Clinical trial NCT04690855
Conditions: Breast Cancer Triple Negative Breast Cancer
Sponsor: Mylin A. Torres, MD
Start date: 2021-10-04; Completion date: 2022-12-20
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase II study designed to assess efficacy and safety of talazoparib, high dose radiation, and atezolizumab in patients with metastatic TNBC that is PD-L1 positive. A total of 23 gBRCA pathogenic variant negative patients will be enrolled. All patients will be treated with induction talazoparib of 1mg PO daily starting Day 1. Patients will then receive 8 Gy x 3 fractions to 2-4 metastatic lesions beginning Day 12,13, or 14 and given QOD. 840 mg of atezolizumab will be given intravenously (IV) on Day 15 of the 1st cycle and then on Day 1 and Day 15 of the remaining cycles. The sequence of administration is not specified on the days in which talazoparib and atezolizumab are given on the same day. Each cycle equals 28 days. Treatment will continue until progression or severe toxicity.

A safety lead in of up to 6 patients will be performed. Immune-related and non-immune related adverse events will be tracked up to 12 weeks post initiation of atezolizumab, as the majority of treatment-related toxicities from talazoparib, radiation, and atezolizumab occur within this time period.

Detailed description:

Arms: arm 1: All patients will be treated with induction talazoparib of 1mg PO daily starting Day 1. Patients will then receive 8 Gy x 3 fractions to 1-4 metastatic lesions beginning Day 12,13, or 14 and given QOD. 840 mg of atezolizumab will be given intravenously (IV) on Day 15 of the 1st cycle and then on Day 1 and Day 15 of the remaining cycles. The sequence of administration is not specified on the days in which talazoparib and atezolizumab are given on the same day. Each cycle equals 28 days. Treatment will continue until progression or severe toxicity.

A safety lead in of up to 6 patients will be performed. Immune-related and non-immune related adverse events will be tracked up to 12 weeks post initiation of atezolizumab, as the majority of treatment-related toxicities from talazoparib, radiation, and atezolizumab occur within this time period.
Interventions: intervention 1: Talazoparib intervention 2: Atezolizumab intervention 3: Radiation
Intervention descriptions: intervention 1: Talazoparib 1 mg Orally Day 1 to Day 28 intervention 2: Atezolizumab 840 mg IV over 60 minutes Day 15 of Cycle 1 then Day 1 and Day 15 of subsequent Cycles intervention 3: Radiation 8 Gy will be given in 3 fractions QOD beginning Day 12, 13 or 14 of Cycle 1 but 24-72 hours prior to 1st dose of Atezolizumab

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
HCRN BRE19-433 
 
A Multi-institutional Phase II Study to Evaluate Efficacy and Safety of TAlazoparib, 
Radiotherapy and Atezolizumab in gBRCA 1/2 negative Patients with PD-L1+ Metastatic Triple 
Negative Breast Cancer (TARA) 
 
Sponsor Investigator 
Mylin A. Torres, MD 
Co-Leader Cancer Prevention and Control Program 
Winship Cancer Institute 
Professor 
Department of Radiation Oncology 
Emory University School of Medicine 
Email:  matorre@emory.edu 
 
Co-Investigators
Manali Bhave, MD  
Assistant Professor 
Department of Hematology and Medical 
Oncology 
Winship Cancer Institute 
Emory University School of Medicine 
Manali.ajay.bhave@emory.edu 
 
 
David Schuster, MD 
Director  
Division of Nuclear Medicine and 
Molecular Imaging  
Professor  
Department of Radiology and Imaging 
Sciences  
Emory University Atlanta, GA  
Email: dschust@emory.edu
 
Statistician 
Jeffery Switchenko, PhD  
Biostatistics & Bioinformatics Shared Resource at Winship Cancer Institute  
Department of Biostatistics & Bioinformatics, Emory University  
1518 Clifton Road/Atlanta, Georgia 30322 
Email: jswitch@emory.edu 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
 
Trial Supported by  
Pfizer 57078757 
Genentech RO-IIS-2019-20436 
 
Investigational New Drug (IND) #: 153018 
 
Initial Protocol Version Date: 28OCT2020 
Protocol Amendment Version Date:  
16MAR2022 
08JUN2022 
10AUG2022 
 
 


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PROTOCOL SIGNATURE PAGE 
 
A Multi-institutional Phase II Study to Evaluate Efficacy and Safety of TAlazoparib, 
Radiotherapy and Atezolizumab in gBRCA 1/2 negative Patients with PD-L1+ Metastatic Triple 
Negative Breast Cancer (TARA) 
 
 
VERSION DATE: 10AUG2022 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable institutional review board(s). 
 
