIS .............................................................. 6 
1.1 Primary Objectives ...................................................................................................................... 6 
1.1.1 
To evaluate the feasibility of using Talazoparib prior to initiating standard                   
 
neoadjuvant therapies ................................................................................................ 6 
1.1.2 
To evaluate the toxicity profile in women taking Talazoparib in the neoadjuvant      
 
setting......................................................................................................................... 6 
1.1.3 
In an expansion cohort, to estimate the pathologic complete response to talazoparib 
 
in 4 and up to 6 months of therapy prior to definitive surgery. …………................6 
1.2 
Secondary Objectives .............................................................................................................. 6 
1.2.1 
To provide first estimate of clinical response to Talazoparib in the neoadjuvant setting 
in  a pilot trial setting ................................................................................................................ 6 
1.2.2 
To evaluate biomarkers of therapy efficacy as well as initiate patient derived 
 
xenograft  (PDX) models:.......................................................................................... 6 
1.3 
Research Hypothesis................................................................................................................ 6 
2.0 BACKGROUND ...................................................................................................................... 7 
2.1 
Breast Cancer ............................................................................................................................ 7 
2.2 
Primary Systemic Therapy: Historical Perspective ......................................................... 7 
2.3 
Pathological Assessment ......................................................................................................... 8 
2.4 
Phase II and III Randomized PST Breast Cancer Trials ............................................... 8 
2.5 
Current Primary Systemic Chemotherapy Regimens ................................................... 10 
2.6 
Primary Systemic Therapy in Operable Breast Cancer ............................................... 11 
2.7 
Role of the Pathological Complete Response in Breast Cancer .................................. 12 
2.8 
BRCA mutations .................................................................................................................... 13 
2.9 
PARP inhibitors...................................................................................................................... 14 
2.10 Talazoparib .............................................................................................................................. 15 
2.10.1 
Nonclinical Study Findings for Talazoparib ....................................................... 16 
2.10.2 
Preliminary Clinical Study Findings for Talazoparib ....................................... 16 
2.10.3     Preliminary Findings from this Trial as of 3/11/2016. ....................................... 18 
3.0 RATIONALE FOR THE CURRENT STUDY ................................................................... 18 
4.0 TREATMENT PLAN............................................................................................................ 19 
4.1 
Study Design ............................................................................................................................ 19 
4.2 
Eligibility .................................................................................................................................. 19 
4.2.1 
Inclusion Criteria: ................................................................................................. 19 
4.2.2 
Exclusion Criteria: ................................................................................................ 20 


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4.3 Treatment Administration Plan .............................................................................................. 21 
4.3.1 
Study Visits ............................................................................................................. 22 
4.3.2 
Biopsies/Correlative Studies ................................................................................. 22 
4.3.3 
Progression While on Study.................................................................................. 23 
4.3.4 
Surgery ................................................................................................................... 23 
4.4 Duration of Study ....................................................................................................................... 23 
4.5 STUDY DESIGN SCHEMA (Original Study Schema) ..................................................... 24 
4.6 
Dose modification ................................................................................................................... 25 
4.7 
Concurrent and supportive care......................................................................................... 26 
4.8 
Criteria for discontinuation of study drug ....................................................................... 26 
4.9 
Criteria for Feasibility and Response ................................................................................ 27 
5.0 CORRELATIVE STUDIES ................................................................................................. 29 
5.1 Biopsies .......................................................................................................................................... 29 
5.2 
Patient Derived Xenografts (PDX) ..................................................................................... 29 
5.3 
Circulating Biomarkers ........................................................................................................ 31 
6.0 STUDY DRUG COMPLIANCE AND ACCOUNTABILITY .......................................... 33 
6.1 
Assessment of Compliance ................................................................................................... 33 
6.2 
Assessment of Accountability .............................................................................................. 33 
7.0 
ADVERSE EVENT REPORTING AND DATA COLLECTION ............................... 33 
7.1 
Adverse Events ....................................................................................................................... 33 
7.2 
Adverse Event Reporting Guidelines ................................................................................ 34 
7.3 
Investigator Communication with Supporting Companies.......................................... 35 
7.4 
Monitoring ............................................................................................................................... 36 
7.5 
Adverse Event Data Collection ........................................................................................... 36 
7.6 
AE/SAE Follow up ................................................................................................................. 37 
7.7 
Product Complaints Reporting ............................................ Error! Bookmark not defined. 
8.0 STATISTICAL ANALYSIS ................................................................................................. 37 
9.0 PUBLICATION OF TRIAL RESULTS ............................................................................. 38 
10.0 STUDY CALENDAR .......................................................................................................... 38 
11.0 References ............................................................................................................................. 40 
 
 
 
 
 
 


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List of Abbreviations 
 
 
AE 
 
Adverse Event 
ALT 
 
alanine aminotransferase 
AST 
 
aspartate aminotransferase 
b.i.d.   
bis in diem/twice a day 
Chem-12 
Comprehensive metabolic panel 
CRF 
 
Case Report/Record Form 
CS&E  
Clinical Safety and Epidemiology 
CR 
 
Clinical Research 
CRO   
Contract Research Organization 
DFS 
 
Disease-free survival 
ECG  
Electrocardiogram 
IEC 
 
Independent Ethics Committee 
i.v. 
 
intravenous(ly) 
IRB  
 
Institutional Review Board 
LFT 
 
Liver Function Test 
o.d.  
 
omnia die/once a day 
OS  
 
overall survival 
pCR 
 
pathologic complete response 
p.o. 
 
 per os/by mouth/orally 
PST   
preoperative systemic therapy 
RCB  
residual cancer burden 
REB 
 
Research Ethics Board 
SAE 
 
Serious Adverse Event 
SOP   
Standard Operating Procedure 
TNBC  
Triple negative breast cancer 
WHO  
World Health Organization 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0 OBJECTIVES AND RESEARCH HYPOTHESIS 
 
1.1 Primary Objectives 
 
1.1.1 To evaluate the feasibility of using talazoparib prior to initiating standard   
 
              
 
neoadjuvant therapies 
 
1.1.2 To evaluate the toxicity profile in women taking talazoparib in the neoadjuvant  
   
 
setting 
 
1.1.3 In an expansion cohort, to estimate the pathologic complete response to talazoparib in 4 and    
 
up to 6 months of therapy prior to definitive surgery. 
 
1.2 
Secondary Objectives 
 
1.2.1 To provide first estimate of clinical response to talazoparib in the neoadjuvant setting in a 
 
pilot trial setting. 
 
1.2.2 To evaluate biomarkers of therapy efficacy as well as initiate patient derived xenograft 
 
(PDX) models: 
• 
Targeted or whole exome sequencing for BRCA pathway mutations and other somatic 
and germline alterations 
• 
RNA sequencing 
• 
Evaluation of changes in immune response 
• 
Transcriptional profile to assess TNBC subtype, BRCA-ness signature and putative 
PARP sensitivity predictors 
• 
Functional proteomics with reverse phase protein array (RPPA) 
• 
Generate PDX models and mammosphere cultures from patient derived tumors 
• 
PTEN, gamma-H2A.X, Ki-67 and cleaved caspase 3 by IHC 
 
 
1.3 
Research Hypothesis 
 
Sequential administration of Talazoparib followed by an anthracycline and taxane regimen in 
patients with a known BRCA deleterious mutation will be well tolerated and show response to 
single agent therapy. 
 
A biomarker-defined population can be identified in which a higher pCR rate is observed in 
subjects treated with Talazoparib followed by anthracycline and taxane systemic therapy. 
 
PDX models will provide models to understand sensitivity and resistance mechanisms. 


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2.0 BACKGROUND 
 
2.1 
Breast Cancer 
 
Invasive breast cancer is the most common malignancy in women worldwide. In the United States, 
breast cancer is the most common female cancer, the second most common cause of death in 
women (after lung cancer), and is the main cause of death in women between the ages of 45 and 55. 
[1] However, over the last decade the mortality rate has declined in the United States and United 
Kingdom largely because of widespread use of mammography, breast cancer screening programs, 
advances in evaluation technique, and more effective adjuvant treatments. [2] 
 
Studies that compared preoperative (neoadjuvant or primary systemic therapy) and adjuvant 
chemotherapy in patients with early stage breast cancer have shown no difference in overall 
survival or disease free survival. [3] Primary systemic therapy (PST) is increasingly being used in 
the management of patients with early breast cancer. Neoadjuvant chemotherapy allows for 
monitoring of response to chemotherapy and enhances chances of breast conservation surgery 
and/or a better cosmetic outcome following mastectomy in patients with locally advanced breast 
cancer. [4, 5] Additionally, the neoadjuvant setting is ideal for correlative studies to identify breast 
cancer patients likely to best respond to therapy. The provision of a surgical specimen, at the end of 
therapy, allows for a more rapid assessment of response (pathological responses) than adjuvant 
trials. Pathological complete response (pCR) is widely accepted as a valuable prognostic indicator 
of long-term outcome after neoadjuvant therapy. [6] 
 
2.2 
Primary Systemic Therapy: Historical Perspective 
 
The rationale for considering the evaluation of primary systemic therapy (PST) in patients with 
operable breast cancer began to evolve as clinical observations demonstrated the utility of this 
approach in patients with locally advanced breast cancer (LABC), [7-9]  and inflammatory breast 
cancer (IBC). In addition, preclinical observations, [10, 11] and mathematical models of tumor 
growth, dissemination, and development of resistance to chemotherapy support the use of PST 
rather than adjuvant therapy. These could lead to achieve longer disease-free survival (DFS) and 
overall survival (OS), presumably through early treatment of systemic micrometastatic disease. 
Since its initial use in the early 1970s, PST has become the standard of care for management of 
LABC and IBC, and increasingly been used for treatment of large operable and more recently for 
early-stage breast cancer. 
 
Chemo-, hormone-, and anti-HER2 therapies are potential PST options for the different sub- types 
of breast cancer. PST provides several advantages, including down-staging allowing surgery for 
non-operable breast cancer, and increasing breast-conservative surgery rate in patients with large 
operable breast cancer.  It also provides an early surrogate factor, pCR, for long-term outcome and 
in-vivo model to assess clinical benefit and finally a research tool for understanding breast cancer 
biology and treatment mechanisms of action(s). pCR has also been recently added as an appropriate 
endpoint for FDA approval pathways in breast cancer. 


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2.3 
Pathological Assessment 
 
A variety of endpoints can be used to measure outcomes of PST for breast cancer other than 
directly measuring survival (DFS, and OS), which requires a large number of patients and long 
term follow-up. These endpoints included clinical response, radiologic response, rate of breast 
conservative surgery (BCS), and pathologic response. The results of several studies have been 
shown that pCR is predictive of long-term survival. [12-15] At present, the achievement of pCR 
has emerged as the primary end point of most interest in the clinical research literature. Attainment 
of pCR is associated with a favorable prognosis; such patients have a far lower risk of subsequent 
recurrence than do patients with residual invasive tumor at the time of surgery, and also seem to 
have improved overall survival. Despite the strong evidence of predictive value of pCR in this 
context, there is no consensus on the measurement of this important endpoint. Clinical and 
pathological responses are both frequently used as objective measurements of effectiveness of PST.  
Three of the most commonly used criteria in the literature are those by Sataloff et al [15], Feldman 
et al, [12] and most recently Symmans and collaborators from the University of Texas, MD 
Anderson Cancer Center. The first 2 sets of criteria have some overlap but, for the most part, differ 
from each other. 
 
