Triple-Negative First-Line Study: Neoadjuvant Trial of Nab-Paclitaxel and MPDL3280A, a PDL-1 Inhibitor in Patients With Triple Negative Breast Cancer
Phase: PHASE2
Conditions: Breast Adenocarcinoma, Invasive Breast Carcinoma, Triple-Negative Breast Carcinoma
Sponsor: M.D. Anderson Cancer Center

 
 
 
 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2014-1043 
Protocol Title 
Triple-Negative First-Line Study: 
Neoadjuvant trial of nab-paclitaxel and MPDL3280A, a pdl-1 inhibitor in 
patients with triple negative breast cancer. 
Protocol Phase 
II 
Protocol Version 
18 
Version Date 
6/17/2021 
 
Protocol PI 
Clinton Yam 
Department 
Breast Medical Oncology 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
127396 
 
 
 
 
 
 
 
 

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Triple-Negative First-Line Study: 
Neoadjuvant trial of nab-paclitaxel and Atezolizumab (MPDL3280A), a pdl-1 inhibitor in patients 
with triple negative breast cancer. 
 
 
 
Study Chair:              Clinton Yam, MD 
Assistant Professor Department of Breast Medical Oncology 
The University of Texas MD Anderson Cancer Center 
 
 
 
 
 
 
Collaborators: 
W. Fraser Symmans, MD 
Professor, Pathology 
The University of Texas MD Anderson Cancer Center 
 
Jennifer K. Litton, MD 
Professor, Department of Breast Medical Oncology 
The University of Texas MD Anderson Cancer Center 
 
Debu Tripathy, MD 
Chair, Department of Breast Medical Oncology 
The University of Texas MD Anderson Cancer Center 
 
Lumarie Santiago, MD 
Associate Professor, Department of Diagnostic Radiology - Breast Imaging 
The University of Texas MD Anderson Cancer Center 
 
Rosalind Candelaria, MD 
Assistant Professor, Department of Diagnostic Radiology – Breast Imaging 
The University of Texas MD Anderson Cancer CenterGaiana Margishvili Rauch, MD PhD 
Associate Professor, Department of Diagnostic Radiology – Breast Imaging 
The University of Texas MD Anderson Cancer Center 
 
Beatriz Elena Adrada, MD 
Associate Professor, Department of Diagnostic Radiology – Breast Imaging 
The University of Texas MD Anderson Cancer Center 
 
Kristofer Jennings, PhD 
Assistant Professor, Department of Biostatistics 
The University of Texas MD Anderson Cancer Center 
 
 
 

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TABLE OF CONTENTS 
List of Abbreviations ................................................................................................... 7 
1.0 
STUDY SUMMARY .................................................................................................... 8 
2.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................... 9 
2.1 
Primary Objective & Hypothesis .............................................................................. 9 
2.2 
Secondary Objectives & Hypotheses ...................................................................... 9 
2.3 
Exploratory Objective .............................................................................................. 9 
3.0 
BACKGROUND & RATIONALE ........................................................................... 10 
3.1 
Background ........................................................................................................... 10 
3.1.1 
Overview of Triple Negative Breast Cancer ................................................. 10 
3.1.2 
Neoadjuvant Chemotherapy: Historical Perspective ................................... 10 
3.1.3 
Pathologic Assessment after NACT .............................................................. 10 
3.1.4 
MD Anderson Cancer Center TNBC Triaging Protocol (MDACC 2014-0185)
 ............................................................................................................................. 11 
3.1.5 
Immunotherapy and Breast Cancer ............................................................... 12 
3.2 
Atezolizumab ......................................................................................................... 14 
3.2.1 
Background: Atezolizumab.............................................................................. 14 
3.2.2 
Summary of Nonclinical Studies ..................................................................... 14 
3.2.3 
Clinical Experience with Atezolizumab .......................................................... 14 
3.2.4 
Clinical Activity .................................................................................................. 18 
3.2.5 
Nab-paclitaxel and Combination Treatment with atezolizumab ................ 19 
3.3 
Rationale ............................................................................................................... 20 
3.3.1 
Rationale for the Study and Selected Subject Population ......................... 20 
3.3.2 
Rationale for Dose Selection/Regimen/Modification ................................... 21 
4.0 
PATIENT ELIGIBILTY ............................................................................................. 22 
4.1 
Inclusion Criteria .................................................................................................... 22 
4.2 
Exclusion Criteria ................................................................................................... 23 
5.0 
TREATMENT PLAN ................................................................................................ 26 

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5.1 
Study Design ......................................................................................................... 26 
5.2 
Concurrent and Supportive Care ........................................................................... 28 
5.2.1 
Concomitant Therapy ....................................................................................... 28 
5.2.2 
Excluded Therapy ............................................................................................. 29 
5.3 
Duration of Study ................................................................................................... 30 
5.4 
Progression While on Study .................................................................................. 30 
5.5 
Subject Withdrawal/Discontinuation Criteria .......................................................... 30 
5.6 
Patient Discontinuation .......................................................................................... 30 
5.7 
Study Treatment Discontinuation .......................................................................... 31 
5.8 
Study and Site Discontinuation .............................................................................. 31 
6.0 
EXPECTED TOXICITIES AND DOSING DELAYS/MODIFICATIONS ........... 32 
6.1 
General Plan to Manage Safety Concerns ............................................................ 32 
6.1.1 
Administration of first and subsequent infusions of Atezolizumab ............ 33 
6.1.2 
Management of Atezolizumab ........................................................................ 34 
6.1.3 
Nab-Paclitaxel Dose Modification and Management of Specific Adverse Events
 ............................................................................................................................. 35 
6.2 
Nab—PACLITAXEL DOSING ............................................................................... 35 
6.2.1 
Dosing ................................................................................................................. 35 
6.2.2 
Nab-paclitaxel dose reductions ...................................................................... 37 
6.2.3 
Study Drug: Atezolizumab ............................................................................... 39 
7.0 
Correlative Studies ................................................................................................. 41 
7.1 
Tissue .................................................................................................................... 41 
7.1.1 
Characterization of TIL – Fresh tumor specimens ...................................... 41 
7.1.2 
Characterization of TIL–Formalin-fixed, paraffin-embedded (FFPE) specimens.
 ............................................................................................................................. 41 
7.1.3 
Characterization of the tumor-immune microenvironment – Formalin-fixed, paraffin-
embedded (FFPE) specimens. ............................................................................. 42 
7.2 
Peripheral blood mononuclear cells (PBMC) ......................................................... 43 
7.2.1 
Immunophenotyping. ........................................................................................ 43 

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7.2.2 
T cell repertoire analysis .................................................................................. 43 
7.2.3 
Serum ................................................................................................................. 43 
8.0 
STUDY CALENDAR ................................................................................................ 45 
9.0 
MEASUREMENT OF EFFECT .............................................................................. 48 
9.1 
Response Criteria .................................................................................................. 48 
9.2 
Disease-Free Survival ........................................................................................... 48 
9.3 
Definition of Residual Cancer Burden ................................................................... 48 
10.0 
ADVERSE EVENT REPORTING REQUIREMENTS ......................................... 50 
10.0 
Assessment of Safety ............................................................................................ 50 
10.1 
Risks Associated with Atezolizumab ..................................................................... 50 
10.2 
Safety Parameters and Definitions ........................................................................ 50 
10.2.1 Adverse Events ................................................................................................. 50 
10.2.2 Serious Adverse Events (SAE) Reporting .................................................... 51 
10.3 
Methods and Timing for Assessing and Recording Safety Variables .................... 52 
10.3.1 Adverse Event Reporting Period .................................................................... 52 
10.3.2 Assessment of Adverse Events ...................................................................... 52 
10.4 
Procedures for Eliciting, Recording, and Reporting Adverse Events ..................... 53 
10.4.1 Eliciting Adverse Events .................................................................................. 53 
10.4.2 Specific Instructions for Recording Adverse Events ................................... 53 
10.4.3 Additional Reporting Requirements for IND ................................................. 58 
10.4.4 IND Annual Reports.......................................................................................... 59 
10.5 
Study Close-Out .................................................................................................... 59 
10.6 
Study Medication Accountability ............................................................................ 59 
10.7 
Product Complaint ................................................................................................. 59 
11.0 
STATISTICAL ANALYSIS PLAN .......................................................................... 60 
11.1 
Statistical Analysis Plan Summary ........................................................................ 60 
12.0 
REFERENCES .......................................................................................................... 61 
1. 
Lehmann BD, Bauer JA, Chen X, et al: Identification of human triple-negative breast 
cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 
121:2750-67, 2011 ................................................................................................ 61 

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2. 
Rouzier R, Perou CM, Symmans WF, et al: Breast cancer molecular subtypes respond 
differently to preoperative chemotherapy. Clin Cancer Res 11:5678-85, 2005 ..... 61 
3. 
Carey LA, Dees EC, Sawyer L, et al: The Triple Negative Paradox: Primary Tumor 
Chemosensitivity of Breast Cancer Subtypes. Clinical Cancer Research 13:2329-2334, 
2007 ....................................................................................................................... 61 
4. 
Liedtke C, Mazouni C, Hess KR, et al: Response to neoadjuvant therapy and long-term 
survival in patients with triple-negative breast cancer. J Clin Oncol 26:1275-81, 2008
 ............................................................................................................................... 61 
5. 
Kaufmann M, Hortobagyi GN, Goldhirsch A, et al: Recommendations from an 
international expert panel on the use of neoadjuvant (primary) systemic treatment of 
operable breast cancer: an update. J Clin Oncol 24:1940-9, 2006 ....................... 61 
6. 
Buzdar AU: Preoperative chemotherapy treatment of breast cancer--a review. Cancer 
110:2394-407, 2007 .............................................................................................. 61 
7. 
Gralow JR, Burstein HJ, Wood W, et al: Preoperative therapy in invasive breast cancer: 
pathologic assessment and systemic therapy issues in operable disease. J Clin Oncol 
26:814-9, 2008 ...................................................................................................... 61 
8. 
Gunduz N, Fisher B, Saffer EA: Effect of surgical removal on the growth and kinetics of 
residual tumor. Cancer Res 39:3861-5, 1979 ........................................................ 61 
9. 
Bear HD, Anderson S, Smith RE, et al: Sequential preoperative or postoperative 
docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast 
cancer:National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 
24:2019-27, 2006 .................................................................................................. 61 
10. 
Symmans WF, Peintinger F, Hatzis C, et al: Measurement of residual breast cancer 
burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414-22, 
2007 ....................................................................................................................... 61 
11. 
Houssami N, Macaskill P, von Minckwitz G, et al: Meta-analysis of the association of 
breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. 
Eur J Cancer 48:3342-54, 2012 ............................................................................ 61 
12. 
Denkert C, Loibl S, Salat C, et al: Increased tumor-associate lymphocytes predict benefit 
from addition of carboplatin to neoadjuvnat therapy for triple-negative and HER2-positive 
early breast cancer in the GeparSixto trial. [S1-06] San Antonio Breast Cancer 
Symposium 2013 2013 .......................................................................................... 61 
13. 
Adams S, Gray RJ, Demaria S, et al: Prognostic Value of Tumor-Infiltrating Lymphocytes 
in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast 
Cancer Trials: ECOG 2197 and ECOG 1199. J Clin Oncol, 2014 ......................... 62 
14. 
Schreiber RD, Old LJ, Smyth MJ: Cancer immunoediting: integrating immunity's roles in 
cancer suppression and promotion. Science 331:1565-70, 2011 ......................... 62 
15. 
Aad G, Abbott B, Abdallah J, et al: Search for new particles in two-jet final states in 7 TeV 
proton-proton collisions with the ATLAS detector at the LHC. Phys Rev Lett 105:161801, 
2010 ....................................................................................................................... 62 
16. 
Brahmer JR, Tykodi SS, Chow LQ, et al: Safety and activity of anti-PD-L1 antibody in 
patients with advanced cancer. N Engl J Med 366:2455-65, 2012 ....................... 62 

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17. 
Mittendorf EA, Philips AV, Meric-Bernstam F, et al: PD-L1 expression in triple-negative 
breast cancer. Cancer Immunol Res 2:361-70, 2014 ............................................ 62 
18. 
Zitvogel L, Apetoh L, Ghiringhelli F, et al: The anticancer immune response: indispensable 
for therapeutic success? The Journal of Clinical Investigation 118:1991-2001, 2008
 ............................................................................................................................... 62 
19. 
Carson WE, Shapiro CL, Crespin TR, et al: Cellular Immunity in Breast Cancer Patients 
Completing Taxane Treatment. Clinical Cancer Research 10:3401-3409, 2004 .. 62 
20. 
Topalian SL, Hodi FS, Brahmer JR, et al: Safety, Activity, and Immune Correlates of Anti–
PD-1 Antibody in Cancer. New England Journal of Medicine 366:2443-2454, 201262 
21. 
Robidoux A, Buzdar AU, Quinaux E, et al: A Phase II Neoadjuvant Trial of Sequential 
Nanoparticle 
Albumin-Bound 
Paclitaxel 
Followed 
by 
5-
Fluorouracil/Epirubicin/Cyclophosphamide in Locally Advanced Breast Cancer. Clinical 
Breast Cancer 10:81-86, 2010 .............................................................................. 62 
22. 
Dranitsaris G, Coleman R, Gradishar W: nab-Paclitaxel weekly or every 3 weeks 
compared to standard docetaxel as first-line therapy in patients with metastatic breast 
cancer: an economic analysis of a prospective randomized trial. Breast Cancer Research 
and Treatment 119:717-724, 2010 ........................................................................ 62 
23. 
Herbst RS, Soria JC, Kowanetz M, et al: Predictive correlates of response to the anti-PD-
L1 antibody MPDL3280A in cancer patients. Nature 515:563-7, 2014.................. 62 
24. 
Manuel M, Tredan O, Bachelot T, et al: Lymphopenia combined with low TCR diversity 
(divpenia) predicts poor overall survival in metastatic breast cancer patients. 
Oncoimmunology 1:432-440, 2012 ....................................................................... 62 
25. 
Di Giacomo AM, Danielli R, Calabro L, et al: Ipilimumab experience in heavily pretreated 
patients with melanoma in an expanded access program at the University Hospital of 
Siena (Italy). Cancer Immunol Immunother 60:467-77, 2011 ................................ 62 
 
 
 