 
PLEASE COMPLETE AND EMAIL A COPY TO HCRN 
 
 
 


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SYNOPSIS 
TITLE 
A Multi-institutional Phase II Study to Evaluate Efficacy and 
Safety of TAlazoparib, Radiotherapy and Atezolizumab in 
gBRCA 1/2 negative Patients with PD-L1+ Metastatic Triple 
Negative Breast Cancer (TARA) 
SHORT TITLE 
Study to Evaluate Efficacy and Safety of TAlazoparib, 
Radiotherapy and Atezolizumab in gBRCA 1/2 negative Patients 
with PD-L1+ Metastatic Triple Negative Breast Cancer  
PHASE  
2 
OBJECTIVES 
Primary Objective 
Estimate objective response rate (ORR) of talazoparib, high dose 
radiotherapy and atezolizumab, eight weeks after the first dose of 
atezolizumab in non-irradiated lesions of gBRCA1/2 pathogenic 
variant negative mTNBC patients whose tumors are PD-L1 
immune cell (IC)-positive. 
 
Secondary Objectives 
• Determine the frequency and severity of adverse events 
using CTCAE v 5.0 after induction talazoparib followed by 
concurrent talazoparib, high dose radiation, and 
atezolizumab given as second or third-line treatment for PD-
L1 positive metastatic triple negative breast cancer 
(mTNBC) (≥ 2 lesions)  
• Obtain progression free survival (PFS) data in gBRCA1/2 
negative mTNBC patients with PD-L1 positive infiltrate 
treated with talazoparib, radiation, and atezolizumab 
• Obtain overall survival (OS) data in gBRCA1/2 negative 
mTNBC patients with PD-L1 positive infiltrate treated with 
talazoparib, radiation, and atezolizumab 
• Determine ORR by immune-related RECIST (irRECIST) 
• Determine duration of overall response (DOR) to 
talazoparib, high dose radiation, and atezolizumab given in 
the second or third-line setting to BRCA1/2 negative 
mTNBC patients with PD-L1 positive infiltrate 
• Determine disease control rate (DCR) in gBRCA1/2 
negative mTNBC patients with PD-L1 positive infiltrate 
treated with talazoparib, high dose radiation, and 
atezolizumab given in the second or third-line setting  
• Determine time to progression (TTP) in gBRCA1/2 negative 
mTNBC patients with PD-L1 positive infiltrate treated with 
talazoparib, high dose radiation, and atezolizumab given in 
the second or third-line setting 