In general, 60% to 90% of patients with invasive breast cancer show clinical response, however, 
only 3% to 30% of patients achieve pCR. Two large studies using PST, NSABP B-18 and B-27 
defined pCR as no residual invasive cancer in the breast after PST and at the time of surgery, 
whereas other studies also take node status and noninvasive cancer into account. An International 
Expert Panel recently recommended that pCR be defined as no invasive or noninvasive tumors in 
the breast and axillary tissues removed at the time of surgery. [7] 
 
Symmans et al [16] showed a continuous index combining pathologic measurements of the primary 
tumor (size and cellularity) and nodal metastases (number and size) and tested as an independent 
predictor of distant relapse-free survival. Patients with minimal residual disease (RD) (RCB-I) 
carried the same prognosis as pCR (RCB-0). On the other hand, patients with extensive RD (RCB-
III) had poor prognosis. RCB was independently prognostic in a multivariate model that included 
age, pretreatment clinical stage, hormone receptor status, hormone therapy, and pathologic 
response (pathologic complete response [pCR] vs. RD; hazard ratio = 2.50; 95% CI 1.70 to 3.69; P 
< .001).  Seventeen per cent of patients had minimal RD (RCB-I). These patients carried the same 
prognosis as pCR (RCB-0).  Extensive RD (RCB-III) was seen in 13% of patients.  It was 
associated with poor prognosis, regardless of hormone receptor status, adjuvant hormone therapy, 
or pathologic American Joint Committee on Cancer stage of residual disease. The calculation 
formula and detailed description can be found at a dedicated Web site: 
http://www.mdanderson.org/breastcenter_RCB. 
 
 
2.4 
Phase II and III Randomized PST Breast Cancer Trials 
 
Several large Phase III trials investigated the efficacy of chemotherapy when administered as PST 
compared with adjuvant systemic treatment. 
 


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In 1998 the National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a large 
phase III study (NSABP P-18) to compare PST and post-operative chemotherapy.  [6, 17, 18] 
  
 
A total of 1,523 patients with T1-3 N0-1 M0 breast cancer were randomized to receive four cycles 
of doxorubicin and cyclophosphamide (AC) either as PST or adjuvant therapy. Breast tumor size 
was reduced in 79% of patient after PST, and 36% had a clinical complete response (cCR) rate, 
43% clinical partial response (cPR), and a 13% pCR. Clinical nodal response was observed in 89% 
of patients with node-positive disease; 73% had nodal cCR, and 44% of these patients had pCR.  At 
9 years, the authors reported no difference in DFS (67% for both groups) or OS (69% PST vs. 70% 
adjuvant groups; P = .80).  However, there was a favor trend in favor of PST in women less than 50 
years old (HR 0.85, P = .053). The investigators reported that the use of PST improved BCS from 
60% to 67% (P < .01). Even with improved rates of BCS, there was no statistically significant 
difference in the rate of local recurrence between treatment groups (P = 
.12). A marginal increase in the rate of local recurrence for patients who were converted from 
proposed mastectomy to segmental mastectomy (15.9%) was seen when compared with patients 
who were eligible to undergo segmental mastectomy as per initial plan (9.9%) (P = .04). This 
difference loses statistical significance after controlling for age and initial clinical tumor size. 
 
NSABP B-27, a large prospective randomized trial, [14, 19] was designed to evaluate whether the 
addition of docetaxel to AC PST would prolong DFS and OS and improve clinical and pathologic 
tumor response rates.  Women with operable breast cancer (n = 2,411) were randomly assigned to 
receive either 4 cycles of PST AC followed by surgery (Group 1), 4 cycles of AC followed by 4 
cycles of docetaxel, followed by surgery (Group 2), or 4 cycles of AC followed by surgery and then 
4 cycles of docetaxel (Group 3).  The addition of docetaxel to AC increased pCR rate (26.1% vs 
13.7%; P < .001).  pCR was a significant predictor of OS (HR 0.33, P < 
.0001).  The pathologic nodal status after chemotherapy was also a significant prognostic factor for 
OS (P < .0001). 
However, this study did not prospectively assess the role of docetaxel in 
patients with residual disease after PST AC.  There was no stratification after AC. The patients with 
all eight cycles of PST administered up front had a trend toward improvement in RFS. [14] One 
caveat with this study is that at the time it was conducted, all patients received tamoxifen, which 
was initiated concurrently with chemotherapy, regardless of hormone-receptor status. The 
simultaneous administration of tamoxifen and chemotherapy may have decreased the benefit from 
chemotherapy. 
 
The European Organization for Research and Treatment of Cancer (EORTC) Trial 10902 
randomized 698 patients with stage I to IIIB breast cancer to receive four cycles of PST or adjuvant 
FEC-100. [20] The primary objective of this study was to determine the impact of timing of therapy 
on DFS and OS. After a follow-up of 4-years the OS was 82% for PST group compared to 84% for 
those treated in the adjuvant setting (P = .38). For patient who received PST, the overall response 
rate (ORR) (cCR + cPR) was 49% and cCR 7%. Thirteen of 350 patients (4%) in the PST group 
had a pCR. For this study, response was determined by both clinical examination and changes with 
the mammogram, possibly explaining the low overall clinical CR. PST was associated with an 
increased rate of 35% BCS compared to 22% for the control group. The rate of locoregional 
recurrence was equivalent between treatment groups. 
 
The European Cooperative Trial in Operable (ECTO) Breast Cancer randomly tested the efficacy 
of postoperative chemotherapy doxorubicin followed by cyclophosphamide, methotrexate, and 


2014-0045 
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5-fluorouracil (CMF) or doxorubicin and paclitaxel (AP) followed by CMF versus PST consisting 
in AP followed by CMF.  [21, 22] A total of 1,355 patients entered the study. Overall, PST induced 
a clinical response in 78% of the patients and pCR 23%. There was no significance in RFS when 
AP/CMF was given before surgery compared with the same regimen given after surgery (HR, 1.21; 
P = .18) However, the rate of breast-conserving surgery was significantly higher with preoperative 
chemotherapy (63% vs. 34%; P < .001) 
 
The wide variety of PST clinical trials recently completed or ongoing in early breast cancer reflects 
the pressing need to identify the most effective agents and regiments to optimize both surgical and 
long-term outcomes for these patients. 
 
Lastly, Buzdar el al [23] compared two taxane schedules (weekly paclitaxel [WP] x 12 versus 3- 
week docetaxel plus capecitabine (DC) x 4 cycles, followed by: FEC-100 x 4 cycles. Patients were 
randomized 1:1 and stratified by the timing of therapy (PST vs. adjuvant). A total of 216 patients 
were treated with PST and 107 were randomized to WP arm and 109 to DC arm. The pCR rates 
were 18.7% and 17.4% on each arm, respectively (P = .81). The DC arm had higher incidence of 
hand foot syndrome, and myelosuppression, and WP treatment higher neurotoxicity. The primary 
endpoint was DFS, and the secondary endpoint pCR. The study was designated to include 930 
patients to have 80% power. After interim analysis in June 2008 by the data monitoring committee 
the study was closed due to futility. The authors concluded that WP and DC in the PST setting had 
same efficacy and WP was associated with better tolerance and less toxicity. 
 
 
2.5 
Current Primary Systemic Chemotherapy Regimens 
 
Pathological complete response rates are generally higher with anthracycline-based combinations 
than with regimens not containing anthracyclines (doxorubicin or Epirubicin). Consequently, most 
PST regimens for breast cancer are anthracycline-based combination: AC 
(doxorubicin/Cyclophosphamide); FAC (fluorouracil/doxorubicin/cyclophosphamide); CE 
(cyclophosphamide/epirubicin); and FEC (fluorouracil/epirubicin/cyclophosphamide). However, 
other non-anthracycline based drug combinations, such as CMF 
(cyclophosphamide/methotrexate/fluorouracil) with or without a taxane, are also in common use. 
Increased duration of chemotherapy administration from 12 to 18 weeks or longer improves pCR 
rates. [5] The addition of paclitaxel or docetaxel to anthracyclines based regimes has resulted in 
pCR of up to 28.2%. [24] The Aberdeen study showed that tumors that did not respond to an 
anthracycline-based regimen may respond to docetaxel. Additionally sequential and non- 
concomitant addition of taxane to anthracycline-based chemotherapy results in higher pCR rates. 
[25] 
 
Additionally, from data presented at the San Antonio Breast Cancer Symposium in 2013 by Sikov, 
et al [26] evaluated the addition of both carboplatin and bevacizumab in a 2 x 2 trial design to 
neoadjuvant weekly paclitaxel and AC. There was a 13% absolute difference in pCR. However, 
given toxicity profile, this combination has been administered but as of the date of this protocol, not 
added to the Institutional or NCCN guidelines. Therefore given that this trial is being written while 
there is a shifting landscape of neoadjuvant regimens in the neoadjuvant setting, we will refer to the 
physician’s treatment of choice that includes a taxane, anthracycline and may or may not include 
carboplatin. 
 
 


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Table 1 shows multiple studies in the literature reporting pCR rates 
 
Table 1:  Pathological Response Rates in the Literature 
 
Trial/Reference 
No. of Patients 
Agent(s) 
No. of Cycles 
pCR (%) 
Fisher [6] 
15
23
AC 
X 
4
9 
Buzdar [27] 
87 
Paclitaxel 
X 
4
9 
Amat [28] 
80 
Docetaxel 
X 
6
20 
NSABP B27 
[19] 
15
02 
AC 
X 
4 
13 
Aberdeen [29] 
47 
CVAP-Docetaxel 
X4 and x4 
34 
Green [24] 
25
8 
T-FAC 
12 w and x 4 
15.7 (q3w Pac) 
28.1 (qw Pac) 
SWOG0012 [30] 
26
5
AC-Pac 
X 4 and 12 w 
17% 
CALGB 40603 
(Alliance)[26] 
45
4 
TNBC only 
Paclitaxel +/- 
carbo-AC 
second 
comparison was 
with 
bevacizumab 
X12w and x 4 
54 vs 41% for 
addition of 
carbo 
 
AC = doxorubicin and cyclophosphamide; CVAP = cyclophosphamide, vincristine, doxorubicin 
and prednisone; FAC = Fluorouracil, doxorubicin, and cyclophosphamide; T = Paclitaxel. 
 
 
2.6 
Primary Systemic Therapy in Operable Breast Cancer 
 
The Breast Medical Oncology Department at MD Anderson has been one of the pioneers in the use 
of neoadjuvant chemotherapy for the treatment of breast cancer. The sequential or concurrent 
administration of taxane and anthracycline constitute the backbone of early breast cancer treatment. 
 