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List of Abbreviations 
AE 
Adverse event 
ALT 
ATA 
Alanine aminotransferase 
Antitherapeutic antibody 
AST 
BCS 
Aspartate aminotransferase 
Breast conserving surgery 
CMP 
Comprehensive metabolic panel 
CRC 
CTLA-4 
Colorectal cancer 
Cytotoxic T-lymphocyte associated protein 4 
DFS 
Disease-free survival 
ECG 
ER 
FDA 
FFPE 
IRB 
IND 
HBV 
HCV 
HR 
Electrocardiogram 
Estrogen receptor 
Food and Drug Administration 
Formalin-fixed paraffin embedded 
Institutional review board 
Investigational new drug 
Hepatitis B virus 
Hepatitis C virus 
Hormone receptor 
IV 
intravenous(ly) 
IRB 
LFT 
NCI CTCAE 
NK 
NACT 
NSCLC 
Institutional Review Board 
Liver function test 
National Cancer Institute common terminology criteria for adverse events 
Natural Killer 
Neoadjuvant chemotherapy 
Non-small cell lung cancer 
OS 
pCR 
PBMC 
PK 
PR 
PD-L1 
PD-1 
Overall survival 
Pathologic complete response 
Peripheral blood mononuclear cell 
Pharmacokinetics 
Progesterone receptor 
Programmed death ligand 1 
Programmed death 1 
RCC 
RCB 
RD 
Renal cell carcinoma 
Residual cancer burden 
Residual disease 
SAE 
Serious adverse event 
TNBC 
TIL 
TSH 
Triple negative breast cancer 
Tumor infiltrating lymphocyte 
Thyroid stimulating hormone 

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1.0 STUDY SUMMARY 
 
Abbreviated Title 
Ph 2 of atezolizumab plus Nab-Paclitaxel in TNBC 
Study Phase 
Phase 2 
Clinical Indication 
TNBC 
Route of administration 
IV 
Accrual Goal 
37 
Estimated duration of 
enrollment 
24 months 
Duration of Participation 
3 years, 6 months on active therapy 
 
 
 

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2.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
2.1 
Primary Objective & Hypothesis 
To evaluate the rate of pathologic complete response (pCR)/RCB-0 + residual cancer burden 
(RCB)-I responses in patients with triple negative breast cancer (TNBC), who were non-
responders to initial anthracycline and cyclophosphamide chemotherapy, treated with 
atezolizumab in combination with nab-paclitaxel in the neoadjuvant setting. Pathologic complete 
response will be defined as no residual invasive disease in the breast or regional lymph nodes. 
Hypothesis: 
 (1)  Among patients with TNBC who were non-responders to initial anthracycline and 
cyclophosphamide chemotherapy, the combination of atezolizumab and nab-paclitaxel 
administered in the neoadjuvant setting will increase pCR and RCB-I rates. 
 
2.2 
Secondary Objectives & Hypotheses 
1. To estimate Progression Free Survival (PFS) distribution of TNBC patients who were 
non-responders to initial anthracycline and cyclophosphamide chemotherapy, treated 
with atezolizumab in combination with nab-paclitaxel in the neoadjuvant setting. 
2. To determine the safety of atezolizumab in combination with nab-paclitaxel in the 
neoadjuvant setting  
Hypotheses: 
(1) Among patients with TNBC who were non-responders to initial anthracycline and 
cyclophosphamide chemotherapy, the combination of atezolizumab and nab-paclitaxel 
administered in the neoadjuvant setting will increase 3-year DFS distribution. 
(2) The combination of atezolizumab and nab-paclitaxel will be safe in TNBC patients. 
2.3 
Exploratory Objective 
(1) To investigate the association between biomarkers in the peripheral blood and tumor 
tissue with efficacy for TNBC patients treated with atezolizumab in combination with nab-
paclitaxel in the neoadjuvant setting. 
 

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3.0 BACKGROUND & RATIONALE 
3.1 
Background 
3.1.1 
Overview of Triple Negative Breast Cancer 
TNBC is a subtype of invasive breast cancer that lacks estrogen receptor (ER), progesterone receptor 
(PR) and HER2 expression. TNBC has an especially poor prognosis in patients whose tumor does not 
respond to anthracycline and taxane-based chemotherapy. As a subset of breast cancer, TNBC is 
especially challenging to treat due to its heterogeneity as these tumors are grouped together only 
because of their lack of ER, PR and HER2 expression.  In a study by Lehman, et al, by using gene 
expression profiles, 6 subtypes of TNBC have emerged each with its own intrinsic biology and likely 
responsiveness to therapy.1 To date there are no targeted therapies for TNBC, therefore chemotherapy 
remains the mainstay of treatment.  Data in the neoadjuvant (preoperative) setting shows that patients 
with TNBC have a higher sensitivity and pCR rate to standard systemic chemotherapy than do patients 
with other subtypes of breast cancer, such as endocrine sensitive cancers.2,3 However, for those patients 
that do not obtain a pCR or minimal residual cancer burden (RCB-I), their survival outcomes are 
significantly worse.4 Therefore measuring the response to chemotherapy and quantifying the residual 
disease by the RCB method yields important prognostic information, identifying patients who may benefit 
from additional therapy as part of a clinical trial (please see below, section 9.3 for a complete description 
of assessing for RCB). 
3.1.2 
Neoadjuvant Chemotherapy: Historical Perspective 
Since its initial use in the early 1970s, neoadjuvant chemotherapy (NACT) has become the standard of 
care for management of locally advanced breast cancer and inflammatory breast cancer. 5-7  It has since 
been used increasingly for the treatment of early-stage breast cancer. Preclinical observations8,9 and 
mathematical models of tumor growth, dissemination, and development of resistance to chemotherapy 
support the use of NACT. In addition, the available data suggest that use of NACT could lead to improved 
DFS and overall survival (OS) rates, presumably through early treatment of systemic micrometastatic 
disease.  NACT also provides several advantages, including providing an early surrogate marker (pCR), 
for long-term outcome.4  As pCR has been demonstrated to correlate with long term DFS and OS, it has 
recently been identified as an appropriate endpoint for Food and Drug Administration (FDA) approval 
pathways in breast cancer.  Other purported advantages of NACT include:  1) down-staging allowing 
surgery for non-operable breast cancer, and increasing breast-conserving surgery (BCS) rates in 
patients with large operable tumors, 2) providing an in-vivo model to assess response to therapy, and 
3) serving as a research tool for understanding breast cancer biology and treatment mechanisms of 
action.   
 
3.1.3 
Pathologic Assessment after NACT 
A variety of endpoints can be used to measure outcomes in trials evaluating NACT 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 include clinical response, radiologic response, rate of BCS, and 
pathologic response. The results of several studies have been shown that pCR (for the purposes of this 
study defined as no residual invasive cancer in the breast or regional lymph nodes) is predictive of long-
term survival.2,4,6,9  Attainment of pCR is associated with a favorable prognosis, with patients attaining a 
pCR having a  lower risk of subsequent recurrence and improved OS compared with patients with 
residual invasive tumor.  

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Symmans et al. showed a continuous index combining pathologic measurements of the primary tumor 
(size and cellularity) and nodal metastases (number and size) is an independent predictor of distant 
relapse-free survival.10 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-II/III) had poor prognoses. RCB 
was independently prognostic in a multivariate model that included age, pretreatment clinical stage, 
hormone receptor (HR) status, hormone therapy, and pathologic 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). Extensive 
RD (RCB-III) was seen in 13% of patients.  RCB-III was associated with poor prognosis, regardless of 
HR status, adjuvant hormone therapy, or pathologic American Joint Committee on Cancer stage of 
residual disease. The calculation formula and detailed description of the RCB can be found at a 
dedicated Web site: http://www.mdanderson.org/breastcenter_RCB. 
Given the fact that patients that achieve a pCR (RCB-0) or have minimal RD (RCB-I) have the same 
excellent prognosis, evaluating the combination of these outcomes in patients who had previously not 
shown significant response to NACT makes biological sense as a combined outcome measure when 
novel therapeutics or therapeutic strategies are being investigated in the neoadjuvant setting. 
3.1.4 
MD Anderson Cancer Center TNBC Triaging Protocol (MDACC 2014-0185) 
Approximately 50% of patients with TNBC treated with standard taxane/anthracycline-based NACT will 
have either pCR (RCB-0) or minimal RD (RCB-I) at the time of surgical resection. Those patients have 
identical and exceptionally good long-term prognosis (less than 10% risk of developing distant metastatic 
disease within 5 years). Unfortunately, those with more extensive RD (RCB-II/III) have a much worse 
prognosis, with more than 50% of patients developing distant metastatic disease within 5 years of initial 
diagnosis.4 
Clinical trials of NACT in breast cancer have demonstrated that patients without response to their first 
chemotherapeutic regimen have a low chance (5%) of achieving pCR after their second neoadjuvant 
chemotherapy regimen. However, this has not been the case with targeted regimens such as 
trastuzumab in HER2+ tumors, suggesting that intrinsic resistance to chemotherapy can be overcome 
with appropriate targeted therapy.11 Though several novel agents have been tested for treatment in 
TNBC, so far none have been successful. It has been proposed that this might be due to the molecular 
heterogeneity of tumors classified within the “catch all” category of TNBC. 
Given the disparity of treatment outcomes from NACT for TNBC, this parent protocol (MDACC 2014-
0185) is a diagnostic platform to identify patients whose tumors are likely or unlikely to achieve pCR or 
RCB-I, in order to direct predicted responders toward standard chemotherapy and to direct predicted 
chemotherapy insensitive patients toward potentially more effective experimental therapies within 
clinical trials.  This will be done with 2 methods. The first is radiographic evaluation of the tumor to 
measure response.  The second is using a molecular predictor of sensitivity to neoadjuvant/adjuvant 
systemic therapy for clinical Stage II-III breast cancer that is independently associated with excellent 
distant recurrence-free survival in those predicted to have chemotherapy-sensitive  disease 
(HR+/HER2- or TNBC) developed at MDACC by Dr. Symmans and colleagues.  This predictor has been 
described more fully in the parent protocol (see appendix G of this trial).  Retrospective validation studies 
have been completed to support the use of this genomic testing to molecularly triage therapy for patients 
with localized breast cancer. 
The study schema for the parent triaging protocol is below: 

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3.1.5 
Immunotherapy and Breast Cancer 
Immunotherapy is a rapidly evolving field for the treatment of breast cancer, specifically TNBC. Studies 
have shown that tumor-infiltrating lymphocytes (TIL) have both prognostic and predictive significance in 
TNBC patients.   TIL as a positive prognostic biomarker was first reported using baseline samples from 
the phase III BIG02-98 adjuvant therapy trial investigating the addition of docetaxel to anthracycline in 
node-positive breast cancer. 12  TIL were evaluated on hematoxylin & eosin stained sections and for 
each 10% increase in intratumoral and stromal TIL, there was a 17% and 15% reduced risk of relapse 
and 27% and 17% reduced risk of death respectively.  The significance of stromal TIL was recently 
confirmed in TNBC samples collected during two Eastern Cooperative Oncology Group (E2197 and 
E1199) adjuvant therapy trials. 13  The presence of TIL have also been shown to have predictive value 
with the presence of TIL being associated with higher pCR rates independent of other clinicopathologic 
prognostic factors in patients receiving NACT. 12 
 
Despite the presence of an immune response, tumors continue to grow, a process that has been referred 
to as “immune escape.”  Tumor cell escape can occur through multiple different mechanisms. 14  Tumor 
cells themselves promote an immunosuppressive microenvironment by producing suppressive 
cytokines including TGF-β, VEGF, or indoleamine 2,3-dioxygenase.  The tumor microenvironment also 
contains immune cells such as regulatory T cells and myeloid-derived suppressor cells that function to 
suppress the immune response.  At the individual tumor cell level, alterations leading to decreased 
immune recognition (such as loss of tumor antigens, downregulation of major histocompatibility complex 
molecules, or loss of antigen processing function within the tumor cell), or increased resistance to the 
cytotoxic effects of immunity (such as via induction of anti-apoptotic mechanisms) can promote tumor 

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growth.  Finally, tumor cells can upregulate T cell-inhibitory molecules such as programmed death ligand 
1 (PD-L1), one of two known ligands for programmed death-1 (PD-1), a T cell inhibitory molecule. 
 
Activating the immune system for therapeutic benefit in cancer is an area of active investigation.  Multiple 
forms of immunotherapy have been described including vaccines targeting tumor antigens, adoptive T 
cell therapy, and monoclonal antibodies targeting T cell-inhibitory molecules including PD-1 (or it’s ligand 
PD-L1) or the related cytotoxic T-lymphocyte associated protein 4 (CTLA-4).   Clinical trials of 
ipilimumab, a mAb targeting CTLA-4, in patients with metastatic melanoma showed improvements in 
OS leading to FDA approval for this indication. 15  In September 2014, the anti-PD-1 antibody 
pembrolizumb was the first agent targeting the PD-1/PD-L1 interaction to receive FDA approval.  
Pembrolizumab is approved for use in patients with advanced or unresected melanoma not responding 
to other therapies.  Several trials evaluating other mAbs targeting PD-1 and PD-L1 have shown promise 
in other tumor types including non-small cell lung cancer and renal cell carcinoma. 16  There is data 
suggesting that PD-L1 expression on the tumor may be a biomarker predicting response to this class of 
therapy. 16   In a study recently published by our group, we showed PD-L1 expression in 20% of TNBC 
tumors suggesting that targeting PD-1 or PD-L1 may have therapeutic benefit in TNBC. 17  Ongoing 
studies are evaluating these agents in patients with metastatic TNBC.  Included among these is a phase 
I trial being conducted by Genentech evaluating their anti-PD-L1 antibody MPDL2380A in combination 
with nab-paclitaxel.   
 
3.1.6 Clinical Response with Immunotherapies 
Evaluating response to immunologic agents in patients with solid tumors has been challenging.  Previous 
evaluations such as the RECIST criteria have looked to pure percentages of growth as a means of 
response or progression.  This has been demonstrated to be challenging in patients who are receiving 
immunotherapies.  Although some reported results have shown tumor regression, others have shown 
delayed response or even growth of the tumor prior to long term regression.  The growth of the tumor in 
several cases of patients who have had solid tumors, received immunologic agents and then eventually 
had significant responses had early increase in size of the tumor felt to be consistent with T cell or 
immunologic infiltration of the tumor.18-20 
Given this observation, the immune related Response Criteria (irRC) criteria was developed18: 
Tumor Burden = the sum of perpendicular diameters (SPD) of the index lesion + SPD of any new 
measurable lesions.   
 
A patient has been considered to be progressing if the tumor burden as defined above does not increase 
by 25% as compared with the baseline at 2 consecutive time points at least 4 weeks apart. 
 
With regards specifically in metastatic triple negative breast cancer, 2 studies were presented at the 
2014 San Antonio Breast Cancer Symposium.  Nanda et al. presented a Phase I study of MK-3475 
which is a PD-1 inhibitor in metastatic triple negative breast cancer patients.  Thirty-two women were 
treated after multiple previous lines of therapy.  Five of the patients had a partial response and have 
continued on therapy with a durable response >40 weeks.  One of the patients had initial progression 
and then continued with stable disease.21  At the same meeting, Emens et al. presented 12 patients 
treated with atezolizumab and two patients had a new lesion identified and then went onto have 
significant tumor response.22 
 

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To our knowledge this will be the first instance of evaluating this response in the neoadjuvant setting. 
 
 
 
 
3.2 
 Atezolizumab 
3.2.1 
Background: Atezolizumab 
Atezolizumab is a human immunoglobulin (Ig) G1 monoclonal antibody consisting of two heavy chains 
(448 amino acids) and two light chains (214 amino acids) and is produced in Chinese hamster ovary 
cells.  Atezolizumab was engineered to eliminate Fc-effector function via a single amino acid 
substitution (asparagine to alanine) at position 298 on the heavy chain, which results in a non-
glycosylated antibody that has minimal binding to Fc receptors and prevents Fc-effector function at 
expected concentrations in humans.  Atezolizumab targets human PD-L1 and inhibits its interaction 
with its receptors, PD-1 and B7.1 (CD80).  Both of these interactions are reported to provide inhibitory 
signals to T cells. 
Atezolizumab is being investigated as a potential therapy against solid tumors and hematologic 
malignancies in humans. 
3.2.2 
Summary of Nonclinical Studies 
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and in vivo activity, 
to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an acceptable safety profile, and 
to identify a Phase I starting dose.  Comprehensive pharmacology, PK, and toxicology evaluations 
were, thus, undertaken with atezolizumab. 
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in mice and 
cynomolgus monkeys to support intravenous (IV) administration and to aid in projecting the 
appropriate starting dose in humans.  Given the similar binding of atezolizumab for cynomolgus 
monkey and human PD-L1, the cynomolgus monkey was selected as the primary and relevant 
nonclinical model for understanding the safety, pharmacokinetics, and toxicokinetics of atezolizumab.  
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab supported 
entry into clinical studies, including providing adequate safety factors for the proposed Phase I starting 
doses.  The results of the toxicology program were consistent with the anticipated pharmacologic 
activity of down-modulating the PD-L1/PD-1 pathway and supported entry into clinical trials in patients. 
Refer to the atezolizumab Investigator’s Brochure for details on the nonclinical studies. 
3.2.3 
Clinical Experience with Atezolizumab 
3.2.3.1 
Ongoing Clinical Studies 
Current studies of atezolizumab include one ongoing Phase Ia monotherapy study, three ongoing 
combination studies, five Phase II studies, and one Phase III study.  Details of all ongoing studies can 
be found in the atezolizumab Investigator’s Brochure. 
Phase Ia Study PCD4989g 
Study PCD4989g is a multicenter, first-in-human, open-label, dose-escalation study evaluating the 
safety, tolerability, immunogenicity, pharmacokinetics, exploratory pharmacodynamics, and preliminary 

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evidence of biologic activity of atezolizumab administered as a single agent by IV infusion every 3 
weeks to patients with locally advanced or metastatic solid malignancies or hematologic malignancies.  
Ongoing expansion cohorts are studying the efficacy in patients with pancreatic cancer, bladder 
cancer, breast cancer, esophageal cancer, prostate cancer, small-cell lung cancer, malignant 
lymphoma, multiple myeloma, and other less common tumor types. 
This multicenter Phase I study was presented at the San Antonio Breast Cancer Symposium in 
December, 2014.  The published study abstract describes that the study selectively enrolled a cohort 
of patients with PD-L1-positive metastatic TNBC. PD-L1 positivity was centrally evaluated based on 
the PD-L1 immunohistochemistry (IHC) status of tumor-infiltrating immune cells (ICs). Eligible patients 
received atezolizumab 15 or 20 mg/kg IV every 3 weeks for up to 1 year. The objective response rate 
(ORR) was assessed by RECIST v1.1. Atezolizumab immune correlates were evaluated for tumor and 
circulating biomarkers. 
Twelve patients were treated with atezolizumab and evaluable for safety. All 4 patients (33%) with 
visceral metastases had liver metastases, and 1 patient (8%) had bone metastases. 92% of patients 
received ≥ 2 prior therapies. Prior chemotherapies included anthracycline (92%), taxane (75%) and 
platinum (42%). Grade 3-4 treatment-related adverse events (AEs) occurred in 8% of patients (1 event 
of Grade 3 adrenal insufficiency). One patient had an immune-related AE (Grade 2 pyrexia). No 
treatment-related deaths were observed. Nine patients were dosed by November 16, 2013 and 
evaluable for efficacy. The ORR was 33%, including 1 CR and 2 PRs. Responders included patients 
with visceral metastases at baseline. At the time of the clinical data cut-off, all responses occurred 
within 6 weeks of the first dosing of atezolizumab, and all of the responses were ongoing. The median 
duration of response had not been reached. One patient achieved stable disease as best response. 
Two additional patients had tumor shrinkage (-43% and -44% change in target lesions, respectively) 
but were not counted as RECIST responders due to the appearance of new lesions, which is likely 
attributable to pseudo-progression. In conclusion atezolizumab treatment was well tolerated and was 
associated with objective clinical activity in patients with pretreated metastatic TNBC.  
Phase Ib Study GP28328 
Ongoing Phase Ib Study GP28328 is evaluating the safety and pharmacology of atezolizumab 
administered with bevacizumab alone (Arm A) or with bevacizumab plus leucovorin, 5-fluorouracil, and 
oxaliplatin (FOLFOX; Arm B) in patients with advanced solid tumors.  Additional cohorts have been 
included to investigate atezolizumab in combination with carboplatin plus paclitaxel, in combination 
with carboplatin plus pemetrexed, in combination with nab-paclitaxel in patients with advanced TNBC, 
and in combination with carboplatin plus nab paclitaxel, pemetrexed, and cisplatin in patients with 
advanced or metastatic non-small cell lung cancer (NSCLC). 
As of 10 May 2014, 90 patients had been enrolled in this study: A total of 88 of 90 patients (97.8%) 
reported at least one adverse event while on study drug. The majority of these were Grade 1 and 2 in 
severity. The five most commonly reported adverse events included fatigue, nausea, diarrhea, 
decreased appetite and pyrexia. However, none of the toxicities were felt to be additive to the 
chemotherapy toxicity.   
 
Therefore this agent has shown to have activity in patients with resistant TNBC in addition to an 
acceptable safety profile when given in combination with nab-paclitaxel, which would be considered a 
standard therapy after anthracycline-based chemotherapy for early stage breast cancer. 
 

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Phase Ib Study GP28384 
Ongoing Phase Ib Study GP28384 is evaluating the safety and pharmacology of atezolizumab 
administered in combination with vemurafenib in patients with previously untreated BRAF V600-
mutation−positive metastatic melanoma. 
Phase Ib Study GP28363 
Ongoing Phase Ib Study GP28363 is evaluating the safety and pharmacology of atezolizumab 
administered in combination with cobimetinib (MEK inhibitor) in locally advanced or metastatic solid 
tumors. 
Phase II Study GO28625 (FIR) 
Ongoing, single-arm, Phase II Study GO28625 is evaluating the safety and efficacy of atezolizumab 
monotherapy in PD-L1−positive patients with NSCLC.  In particular, this study is evaluating whether 
archival or fresh tumor tissue is more predictive of response to atezolizumab.  Safety and efficacy data 
are not yet available for this study.  
Phase II Study GO28753 (POPLAR) 
Study GO28753 is a randomized, open-label, Phase II study in patients with locally advanced or 
metastatic NSCLC who have failed a prior platinum-containing regimen.  Patients in the control arm of 
Study GO28753 will receive docetaxel alone.  Eligible patients will be enrolled regardless of PD-L1 
status and will be stratified by PD-L1 expression.  The primary endpoint is overall survival (OS) for 
both the PD-L1−positive population and the overall study population. 
Phase II Study GO28754 (BIRCH) 
Ongoing, single-arm, Phase II Study GO28754 is evaluating the safety and efficacy of atezolizumab 
monotherapy in PD-L1−positive patients with NSCLC.  Safety and efficacy data are not yet available 
for this study. 
Phase II Study WO29074 
Ongoing Phase II Study WO29074 is evaluating the safety and efficacy of atezolizumab monotherapy 
or the combination of atezolizumab and bevacizumab versus sunitinib in treatment-naïve patients with 
renal cell carcinoma (RCC).  Safety and efficacy data are not yet available for this study. 
Phase II Study GO29293 
Ongoing Study GO29293 is a single-arm, open label, Phase II study to assess the clinical benefit of 
atezolizumab as a single agent in patients with locally advanced or metastatic UBC.  The co-primary 
endpoints of this study are independent review facility (IRF)-assessed objective response rate (ORR) 
according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) and 
investigator-assessed ORR according to modified Response Evaluation Criteria in Solid Tumors 
(RECIST) criteria. 
Phase III Study GO28915 (OAK) 
Study GO28915 is a randomized, open-label, Phase III study in patients with locally advanced or 
metastatic NSCLC who have failed a prior platinum-containing regimen.  Patients in the control arm of 
Study GO28915 will receive docetaxel alone.  Eligible patients will be enrolled regardless of PD-L1 
status and will be stratified by PD-L1 expression.  The primary endpoint is OS for both the PD-
L1−positive population and the overall study population. 

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3.2.3.2 
Clinical Safety 
The presented safety data for atezolizumab have been derived mainly from the treatment of patients in 
Phase Ia Study PCD4989g. As of 11 May 2015, there were 558 safety evaluable patients from the 
Phase Ia Study PCD4989g.  The median duration of treatment was 12.14 weeks (range: 0.0-71.4 
weeks), and the median number of atezolizumab cycles administered was 5.0 (range: 1−19 cycles).  
Currently, no maximum tolerated dose, no dose-limiting toxicities and no clear dose-related trends in 
the incidence of adverse events have been determined.  
Adverse Events (AEs) 
In all 558 treated patients in Study PCD4989g, 520 (93%) patients experienced an adverse event 
regardless of attribution to atezolizumab. Treatment-related adverse events (per investigator’s 
assessment of causality) were reported in 376 patients (67.4%). The majority of these AEs were 
Grade 1 or 2 in maximum severity based on the National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0).   
The most frequently observed adverse events ( ≥ 10% of patients) included fatigue, decreased 
appetite, nausea, pyrexia, constipation, cough, dyspnea, diarrhea, headache, back pain, vomiting, 
anemia, arthralgia, rash, insomnia, asthenia, abdominal pain, chills, pruritus, generalized pain, and 
peripheral edema.   
Grade 3-4 adverse events were reported in 239 patients (42.8%) of which 66 (11.8%) were considered 
related by the investigator.  Grade 3 and 4 AEs considered related included dyspnea, pneumonitis, 
increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased 
gamma glutamyltransferase (GGT), lymphocyte count decreased, cardiac tamponade, asthenia, 
autoimmune hepatitis, pneumonia, influenza, and hypoxia. Safety findings in the TNBC cohort of study 
PCD4989g are consistent with the data observed in the overall study population. 
Refer to the Atezolizumab Investigator’s Brochure for additional details regarding clinical safety. 
 
Immune-Related Adverse Events 
Given the mechanism of action of atezolizumab, events associated with inflammation and/or immune-
mediated AEs have been closely monitored during the atezolizumab clinical program.  These include 
potential dermatologic, hepatic, endocrine, gastrointestinal, and respiratory events. 
Refer to the Atezolizumab Investigator’s Brochure for additional details regarding immune mediated 
AEs and identified risks (Adverse Drug Reactions) observed in patients treated with atezolizumab. 
   
Preliminary Clinical Safety in Combination with Platinum-Based Doublet Chemotherapy: Phase 
1b Study GP28328 
Study GP28328 is a trial of the safety and pharmacology of atezolizumab administered with 
bevacizumab and/or chemotherapy in patients with advanced solid tumors. Arm A evaluates 1200 mg 

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atezolizumab + bevacizumab administered q3w in patients with multiple solid tumor types, including 
separate expansion cohorts in colorectal cancer (CRC) and renal cell carcinoma (RCC). Arm B 
evaluates atezolizumab + bevacizumab and FOLFOX administered q2w in patients with multiple solid 
tumor types, including colorectal cancer and breast cancer. Arms C, D, and E evaluate atezolizumab 
administered q3w in chemotherapy-naïve non-small cell lung cancer (NSCLC) patients in combination 
with carboplatin + paclitaxel, carboplatin + pemetrexed, and carboplatin + nab-paclitaxel, respectively. 
As of 10 May 2014, preliminary safety data are available from 90 treated patients. Of these patients, 
88 (98%) reported one or more AEs. The five most commonly reported AEs included fatigue, nausea, 
diarrhea, decreased appetite and pyrexia. Immune mediated events were infrequently reported. The 
following were observed in the overall population:  rash (11.1%), ALT increased (5.6%), AST 
increased (5.6%) and hypothyroidism (1.1%). 
No additive adverse effects were observed when atezolizumab was administered in combination with 
either bevacizumab or nab-paclitaxel chemotherapy.  
3.2.4 
Clinical Activity 
Anti-tumor activity, including RECIST-based responses (i.e., RECIST v1.1 responses), have been 
observed in patients with different tumor types, including NSCLC, RCC, melanoma, bladder cancer, 
CRC, head and neck cancer, gastric cancer, breast cancer, and sarcoma treated with 
atezolizumab monotherapy in Study PCD4989g.  Among 386 evaluable patients enrolled prior to 1 
July 2013 (data cutoff of 1 January 2014), there were 47 patients with responses with a 
median duration of response of 75.7 weeks (range: 11.7+ to 85.9+ weeks, where “+” denotes 
censored value).  The majority of these responses have been durable, with 72.3% (34/47) of 
responses ongoing as of the clinical cutoff date. 
Analyses of tumor-infiltrating immune cells for PD-L1 expression on baseline tumor tissue 
have been performed for Study PCD4989g. Preliminary results from Study PCD4989g 
suggest that PD-L1 expression in tumor-infiltrating immune cells is likely to be associated 
with response to atezolizumab. 
 