PST has several potential advantages compared with the traditional strategy of surgery followed by 
adjuvant chemotherapy. PST reduces the size of the primary tumor and lymph node metastasis in 
greater than 80% of cases, increasing the probability that breast-conserving surgery can be 
performed. [12-15] A second advantage of this sequencing schedule is that it permits the 
assessment of response of the primary tumor to the particular chemotherapy regimen. This 
assessment allows the opportunity to “cross-over” to a different regimen for an individual patient if 


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there is minimal or no response to the first regimen. These and other theoretic advantages for PST 
must be balanced carefully with other aspects of individual patient management. 
 
One of the first considerations for studying PST for breast carcinoma was to investigate whether 
earlier delivery of chemotherapy offered the possibility of improved survival in patients with 
locally advanced breast carcinoma. To test these concepts, the National Surgical Adjuvant Breast 
and Bowel Project (NSABP) began the B-18 trial to test whether sequencing chemotherapy before 
surgery would improve outcomes. [12-14] The trial enrolled 1523 patients with early- stage, 
operable breast carcinoma and randomized them to receive four cycles of 
doxorubicin/Cyclophosphamide (AC) either before or after surgical treatment. The primary end 
points of this trial were disease-free survival (DFS) and overall survival (OS). With respect to these 
end points, the trial was a negative study. After 9 years, the OS and DFS were nearly identical 
between the two groups (P = .80, P =0.5, respectively). A second large randomized prospective trial 
that directly compared the sequencing of chemotherapy and surgery was performed by the 
European Organization of Research and Treatment of Cancer (EORTC). [15] This trial randomized 
698 patients to preoperative or postoperative chemotherapy comprised of four cycles of FEC (5-
Fluorouracil, Epirubicin, and Cyclophosphamide). Like the NSABP B-18 trial, the EORTC study 
demonstrated equivalent survival and rates of distant metastases between the two treatment arms. 
 
Gianni el al, [16] randomized 1,355 patients with breast cancer > 2 cm to three groups: adjuvant 
doxorubicin (A) followed by cyclophosphamide, methotrexate, and 5-FU (CMF) (Sx→A→CMF); 
adjuvant doxorubicin and paclitaxel (AT) followed by CMF (Sx→AT→CMF); and neoadjuvant 
AT followed by CMF (AT→CMF→Sx). pCR rates in the neoadjuvant arm were 23% in breast 
only and 20% in breast plus axilla patients. The breast conservative treatment rate was also better in 
this arm (65% vs. 34%; P <.001). At 5 years of follow up, adjuvant chemotherapy was similar to 
PST in terms of freedom for progression (P =.24) and OS (P = .81) 
 
A recent meta-analysis addressed directly the question of neoadjuvant versus adjuvant 
chemotherapy. [17] Nine randomized clinical trials involving 3,946 patients were included. pCR 
rates were highly variables among these trials. Six trials had a higher rate of BCT after PST. No 
difference was observed between the two arms for death, disease progression, or distant recurrence. 
Surprisingly, PST was associated with a higher locoregional recurrence (risk ratio, [RR] 1.22; P = 
.15). This greater risk was largely attributed to those trials in which radiation alone without surgery 
was used in patients who achieved a clinical complete response to PST. (RR, 1.53; P =.009). 
 
2.7 
Role of the Pathological Complete Response in Breast Cancer 
 
A pathological complete response (pCR) implies the absence of residual invasive disease following 
PST. Pathological complete response is associated with long-term survival, and has been adopted 
as the primary end point for neoadjuvant trials.  While it is generally held that a definition of pCR 
should include patients without residual invasive carcinoma in the breast (pT0), the presence of 
nodal metastasis, minimal residual cellularity, and residual in situ carcinoma are not consistently 
defined as pCR or residual disease (RD). When there is no residual invasive cancer in the breast, 
the number of involved axillary lymph nodes is inversely related to survival. [18] Conversely, 
patients who convert to node-negative status after treatment have excellent survival, even if there is 
RD in the breast. [19] Symmans and collaborators, [31] recently introduced a residual breast cancer 
burden (RCB) index as a novel independent new risk factor that improves the prediction of distant 
relapse after PST compared with currently used risk factors. RBC can be divided in four categories: 
patients with minimal residual disease (RBC-I) have the same 5-year prognosis as those with pCR 


2014-0045 
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13 
 
(RBC-0), irrespective of the type of neoadjuvant chemotherapy administered, adjuvant hormonal 
therapy, or the pathologic stage of RD. Extensive RD (RBC-III) was associated with poor 
prognosis, irrespective of the type of neoadjuvant chemotherapy administered, adjuvant hormonal 
therapy or the pathologic stage of RB. 
 
2.8 
BRCA mutations 
The BRCA genes were first described in families with breast and ovarian cancers through the use 
of genetic linkage analysis.[32-34] Since that time, over 5000 different mutations in these genes 
have been identified including both private and founder mutations.[35]  Overall these mutations are 
estimated at 0.1% in the general population. [36-38] 
 
A recent meta-analysis of ten studies estimated the lifetime risk of breast cancer in BRCA1 
mutation-carriers to be 47-66% and 40-57% in BRCA2 mutation-carriers.  The ovarian cancer risk 
was estimated at 35-46% in BRCA1 mutation-carriers and 13-23% in BRCA2 mutation 
carriers.[39]  Other studies have estimated these risks to be even higher.[40]  Given this increasing 
risk of cancers, women with cancers in the family at young age, or multiple cases of breast and/or 
ovarian cancer have sought genetic testing, not only to further manage their own cancer risk, but 
also to share with their family members. 
 
In an analysis by Arun, et al. women with a known BRCA mutation who received neoadjuvant 
therapy at The University of Texas MD Anderson Cancer Center were evaluated.[41]  Of the 
BRCA1 carriers, 26/57 (46%) achieved a pCR.  In the multivariate model, both BRCA1 and triple 
receptor negative breast cancer (TNBC) were independent predictors of pCR.  In this cohort >80% 
of the patients received an anthracycline and taxane based therapy.  Other studies have shown a 
significant increase in response to platinum-based therapy in a similar cohort. Silver, et al. 
evaluated 28 women with TNBC who received 4 cycles of cisplatin at 75 mg/m2 every 21 days 
with 22% achieving a pCR.[42]  Both of the BRCA1 mutation carriers had a pCR in this small 
cohort.  Therefore neoadjuvant chemotherapy in BRCA mutation carriers will be important to 
further identify responders and non-responders. 
 
Interestingly, some studies suggest that BRCA mutation carriers are less sensitive to taxane 
chemotherapy in the metastatic setting.[43] Therefore BRCA mutation status as well as optimizing 
PST will be ever more important in the early breast cancer setting and may have implications as to 
the systemic regimes evaluated in clinical trials and ultimately chosen for patient care in the future. 
 
At our institution, women and men are referred to the Clinical Cancer Genetics service where they 
are seen and counseled by a genetic counselor as well as a physician.  This service is staffed in the 
Breast Center by Dr. Jennifer Litton and Dr. Banu Arun and there are 4 dedicated breast genetic 
counselors as well as 2 additional counselors in the Gynecologic Oncology Clinic.  In 2012 there 
was a total of 1708 genetics consultations through Clinical Cancer Genetics with 818 being in the 
Breast Center and 216 in Gynecologic Oncology.  Additionally, since the inception of this service, 
we have identified over 1000 patients at our institution with a BRCA mutation with that number 
expected to increase given the increase in awareness and through outreach through the Women’s 
Moonshot Program. 
 
Once a consultation is done, blood is obtained with a usual turn-around time of 2 weeks. Patients 
eligible for this protocol and who meet National Testing Guidelines [44] will have a genetics 
consultation expedited so as not to delay start of preoperative systemic therapy. 
 


2014-0045 
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14 
 
 
2.9 
PARP inhibitors 
 
Poly-(adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a family of enzymes responsible 
for multiple cellular processes, including DNA repair through the base excision repair (BER) 
process as well as maintains genetic stability.[45]During DNA repair, when a cell is BRCA 
deficient, the DNA is unable to be repaired through homologous recombination (HR) and therefore 
depends on BER.  PARP inhibitors (PARPi) work by also blocking BER. Therefore when both HR 
and BER DNA repair pathways are impaired, DNA repair is thwarted causing “synthetic 
lethality.”[46] Although PARPi have been tested in TNBC, solid tumors, most activity has been 
seen to date as single agents concentrated in patients with known BRCA mutations. 
 
Several trials have evaluated PARPi in both triple receptor negative breast cancer (TNBC) as well 
as in BRCA mutation carriers.  Due to overlapping toxicities of cytopenias, it has been difficult to 
give in combination with other systemic chemotherapies such as the taxanes or platinum 
compounds. [47, 48] 
 
Below is a brief overview of selected studies that have reported to date.  Of note, Iniparib is not 
included as it was not shown to have superior efficacy when added to gemcitabine and carboplatin 
and later was not found to inhibit PARP. [49] 
 
 
 
Study 
Phase 
N 
Intervention 
Outcome 
Toxicity 
MTD 
Fong et 
I 
60, 23 
Olaparib 600 
Of evaluable 
Grade 4 
al. 
BRCA vs. 400 vs. 
BRCA+ pts: PR or thrombocytopenia 
2009[50] 
+ 
200 mg  BID 
and 12/19 with 
CBR 
Dent, et 
al. 
2013[47] 
I 
19, all 
TNBC 
Olaparib 200 
mg BID + 
weekly paclitaxel 
at 90mg/m2 
37% with a 
PR and one 
with a durable 
response remains 
on single agent 
olaparib 
Neutropenia 
(n=7/9 in first 
cohort, 5 of which 
were grade 3 or 
higher) 
Nausea and 
diarrhea 
Neutropenia 
required 
opening of 
second 
cohort to be 
given with 
G-CSF 
Lee et al. 
ASCO 
Annual 
Meeting 
2013 
I 
45, 37 
ovarian 
and 8 
breast 
Escalating 
Olaparib and 
carboplatin- AUC 3 
day 8 and  q 21 
days 
Thrombocytopenia, 
neutropenia, 
anemia 
Kummar, 
et al. Clin 
2012[51] 
I 
35, 
solid 
tumor 
and 
lympho 
ma 
patients 
Escalating 
doses of 
velaparib 20- 
60 mg x 7 days and 
metronomic cyclo- 
phosphamide 50 mg 
daily 
Partial response in 7 
breast cancer 
patients, 6 of whom 
were BRCA 
mutation carriers 
Thrombocytopenia, 
neutropenia, anemia 


2014-0045 
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15 
 
Rajan et 
al. 
2012[48] 
I 
21 
patients 
with 
solid 
tumors 
Olaparib 100 
mg daily on 
days 1-4, de-
escalated to  
day one only, 
+gemcitabine and 
cisplatin 
PARP levels less 
effectively inhibited 
given in shorter 
duration. Only 2 
patients had a partial 
response 
 
Thrombo-
cytopenia, 
febrile 
neutropenia 
Somlo et 
al. ASCO 
Annual 
Meeting 
2013 
I 
12 
BRCA
1, 15 
BRCA
2 and 1 
had 
both
Escalating Velaparib 
BID and carboplatin 
AUC 6 
CBR 74% median 
PFS 7.8 months 
Thrombocytopenia 
(requiring de- 
escalation of 
carboplatin) 
MTD 
carboplatin 
AUC 5 and 
velaparib150 
BID 
Bell-
McGuinn 
et al. 
ASCO 
Annual 
Meeting 
I 
59 
advanc 
ed solid
tumors 
39 
ovarian 
Escalating 
velaparib and 
carboplatin 
AUC 4 day 1, 
gemcitabine 
800 mg/m2 
Neutropenia, 
leukopenia, 
Thrombocytopenia 
and anemia 
Tutt et al. 
2010[52] 
II 
54, 27 
at 400 
mg bid, 
then 27 
at 100 
mg 
BID 
Olaparib 
ORR 41% at 400 mg 
BID  
ORR 22% 
at 100 mg 
Nausea, vomiting, 
fatigue, anemia 
Gelmon 
et al. 
2011[53] 
II 
open 
label 
91, 65 
with 
ovarian 
cancer 
and 26 
with 
breast 
cancer 
Olaparib 400 
mg po BID 
No objective 
responses in breast 
cancer cohort 
 
Malireddy 
et al. 
ASCO 
Annual 
Meeting 
TIP 2013 
Phase II 
in 
progress 
for 
residual 
disease 
 
Rucaparib IV + 
cisplatin 75 mg/m2 
IV q 3 weeks x 4 
 
 
 
 
2.10 
Talazoparib 
 
Talazoparib is an oral PARP inhibitor manufactured by Pfizer.  For complete product information 
please refer to the Appendix for the Investigator’s Brochure. 


2014-0045 
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16 
 
 
 
 
 
  
 
Talazoparib has been shown to have effective synthetic lethality in BRCA and PTEN deficient cell 
lines and xenograft models and was additionally been found to be orally more potent than other 
available PARP inhibitors currently being tested. 
  
 
Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) represents a family of enzymes, of 
which at least 2 (PARP1 and PARP2) play important roles id deoxyribonucleic acid (DNA) repair. 
The study drug, talazoparib, is a potent and specific inhibitor of PARP 1 and 2 with activity in 
tumor cell lines bearing DNA repair deficiencies.  PARP inhibition induces synthetic lethality in 
tumor cells bearing mutations in the genes encoding breast cancer susceptibility gene 1 (BRCA1) 
and breast cancer susceptibility gene 2 (BRCA2), both of which are key components in the pathway 
of repair for DNA double-strand breaks. Treatment with a PARP inhibitor results in cell cycle 
arrest and apoptosis. 
 
2.10.1 Nonclinical Study Findings for Talazoparib 
 
The nonclinical study findings for talazoparib are described in full in the IB.  The main nonclinical 
findings were early hematological changes and subsequent bone marrow and lymphoid organ 
depletion, as well as focal necrosis, after repeat administration of talazoparib. These findings were 
in accordance with the mechanism of action and the exposure/ distribution pattern of the study drug 
and were reversible. The hematological changes, which consisted of decreases in the reticulocyte, 
platelet, red blood cell (RBC) and white blood cell (WBC) counts, were a sensitive and early 
marker of target organ toxicity and were used to clinically monitor safety. 
 
2.10.2 Preliminary Clinical Study Findings for Talazoparib 
 
Two Phase I studies (PRP-001 and PRP-002) of talazoparib are ongoing and one Phase 3 study 
(673-301) was initiated third quarter, 2013. 
 
Medivation initiated the first-in-human study of talazoparib (PRP-001) in the first quarter of 2011. 
This is a Phase 1, single-arm, open-label, dose-escalation study of once daily, orally administered 
talazoparib for advanced or recurrent solid tumors (those that have defects in DNA repair).  PRP-
002, a Phase 1, 2-arm, open-label, dose-escalation study for talazoparib for the treatment of 


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17 
 
subjects with advanced hematological malignancies was initiated in July 2011.  This study enrolled 
subjects with acute myeloid leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia or 
mantle cell lymphoma. 
 
The primary objective of the Phase 1 studies is to establish the maximum tolerated dose (MTD) of 
once daily, orally administered talazoparib, and to assess the safety, pharmacokinetics (PK), 
pharmacodynamics and preliminary efficacy in an expanded cohort of subjects with genetically 
defined tumors. 
 
In June 2013, preliminary data from PRP-001 were presented at the American Society of Clinical 
Oncology (ASCO) 2013 that are described below [54].  As of June 2013, 70 subjects (60 women/10 
men) enrolled into the study; 39 subjects (33 women/6 men) with solid tumors were enrolled in the 
dose escalation phase of the study in 9 cohorts ranging from 25 to 1100 µg/day that defined a MTD 
of 1000 µg/day.  On defining the MTD, 31 subjects with breast cancer, ovarian, and pancreas 
cancer with deleterious germline mutations; a small cell lung cancer; and Ewing’s sarcoma, were 
enrolled in the expansion phase of the study to further characterize safety and efficacy.  The median 
(range) age for all 70 subjects was 51.5 years (18 to 81), performance status (PS) was 0 (0 to 1) and 
number of prior therapies was 4 (1 to 13), with 47 subjects having deleterious BRCA mutations.  
Tumors (number with deleterious BRCA ½ mutations) included 34 ovarian/primary peritoneal (28); 
20 breast (18); 8 Ewing’s; 4 pancreas; 2 colon; 1 prostrate (1), and 1 mullerian carcinosarcoma. A 
total of 27 and 21 subjects had BRCA1 and BRCA2 mutations, respectively. 
 
Dose-limiting thrombocytopenia occurred in 1 of 6 subjects at 900 µg/day and 2 of 5 subjects at 
1100 µg/day, respectively.  Based on these results, the MTD was defined at a dose of 1000 
µg/day.  Related adverse events (AEs) occurring in >10% of all 70 subjects included fatigue (30%), 
nausea (29%), alopecia (21%), anemia (20%), thrombocytopenia (19%), and neutropenia (11%).  
One subject had drug-related Grade 4 thrombocytopenia. Grade 3 related AEs included fatigue in 1 
subject (1%), anemia and thrombocytopenia each in 9 subjects (13%) and neutropenia in 4 subjects 
(6%).  Dose reductions occurred in 11 subjects due to myelosuppression.  No subjects discontinued 
due to AEs. 
 
Inhibition of PARP activity in peripheral blood mononuclear cell was observed at doses > 100 
µg/day.  Talazoparib plasma concentrations peaked 1 to 2 hours post-dose; in general, exposure 
increased dose proportionally.  Steady state plasma concentrations were reached by the end of the 
second week of daily dosing; mean maximum plasma concentration (Cmax): 0.30 to 25.4 ng/mL 
and area under the concentration time curve from 0 to 24 hours (AUC0-24): 3.96 to 203 ng-hr/mL 
across the 25 to 1100 µg/day dose range after 28 days of daily dosing. 
 
Objective (response evaluation criteria in solid tumors [RECIST] v.1.1) and/or cancer antigen 
(CA)-125 responses occurred at doses > 100 µg/day in 11 of 25 (44%) and 19 of 27 (70%) subjects 
with BRCA-carrier ovarian and peritoneal cancer, respectively.  Clinical benefit (complete 
response [CR]/partial response [PR]/stable disease [SD]>24 weeks) occurred in 23 of 28 subjects 
(82%) with BRCA-carrier ovarian and peritoneal cancer. 
 
Objective responses (ORs) occurred in 10 of 18 (56%) BRCA-carrier breast-cancer subjects. 
Clinical benefit (CR/PR/SD>12 weeks) occurred in 14 of 18 (78%) of BRCA-carriers. 
 


2014-0045 
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18 
 
Overall, talazoparib was well tolerated with impressive anti-tumor activity in subjects with BRCA 
mutations with a single agent recommended Phase 2 trial dose of 1000 µg/day due to dose- limiting 
thrombocytopenia. 
 
Study 673-301, initiated on 30 October 2013, is an open-label, randomized, parallel, 2-arm study of 
talazoparib versus protocol-specific physician’s choice therapy in subjects with germline BRCA 
mutation locally advanced and/or metastatic breast cancer. As of 30 November 2013, a total of 3 
subjects had been enrolled in the study. 
  
 
2.10.3 Preliminary Findings from this Trial as of 3/11/2016. 
 
As this study was initially written as a feasibility to see if patients could tolerate therapy and if 20 
patients could accrue within 2 years, the team has reviewed the current status of this trial as of 
3/11/2016.  At this time 13 patients have been enrolled.  Although approval was 04/2016, it was not 
until 08/2016 when enrollment was able to initiate and in that time 13 patients have been accrued.  
Therefore the concern that this trial could not accrue is no longer present.  Additionally, the second 
objective was to review for Grade IV toxicity and to date there have been no reported Grade IV 
toxicities.  When evaluating the 3 dimensional volume of an oval in this setting, there has been 
dramatic reductions in the size of the tumors with 2 months of talazoparib.  In the first 11 patients 
who have completed 2 months of therapy, the average shrinkage has been 76% decrease (Length x 
width x height x π)/6, (range =29-97% decrease in volume). One of the 13 patients have completed 
all therapy and has obtained a pathologic complete response.  Given the extraordinary amount of 
response with this single agent therapy, obtaining an estimate of pathologic response will be 
necessary in order to properly construct and power a potential registration neoadjuvant trial. 
In the first 13 patients enrolled in the pilot study, we observed 0 grade 4 or higher AEs. To estimate 
the probability of excessive toxicity given that we have observed 0/11 toxicities, we invoke the 
beta-binomial probability model. Assuming an uninformative beta (1, 1) prior, the posterior 
probability that the toxicity rate > 30% (i.e., Pr (Ptox > 0.3 | data)) is 1.4%. A 90% credible interval 
on the estimated toxicity rate is 0% to 22%. 
 
3.0 RATIONALE FOR THE CURRENT STUDY 
 
Patients with BRCA mutations have tumors that have demonstrated defects in homologous 
recombination (HR) and have been shown in several trials to have response to PARP inhibitors. 
Therefore understanding the mechanisms of response and resistance to PARP inhibitors as well as 
identifying patients who may not avoid prolonged cytotoxic therapy would be best studied in the 
neoadjuvant setting. 
 
It is important prior to the outset of a larger randomized clinical trial to evaluate this strategy in a 
pilot setting.  First we need to understand if it is safe to give preoperative talazoparib under close 
monitoring.  If we discover significant benefit, we may proceed with tailoring the definitive clinical 
trial by evaluating pCR as an endpoint that may include less toxic regimens due to response to 
PARPi. 
 


2014-0045 
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19 
 
Secondly, we need to assess the feasibility of accruing to such a study as patients may not wish to 
extend their preoperative therapy and combination studies of PARPi with chemotherapy has been 
limited due to overlapping toxicities of cytopenias, nor will they want to wait the 2 weeks until 
BRCA testing results become available, although this has not been shown to be detrimental to 
outcomes to date and is a current strategy in other molecular triaging protocols. 
 