3.2.4.1 
Clinical Pharmacokinetics and Immunogenicity 
On the basis of available preliminary PK data (0.03−20 mg/kg), atezolizumab appeared to show linear 
pharmacokinetics at doses ≥ 1 mg/kg.  For the 1-mg/kg and 20-mg/kg dose groups, the mean 
apparent clearance  and the mean volume of distribution at steady state (Vss) had a range of 3.11 to 
4.14 mL/kg and 48.1 to 67.0 mL/kg, respectively, which is consistent with the expected profile of an 
IgG1 antibody in humans. 
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in all dose 
cohorts and was associated with changes in pharmacokinetics for some patients in the lower dose 
cohorts (0.3, 1, and 3 mg/kg).  The development of detectable ATAs has not had a significant impact 
on pharmacokinetics for doses from 10 to 20 mg/kg.  Patients dosed at the 10-, 15-, and 20-mg/kg 
dose levels have maintained the expected target trough levels of drug despite the detection of ATAs.  
To date, no clear relationship between detection of ATAs and AEs or infusion reactions has been 
observed. 
3.2.4.2 Rationale for atezolizumab Dosage 
Currently available PK and ATA data from Study PCD4989g suggest that the 15-mg/kg atezolizumab 
q3w regimen (or fixed-dose equivalent) for Phase II and Phase III studies would be sufficient to both 

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maintain trough concentration (Ctrough) ≥ 6 µg/mL and further safeguard against both interpatient 
variability and the potential effect of ATAs that could lead to subtherapeutic levels of atezolizumab A 
relative to the 10-mg/kg atezolizumab q3w regimen (or fixed-dose equivalent).  From inspection of 
available observed Ctrough data, moving further to the 20-mg/kg atezolizumab q3w regimen does not 
appear to be warranted to maintain targeted Ctrough levels relative to the proposed 15-mg/kg 
atezolizumab q3w level.  
Simulations do not suggest any clinically meaningful differences in exposure following a fixed dose or 
a dose adjusted for weight.  On the basis of this analysis, a fixed dose of 1200 mg has been selected 
when atezolizumab is administered q3w (equivalent to an average body weight−based dose of 
15 mg/kg).   
3.2.5 
Nab-paclitaxel and Combination Treatment with atezolizumab 
Preliminary safety data from study GP28328 indicate that atezolizumab can be safely combined with 
chemotherapy (several combinations have been evaluated and determined to be well tolerated; refer 
to the Atezolizumab Investigator’s Brochure for details).  Specifically, atezolizumab was tested in 
combination with carboplatin + Nab-paclitaxel in patients with previously untreated NSCLC; refer to the 
Atezolizumab Investigator’s Brochure for details. No exacerbation of chemotherapy-associated 
adverse events was reported. 
Adverse events commonly reported in 2 or more patients in Arm F (atezolizumab in combination with 
nab-paclitaxel) included dermatitis, upper respiratory infection, alopecia, peripheral sensory 
neuropathy, fever, constipation, neutrophil count decreased, anemia, diarrhea, headache, nausea and 
fatigue. 
 
There is increasing evidence that in addition to causing tumor cell death, certain conventional 
chemotherapies may have immunogenic effects.18 Clinical evidence exists to suggest that T-cell and 
natural killer (NK)-cell functions are enhanced in patients with breast cancer (stage II/III) treated with 
taxanes, as compared to patients who did not receive taxanes.19 In addition tumor cell killing by 
cytotoxic chemotherapy can be expected to expose the immune system to high levels of tumor 
antigens, and invigorating tumor-specific T-cell immunity in this setting by inhibiting PD-L1/PD-1 
signaling may result in deeper and more durable responses compared to standard chemotherapy 
alone.   
Refer to the atezolizumab Investigator’s Brochure for details regarding nonclinical and clinical 
pharmacology of atezolizumab. 
 
 

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3.3 
Rationale 
3.3.1 
Rationale for the Study and Selected Subject Population 
As previously discussed, approximately 50% of patients with TNBC treated with standard taxane and 
anthracycline-based neoadjuvant chemotherapy (NACT) will have either pCR (RCB-0) or minimal RD 
(RCB-I) at the time of surgical resection. Those patients have identical and exceptionally good long-
term prognosis with a less than 10% risk of developing distant metastatic disease within 5 years. 
Unfortunately, those with more extensive RD (RCB II-III) have a much worse prognosis, with greater 
than 50% of patients developing distant metastatic disease within 5 years of initial diagnosis. 
Additionally, clinical trials of NACT in breast cancer have demonstrated that patients without a 
response to their first NACT regimen have a very low chance (5%) of achieving pCR after their second 
NACT regimen. Evaluating the rate of pCR and RCB-I responses in patients treated with atezolizumab 
in combination with nab-paclitaxel in the neoadjuvant setting is therefore a clinically meaningful 
endpoint. 
Studies have shown that an immune infiltrate has both prognostic and predictive significance in TNBC 
patients.  However, despite the presence of TIL, this immune response is not able to cure TNBC. A 
promising approach to augmenting antitumor immunity is blockade of T cell inhibitory molecules such 
as CTLA-4 or PD-1.  In a study recently published by our group, we showed PD-L1, one of the known 
ligands for PD-1, to be expressed in 20% of TNBC tumors. [9] This suggests that targeting PD-1 or PD-
L1 may have therapeutic efficacy in TNBC. 
Treatment with chemotherapy results in tumor cell death which may result in the release of antigens 
and generation of an immune response against these antigens.  It is possible that the generated 
immune response could be augmented by treatment with atezolizumab and that persistence of this 
immune response could lead to improvements in longer term outcomes, thus justifying evaluating the 
impact of atezolizumab in combination with nab-paclitaxel on DFS, one of the trial’s secondary 
endpoints.  Another secondary endpoint is to confirm the safety of the combination of atezolizumab 
with nab-paclitaxel.  This combination has been shown to be safe in a small population of patients with 
metastatic TNBC however safety must be confirmed in patients with earlier stage, potentially curable 
disease being treated in the neoadjuvant setting. 
Published data from other studies evaluating antibodies targeting the PD-1/PD-L1 interaction have 
suggested that PD-L1 expression may be a biomarker predicting response to treatment.20  These data 
are from a small subset of 42 patients enrolled on a phase I trial evaluating the anti-PD-1 antibody 
nivolumab.  An objective response was seen in 9 of 25 patients whose tumors stained positive for PD-
L1 but in none of 17 patients whose tumors were negative.  Additional studies are required to further 
investigate PD-L1 expression as a biomarker as well as to identify other biomarkers that may predict 
response to immune checkpoint inhibitors thus providing rationale for the proposed exploratory 
objective for this study. 
Nab-paclitaxel has been tested in the neoadjuvant setting at 100 mg/m2 IV weekly x 12 weeks and 
found to be safe and tolerable.21  As this is the preferred dosing of nab-paclitaxel in the neoadjuvant 
setting, this is the dosing regimen chosen for this study. 
Taken together, these data provide the rationale for the proposed clinical trial evaluating atezolizumab 
in combination with nab-paclitaxel, in the neoadjuvant setting to TNBC patients who have failed to 
respond to anthracycline-based chemotherapy.  We hypothesize that this combination will lead to 
increased response rates which have been shown to predict for improved survival outcomes. 

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3.3.2 
Rationale for Dose Selection/Regimen/Modification 
The fixed dose of 1200 mg (equivalent to an average body weight−based dose of 15 mg/kg) and q3w 
schedule was selected on the basis of both nonclinical studies and available clinical data from Study 
PCD4989g.   
Patients will be dosed with a standard dosing regimen of nab-paclitaxel (100 mg/m2) weekly x 12 
weeks for the first part of this study, before surgery.22 This weekly regimen of nab-paclitaxel was 
established in a Phase 2 study conducted in patients with previously untreated metastatic breast 
cancer.   
 
 

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4.0 PATIENT ELIGIBILTY 
4.1 
Inclusion Criteria 
In order to be eligible for participation in this 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 1.5 cm, or at least 1 biopsy confirmed involved lymph node >1.5 
cm, on imaging by either mammography, ultrasound or breast MRI. 
 
3) 
ER and PR expression both <10% by immunohistochemistry (IHC) and HER2 negative or non-
amplified as determined by the current ASCO-CAP criteria which are as follows: HER2 testing 
by IHC as 0 or 1+.  If HER2 is 2+, ISH (in situ hybridization) must be performed.  HER2 is positive 
for gene amplification if: 
 
 
IHC 3+ based on circumferential membrane staining that is 
complete, intense  
 
ISH positive based on: 
Single-probe average HER2 copy number ≥6.0 signals/cell. 
Dual-probe HER2/CEP17 ratio ≥2.0;c,e with an average HER2 copy number 
≥4.0 signals/cell 
Dual-probe HER2/CEP17 ratio ≥2.0;c,e with an average HER2 
copy number <4.0 signals/cell 
Dual-probe HER2/CEP17 ratio < 2.0;c,e with an average HER2 
copy number ≥6.0 signals/cell 
 
4) 
No prior treatment for primary invasive adenocarcinoma of the breast such as irradiation, 
chemotherapy, hormonal therapy, immunotherapy, investigational therapy or surgery other than 
the anthracycline and cyclophosphamide chemotherapy with or without 5-fluorouracil. Treatment 
for ductal carcinoma in situ is allowed, such as surgery, hormonal therapy and radiotherapy. 
 
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: 
• 
ANC ≥ 1500 cells/µL 
• 
WBC counts > 2500/µL 
• 
Lymphocyte count ≥ 300/µL 
• 
Platelet count ≥ 100,000/µL;  
• 
Hemoglobin ≥ 9.0 g/dL 
• 
Total bilirubin ≤ 1.5 × upper limit of normal (ULN) with the following exception: 
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be 
enrolled. 
• 
AST and ALT ≤ 3.0 × ULN  
 

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• 
Alkaline phosphatase ≤ 2.5 × ULN  
• 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min on the basis of the 
Cockcroft-Gault glomerular filtration rate estimation: 
(140 − age) × (weight in kg) × (0.85 if female) 
72 × (serum creatinine in mg/dL) 
• 
INR and aPTT ≤ 1.5 × ULN 
This applies only to patients who do not receive therapeutic anticoagulation; patients 
receiving therapeutic anticoagulation (such as low-molecular-weight heparin or 
warfarin) should be on a stable dose. 
 
8)    
Men or women 18 years of age or older. 
 
9) 
Women of childbearing potential must be using an adequate method of contraception to avoid 
pregnancy throughout the study and for up to 6 months after the last dose of investigational 
product in such a manner that the risk of pregnancy is minimized. Men on study and for at least 
6 months after the last dose of nab-paclitaxel also must be using contraception. Women of 
childbearing potential (WOCBP) are women who have not been postmenopausal greater than 1 
year or undergone a hysterectomy and/or bilateral oophorectomy. 
 
10) 
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. 
 
11)  
Classified as having insufficient tumor shrinkage by imaging (<80% shrinkage after 4 cycles of 
anthracycline-based chemotherapy based upon diagnostic imaging.  
 
 
4.2 
Exclusion Criteria 
1) Women who are pregnant or breast-feeding.  
 
2) Known metastatic disease 
 
3) Disease free of prior malignancy for < 5 years with the exception of curatively treated basal cell 
carcinoma of the skin, carcinoma in situ of the cervix, or transitional cell carcinoma. 
 
4) Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 
 
5) Has had major surgery within 21 days before Cycle 1, Day 1 
 
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 

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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) History or risk of autoimmune disease, including but not limited to systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, 
Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, 
vasculitis, or glomerulonephritis 
– Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible. 
– Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be 
eligible. 
– Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted 
provided that they meet the following conditions: 
Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular 
manifestations 
Rash must cover less than 10% of body surface area (BSA) 
Disease is well controlled at baseline and only requiring low potency topical steroids 
(e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 
0.05%, aclometasone dipropionate 0.05%) 
No acute exacerbations of underlying condition within the last 12 months (not requiring 
psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors; high potency or oral steroids) 
 
 (See Appendix F for a more comprehensive list of autoimmune diseases) 
 
11) Known to be human immunodeficiency virus positive 
12) Patients with prior allogeneic stem cell or solid organ transplantation 
13) History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in 
the radiation field (fibrosis) is permitted. 
14) Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] 
test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved 
HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B 

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core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) 
antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 
15) Active tuberculosis 
16) Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation 
that such a live, attenuated vaccine will be required during the study. 
Influenza vaccination should be given during influenza season only (approximately October to 
March).  Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 
weeks prior to Cycle 1, Day 1 or at any time during the study. 
17) Treatment with systemic immunostimulatory agents (including but not limited to interferons or IL-
2) within 4 weeks or five half-lives of the drug, whichever is shorter, from Cycle 1 Day 1. 
18) Treatment with systemic corticosteroids or other systemic immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 1 week prior to 
Cycle 1 Day 1, or anticipated requirement for systemic immunosuppressive medications during 
the trial. Patients who have received acute, low-dose, systemic immunosuppressant medications 
(e.g., dexamethasone prior to the anthracycline-based chemotherapy for nausea) may be 
enrolled in the study. 
 
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed. 
 
19) 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 
 
20) Known hypersensitivity to any of the components of atezolizumab or nab-paclitaxel 
 
21) History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
 
 
 
 

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5.0 TREATMENT PLAN 
 
NOTE: MPDL3280=Atezolizumab 
5.1 
Study Design 
In this study, we intend to assess the ability of the addition of atezolizumab to nab-paclitaxel 
administered in the neoadjuvant setting to increase response rates in patients with TNBC that are 
identified as non-responders to standard chemotherapy.   
Patients may be identified as part of the MD Anderson triaging protocol as previously described.  
Patients will be administered atezolizumab in combination with nab-paclitaxel after which they will 
undergo surgery.  Following surgery, patients will continue on atezolizumab for an additional 3 months 
to complete 6 months total of atezolizumab therapy.   
The trial will allow us to test the hypothesis that among patients with TNBC who were non-responders 
to initial anthracycline and cyclophosphamide chemotherapy, the combination of atezolizumab and nab-
paclitaxel administered in the neoadjuvant setting will increase pCR rates.  The trial’s primary endpoint 
is to evaluate the pCR and RCB-I rates in patients treated with atezolizumab in combination with nab-
paclitaxel with a secondary endpoint of determining 3 year DFS. 

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Atezolizumab will be administered at 1200mg IV every 3 weeks (q3w x 4 doses) for 12 weeks in the 
neoadjuvant setting in combination with nab-paclitaxel (100 mg/m2 IV weekly for 12 weeks).  
Within 4 weeks after surgery, patients will start another 4 cycles of atezolizumab (1200mg IV q3w) in the 
adjuvant setting to complete a total of 8 cycles of treatment with MPDL3280A.  
Thirty-seven patients will be enrolled in this study.  
Due to scheduling, study visits may occur +/- 3 days from the required time point. It may be necessary 
to perform assessments at unscheduled time points if deemed clinically necessary by the investigator. 
All patients will undergo definitive breast surgery after four cycles (12 weeks) of atezolizumab + nab-
paclitaxel study treatment. Surgery will be expected within 6 weeks of the completion of neoadjuvant 
chemotherapy. 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 response (defined per protocol) by breast-specific pathologists at the MD 
Anderson Cancer Center. 
Tissue analysis will be performed on biologic specimens from patients enrolled on the phase II portion 
of the parent study and receiving the combination of atezolizumab with nab-paclitaxel in the neoadjuvant 
setting. Biopsies prior to and at the end of the anthracycline portion of the parent clinical trial are already 
being collected as part of the parent protocol 2014-0185. Ideally up to 4 additional core biopsies (passes) 
will be collected at the same time point for the purposes of this trial (2014-1043), provided enough 
material is available.   
A portion of the surgical specimen at the time of the definitive surgery will be collected for further 
correlative studies. Any evaluable or measurable disease must be documented at screening and 
reassessed at each subsequent tumor evaluation by scheduled ultrasound.  Ultrasounds will be done 
prior to initiation of therapy and at 6 weeks while on study therapy +/- 1 week as standard of care.   
If there is increase in size of the mass on ultrasound as defined by: 
The sum of perpendicular diameters of the index lesion in addition to the sum of the perpendicular 
diameters of a new lesion when compared to the baseline measurement at the entry onto this study as 
measured at 2 separate time points at least 4 weeks apart, the patient will come off study and move 
forward with surgery. 
 
If there is growth, but less than 25% as defined above, then a second ultrasound will be ordered at 4 
weeks +/- 3 days to evaluate for progression.  If Progression at that time is identified, the patient will go 
to surgery, however the study medication will continue as defined in the protocol after surgery. 
The treating physician can order ultrasounds sooner at their discretion if there are concerns of 
progression of disease.  
Should growth be observed on the breast ultrasound performed per standard of care after about 6 weeks 
of study therapy, a biopsy can be performed. If the disease is shown to have increased immune infiltrate 
the patient can continue on therapy.   
If a new site of disease or lymph node is identified and confirmed by biopsy to be a new sight of 
carcinoma and not immune-infiltrate, that patient would be considered to have progression of disease 
and the patient would discontinue study treatment. 

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Therapy will be discontinued should the treating physician determine that the response is consistent 
with progression of disease.  
Laboratory assessments will include the following: 
• 
Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential 
[neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other cells], and platelet count) 
• 
Serum chemistries (glucose, BUN, creatinine, sodium, potassium, magnesium, chloride, 
bicarbonate, calcium, phosphorus, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total 
protein, and albumin) 
• 
Coagulation (aPTT and INR) 
• 
Pregnancy test (for women of childbearing potential, including women who have had a tubal 
ligation) x 1 as part of the screening process for eligibility of this study. 
• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) 
• 
Thyroid function testing (TSH, free T3, and free T4),  
• 
Epstein-Barr virus (EBV) serology (EBNA IgG), Hepatitis B virus (HBV) serology (HBsAg, 
antibodies against HBsAg, hepatitis B core antigen), and HCV serology (anti-HCV) as clinically 
indicated 
– 
HBV DNA test is required for patients who have known positive serology for anti-HBc  
– 
HCV RNA test is required for patients who have known positive serology for anti-HCV 
Please see study calendar in Section 8.0 for full details of scheduling of laboratory assessments. 
5.2 
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, 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. 
Research Electronic Data Capture (REDCap) must capture the concurrent use of all other drugs, over-
the-counter medications, or alternative therapies including herbal supplements. 
 
 
 
 
5.2.1 
Concomitant Therapy 
Concomitant therapy includes any prescription medications or over-the-counter preparations used by a 
patient between the 7 days preceding the screening evaluation and the treatment discontinuation visit. 
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or cimetidine or another H2 receptor antagonist, as 

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per standard practice.  Serious infusion-associated events manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be 
managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and β2-
adrenergic agonists; see Appendix H). 
Systemic corticosteroids and TNFα inhibitors may attenuate potential beneficial immunologic effects of 
treatment with atezolizumab but may be administered at the discretion of the treating physician.  If 
feasible, alternatives to corticosteroids should be considered.  Premedication may be administered for 
Cycles ≥ 2 at the discretion of the treating physician.  The use of inhaled corticosteroids and 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical 
insufficiency is allowed.  Megestrol administered as appetite stimulant is acceptable while the patient 
is enrolled in the study.   
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or therapeutic 
anticoagulation therapy (such as low-molecular-weight heparin or warfarin at a stable dose level), or 
other allowed maintenance therapy (see Section 5.2) should continue their use. Males and females of 
reproductive potential should use highly effective means of contraception.  
5.2.2 
Excluded Therapy 
Any concomitant therapy intended for the treatment of cancer, whether health authority-approved or 
experimental, is prohibited in the neoadjuvant setting.  This includes but is not limited to the following: 
• 
Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational agents, or herbal 
therapy (except for maintenance therapies outlined in Section 5.2) 
It is strongly recommended that:  
• 
Traditional herbal medicines not be administered because the ingredients of many herbal 
medicines are not fully studied and their use may result in unanticipated drug-drug interactions 
that may cause, or confound assessment of, toxicity 
• The use of a RANKL inhibitor (denosumab) be discontinued during the study; this agent could 
potentially alter the activity and the safety of atezolizumab 
 
Initiation or increased dose of granulocyte colony-stimulating factors (e.g., granulocyte 
colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, and/or pegfilgrastim)  
should only be done for rescue from clinically significant neutropenia and not routinely dosed between 
nab-paclitaxel weekly dosing, instead nab-paclitaxel should be delayed and dose reduced as 
discussed in section  6.2.2   
Patients are not allowed to receive immunostimulatory agents, including but not limited to IFN-α, IFN-γ, 
or IL-2, during the entire study.  These agents, in combination with atezolizumab, could potentially 
increase the risk for autoimmune conditions. 
Patients should also not be receiving immunosuppressive medications, including but not limited to 
cyclophosphamide, azathioprine, methotrexate, and thalidomide.  These agents could potentially alter 
the activity and the safety of atezolizumab.  Systemic corticosteroids and anti-TNFα agents may 

30 
 
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attenuate potential beneficial immunologic effects of treatment with atezolizumab but may be 
administered at the discretion of the treating physician.  If feasible, alternatives to these agents should 
be considered. 
In addition, all patients (including those who discontinue the study early) should not receive other 
immunostimulatory agents for 10 weeks after the last dose of atezolizumab. 
Any patient anticipated to receive administration of a live, attenuated vaccine within 4 weeks before 
Cycle 1, Day 1 or anticipation that such a live, attenuated vaccine will be required during the study 
is excluded 
– 
Influenza vaccination should be given during influenza season only (approximately October to 
March).  Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 
weeks prior to Cycle 1, Day 1 or at any time during the study. 
 
5.3 
Duration of Study 
The study is expected to complete accrual within 2 years from study initiation. The duration of 
chemotherapy treatment per subject will be approximately 6 months on atezolizumab + nab-paclitaxel 
(3 months in the neoadjuvant setting) followed by 3 months of atezolizumab in the adjuvant setting.  As 
part of the parent protocol, patients will be followed for survival endpoints for 3 years. 
5.4 
Progression While on Study 
Subjects who progress while on atezolizumab + nab-paclitaxel will automatically be considered non-
responders to atezolizumab + nab-paclitaxel 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 that is in the patient’s 
best interest.  Progression will be defined as a greater than 25% of the sum of perpendicular diameters 
of the index lesion in addition to the sum of the perpendicular diameters of a new lesion when compared 
to the baseline measurement at the entry onto this study as measured at 2 separate time points at least 
4 weeks apart. 
5.5 
Subject Withdrawal/Discontinuation Criteria 
5.6 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  In addition, 
the investigator has the right to withdraw a patient from the study at any time.  Reasons for withdrawal 
from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator determines may jeopardize the patient’s safety if he or 
she continues in the study 
• 
Investigator determines it is in the best interest of the patient 
• 
Patient non-compliance 
• 
Pregnancy 
 

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Every effort should be made to obtain information on patients who withdraw from the study.  The 
primary reason for withdrawal from the study should be documented in REDCap. 
However, patients will not be followed for any reason after consent has been withdrawn.  Patients who 
withdraw from the study prior to surgery will be replaced. 
 
5.7 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Toxicity that jeopardizes the patient’s safety in the opinion of the treating physician and/or 
principle investigator 
• 
Progression of disease 
 
The primary reason for study treatment discontinuation should be documented in REDCap.  Patients 
who discontinue study treatment prior to surgery will be replaced. 
 
5.8 
Study and Site Discontinuation 
The Supporter has the right to terminate this study at any time.  Reasons for terminating the study may 
include, but are not limited to, the following: 
• 
The incidence or severity of AEs in this or other studies indicates a potential health hazard to 
patients. 
 
The Supporter will notify the investigator if the Supporter decides to discontinue the study.   
The Supporter has the right to close a site at any time.  Reasons for closing a site may include, but are 
not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline for Good 
Clinical Practice (GCP) 
• 
No study activity (i.e., all patients have completed and all obligations have been fulfilled) 
 
Removal from study 
 
Data will be collected until 3 years post the final cycle of study treatment is completed as part of their 
participation in the parent trial. The patient will then come off study with regards to data collection. 
 
Should a patient withdraw consent, then the patient will be removed from study at that time and no 
further data will be collected. 
 

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6.0 EXPECTED TOXICITIES AND DOSING DELAYS/MODIFICATIONS 
6.1 
General Plan to Manage Safety Concerns 
Measures will be taken to ensure the safety of patients participating in this trial, including the use of 
stringent inclusion and exclusion criteria and close monitoring.   
Eligibility Criteria 
Eligibility criteria were selected to guard the safety of patients in this trial.  Results from the nonclinical 
toxicology studies with atezolizumab, as well as the nonclinical/clinical data from other PD-L1/PD-1 
inhibitors, were taken into account. 
Monitoring 
Safety will be evaluated in this study through the monitoring of all serious and non-serious AEs, 
defined and graded according to NCI CTCAE v4.0.  Patients will be assessed for safety (including 
laboratory values) according to the study calendar. If a dose is held due to toxicity, a patient may 
resume treatment from the treatment cycle that was held, once the toxicity has resolved and/or as 
clinically indicated. Patients will be followed for safety for 30 days following the last dose of study 
treatment or until receipt of another anticancer therapy, whichever comes first.   
General safety assessments will include serial interval histories, physical examinations, and specific 
laboratory studies, including serum chemistries and blood counts (see study calendar for the list and 
timing of study assessments).  All serious adverse events (SAEs) and protocol-defined events of 
special interest (see Section 10.4.2.11) will be recorded including those considered unrelated or 
expected).  In addition, the investigators will review and evaluate observed AEs on a regular basis. 
Patients who have an ongoing study treatment−related AE upon study completion or at discontinuation 
from the study will be followed until the event has resolved to baseline grade, the event is assessed by 
the investigator as stable, new anticancer treatment is initiated, the patient is lost to follow-up, the 
patient withdraws consent, or until it has been determined that study treatment or participation is not 
the cause of the AE. 

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6.1.1 
Administration of first and subsequent infusions of Atezolizumab 
First Infusion 
Subsequent Infusions 
• 
No premedication is administered 
• 
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before starting 
infusion. 
• 
Infuse (one vial in 250 mL NaCl) over 60 (± 15) 
minutes. 
• 
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) during the infusion at 15, 30, 45, 
and 60 minutes (± 5-minute windows are 
allowed for all timepoints), and if clinically 
indicated. 
• 
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) at 30 (± 10) minutes after the 
infusion, and if clinically indicated. 
• 
Patients will be informed about the possibility of 
delayed post-infusion symptoms and instructed 
to contact their study physician if they develop 
such symptoms. 
• 
If patient experienced infusion-related 
reaction during any previous infusion, 
premedication with antihistamines may be 
administered for Cycles ≥ 2 at the discretion 
of the treating physician. 
• 
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before 
starting infusion. 
• 
If the patient tolerated the first infusion well 
without infusion-associated adverse events, 
the second infusion may be administered 
over 30 (± 10) minutes. 
• 
If the patient had an infusion-related reaction 
during the previous infusion, the subsequent 
infusion must be administered over 60 (± 15) 
minutes. 
• 
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) during the infusion if clinically 
indicated.  
• 
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) 30 (± 10) minutes after the 
infusion, and if clinically indicated. If no 
reaction occurs, continue subsequent 
infusions over 30 (± 10) minutes with same 
schedule for recording vital signs. 
 
 
 

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6.1.2 
Management of Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice.  Additional tests, such as autoimmune serology or biopsies, 
may be used to determine a possible immunogenic etiology. 
Although most immune-mediated adverse events observed with immunomodulatory agents have been 
mild and self-limiting, such events should be recognized early and treated promptly to avoid potential 
major complications.  Discontinuation of atezolizumab may not have an immediate therapeutic effect 
and, in severe cases, immune mediated toxicities may require acute management with topical 
corticosteroids, systemic corticosteroids, or other immunosuppressive agents. 
The primary approach to Grade 1-2 immune-mediated adverse events is supportive and symptomatic 
care with continued treatment with atezolizumab; for higher grade immune mediated adverse events, 
atezolizumab should be held and oral/parenteral steroids administered.  Recurrent Grade 2 immune 
mediated adverse events may also mandate holding atezolizumab or the use of steroids.  
Consideration for benefit-risk balance should be made by the investigator, with consideration of the 
totality of information as it pertains to the nature of the toxicity and the degree of clinical benefit a given 
patient may be experiencing prior to further administration of atezolizumab.  Atezolizumab should be 
permanently discontinued in patients with life-threatening immune mediated adverse events. 
See the Atezolizumab Investigator’s Brochure for details on management of gastrointestinal, 
dermatologic, endocrine, pulmonary toxicity, hepatotoxicity, potential pancreatic or eye toxicity and 
other immune-mediated adverse events.   
 