Also, this study will be an information rich study to understand mechanism and resistance to 
PARPi in the setting of preoperative chemotherapy as well as the importance of developing patients 
derived xenografts of BRCA mutation carriers as well as mammosphere cultures as these do not yet 
exist to our knowledge and will be important models to move forward in studying response and 
resistance. 
 
Expansion Phase: After the first 13 patients were enrolled, discussions with the investigators and the 
sponsors discussed the results available from these patients with an average tumor volume decrease 
of 76%, median decrease of 88% after just 2 months of therapy.  Given that it was felt that an 
amendment would be pursued and once approved by the IRB and IND offices, to cease the feasibility 
portion of the study and to move forward with an expansion cohort where patients who are responding 
to oral therapy could continue to 4 and up to 6 months of therapy, proceed to surgery so that a 
pathologic response could be estimated to inform a randomized neoadjuvant clinical trial. 
 
4.0 TREATMENT PLAN 
 
4.1 
Study Design 
 
This is a non-randomized pilot study to assess feasibility and safety of using talazoparib in the 
neoadjuvant setting for women with invasive breast cancer who carry a BRCA deleterious 
mutation. An initial feasibility portion of the study was conducted to estimate toxicity, response, 
and ability to accrue. After 13 patients were accrued to the study an expansion cohort was added 
and once approved by the IRB, would close the feasibility portion of this study. 
 
4.2 
Eligibility 
 
4.2.1 Inclusion Criteria: 
 
To be included in the study, the subject must have: 
 
 
1) 
Signed, written informed consent 
 
2) 
Histologically confirmed primary invasive adenocarcinoma of the breast with the size of 
 
the primary tumor being at least 1 cm on imaging by either mammography, ultrasound or  
 
breast MRI. 
 
3) 
Negative HER-2/neu - disease defined as patients with FISH ratio <2.0 or <6.0 HER2 
 
gene copies per nucleus, and IHC staining scores of 0, 1+, or 2+. 
 


2014-0045 
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20 
 
4) 
No treatment for current primary invasive adenocarcinoma of the breast such as irradiation, 
 
chemotherapy, immunotherapy, investigational therapy or surgery. Previous treatment for 
breast and/or ovarian cancer with chemotherapy, endocrine therapy, surgery and radiation are all 
allowed if >/= 3 years prior to current diagnosis and there is no clinical evidence of metastatic 
disease. 
 
5) 
ECOG performance status of 0-1. 
 
6) 
Baseline MUGA or echocardiogram scans with LVEF of > 50%. 
 
7) 
Patient must have adequate organ function as determined by the following laboratory 
 
values: 
 
 
a. 
ANC≥1,500 /μL 
 
 
b. 
Platelets ≥100,000 / μL 
 
 
c. 
Hgb ≥ 9 g/dL 
 
 
d. 
Creatinine clearance >50 ml/min 
 
 
e. 
Total bilirubin ≤ 1.5 X ULN 
 
 
f. 
ALT and AST < 2.5 X ULN 
 
8)   Men or women 18 years of age or older. 
 
 
9) 
Negative serum or urine pregnancy test for women within 72 hours of receiving the first 
 
dose of the study medication for women of childbearing potential as per institutional 
 
guidelines. Women will be considered not of childbearing potential and exempt from 
 
pregnancy testing if they are either a) older than 50 and amenorrheic for at least 12 
 
consecutive months following cessation of all exogenous hormonal treatments, or b) have 
 
documentation of irreversible surgical sterilization by hysterectomy, bilateral 
 
oophorectomy or bilateral salpingectomy, but not tubal ligation. 
 
10) 
Women of childbearing potential (WOCBP) must be using an adequate method of 
 
contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last 
 
dose of investigational product. Men on study also must be using contraception. 
 
11) 
Identified deleterious mutation in BRCA 1 or 2 genes (this does not include variants of  
 
uncertain significance). 
 
12) 
Eligible to receive standard of care chemotherapy and/or surgery based upon standard 
 
practices or institutional guidelines. 
 
 
 
4.2.2 Exclusion Criteria: 
 
 
1) 
Women who are pregnant (including positive pregnancy test at enrollment or prior to 
 
study drug administration) or breast-feeding. 
 


2014-0045 
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21 
 
2) 
Disease free of prior malignancy for < 3 years with the exception of curatively treated 
 
basal carcinoma of the skin or carcinoma in situ of the cervix. 
 
3) 
Any other previous antitumor therapies for the current cancer event.  
 
4) 
Has had major surgery within 21 days before Cycle 1, Day 1 
 
5) 
Gastrointestinal tract disease or defect with associated malabsorption syndrome. 
 
6) 
Uncontrolled inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) 
 
7) 
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 
 
8) 
Serious intercurrent infections or non-malignant medical illness that are uncontrolled or 
 
the control of which may be jeopardized by this therapy. 
 
9) 
Psychiatric disorders or other conditions rendering the subject incapable of complying 
 
with the requirements of the protocols. 
 
10) 
Unable to take oral medications 
 
11) 
Known to be human immunodeficiency virus positive 
 
12) 
Known active hepatitis C virus, or known active hepatitis B virus 
 
13) 
Concurrent disease or condition that would interfere with study participation or safety, 
 
such as any of the following: 
 
 
 
• 
Active, clinically significant infection either grade > 2 by National Cancer 
 
 
 
Institute (NCI) Common Terminology Criteria for Adverse Events   
 
 
 
(CTCAE) v4.03 or requiring the use of parenteral anti-microbial agents  
 
 
 
within 14 days before Day 1 of study drug 
 
 
 
• 
Clinically significant bleeding diathesis or coagulopathy, including known 
 
 
 
platelet function disorders 
 
 
 
• 
Non-healing wound, ulcer, or bone fracture 
 
14) 
Known hypersensitivity to any of the components of talazoparib 
  
 
 
4.3 Treatment Administration Plan 
 
All subjects will be registered in CORe and the data will be entered in PMDS/CORe, the 
electronic CRF. Given the early responses seen in the first 11 patients with 2 months of 
talazoparib, understanding the pCR rate of single agent talazoparib in this setting will be 


2014-0045 
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22 
 
paramount to developing the randomized neoadjuvant trial.  Therefore after the first 13 patients 
were accrued, the trial was amended to change to an expansion cohort to better estimate 
pathologic response. 
 
EXPANSION COHORT 
An expansion cohort of 20 patients will be accrued.  Talazoparib will be administered orally at 1 
mg per day for at least 4 and up to 6 cycles. Each cycle will consist of 28 days (+/-3 days). At 
the time of surgery, residual disease will be quantified by residual cancer burden.  After surgery, 
the patient and physician may proceed to receive or not receive physician’s choice of systemic 
therapy. Dose modifications will continue as per section 4.6.  
 
Talazoparib is considered a cytotoxic agent; precautions regarding appropriate secure storage 
and handling must be used by healthcare professionals, including personal protective clothing, 
disposable gloves, and equipment. Subjects should be advised that oral anticancer agents are 
toxic substances and that (other than the subject) caregivers should always use gloves when 
handling the capsules. 
 
  Once the Expansion cohort amendment portion of this trial is approved by the IRB and ready        
  to initiate accrual, we will stop accruing to the feasibility portion of this trial. 
 
 
 
4.3.1 Study Visits 
 
Study visits are as outlined in Section 10.  Due to scheduling, these visits can occur +/- 3 days from 
the required time of follow-up.  Given that there may be cytopenias associated with this therapy, 
weekly CBCs will be obtained (+/- 7 days). During the expansion phase CBC’s will be every 2 
weeks x 3 and then monthly after that. On days where no other testing is required these blood tests 
can occur at any CLIA-certified laboratory (Cycle 1, Day 15). The Principal Investigator or treating 
physician must review all outside lab results, determine clinical significance for abnormal labs, and 
sign and date the report. 
 
4.3.2 Biopsies/Correlative Studies 
 
Ideally up to 4 core biopsies will be obtained at each time point if enough material is available, for 
a total of up to 12 core biopsies for the trial.  Up to two fine needle aspirates (FNAs) will also be 
obtained at each time point for a total of up to 6 FNA’s for the trial, which will be used for the 
patient derived xenograft models. Pre-study biopsies, as well as biopsies within 7 days prior to the 
completion of 2 months of talazoparib will be collected via diagnostic imaging, in addition to a 
portion of the surgical specimen at the time of the definitive surgery.  
For the expansion cohort, only pre-study biopsies will be collected.  
Ultrasounds will be done after cycle 1 and cycle 2 on the pilot phase of the protocol.  For the 
expansion cohort, breast ultrasounds will be performed after every 2 cycles (+/- 7 days). Therapy 
will be discontinued if the Physician or PI indicates clinically significant progression of disease. A 
biopsy of the tumor at the time of progression will be obtained prior to switching to the standard of 
care treatment of the physician’s choice. Tissue samples at the time of progressive disease may 


2014-0045 
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23 
 
occur at the time of surgery in the form of residual tissue and therefore a biopsy would not be 
required. 
 
During the expansion phase of this trial, ultrasounds will be obtained every 2 cycles (+/- 1 week), 
and at progression with biopsy if progression occurs and further systemic therapy is given prior to 
definitive surgery.  
 
These tissue specimens will be evaluated for response and biological markers of response and/or 
resistance. 
 
4.3.3 Progression While on Study 
 
Subjects who progress while on talazoparib will automatically be considered non-responders to 
talazoparib and will proceed to the standard of care therapy of the treating physician’s choice or 
proceed to surgery if the treating physician feels that is in the patient’s best interest. A biopsy of the 
tumor will be obtained prior to switching to the standard of care regimen of the physician’s choice. 
 
If progressive disease occurs while on standard of care treatment, the subjects should remain in the 
study until after they have undergone definitive surgery.  
 
As an exploratory endpoint, during the tumor core biopsy, patients will also be offered an optional 
contralateral breast core biopsy to evaluate biomarker changes in the unaffected, yet high risk, 
breast tissue. BRCA mutation carriers have an up to 60% risk of developing new contralateral 
breast cancer. Since no prevention agents exist for BRCA mutation carriers, this preliminary data 
would help us to further understand the potential (preventative) effects of PARP inhibitors in high 
risk breast tissue. Without any preliminary knowledge, it will not be possible to conduct a 
preventative study with PARP inhibitors in women without breast cancer. Biomarkers that will be 
evaluated will be similar to the ones that will be evaluated in the tumor core biopsy (section 1.2.1) 
with the exception of the generation of PDX models and transcriptional profile to assess TNBC 
subtype. Currently there is no data in the literature related to biomarker changes in high risk breast 
tissue in women treated with PARP inhibitors. 
 
4.3.4 Surgery 
 
In the initial cohort, patients will undergo definitive breast surgery 4 -6 weeks from last dose of 
systemic chemotherapy.  
For those patients that are a part of the Expansion Cohort, they will undergo definitive breast 
surgery within 6 weeks of the last dose of talazoparib. Tumors must be removed by either 
lumpectomy or mastectomy with clinically appropriate axillary surgery.  The surgical specimens 
(breast and axillary lymph node tissue) will be evaluated for pathological complete response 
(defined per protocol) by central Pathologists at M.D. Anderson Cancer Center.  Any further post-
operative therapy, either local or systemic will be at the discretion of the treating physician. 
  
 
4.4 Duration of Study 
 
The study is expected to complete accrual within 3 years from study initiation. The duration of 
chemotherapy treatment per subject will be approximately 2 months on talazoparib followed by 6 
months of a standard of care regimen of the treating physician’s choice.  


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Additionally, from data presented at the San Antonio Breast Cancer Symposium in 2013 by Sikov, 
et al[26] evaluating the addition of both carboplatin as discussed in the background, the treating 
physician may choose to add or not add carboplatin to this standard of care regimen as well. 
 
For those patients participating in the Expansion Cohort, all systemic therapy will be at the 
discretion of the treating physician after surgery. 
 
Participants will be followed until the time of surgery. Any available remaining tissue collected 
from this surgery will be used for the correlative studies. 
 
 
 
 
 
 
 
 
4.5 STUDY DESIGN SCHEMA (Original Study Schema) 
 
 
 
* Therapy will be discontinued at progression of disease. A biopsy of the tumor at the time of 
progression will be obtained prior to switching to the standard of care regimen of the physician’s 
choice. Tissue samples at the time of progressive disease may occur at the surgical visit in the form 
of residual tissue and therefore a biopsy would not be required. (See Section 4.3.2). 
 
 
 
 
 
 
Talazoparib 


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Expansion Cohort 
   
*Therapy will be discontinued at progression of disease. A biopsy of the tumor at the time of 
progression will be obtained prior to switching to the standard of care regimen of the physician’s 
choice. Tissue samples at the time of progressive disease may occur at the surgical visit in the form 
of residual tissue and therefore a biopsy would not be required. 
 
During the expansion phase, ultrasounds will be obtained every 2 cycles (+/- 1 week), and at 
progression with a biopsy if progression occurs and further systemic therapy is given prior to 
definitive surgery.  
 
 
 
4.6 
Dose modification 
 
 
Talazoparib Dosing 
 
Talazoparib should be taken orally once daily (i.e., continuous daily dosing) at approximately the 
same time each day (preferably in the morning).  
Patients will document the time of dosing on a “pill diary calendar”. This will be reviewed by the 
study team at the end of each cycle, along with reconciliation and documentation of any remaining 
study drug. The completed pill diaries will be kept by the study team. 
Daily dosing of talazoparib can be interrupted for recovery from toxicity for up to 28 days. 
Thereafter, treatment at the same or a reduced dose can be considered based on a discussion 
between sponsor or designee and investigator if evidence of response or clinical benefit to 
talazoparib is noted. 
 
 
 


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Dose modifications should be made based on observed toxicity as follows: 
 
• 
Grade 1 or 2 toxicity: No requirement for dose interruption or dose reduction. 
 
If the toxicity persists at grade 2, a dose reduction to the next lower dose level (e.g. from 
 
1.0 mg/day to 0.75 mg/day) may be implemented at the discretion of the Investigator 
 
• 
Grade 3 toxicity: Daily dosing should be stopped. 
 
Talazoparib dosing may resume at the next lower dose level (e.g., from 1.0 mg/day to 
 
0.75 mg/day, 0.75 mg/day to 0.5 mg/day) when toxicity resolves to grade 1 or returns to 
 
baseline. Subject must discontinue study drug and move to standard therapy if drug is 
 
held more than 28 days. 
 
• 
Grade 4 toxicity: Daily dosing should be stopped. 
 
With the approval of the PI, talazoparib may be resumed at a lower dose level (1 or 2 
 
dose level decrease) when the toxicity has resolved to grade 1 or baseline. Subject must 
 
discontinue study drug and move to standard therapy if drug is held more than 28 days. 
 
 
                        Dose Modifications for Toxicities Dose Level 
 
 
Initial dose level 
 
 
1.0 mg/day 
 
 
First dose level reduction 
 
0.75 mg/day 
 
 
Second dose level reduction  
0.5 mg/day 
 
 
Third dose level reduction 
 
0.25 mg/day 
  
 
 
 
 
4.7 
Concurrent and supportive care 
 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
patient are allowed, including drugs given prophylactically (e.g., Antiemetics +/- steroids, colony 
stimulating factors), with the following exceptions: 
 
• 
No other investigational therapy should be given to patients. 
 
• 
No anticancer agents other than the study medications administered as part of this study 
 
protocol should be given to patients. 
 
 
The concurrent use of all other drugs, over-the-counter medications, or alternative therapies 
including herbal supplements will be captured in the electronic medical record. 
 
 
4.8 
Criteria for discontinuation of study drug 
 
 
All patients will be analyzed on an intent-to-treat basis. Treatment will continue until one of the 
following criteria is met: 
 


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Patients who develop progression of disease while on talazoparib therapy will proceed with 
standard of care therapy.  Management of the systemic therapy and further local therapy will then 
be per the treating physician’s preferences. 
 
If a patient develops unacceptable toxicity (defined as toxicity necessitating the discontinuation of 
study drug) the patient will be removed from the study treatment plan. Further treatment will be 
individualized for these patients. 
 
Completion of all prescribed protocol therapy. 
 
In the judgment of the investigator that the treatment is not in the best interest of the patient. 
Removal from study 
Data will be collected until the day after surgery. The patient will then come off study with regards 
to data collection. 
 
Should a patient withdraw consent, the patient will be removed from study at that time and no 
further data will be collected. 
  
 
 
 
4.9 
Criteria for Feasibility and Response 
 
A primary objective of this study is to assess the toxicity profile of women taking single agent 
talazoparib prior to surgery. A secondary objective is preliminary correlation of biomarkers with 
treatment efficacy. 
 
As there is currently no data available regarding these endpoints, this feasibility study will provide 
the first available data in order to plan a larger randomized clinical trial with pCR as an endpoint. 
 
We will start monitoring the aggregate toxicity rate after 7 patients have been enrolled.  If greater 
than 33% of the patients enrolled have either a grade 4 toxicity possibly, probably, or definitely 
related to the treatment as attributed by the Principal Investigator, or requires a delay in treatment 
for greater than 4 weeks due to toxicity, we will suspend accrual to the trial 
 
The secondary endpoint will be to assess response as per radiographic evaluation of the tumor by 
ultrasound during the 2 cycles of single agent talazoparib. Bi-dimensional measurements will be 
used to evaluate response. A 20% increase in bi-dimensional primary tumor size or 20% increase in 
the size of any measurable, biopsy-proven regional lymphadenopathy will constitute progression 
and removal from the talazoparib single agent treatment.   In addition, pathologic complete 
response (pCR) and RCB will be measured and documented in the pathology report. pCR is defined 
in this study as complete absence of any viable invasive cancer cells in the resected breast and 
lymph nodes. 
 
In cases where 3 dimensional measurements are given by the radiologist, the volume of the lesion 
will be estimated by: 
 


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(Length x width x height x π)/6.  And changes in tumor volume can then be estimated. If using the 
3 dimensional measurements, there is a > 20% increase in the volume measurement, the patient will 
be taken off of study and then proceed with physician’s choice chemotherapy. 
 
In the Expansion Cohort, the endpoint will be pathologic response and residual cancer burden 
(RCB). 
 
In the initial phase of this study, feasibility will be considered achieved if the treatment is proven 
safe and all 20 patients are able to be accrued within 2 years from initiating accrual.  
 
However, after the initial 13 patients were accrued, given the significant response to single agent 
therapy, the protocol was amended to allow an expansion group of patients to continue to 4 and up 
to 6 months, then proceed to surgery and receive systemic therapy after surgery in the adjuvant 
setting. 
 
4.10   Definition of Residual Cancer Burden 
 
The residual cancer burden (RCB) as a continuous variable derived from the primary tumor 
dimensions, cellularity of the tumor bed, and axillary nodal burden. RCB can also be divided into 
four classes (RCB-0 to RCB-III) and may be collected as part of the study when all information is 
available in order to calculate. 
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: 
 
 
 
1. 
The largest two dimensions (mms) of the residual tumor bed in the breast (largest tumor bed 
if multicentric disease) 
 
2. 
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 di > 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") 
 
3. 
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. 
 


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• 
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%. 
 
4. 
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% 
 
5. 
The number of positive (metastatic) lymph nodes 
 
6. 
The largest diameter (mm) of the largest nodal metastasis 
 
 
The RCB can be accessed online: www.mdanderson.org/breastcancer_RCB 
5.0 CORRELATIVE STUDIES  
 
5.1 Biopsies 
Up to four core biopsies at each time point, will be obtained prior to initiation of therapy with 
talazoparib, within 7 days prior to the completion of talazoparib (prior to initiation of systemic 
chemotherapy) and residual tissue available after surgery will be collected once all diagnostic 
testing needed for patient care is completed. Additionally, up to two FNA’s will be collected at 
each time point to be used for the patient derived xenograft models. For expansion cohort patients, 
biopsies will only be obtained prior to the initiation of 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 is able to be obtained: 
• 
Targeted or whole exome sequencing for BRCA pathway mutations and other somatic 
 
and germline alterations 
• 
RNA sequencing 
• 
Evaluation of changes in immune response 
• 
Transcriptional profile to assess TNBC subtype, BRCA-ness signature and putative 
 
PARP sensitivity predictors 
• 
Functional proteomics with reverse phase protein array (RPPA) 
• 
Generate PDX models and mammosphere cultures from patient derived tumors 
• 
PTEN, gamma-H2A.X, Ki-67 and cleaved caspase 3 by IHC 
 
 
5.2 
Patient Derived Xenografts (PDX) 
Fresh tumor tissue obtained from patients with BRCA1/2 mutant breast cancer will be used to: 


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• 
Process the tumor for implanting into the humanized mammary fat pads of NOD  
 
 
SCID mice to create a collection of HIM/PDX models of BRCA1/2 deficient  
 
 
breast cancer. 
 
 
• 
Process the tumor to generate mammosphere cultures for performing  
 
 
 
comprehensive functional genomic screens in vivo. 
 
We intend to build a collection of Human-In-Mouse (HIM) models of BRCA1/2 mutant breast 
cancer. These models will be used to understand the basic biology of BRCA-mutant breast cancer 
and to explore the efficacy of novel targeted therapies. To create these models, we “humanize” the 
4th mammary fat pads of NOD SCID mice by removing mouse mammary epithelia and engrafting 
immortalized human breast fibroblasts to create a human stromal microenvironment. Tumor cells 
obtained from patients with BRCA1/2 mutant breast cancer are then engrafted into the humanized 
mammary fat pads of these mice. A major strength of the HIM model is that it uses tumors that are 
obtained directly from patients and immediately transplanted and propagated in the context of 
humanized mammary fat pads of recipient mice, resulting in a closer resemblance to the human 
tumor counterpart than established cell lines. Once established, the tumors will be expanded in 
mice to generate a collection of BRCA1/2-mutant HIM models. To ensure that our HIMs maintain 
their similarity to the initial tumors we will perform gene expression analysis and IHC at regular 
intervals. We will use these established models as pre- clinical models of BRCA1/2-mutant tumors 
to test the efficacy of various chemotherapeutic agents on human tumors. For example, we will 
assess the anti-tumor effect of cell cycle checkpoint inhibitors alone or in combination with DNA 
damaging agents and PARP inhibitors. Models established from tumors that do not respond to 
therapy will be used to understand resistance mechanisms. 
 