 
 

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6.1.3 
Nab-Paclitaxel Dose Modification and Management of Specific Adverse Events 
Patients who experience severe neutropenia (neutrophil < 500 cells/mm3 for a week or longer) or 
severe sensory neuropathy should have their nab-paclitaxel dosage reduced to 75 mg/m2 for 
subsequent cycles.  For recurrence of severe neutropenia or severe sensory neuropathy, additional 
dose reduction should be made to 50 mg/m2.  For Grade 3 sensory neuropathy, hold treatment until 
resolution to Grade 1 or 2 followed by a dose reduction for all subsequent cycles. 
If Grade 3 hepatic toxicity occurs at any time, the nab-paclitaxel dose should be permanently reduced 
to 75% of the starting dose (i.e., to 75 mg/m2).  Nab-paclitaxel will be permanently discontinued for 
Grade 4 hepatic toxicity. 
If nab-paclitaxel is withheld, hepatic values must recover to Grade </= 1 within 3 weeks or nab-
paclitaxel treatment will be discontinued. 
The investigator should make all efforts to exclude malignant disease progression as a cause of liver 
enzyme derangement. 
6.2 
Nab—PACLITAXEL DOSING 
6.2.1 
Dosing 
Nab-paclitaxel will be dosed at 100 mg/m2 IV weekly x 12 weeks.  Known side effects of nab-
paclitaxel identified in the MDACC research database last updated 4/22/14 include: 
Nab-paclitaxel Side Effects 
 
Common (occurring in more than 20% of patients) 
abnormal EKG  
hair loss (partial or total) 
nausea  
diarrhea 
low blood cell counts (red, 
white, platelets) 
abnormal liver test (possible 
liver damage) 
nerve damage (loss of 
sensory function)  
weakness  
pain (muscle, joint) 
infection  
 
 
 

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Occasional (occurring in 3-20% of patients) 
swelling 
low blood pressure 
(possible 
dizziness/fainting)  
high blood pressure 
chest pain 
sudden stopping of the 
heart 
fast heartbeat 
blood clots in a vein 
(possible pain, swelling, 
and/or redness) 
vomiting  
mouth blisters/sores  
abnormal liver tests (possible 
yellowing of the skin and/or 
eyes)  
nerve damage (possible 
numbness, pain, and/or loss 
of motor function) 
vision problems  
abnormal kidney test 
(possible kidney damage)  
difficulty breathing  
blood clots in the lung 
(possible failure to breathe)  
cough 
allergic reaction (possible 
chest pain, difficulty 
breathing, flushing, and/or 
low blood pressure) 
 
 
Rare but serious (occurring in fewer than 3% of patients 
irregular/slow heartbeat 
decreased blood supply to 
the heart 
heart attack 
heart failure 
severe heart problems  
stroke and/or temporary 
stroke symptoms 
fever 
hand-foot syndrome (palms 
of hands/soles of feet having 
pain, swelling, and blistering)  
severe sunburn-like rash at 
site of previous radiation 
(called radiation recall) 
inflammation of the pancreas 
(possible abdominal pain) 
hole in the intestines 
(possibly leaking contents 
into the abdomen) 
dehydration 
intestinal blockage 
paralysis of the intestines 
blurred vision 
damage to an eye nerve 
 collapsed lung (possible 
difficulty breathing) 
swelling under the central 
part of the eye (vision loss)  

37 
 
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nerve damage (affecting 
movement) 
very severe blistering skin 
disease (with ulcers of the 
skin and digestive tract) 
very severe blistering skin 
disease (loss of large 
portion of skin) 
decreased blood flow to part 
of the bowel (possibly 
causing death of tissue) 
lung inflammation (possible 
difficulty breathing) 
lung damage at the site of 
prior radiation 
 
The following side effects were reported with a similar drug (paclitaxel) and may also be caused by 
nab-paclitaxel: 
decreased brain function due 
to liver damage 
inflammation at the site of 
previous tissue death 
liver damage and/or failure 
lung damage (possible 
difficulty breathing) 
tissue death at the injection 
site caused by drug leakage 
 
6.2.2 
Nab-paclitaxel dose reductions 
Patients may proceed with nab-paclitaxel dosage for ANC >/= 1000 /mm3, platelets >75, 
Hemoglobin >8.0.  
Dosing of nab-paclitaxel should be held for 1 week and dosing can resume once levels reach the 
above specifications with a dose-reduction and/or granulocyte-stimulating factor in the subsequent 
cycles are allowed at the Investigator’s discretion. 
Should the patient experience dose-limiting toxicities from the nab-paclitaxel felt to require a dose-
reduction of nab-paclitaxel by the treating physician and/or per specifications in the package insert for 
nab-paclitaxel, should be dose reduced to: 
Level 0= 100 mg/m2 
Level -1 = 90 mg/m2 
Level -2 = 80 mg/m2 
Level -3 = 70 mg/m2 
If further dose reductions are required after a level of -3 despite growth factor support, patient should 
be discontinued from the nab-paclitaxel and per investigator discretion can continue with the 
investigational intervention, surgery and the post-surgery scheduled infusions. 

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Patients who experience severe neutropenia or severe sensory neuropathy should have their nab-
paclitaxel dosage reduced to 75 mg/m2 for subsequent cycles as detailed in section 6.1.3.  For 
recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be 
made to 50 mg/m2.  For Grade 3 sensory neuropathy, hold treatment until resolution to Grade 1 or 2 
followed by a dose reduction for all subsequent cycles. 
For dose reductions based on hepatic toxicity see Section 6.1.3. 
Patients experiencing > grade 2 non-hematologic drug toxicity that is unresponsive to symptomatic 
support may undergo dose reduction of the responsible drug(s) as indicated. Other drugs within the 
regimen can be continued at full dose per the treating physician’s discretion. 
 
 

39 
 
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6.2.3 
Study Drug: Atezolizumab 
Once marketing authorization is received commercial atezolizumab will be used and will not be 
provided by Genentech for “on-label” studies.  For studies done before marketing authorization and/or 
"out of label", atezolizumab will be provided free of charge by Genentech but switched to commercial 
drug once marketing authorization is received.  Genentech will replace any atezolizumab drug that is 
not reimbursed.  For studies done “out of label,” atezolizumab will be provided free of charge by 
Genentech.  The Investigator of the study will ensure maintenance of complete and accurate records 
of the receipt, dispensation, and disposal or return of all study drug in accordance with 21 Code of 
Federal Regulations (CFR), Part 312.57 and 312.62, and Genentech requirements. 
6.2.3.1 
Formulation 
 
The atezolizumab drug product is provided in a single-use, 20-cc USP/Ph. Eur. Type 1 glass vial as a 
colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution intended for IV administration.  
The vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution but may contain more than 
the stated volume to enable delivery of the entire 20 mL volume.  The atezolizumab drug product is 
formulated as 60 mg/mL atezolizumab in 20 mM histidine acetate, 120 mM sucrose, 0.04% 
polysorbate 20, pH 5.8. 
Atezolizumab must be refrigerated at 2°C − 8°C (36°F − 46°F) upon receipt until use.  Atezolizumab 
vials should not be used beyond the expiration date provided by the manufacturer.  No preservative is 
used in the atezolizumab drug product; therefore, each vial is intended for single use only.  Discard 
any unused portion of drug left in a vial.  Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. 
For further details, see the atezolizumab Investigator’s Brochure. 
6.2.3.2 
Dosage, Administration, and Storage 
The dose level of atezolizumab to be tested in this study is 1200 mg (equivalent to an average body 
weight−based dose of 15 mg/kg) administered by IV infusion every 3 weeks (21 [± 2] days).  
atezolizumab will be delivered in infusion bags with IV infusion lines that have product contacting 
surfaces of polyvinyl chloride (PVC) or polyolefin and 0.2 µm in-line filters (filter membrane of 
polyethersulfone [PES]).  No incompatibilities have been observed between atezolizumab and PVC or 
polyolefin infusion materials (bags or infusion lines).  
Administration of atezolizumab will be performed in a setting with emergency medical facilities and 
staff who are trained to monitor for and respond to medical emergencies. 
The initial dose of atezolizumab will be delivered over 60 (± 15) minutes.  If the first infusion is 
tolerated without infusion-associated AEs, the second infusion may be delivered over 30 (± 10) 
minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered over 30 
(± 10) minutes.  For the first infusion, the patient’s vital signs (heart rate, respiratory rate, blood 

40 
 
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pressure, and temperature) should be determined within 60 minutes before, during (every 15 [± 5] 
minutes), and 30 (± 10) minutes after the infusion.  For subsequent infusions, vital signs will be 
collected within 60 minutes before and within 30 minutes after the infusion.  Vital signs should be 
collected during the infusion only if clinically indicated.  Patients will be informed about the possibility 
of delayed post-infusion symptoms and instructed to contact their study physician if they develop such 
symptoms. 
No premedication will be allowed for the first dose of atezolizumab.  Premedication may be 
administered for Cycles ≥ 2 at the discretion of the treating physician.  The management of IRRs will 
be according to severity as follows: 
• 
In the event that a patient experiences a mild (NCI CTCAE Grade 1) IRR, the infusion rate should 
be reduced to half the rate being given at the time of event onset.  Once the event has resolved, 
the investigator should wait for 30 minutes while delivering the infusion at the reduced rate.  If 
tolerated, the infusion rate may then be increased to the original rate. 
• 
In the event that a patient experiences a moderate IRR (NCI CTCAE Grade 2) or flushing, fever, 
or throat pain, the infusion should be immediately interrupted and the patient should receive 
aggressive symptomatic treatment.  The infusion should be restarted only after the symptoms 
have adequately resolved to baseline grade.  The infusion rate at restart should be half of the 
infusion rate that was in progress at the time of the onset of the IRR. 
• 
For severe or life-threatening IRRs (NCI CTCAE Grade 3 or 4), the infusion should be stopped 
immediately, and aggressive resuscitation and supportive measures should be initiated.  Patients 
experiencing severe or life-threatening IRRs will not receive further infusion and will be further 
managed as clinically indicated until the event resolves. 
For further details on the storage and preparation of atezolizumab, see the Pharmacy Manual and the 
Investigator’s Brochure. 
 
 

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7.0 CORRELATIVE STUDIES 
Tumor tissue and peripheral blood will be collected prior to beginning therapy with atezolizumab and 
nab-paclitaxel and at selected timepoints on treatment as well as at the time of surgery.  Residual 
sample material available after completion of the designated analyses may be used in the future for 
identification of additional predictive biomarkers or to enhance understanding of disease biology.  If 
biomarker samples are drawn but study drug(s) is not administered, samples will be retained.  A 
description of each assay system is described below. 
7.1 Tissue 
Tissue samples will be obtained prior to beginning atezolizumab and nab-paclitaxel (core biopsies) 
and at the time of surgical resection.  Prior to beginning atezolizumab and nab-paclitaxel, at least two 
core biopsies will be obtained; one to be processed fresh to assess for TIL by flow cytometry, and the 
second to be formalin fixed paraffin embedded (FFPE) for assessment of the immune cell infiltrate and 
PD-L1 expression by immunohistochemistry and immunofluorescence.  At the time of surgical 
excision, the attending breast pathologist presenting in the pathology lab to gross the resected 
specimen will determine if there is enough residual tumor available to provide a fresh specimen for TIL 
analysis.  FFPE slides from the resected surgical specimen will also be obtained. 
If available up to 10 tissue slides from any one of the research biopsies or surgical sample will be sent 
to Genentech for the following assessments: 
• 
Assessment of PDL1 tumor protein expression 
• 
Evaluation of intratumoral CD8+ T cells as potential favorable prognostic factor in TNBC 
• 
Analysis of tumor-derived RNA expression (Fluidigm or Nanostring) 
 
7.1.1 Characterization of TIL – Fresh tumor specimens 
Fresh tumor tissues will be used to generate a single cell suspension to evaluate the immune cell 
infiltrate and expression of T cell co-stimulatory/inhibitory molecules by flow cytometry.  The following 
antibodies will be used:  aqua live/dead, CD3, CD4, CD8, CD25, and CD127 to identify effector and 
regulatory T cells.  CD45, CD11c, CD14 and CD335 will be used to identify myeloid cells, dendritic 
cells, monocytes and natural killer cells respectively.  Antibodies to evaluate T-cell co- 
stimulatory/inhibitory molecules will include but may not be limited to OX-40, GITR, 4-1BB, ICOS, PD-
1 and CTLA-4. 
7.1.2 Characterization of TIL–Formalin-fixed, paraffin-embedded (FFPE) specimens. 
A recent report on predictive correlates of response to the atezolizumab antibody in cancer patients 
showed that patients with tumors expressing PD-L1 in tumor infiltrating immune cells were more likely 
to respond to therapy.23  This correlative work was performed on tumors obtained from patients with 
non-small cell lung cancer, melanoma, renal cell carcinoma, head and neck squamous cell carcinoma, 
gastric cancer, colorectal cancer and pancreatic cancer although preliminary work presented at the 
2014 San Antonio Breast Cancer symposium demonstrated similar results).  PD-L1 expression in pre- 
and post-treatment specimens will be determined by immunohistochemistry using an anti-PD-L1 
antibody.      

42 
 
[Type here] 
 
 
To evaluate for co-localization of PD-L1 and select tumor-infiltrating immune cells, multispectral, 
multiplexed immunofluorescence will be performed using tyramide signal amplification (TSA) 
technology.  TSA signal molecules are covalently bound to tyrosine residues in proteins proximal to 
the target allowing for the resolution and stability required for multiplex assays.  The panel includes 
antibodies against CD3 (T cells), CD20+ (B cells), CD163 (macrophages), and CD11c (dendritic cells).  
In addition, the panel includes an antibody against PD-L1 and an antibody against cytokeratin to 
differentiate tumor cells.  Briefly, slides will be stained with the indicated antibodies after which 
multispectral imaging will be performed using the Vectra Automated Quantitative Pathology imaging 
System and the Lamina Multilabel Slide Scanner (Perkin Elmer).  InForm image analysis software will 
be used to quantify the expression of the various immune cells comprising the infiltrate both in the 
tumor and the surrounding stroma. 
 