Methods: 
In parallel with establishing the HIM models, we will culture BRCA1/2-mutant tumor cells under 
conditions that enrich for tumor initiating cells (TICs). TICs are reportedly responsible for the 
establishment and maintenance of all primary breast tumors and their metastases. TICs can be 
maintained in culture by growing breast cancer cells in defined, serum-free media (Mammocult) on 
low binding plates. Under these conditions, cells do not attach to the plate, but rather grow as 
spheres (mammospheres) that retain a relatively high frequency of TICs. Mammosphere cultures 
will be established by dissociating fresh tumors (obtained directly from biopsies) into single cells 
suspensions and culturing them in vitro in Mammocult media (STEM cell technologies) on 
ultralow attachment plates. These cells can be manipulated in vitro and then placed back in the 
mice for phenotypic analysis. We will use these cultures to perform both gain of function and loss 
of function screens to identify tumor dependencies.  In addition, synthetic lethal screens will be 
conducted in vivo to identify tumor vulnerabilities. 
 
Mouse surgical procedures 
Epithelium will be removed from fat pads of the 4th mammary gland to create "cleared fat pads” in 
NOD-SCID mice. Three week old female mice will be anesthetized with ketamine (86.98 mg/kg 
body weight) and xylazine (13.4 mg/kg body weight) via IP injection. When asleep, tape will be 
applied to the appendages to restrain the animal on its back. An inverted Y-shaped incision will be 
made along the thoracic-inguinal region to expose the mammary glands. Using the dissecting 
microscope, the 4th nipple is located and cauterized, as well as the blood vessel near the junction 
by the lymph node and vessel at a point on the fat pad bridge between the 4th and 5th fat pads. The 
epithelium area is carefully excised and discarded to create a "cleared fat pad" into which human 


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breast tissues can be transplanted without interference from the host's mammary epithelium. 
250,000 human fibroblasts will be injected into the fat pads in a volume of 30 µl. The volume of 
matrigel will be 1/2 to 1/3 of the final volume. The skin will be gathered and the incision will be 
closed with wound clips. The approximate duration of the surgery will be 8-10 minutes. To 
maintain body temperature, mice will be put on bubble wrap during the surgery. After surgery, the 
body temperature will be maintained by placing a heat lamp at a distance which controls body heat 
throughout recovery. Wound clips will be removed after healing has occurred, typically 7-10 days. 
To avoid graft rejection, animals with a compromised immune system will be used as hosts for the 
transplants. 2-3 weeks later, human breast tumor organoids and fibroblasts will be injected into the 
fat pads for development of breast tumor xenografts. Once the xenograft from the first generation 
(P1) reaches a diameter of 1.5 cm – 2 cm, the mice will be euthanized for tumor tissue collection. 
Each tumor will be cut into three pieces. One will be snap frozen in liquid nitrogen for cDNA 
microarray and DNA sequence analysis. Another, will be fixed in formalin and embedded in 
paraffin for conventional pathological studies and immunohistochemistry. The last piece will be 
dissociated to generate organoids, part will be stored in liquid nitrogen and part will be passed into 
10 NOD-SCID mice in the same manner to produce the next generation of tumor xenograft. When 
the xenografts of the second generation reach a diameter of 1.5 cm we will collect the tumors in the 
same manner as before. If all xenografts from the same patient have similar cDNA expression 
profiles and pathological characteristics, we will generate the third generation of xenografts. This 
will continue up until the 10th generation. 
 
5.3 
Circulating Biomarkers 
 
 Blood will be collected for germline normal comparisons. One lavender top tube will be collected 
and isolated for PBMC and cfDNA analysis. PBMCs will be collected at pre-treatment on Day 1, 
on week 2 (Day 8), and week 4 (Day 22) for assessment of PARP levels and 
PAR-producing activity.  The collected blood will be institutionally logged using a research 
specific z-code.  
For the Expansion Cohort - PBMCs will be collected at baseline and at Cycle 3 Day 1 - (Week 9 
Day 1). 
 
 
Plasma for cfDNA will be collected pre-treatment on Day 1, and within 7 days prior to the 
completion of the 2 months of talazoparib.  Plasma will be collected for exploratory proteomic 
analysis.  
During Expansion – cfDNA will be collected at baseline, Cycle 3 Day 1, and if necessary, at the 
time of progression prior to the patient being placed on chemotherapy treatment. 
 
5.4        Sample and Data Sharing 
 
Sample sharing: In some cases samples may be sent to or received from outside collaborators such 
as Broad Institute for next-generation sequencing and/or analysis.  All samples will be sent under a 
specific contract or Material Transfer Agreement (MTA).  We will protect participant’s privacy by 
coding samples and keeping the master list of identifiers accessible to only key project staff.  Data 
will be kept on secure computers and samples will be kept in freezers in locked laboratories and 
buildings.  Additionally in some other cases, samples may be provided from outside collaborators or 
institutions for discovery and research purposes. In such cases, the samples should be obtained under 
IRB-approved protocols at these outside collaborators and institutions to allow them for participation 


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in this protocol and under a specific grant/ contract or Material Transfer Agreement (MTA) with MD 
Anderson Cancer Center. 
Internal/External Sequencing may be done here at MD Anderson, in one of the Core labs such as 
Cancer Genomics Lab, but in some cases samples may be sent to outside collaborators for sequencing 
and/or analysis such as Broad Institute.  Sequencing performed by Broad or any other external 
collaborator will be conducted under specific contract or Material Transfer Agreement (MTA).     
Data Sharing:  Researchers can do more powerful studies when they share with each other the 
information they get from studying human samples.  NGS data may be placed in a local M.D. 
Anderson Institutional Data Repository (IDR), such as the access controlled Confederated Data 
Warehouse; where both deposition of and access to data require governance and approval.   In some 
cases, grant requirements may require deposition of large-scale data into the public Genotypes and 
Phenotypes database (dbGaP) an access controlled database overseen by the National Center for 
Biotechnology Information (NCBI).  In other cases peer reviewed Journals may require data to be 
shared through a resource such as dbGaP.  Data submitted to those repositories will only be shared 
in a de-identified fashion and without associated clinical data or identifiers. This data will be used 
only for research purposes, and the data elements collected and analyzed   will only be those that are 
necessary to conduct this research. 
Database access additional protections: The precedent to publically broadcast sequence data has been 
set by large consortial projects, such as The Cancer Genome Atlas (TCGA) and the Encyclopedia of 
DNA Elements (ENCODE), in order to maximize data utility.   However, we know there is the 
potential for privacy risks associated with the release of sequence data to databases and while the risk 
may be small it could grow in the future as technology advances.  To minimize this potential, we will 
implement good faith efforts to ensure patient confidentiality and reduce patient exposure.   The 
database of Genotypes and Phenotypes and others like it are extremely access restricted.  Only 
authorized researchers may deposit or access the data and either or both efforts require MD Anderson 
institutional approval.  Sequence data will only be broadcast through secure transmission processes.  
All samples will be de-identified with access to the linking table available only to the MD Anderson 
PI and his/her designees.  Only non-identifiable data will be deposited to dbGaP i.e., no linking table 
or access to a linking table will be available.  Research records will be kept separate from medical 
records and patients will not have access to any of the research data. 
 
Protected health information (PHI) may be collected from medical records that are related to health 
and/or disease history including test results, medical procedures, and images (such as X-rays) in 
addition demographic and environmental factors may be requested. Researchers will use this 
information to better understand how genes affect health and response to treatment.   All samples 
will be de-identified with access to the linking table available only to the MD Anderson PI and his/her 
designees.   
 
 


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6.0 STUDY DRUG COMPLIANCE AND ACCOUNTABILITY 
 
6.1 
Assessment of Compliance 
 
To ensure that each patient has been complying adequately with his or her study regime, study 
medication will be returned, counted, and recorded at each patient visit. Copies of all forms 
documenting returned drug and drug accountability records will be retained by the site.  If the 
records show that the patient is taking less than 80% of the required dose, the patient should be 
counseled about her compliance. If compliance continues to be a problem (as per the physician’s 
discretion or his designated appointee) study drug should be stopped and patient removed from 
study. 
 
 
6.2 
Assessment of Accountability 
 
The investigator, or an approved representative, e.g. pharmacist, will ensure that all investigational 
products are stored in a secured area, under recommended storage conditions and in accordance 
with applicable regulatory requirements. All study drug supplies must be kept in a locked limited 
access room. The study drug must not be used outside the context of the protocol. Under no 
circumstances should the investigator or other site personnel supply study drug to other 
investigators, patients, or clinics, or allow supplies to be used other than directed by this protocol. 
Institutional policies will be followed as applicable for drug accountability and disposal of 
investigational drugs. 
 
7.0 
ADVERSE EVENT REPORTING AND DATA COLLECTION 
 
7.1 
Adverse Events 
According to the ICH definition, an adverse event (AE) is any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product, and that 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 medicinal (investigational) product, whether or not considered related 
to the investigational product. 
 
This definition includes intercurrent illnesses or injuries that represent an exacerbation (increase in 
frequency, severity, or specificity) of pre-existing conditions. Whenever possible, it is preferable to 
record a diagnosis as the AE term rather than a series of terms relating to a diagnosis. 
 
Adverse event information will be collected in an ongoing fashion through patient reporting AEs to 
their physician or health care provider. Seriousness and relatedness will be assessed by the treating 
physician, with appropriate reporting. 
 
A designated primary contact person based at the treatment center will be responsible for the 
collection and reporting of AEs for patients participating in the program. 
  


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7.2 
Adverse Event Reporting Guidelines 
Serious Adverse Event Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
 
 
• 
Death 
 
• 
A life-threatening adverse drug experience – any adverse experience that places  
 
 
the patient, in the view of the initial reporter, at immediate risk of death from the  
 
 
adverse experience as it occurred. It does not include an adverse experience that,  
 
 
had it occurred in a more severe form, might have caused death. 
 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
 
• 
A persistent or significant incapacity or substantial disruption of the ability to  
 
 
conduct normal life functions. 
 
• 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
 
• 
Important medical events as defined above, may also be considered serious  
 
 
adverse events. Any important medical event can and should be reported as an SAE if 
 
deemed appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 
• 
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 
 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
 
Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
 
must be reported to the IND Office, regardless of attribution (within 5 working days of 
 
knowledge of the event). All SAEs (expected or unexpected, causally related or not) must 
 
also be reported to Pfizer’s drug safety vendor, Pfizer U.S. Clinical Trial Department within     
24 hours of the Investigator’s awareness as follows: 
 
 
Pfizer U.S. Clinical Trial Dept.  
 
Fax: 1-866-997-8322 
 
  
 
 
Protocol specific reporting criteria: 
 
Pregnancy 
 


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Pregnancy in a subject being treated with the product should be reported immediately (within 24 
hours of becoming aware of the pregnancy) to Pfizer U.S. Clinical Trial Department by using the 
FDA 3500A (MedWatch Form). Every effort should be made to follow the patient through 
resolution of the pregnancy (termination or delivery) and report the resolution of the FDA 3500A 
(MedWatch Form) to Pfizer U.S. Clinical Trial Department as follows: 
 
 
Pfizer U.S. Clinical Trial Dept. 
 
Fax: 866-997-8322 
 
  
 
 
• 
All life-threatening or fatal events, that are unexpected, and related 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 the IND Office. 
 
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
 
reporting to the IND Office and MDACC IRB. 
 
• 
Serious adverse events will be captured from the time of the first protocol-specific 
 
intervention, until 30 days after the last study treatment/intervention, unless the 
 
participant withdraws consent. 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. 
 
• 
Additionally, any serious adverse events that occur after the 30 day time period that are 
 
related to the study treatment must be reported to the IND Office. This may include the 
 
development of a secondary malignancy. 
 
Reporting to FDA: 
 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure that serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
7.3 
Investigator Communication with Supporting Companies 
 
 
SAEs will be required to be reported from the time of first protocol-specific intervention, during the 
course of treatment and within 30 days after the last study visit or 30 days after the last dose of 
study medication, whichever comes first. 
 
Beyond 30 days of treatment, completion of only those SAEs that, in the judgment of the 
investigator, are definitely, possibly or probably related to the study treatment will require 
reporting. Talazoparib serious, related, unlabeled, (unexpected) adverse events will be reported to 
the FDA as required by 21 CFR 312.32 by the Investigator/Sponsor. These reports may be filed 


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utilizing the MDACC SAE form.  The Investigator/Sponsor will provide Pfizer Drug Safety, with a 
copy of this report. 
 
All serious adverse events (SAEs) and pregnancy reports whether or not considered drug-related 
should be reported to Pfizer U.S. Clinical Trial Department (contact information below) within 24 
hours of receipt by the investigator/sponsor by using the Pfizer SAE form. 
 
 
For Comparator Drugs / Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer. 
 
Pfizer will review AE data as documented in the final study report submitted. 
 
Clinicians should not wait to collect additional information that fully documents the event before 
notifying Pfizer U.S. Clinical Trial Dept. of an SAE or pregnancy. Pfizer may be required to report 
certain SAEs to regulatory authorities within 7 calendar days of being notified about the event; 
therefore it is important that clinicians submit additional information requested by Pfizer U.S. 
Clinical Trial Dept. as soon as it becomes available. 
 
Reporting of SAEs to the IRB will be done in compliance with the standard operating procedures 
and policies of the IRB and with applicable regulatory requirements. 
Contact information for Pfizer U.S. Clinical Trial Department is as follows:  
 
 
Pfizer U.S. Clinical Trial Depart. 
 
Fax: 866-997-8322 
 
  
 
 
7.4 
Monitoring 
 
This study will be monitored for compliance by the IND office. 
 
 
7.5 
Adverse Event Data Collection 
 
The following information will be collected for all adverse events: 
 
 
• 
Start and stop dates 
 
• 
Severity (grade) 
 
• 
Relationship to study drug (attribution) 
 
Whether or not the subject discontinued treatment due to the AE 
 
Note all AEs on the Adverse Event Case Report Form (CRF) whether or not related to study drug. 
 
Adverse events will be graded using CTCAE (version 4.03). 
 
AE grading and assignment of attribution require documentation by medical personnel who are 
directly involved in the clinical care of protocol subjects. 


2014-0045 
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37 
 
  
 
7.6 
AE/SAE Follow up 
 
All AEs/SAEs, including laboratory abnormalities, that in the opinion of the investigator are 
clinically significant, will be followed up according to good medical practices. 
 
NOTE: If a subject begins a new anticancer therapy, the adverse event reporting period for non- 
serious adverse events ends at the time the new treatment is started.  Death must be reported if it 
occurs during the serious adverse event reporting period after the last dose of investigational 
product, irrespective of any intervening treatment. 
 
 
 
8.0 STATISTICAL ANALYSIS 
 
Demographic and baseline characteristics will be summarized by treatment arm for all randomized 
patients using descriptive statistics.  Toxicity will be monitored at each of the study visits and 
documented.  The aggregate toxicity rate will be estimated along with 95% confidence intervals, as 
will the proportions of patients in each of the ultrasound response categories (responding, stable, 
progression) and the RCB categories along with 95% confidence intervals. 
 
As there is currently no data available regarding these endpoints, this feasibility study will provide 
the first available data in order to plan a larger randomized clinical trial with pCR as an endpoint. 
 
Feasibility will be considered to be achieved if the treatment is safe and all 20 patients are able to 
be accrued within 2 years from initiating accrual. 
 
We will start monitoring the aggregate toxicity rate after 7 patients have been enrolled.  If greater 
than 33% of the patients enrolled have either a grade 4 toxicity attributable to the treatment, or 
require a delay in treatment for greater than 4 weeks due to toxicity, we will suspend accrual to the 
trial. 
 
Response as evidenced by ultrasonography will be documented.  A partial response by ultrasound 
will be considered if the tumor’s greatest dimension has decreased by 20% or greater. Progression 
will be documented if bi-dimensional primary tumor size or size of any measurable, biopsy-proven 
regional lymphadenopathy has increased by 20% or greater.  Residual Cancer Burden will also be 
calculated when available at the time of definitive surgery. 
 
Biomarker results will be compared between patients with and without pCR as well as by their 
radiographic response using the Wilcoxon rank sum test and Fisher’s exact test. 
 
Expansion Cohort: 
 
After the first 13 patients were accrued and had significant response, with no grade 4 toxicities, an 
expansion cohort was planned to estimate pathologic response.  As RCB0 and RCB1 has similar 
excellent outcomes, we will measure all pathologic response in an additional 20 patients. As this 
cohort will have both hormone receptor positive and negative patients, a single agent therapy with a 


2014-0045 
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38 
 
30% rate of RCB0 and RCB1 would warrant further investigation into a subsequent larger, 
randomized trial.  This estimate will be needed to inform and plan for the subsequent definitive 
study. Should 6 patients of these 20 patients in the expansion experience an RCB0 or RCB1 
pathologic response at the time of surgery, this would estimate the RCB0 + RCB1 response of 30% 
with a 95% confidence Interval of 12% - 54%. 
 
9.0 PUBLICATION OF TRIAL RESULTS 
 
Publications resulting from this trial may be developed by the investigator who will provide Pfizer 
an opportunity (within 30 days before submission or other public disclosure) to prospectively 
review any proposed publication, abstract or other type of disclosure that reports the results of the 
study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.0 STUDY CALENDAR 
10.1 Original Study Schema 
 
 
A +/- 3 day window is allowed for all study assessments. 
 
STUDY WEEK 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
After 
surgery 
STUDY DAY 
-28 to 0 1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
Informed Consent 
X 
Demographics 
X 
Medical History 
X 
General Physical 
X 
Xa 
X 
X 
Vitals Signs, W eight 
X 
Xa 
X 
X 
Performance Status 
X 
Xa 
X 
X 
Baseline Symptoms 
/ Toxicities 
X 
Xa 
X 
X 


2014-0045 
Version 15; July 29, 2019 
 
39 
 
CBC 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistries 
Chem 12 and LFTs 
X 
Xa 
X 
X 
Pregnancy Test 
(Serum or urine) 
X 
Cardiac Scan 
(MUGA or 2DEcho) 
X 
Breast Ultrasound 
X 
X 
 
X 
 
 Biopsies and 
Correlative studies b 
X 
Xb 
 
X 
Blood for PBMCs 
 
Xd 
X 
X 
Blood for cfDNA  
 
Xd 
Xb 
 
 
 
 
a) If screening test performed > 10 days before start of treatment repeat test on Day 1. 
 
b) Must be collected within 7 days prior to the completion of talazoparib treatment.  
   
c)  Four core biopsies and two FNA’s will be collected at each time point. 
 
d) At time points that require both PBMC and cfDNA sample collection, one lavender top  
 
       
 
    tube will be used to collect blood. PBMC and cfDNA will be isolated from the one collection     
        
 
    tube.  
         
e) Negative serum of urine pregnancy test for women within 7 days of receiving the first dose of the study  
 
    medication for women of childbearing potential.  Women will be considered not of childbearing potential      
 
    and exempt from pregnancy testing if they are either a) older than 50 and amenorrheic for at least 12  
 
    consecutive months following cessation of all exogenous hormonal treatments, or b) have documentation of 
 
    irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but 
 
   not tubal ligation


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10.2 Expansion Cohort 
A +/- 3 day window is allowed for all study assessments. 
STUDY WEEK 
1 
2 
3 
4 
5 
6 
7 
8 
9 
13 
17 
21 25 
At 
surgery 
STUDY DAY 
-28 to 0 1 
8 
15 
22 
29 
36 
43 
50 
57 
85 
113 141 169 
Informed Consent 
X 
Demographics 
X 
Medical History 
X 
General Physical 
X 
Xa 
X 
X X 
X 
X 
X 
Vitals Signs, W eight 
X 
Xa 
X 
X X 
X 
X 
X 
Performance Status 
X 
Xa 
X 
X X 
X 
X 
X 
Baseline Symptoms 
/ Toxicities 
X 
Xa 
X 
X X 
X 
X 
X 
CBC 
X 
Xa 
 
X 
 
X 
 
 
 
X X 
X 
X 
X 
Chemistries 
Chem 12 and LFTs 
X 
Xa 
X 
X X 
X 
X 
X 
Pregnancy Test 
(Serum or urine) 
X 
Cardiac Scan 
(MUGA or 2DEcho) 
X 
Breast Ultrasound 
X 
 
 
 
X 
X 
X 
 Biopsies and 
Correlative studiesc 
X 
 
 
X 
Blood for PBMCs 
 
Xd 
 
 
X 
Blood for cfDNA  
 
Xd 
 
X 
 
 
a) If screening test performed > 10 days before start of treatment repeat test on Day 1. 
c)   Up to four core biopsies and up to two FNA’s will be collected at baseline and if progression (Must be 
collected within 7 days prior to the completion of talazoparib treatment); then prior to the initiation of any 
systemic therapy. 
 
d) At time points that require both PBMC and cfDNA sample collection, one lavender top  
 
       
 
    tube will be used to collect blood. PBMC and cfDNA will be isolated from the one collection     
        
 
    tube.  
 
e) Negative serum of urine pregnancy test for women within 7 days of receiving the first dose of the study  
 
    medication for women of childbearing potential.  Women will be considered not of childbearing  
 
    potential and exempt from pregnancy testing if they are either a) older than 50 and amenorrheic for at  
 
    least 12 consecutive months following cessation of all exogenous hormonal treatments, or b) have  
    
 
    documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral    
 
    salpingectomy, but not tubal ligation. 
 


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