7.1.3 
Characterization of the tumor-immune microenvironment – Formalin-fixed, 
paraffin-embedded (FFPE) specimens. 
To better understand the immune and molecular features that are most critical in promoting resistance to 
neoadjuvant therapy, we deconvoluted gene expression data from bulk whole transcriptomic sequencing 
(RNAseq) of pre-treatment tumor biospecimens from 99 consecutive patients with TNBC receiving 
neoadjuvant therapy. Interestingly, lower CD4+ T-cell infiltration was associated with resistance to 
neoadjuvant therapy (p=0.0078) and there was a trend towards an association between higher macrophage 
infiltration and resistance to neoadjuvant (p=0.064). Of note, the degree of CD8+ T-cell infiltration was 
not associated with resistance to neoadjuvant therapy in this cohort of patients (p=0.14). However, 
through the use of multiplex immunofluorescence, we demonstrated that increased spatial separation of 
CD8+ T-cells from tumor cells was associated with resistance to NAT (median 32 µm [pCR] vs 42 µm 
[non-pCR]). Collectively, these data suggest that the precise phenotypic composition of TILs along with 
their degree of interaction with tumor cells may further help predict resistance to NAT in TNBC and 
inform the development of innovative clinical trials for patients with NAT-resistant TNBC. 
 
Building on our preliminary data demonstrating that the specific phenotype of TILs (RNA-based 
predictions) and their interactions with tumor cells are a critical determinant of response to NAT in 
TNBC, we will further characterize the immune cell subpopulations, their activation states, and 
interactions with tumor cells using the Nanostring GeoMx Digital Spatial Profiler (DSP) in collaboration 
with the Department of Translational Molecular Pathology at MD Anderson. The Nanostring GeoMx 
DSP is a cutting edge high-plex protein-based assay which enables simultaneous quantification of up to 
96 protein targets with spatial resolution. In close collaboration with the Department of Translational 
Molecular Pathology, we have put together a list of targets spanning immune cell morphology and 
activation markers, immune-oncology drug targets, tumor cell survival pathway markers, as well as 
phosphorylated protein targets for targetable kinases known to influence anti-tumor immunity (PI3K and 
MAPK pathways). Four µm sections will be stained using Nanostring standard protocol with the 
following morphology biomarkers: pancytokeratin (CK), CD45, CD3 and Syto13; and the DSP Human 
Immuno-oncology Protein panels and signaling pathway panels (Modules: Immune Cell Profiling Core, 
IO Drug Target, Immune Activation Status, Immune Cell Typing, Pan-Tumor, Cell Death, PI3K/AKT 
Signaling, MAPK Signaling) (88 antibodies). We will select up to 6 regions of interest (ROI) for each 

43 
 
[Type here] 
 
 
tumor tissue sample containing tumor and immune cells, we will segment each ROI in up to 3  areas of 
illumination (AOI) representing the different tumor and immune cells, based in the expression of the 
morphology biomarkers  (Malignant cells, CK+; T-cells, CD45+CD3+; and other immune cells, 
CD45+CD3-). For each run we will use appropriate positive and negative control tissue. Indexing oligos 
will be released by the Sequential UV light exposure of each AOI, and will be quantified on NanoString's 
nCounter® system. Heat maps and box plots will be used to visualize protein expression patterns. 
Promising targets will be validated using chromogenic immunohistochemistry. 
 
 
 
7.2 Peripheral blood mononuclear cells (PBMC) 
PBMC samples will be collected prior to beginning atezolizumab + nab-paclitaxel, midway through 
treatment (around week 7), at the time of surgery and at completion of atezolizumab therapy  
 
7.2.1 Immunophenotyping.   
To further explore findings from prior trials evaluating atezolizumab, that showed a non-significant 
increase in activated proliferating CD8+ T cells (CD8+HLA-DR+Ki67+), PBMC will be analyzed by flow 
cytometry for CD3, CD8, HLA-DR and Ki-67.  In addition, the proportion of specific immune cells 
including lymphocyte subsets as well as expression levels of T cell co-stimulatory/inhibitory markers 
will be quantified in PBMC.  Analyses may include, but not necessarily be limited to, the proportion of 
T, B and NK cells, granulocytes, the proportion of memory and effector T cell subsets, and expression 
of levels of PD-1, PD-L1, other B7 family members and ICOS.   
 
7.2.2 T cell repertoire analysis 
Lack of diversity of the peripheral T cell compartment has been shown to correlate with poor overall 
survival in metastatic breast cancer.24 It has therefore been suggested that a diverse and activated 
immune environment is better able to eradicate tumor than a skewed repertoire of naïve and tolerized 
T cells.  In order to explore whether a diverse T cell repertoire is predictive of response to therapy, 
next generation, high-throughput DNA sequencing will be performed on DNA isolated from peripheral 
blood to quantitate the composition of the T cell repertoire prior to, during and at completion of therapy 
with atezolizumab and nab-paclitaxel. 
 
7.2.3 Serum 
Serum samples will be collected prior to beginning atezolizumab + nab-paclitaxel, midway through 
treatment (around week 7), at the time of surgery and at completion of atezolizumab therapy.  
Polyfunctional cytokine responses will be assessed using the Meso Scale Discovery (MSD) platform 
which has the capability to simultaneously measure multiple analytes from a single sample.  A MSD V-
plex platform that measures 40 analytes (including but not limited to:  IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-
6, IL-10, IL-12, IL-15, IL-17, IL-18 and) will be used.   

44 
 
[Type here] 
 
 
7.2.3.1 Storage of Specimens 
All PBMC and serum specimens will either be used immediately to perform the designated assay or 
will be stored in Dr. Mittendorf’s laboratory.  PBMC will be stored in liquid nitrogen, serum will be 
stored at -80º.  Fresh tissue samples will be placed in RPMI then processed immediately for TIL 
analysis by flow cytometry.  FFPE blocks will be maintained until time at which assays will be 
performed.  To perform multiplex immunofluorescence staining, tissue sections will be cut at a 
thickness of 4 microns and placed on positively charged slides. If FFPE tissue availability is an issue, 
slides for multiplex immunofluorescence will be prioritized over tumor for DNA extraction for T cell 
repertoire analysis. 
 
7.2.3.2 Labeling of Specimens 
All specimens will be labeled with the patient’s unique study number and the time point of collection.  
Samples collected prior to initiating therapy with atezolizumab and nab-paclitaxel will be labeled “Pre”, 
those obtained midway through treatment with atezolizumab and nab-paclitaxel will be labeled “Mid”, 
and those obtained at the time of surgery will be labeled “Post”.  PBMC and serum samples obtained 
at the time of completion of atezolizumab treatment will be labeled “6 mo.” 
 
 

45 
 
[Type here] 
 
 
8.0 STUDY CALENDAR 
The Study Calendar summarizes the study procedures to be performed at each visit. Due to 
scheduling, these visits can occur +/- 3 days from the required time point. It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Pre-Surgery 
Study Week 
(Pre-Surgery) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 Surgery 
Study Cycle 
 
1 
2 
3 
4 
 
Cycle Day 
-
28 
to 
0 
1 
8 
15 1 
8 
15 1 
8 
15 1 
8 
15  
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Physical 
X 
X1 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Vital signs5, weight 
X 
X1 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Performance 
Status 
X 
X1 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Baseline 
Symptoms/Toxicity 
review 
 
X 
 
X1 
 
 
X 
 
 
X 
 
 
X 
 
 
 
CBC 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
aPTT and INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistries/LFTs 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TSH, free T4, free 
T3 
X 
X1 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Pregnancy Test 
(serum or urine) 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg, Anti HCV, 
EBNA IgG 
X8 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac scan 
(MUGA or 2D 
ECHO) 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breast Ultrasound6 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Core Biopsy 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
X7 
Surgical Specimen 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood for PBMCs 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Nab-paclitaxel 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Atezolizumab 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

46 
 
[Type here] 
 
 
 
 
 
 
Post-Surgery 
Study Week 
(Post-Surgery) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Study Cycle 
5  
6  
7  
8  
 
Cycle Day 
19 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
 
General Physical 
X1 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Vital signs, weight 
X1 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Performance Status 
X1 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Baseline 
Symptoms/Toxicity 
review 
 
X1 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
CBC 
X1 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Chemistries/LFTs 
X1 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
TSH, free T4, free T3 
X1 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Blood for PBMCs 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Atezolizumab 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
1. 
If screening test was performed >10 days prior to the start of treatment, repeat test on Day 1 
2. 
Serum or urine pregnancy test must be completes within 72 hours of starting the first dose of study 
medication 
3. 
If ECHO or MUGA was performed >3 months prior to study, repeat test within the screening period 
4. 
This biopsy is performed per the parent protocol 2014-0185. Up to 4 Core biopsies will be collected for 
this trial at the end of the anthracycline portion of the parent clinical trial 
5. 
Please see section 6.1.1 for details 
6. 
A window of +/- 7 days is given for ultrasounds as done per standard of care 
7. 
An optional tumor biopsy will be obtained from patients who progressed while on atezolizumab+nab-
paclitaxel prior to switching to the standard of care regimen of the physician’s choice 
8. 
As clinically indicated 
9. 
Treatment with atezolizumab will resume within 4 weeks after surgery. The date of resumption will be the 
first day of the post-surgery (Day 1 of Cycle 5 post surgery). 
 
The Principal Investigator or treating physician must review all lab results, determine clinical 
significance for abnormal labs, and sign and date the report. 
Additional evaluations/testing may be deemed necessary by the Investigator and/or Genentech 
for reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 

47 
 
[Type here] 
 
 
additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
If participating in the parent protocol, disease assessment will continue at least every 6 months 
for a total of 3 years.  This assessment can be done by telephone as well by the research staff 
in Breast Medical Oncology if the patient is unavailable for local visits at The University of Texas 
MD Anderson Cancer Center and documented in the electronic medical record. 

48 
 
 
9.0 MEASUREMENT OF EFFECT 
9.1 
Response Criteria 
For the purposes of imaging evaluation of tumor response for this study, the immune related 
response criteria (irRC) will be used as applicable: 
irCR is complete disappearance of all lesions (whether measurable or not, and no new 
lesions). 
irPR  is a decrease in tumor burden > 50% relative to baseline  
irSD is not meeting either of the above criteria and the absence of progression of disease 
irPD is an increase in tumor burden, whereas Tumor Burden = the sum of perpendicular 
diameters (SPD) of the index lesion + SPD of any new measurable lesions, of > 25% relative 
to the minimum recorded tumor burden and confirmed by a repeat, consecutive assessment 
no less than 4 weeks from the date first documented. 
 
As this is a neoadjuvant study, the final assessment of response will be by pathological 
assessment and Residual Cancer Burden (RCB).   
 
9.2 
Disease-Free Survival 
A secondary objective of this study is to estimate the PFS distribution. PFS is defined as the 
time from enrollment to progression of disease (> 20% increase in tumor size as defined in 
Section 10.1) or death whichever comes first. 
9.3 
Definition of Residual Cancer Burden 
The RCB is a continuous variable derived from the primary tumor dimensions, cellularity of 
the tumor bed, and axillary nodal burden. RCB can be divided into four classes (RCB-0 to 
RCB-III) and will be collected as part of the study. 
RCB-0 (pCR), Minimal RCB (RCB-I), Moderate RCB (RCB-II), and Extensive RCB (RCB-III) 
The following parameters are required from pathologic examination in order to calculate 
Residual Cancer Burden (RCB) after neoadjuvant treatment: 
 
 
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 diameter > 5 cm), then at least 5 
representative cassettes from the largest cross-sectional area are sufficient, 
but should be identified in the original pathology report (e.g. "representative 

49 
 
 
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. 
• 
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 RBC can be accessed online: www.mdanderson.org/breastcancer_RBC. 
 
 

50 
 
 
10.0 ADVERSE EVENT REPORTING REQUIREMENTS 
10.0 Assessment of Safety 
Safety assessments will consist of monitoring and reporting AEs and SAEs per protocol. 
This includes all events of death, and any study-specific issue of concern. 
10.1 
Risks Associated with Atezolizumab 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may 
increase the risk of immune-related AEs, specifically the induction or enhancement of 
autoimmune conditions.  AEs with potentially immune-related causes, including rash, 
hypothyroidism, hepatitis/transaminitis, colitis, myositis, and myasthenia gravis, have been 
observed in Study PCD4989g.   
Although most immune-related AEs observed with immunomodulatory agents have been 
mild and self-limiting, such events should be recognized early and treated promptly to avoid 
potential major complications.25   Recently, Hoffmann-La Roche (Genentech) has informed 
all study PIs of a newly identified risk, immune-related myocarditis. Myocarditis refers to a 
diverse group of heart-specific immune processes classified by a spectrum of clinical and 
histopathological manifestations. It may present as mild dyspnea or chest pain, or more 
severe cardiogenic shock or sudden death. In the absence of an infectious etiology, 
immune-related myocarditis is confirmed by histological evidence of inflammatory infiltrates 
within the myocardium, together with cardiac myocytes degeneration and necrosis of non-
ischemic origin. 
A more detailed safety profile of atezolizumab is provided in the atezolizumab Investigator’s 
Brochure. 
10.2 
Safety Parameters and Definitions 
10.2.1 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of an investigational medicinal product (IMP) or other protocol-imposed 
intervention, regardless of attribution. 
This includes the following: 
• 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms that were not present prior to the AE 
reporting period 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 
• 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention 

51 
 
 
• 
Pre-existing medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period 
 
 
10.2.2 
Serious Adverse Events (SAE) Reporting 
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 in a neonate/infant born to a mother exposed to 
atezolizumab. 
 
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 Serious 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 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.   

52 
 
 
• 
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 dose of drug, 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. 
• 
All adverse events will be recorded in the electronic medical record and scored with 
attributions. The PI or designee will be responsible for determined attributions. In 
addition to the medical record, all adverse events will be recorded in the REDCap 
database along with their determined attributions 
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 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. 
10.3 
Methods and Timing for Assessing and Recording Safety Variables  
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study are collected and reported to the U.S. Food and Drug 
Administration (FDA), appropriate Institutional Review Boards (IRBs), and Genentech, Inc., 
in accordance with CFR 312.32 (Investigational New Drug [IND] Safety Reports).  
10.3.1 
Adverse Event Reporting Period 
After informed consent has been obtained but prior to initiation of study drug, only serious 
adverse events caused by protocol-mandated intervention (e.g., invasive procedures such 
as biopsies, discontinuation of medications) should be reported. 
After initiation of study drug all AEs and SAEs must be reported after informed consent is 
obtained and initiation of study treatment and until 30 days following the last administration 
of study treatment or study discontinuation/termination, whichever is earlier.  After this 
period, investigators should only report SAEs that are attributed to prior study treatment. 
10.3.2 
Assessment of Adverse Events 
All AEs and SAEs, whether volunteered by the patient, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means, will be reported appropriately.  Each reported AE or SAE will be described by its 

53 
 
 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected 
relationship to the study drug (see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should apply 
the following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of atezolizumab, and the AE cannot be readily explained by the patient’s 
clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a 
known pattern of response to atezolizumab; and/or the AE abates or resolves upon 
discontinuation of atezolizumab or dose reduction and, if applicable, reappears upon re-
challenge. 
No 
Evidence exists that the AE has an etiology other than atezolizumab (e.g., pre-existing 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to atezolizumab administration 
(e.g., cancer diagnosed 2 days after first dose of study drug). 
 
Expected AEs are those AEs that are listed or characterized in the Package Insert (PI) or 
current Investigator’s Brochure.  
Unexpected AEs are those not listed in the PI or current Investigator’s Brochure or not 
identified.  This includes AEs for which the specificity or severity is not consistent with the 
description in the PI or Investigator’s Brochure.  For example, under this definition, hepatic 
necrosis would be unexpected if the PI or Investigator’s Brochure only referred to elevated 
hepatic enzymes or hepatitis. 
10.4 
Procedures for Eliciting, Recording, and Reporting Adverse Events  
10.4.1 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all patient evaluation timepoints should be 
adopted.  Examples of non-directive questions include:  
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since you were last here?”  
 
10.4.2 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  
Avoid colloquialisms and abbreviations. 
10.4.2.1 
Diagnosis versus Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 

54 
 
 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, it is 
acceptable to report the information that is currently available.  If a diagnosis is 
subsequently established, it should be reported as follow-up information. 
10.4.2.2 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 10.3.1), 
regardless of attribution, will be reported to the appropriate parties.  When recording a 
death, the event or condition that caused or contributed to the fatal outcome should be 
reported as the single medical concept.  If the cause of death is unknown and cannot be 
ascertained at the time of reporting, report “Unexplained Death.”  Deaths that occur during 
the protocol-specified adverse event reporting period that are attributed by the investigator 
solely to progression of disease should be recorded only in REDCap. 
10.4.2.3 
Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such 
conditions should be reported as medical and surgical history.  A pre-existing medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE only if 
the frequency, severity, or character of the condition worsens during the study.  When 
reporting such events, it is important to convey the concept that the pre-existing condition 
has changed by including applicable descriptors (e.g., “more frequent headaches”). 
10.4.2.4 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE.  If a patient is hospitalized to undergo a medical or surgical 
procedure as a result of an AE, the event responsible for the procedure, not the procedure 
itself, should be reported as the SAE.  For example, if a patient is hospitalized to undergo 
coronary bypass surgery, record the heart condition that necessitated the bypass as the 
SAE. 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for pre-existing conditions, 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study, or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease 
of the study. 
 
10.4.2.5 Pregnancy 
If a female subject becomes pregnant while receiving the study drugs or within 6 months 
after the last dose of study drug, a Pregnancy report CRF should be completed and 
expeditiously submitted (i.e., no more than 24 hours after learning of the pregnancy) to 
Genentech/Roche Drug Safety. Follow-up to obtain the course and outcome of the 

55 
 
 
pregnancy should also occur. Abortion, whether accidental, therapeutic, or spontaneous, 
should always be classified as serious, and expeditiously reported as an SAE. Similarly, any 
congenital anomaly/birth defect in a child born to a female subject exposed to the study 
drugs should be reported as an SAE. An investigator who is contacted by the patient may 
provide information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or obstetrician. 
10.4.2.6 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the ICF to immediately inform the investigator if their 
partner becomes pregnant during the study or within 6 months after completing treatment 
with study drugs.  Male patients who received study treatment should not attempt to father a 
child until end of study.  A Pregnancy report CRF should be completed and expeditiously 
submitted to Genentech/Roche Drug Safety (i.e., no more than 24 hours after learning of the 
pregnancy).Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  
Institutional procedures will be followed to possibly allow additional information on the 
course and outcome of the pregnancy to be collected. An investigator who is contacted by 
the male patient or his pregnant partner may provide information on the risks of the 
pregnancy and the possible effects on the fetus, to support an informed decision in 
cooperation with the treating physician and/or obstetrician. 
10.4.2.7 
Abortions 
Any abortion, whether accidental, therapeutic, or spontaneous, should be classified as an 
SAE (as the Investigator and Supporter consider abortions to be medically significant 
events), recorded in REDCap, and reported to Genentech/Roche Drug Safety expeditiously 
(i.e., no more than 24 hours after learning of the event). 
10.4.2.8 Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner of a 
male patient exposed to study drug should be classified as an SAE, recorded in REDCap, 
and reported to Genentech/Roche Drug Safety expeditiously.  
10.4.2.9 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a patient has 
completed or discontinued study participation if attributed to prior atezolizumab exposure.  If 
the investigator should become aware of the development of cancer or a congenital 
anomaly in a subsequently conceived offspring of a female patient who participated in the 
study, this should be reported as an SAE.  
10.4.2.9a 
 Abnormal Liver Function Tests 

56 
 
 
The finding of an elevated ALT or AST (> 3 x ULN) in combination with either an elevated 
total bilirubin (> 2 x ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury (as defined by Hy's 
law).  Therefore, investigators must report as an adverse event the occurrence of either of 
the following: 
Treatment-emergent ALT or AST > 3 x ULN in combination with total bilirubin > 2 x ULN 
Treatment-emergent ALT or AST > 3 x ULN in combination with clinical jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event CRF and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event), either as a 
serious adverse event or an adverse event of special interest. 
10.4.2.10 
Safety Reconciliation 
The Sponsor-investigator agrees to conduct case transmission verification reconciliation for 
the product ensure that all single case reports have been adequately received by 
Genentech/Roche, via the exchange of a periodic line-listing documenting single case 
reports sent by the sponsor in the preceding month.  Following reconciliation, single case 
reports which have not been received by Genentech/Roche shall be forwarded by the 
sponsor-investigator to Genentech/Roche within FIVE (5) CALENDAR DAYS from request 
by Genentech/Roche 
 
 
10.4.2.11 
Adverse Events of Special Interest  
Adverse events of special interest (AESIs) are defined as a potential safety problem, 
identified as a result of safety monitoring of the IMP. 
The following AEs are considered of special interest and must be reported to the 
Genentech/Roche Drug Safety expeditiously, irrespective of regulatory seriousness criteria:  
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency or 
hyperthyroidism 
• 
Hepatitis 
• 
Transaminitis:  Grade ≥ 2 (AST or ALT > 3 × ULN and bilirubin > 2 × ULN) or 
AST/ALT > 10 × ULN  
• 
Systemic lupus erythematosus 
• 
Guillain-Barré syndrome  
• 
Myasthenia gravis 

57 
 
 
• 
Meningoencephalitis 
• 
Nephritis 
 
• 
Events suggestive of hypersensitivity, cytokine release, influenza-like illness, systemic 
inflammatory response syndrome, systemic inflammatory activation or infusion-reaction 
syndromes 
• 
Suspected Transmission of Infectious Agent via Medicinal Product (STIAMP) 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient exposed to a medicinal 
product.  This term applies only when a contamination of the study drug is suspected 
Adverse Events of special interest will be reported to the IND office via eSAE 
application. The form completed for IND reporting will be forwarded to Genentech for 
reporting purposes. 
 
Communications between the Investigator and Supporting Company  
Investigators must report all SAEs to Genentech/Roche within the timelines described 
below.  The completed MDA SAE should be faxed immediately upon completion to 
Genentech/Roche Drug Safety at: 
E-mail: welwyn.pds-pc@roche.com 
Fax: +44 1707 377 967/ 373 779/ 373 793/ 390 959  
 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available. 
SAE reports and AESIs, whether related or unrelated to atezolizumab, will be transmitted to 
Genentech/Roche within 24 hours of the Awareness Date. 
• 
Non-serious AEs 
The investigator will forward a copy of the Final Study Report to Roche upon completion of 
the Study. In addition to SAEs, pregnancy reports and AESIs, the following Special 
Situations Reports should be collected and transmitted to Roche even in the absence of an 
Adverse Event within 1 business day of awareness date: 
• 
Data related to product usage during pregnancy or breastfeeding 
• 
Data related to overdose, abuse, misuse, inadvertent/erroneous administration, 
medication error or occupational exposure, with or without association with an AE/SAE 
unless otherwise specified in the protocol 
• 
Lack of therapeutic efficacy 
Note:  Investigators should also report events to their IRB as required. 
 

58 
 
 
10.4.3 
Additional Reporting Requirements for IND 
For investigator-initiated IND studies, some additional reporting requirements for the FDA 
apply in accordance with the guidance set forth in 21 CFR § 600.80. 
Events meeting the following criteria need to be submitted to the FDA as expedited IND 
Safety Reports according to the following guidance and timelines: 
7 Calendar Day Telephone or Fax Report 
The investigator is required to notify the FDA of any fatal or life-threatening AE that is 
unexpected and assessed by the investigator to be possibly related to the use of 
atezolizumab.  An unexpected AE is one that is not already described in the 
atezolizumab Investigator’s Brochure.  Such reports are to be telephoned or faxed to 
the FDA and Genentech within 7 calendar days of first learning of the event. 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, 
in a written IND Safety Report, of any serious, unexpected AE that is considered 
reasonably or possibly related to the use of atezolizumab.  An unexpected AE is one 
that is not already described in the atezolizumab Investigator’s Brochure.  
Written IND Safety reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed by 
the investigator with the IND concerning similar events should be analyzed and the 
significance of the new report in light of the previous, similar reports commented on. 
Written IND safety reports with analysis of similar events are to be submitted to the FDA, 
Genentech, and all participating investigators within 15 calendar days of first learning of the 
event.  The FDA prefers these reports on a MedWatch 3500 form, but alternative formats 
are acceptable (e.g., summary letter).  
Contact Information for IND Safety Reports 
FDA fax number for IND safety reports: 
Fax:  (800) FDA-0178 
 
All written IND safety reports submitted to the FDA by the investigator must 
also be faxed to the following: 
Roche Drug Safety  
E-mail: welwyn.pds-pc@roche.com 
Fax: +44 1707 377 967/ 373 779/ 373 793/ 390 959 
The University of Texas MD Anderson Cancer Center IRB 
 

59 
 
 
For questions related to safety reporting, please contact Genentech Drug 
Safety: 
Tel:  (888) 835-2555 
Fax:  (650) 225-4682 or (650) 225-4630 
 
Reporting to the FDA is done through the institutional IND office, as detailed in section 
10.2.2 
 
10.4.4 
IND Annual Reports 
Copies of all IND annual reports submitted to the FDA should be sent by the Investigator to 
Genentech/Roche Drug Safety via e-mail: 
Email:  anti-pdl-1-mpd3280a-gsur@gene.com 
10.5 
Study Close-Out 
Any study report submitted to the FDA should be copied to Genentech.  This includes all 
IND annual reports and the Clinical Study Report (final study report).  Additionally, any 
literature articles that are a result of the study should be sent to Genentech.  Copies of such 
reports should be mailed to the assigned Clinical Operations contact for the study: 
 
Atezolizumab Protocols 
Email:  anti-pdl-1-mpd3280a-gsur@gene.com 
 
10.6 Study Medication Accountability  
The recipient will acknowledge receipt of the drug indicating shipment content and condition.  
Damaged supplies will be replaced. 
Accurate records of all study drug dispensed from and returned to the study site should be 
recorded by using the institution’s drug inventory log or the National Cancer Institute drug 
accountability log. 
All partially used or empty containers should be disposed of at the study site according to 
institutional standard operating procedure.  Return unopened, expired, or unused study drug 
with the Inventory of Returned Clinical Material form as directed by Genentech. 
 
10.7 Product Complaint 
Product complaint information provided orally or in writing from a complaint that alleges 
deficiencies related to identity, quality safety, strength, purity, reliability, durability, 
effectiveness or performance of a product after it has been released and distributed to the 
commercial market or clinical trial will be reported as follows; 
Product complaint with AE (adverse event) should be reported via email/fax to 
usds_aereporting-d@gene.com or 650-238-6067 

60 
 
 
Product complaint without an AE should be reported to 
kaiseraugst.global_impcomplaint_managment@roche.com 
All complaint must be filed within 1 business day for pre-approved products and 15 calendar 
days for approved products. 
Complaints can be reported using Med Watch, CIOMS or any Genentech approved 
reporting form (same as SAEs, AESI, etc.). 
 
 
 
 
11.0 STATISTICAL ANALYSIS PLAN 
11.1 Statistical Analysis Plan Summary 
Counting pCR (RCB-0) or RCB-I as response, we will employ a two-stage Gehan-type design 
with 19 patients in the first stage. If at least one patient responds, we will add 18 more patients 
for a total of 37 patients. This design has a 38% chance of terminating after the first stage if 
the true response rate is 0.05, 14% chance if the true rate is 0.10, 5% if the true rate is 0.15 
and 1% if the true rate is 0.20. If we continue to the second stage and enroll a total of 37 
patients, the exact 95% confidence interval for a 0.15 response rate will extend from 0.05 to 
0.31. 
We will estimate the proportion of patients with pCR (RCB-0) or RCB-I as the response rate 
along with an appropriate 95% confidence interval. We will estimate the proportion of patients 
in the remaining RCB categories with confidence intervals as well. We will estimate the PFS 
distribution using the Kaplan-Meier method from the date of enrollment onto this study until 
the date of progression or death without evidence of progression. Patients alive and disease-
free at the latest clinical evaluation will be censored at the date of that evaluation. We will also 
estimate the OS distribution in a similar fashion. 
Early drop outs (i.e., patients not getting to surgery) should be counted as treatment failures 
(i.e., non-responders with RCB > 1). 
A response summary will be submitted to the IND Medical Monitor after treatment of the 19th 
patient has completed. 
If no RCB-0 or -1 response has been observed prior to enrolling the 20th patient, enrollment 
will stop until all of the 19 patients in the first stage are evaluable and resume only if a response 
has been documented. 
 
 
 

61 
 
 
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