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• Determine adherence to prescribed talazoparib, high dose 
radiation, and atezolizumab in the second or third-line 
setting among PD-L1 positive mTNBC patients 
• Determine best overall tumor response to talazoparib, high 
dose radiation, and atezolizumab in the second or third-line 
setting among PD-L1 positive mTNBC patients 
STUDY DESIGN 
This is a Phase II study designed to assess efficacy and safety of 
talazoparib, high dose radiation, and atezolizumab in gBRCA 1/2 
negative patients with metastatic TNBC that is PD-L1 positive. A 
total of 23 subjects will be enrolled. A safety lead in of 6 patients 
will be performed.  All patients will be treated with induction 
talazoparib of 1mg PO daily starting Day 1. Patients will then 
receive 8 Gy x 3 QOD of radiation to 1-4 extracranial lesions 
starting Day 12, 13 or 14.  840 mg of atezolizumab intravenously 
(IV) will be given ~ Day 15 of the 1st cycle and then on Day 1 
and Day 15 of the remaining cycles. Each cycle equals 28 days. 
Treatment will continue until progression or severe toxicity.   
KEY ELIGIBILITY 
CRITERIA (See 
Section 3 for full 
eligibility criteria) 
1. Biopsy proven metastatic triple negative breast cancer 
(estrogen receptor (</=10%), progesterone receptor (</=10%) 
and no overexpression of HER2 as evaluated by local 
institutions with at least 2 extracranial metastatic lesions on 
imaging. 
2. PD-L1 positive tumor infiltrate as defined as >1% on IHC 
using the SP142 Ventana Assay. 
3. Known gBRCA status (only gBRCA pathogenic variant 
negative patients are eligible). 
4. Patients must have at least 1 extracranial metastatic lesion 
(may be measurable or non-measurable disease by RECIST v 
1.1) that is amenable to high dose radiotherapy and at least one 
additional extracranial lesion of measurable disease by 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
that will not receive radiotherapy on this study. Of note, lesions 
may be in the same organ but must be 2 cm apart. 
5. Measurable disease by Response Evaluation Criteria in Solid 
Tumors (RECIST v1.1)  
6. Patients must have received at least one and no more than three 
previous lines of chemotherapy treatment in the advanced 
setting with or without immune therapy. Patients with disease 
recurrence or progression following neoadjuvant or adjuvant 
cytotoxic chemotherapy are not eligible unless they have 
received at least one line of chemotherapy with or without 
immune therapy in the advanced setting. NOTE: Targeted 
small molecules (e.g. tyrosine kinase inhibitors), hormonal 
agents and monoclonal antibodies that inhibit angiogenesis 
(e.g. bevacizumab, afilbercept) are not counted in the number 


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of lines of therapy. Cytotoxic chemotherapy with or without 
immune therapy for advanced disease prior to protocol 
treatment is not permitted within 2 weeks of the protocol 
treatment.  Patients may or may not have received radiotherapy 
or neoadjuvant or adjuvant chemotherapy in the treatment of 
their initial, non-metastatic breast cancer or metastatic breast 
cancer, but must be entered on study 2 weeks after their last 
dose of radiotherapy, last cycle of chemotherapy and biologic 
therapy (if applicable) for mTNBC and have sufficient 
resolution of side effects per physician assessment at time of 
talazoparib. 
7. Patients must be eligible for radiotherapy, talazoparib, and 
atezolizumab. 
8. Demonstrate adequate organ function within 14 days prior to 
registration. 
9. No evidence of progression of breast cancer within the first 3 
months of prior immune therapy for non-metastatic or 
metastatic breast cancer. 
STATISTICAL 
CONSIDERATIONS 
Sample size is determined using Simon’s 2-stage Minimax design 
to detect a 20% increase in objective response rate (ORR). The 
null hypothesis that the true response rate among gBRCA1/2 
negative patients of 10%, based on the TOPACIO study25, will be 
tested against a one-sided alternative.  In the first stage, 7 patients 
will be accrued.  If there are 0 responses in these 7 gBRCA1/2 
negative patients, the study will be stopped.  Otherwise, 11 
additional patients will be accrued for a total of 18 evaluable 
patients.  This design yields a Type I error rate of 0.1 for one 
sided test and power of 80% when the true response rate is 30% 
in the gBRCA negative patients.  Assuming an attrition rate of 
20%, we will enroll 23 total patients without gBRCA 1/2 
pathogenic variants.  
TOTAL  
NUMBER OF 
SUBJECTS 
N = 18 evaluable subjects: 23 total patients accounting for 
dropout accounting for drop out 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 27 months from time of lead site opening 
ESTIMATED STUDY 
DURATION  
Estimated 36 months 
 
 


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TABLE OF CONTENTS 
 
Schema ............................................................................................................................................8 
1. 
Background and Rationale ..................................................................................................9 
1.1 
Background and Rationale .............................................................................................. 9 
1.2 
PARP Inhibitors and Radiotherapy ............................................................................... 11 
1.3 
PARP Inhibitors and Immune therapy .......................................................................... 11 
1.4 
Radiotherapy and Immune Therapy.............................................................................. 12 
1.5 
Rationale for Radiation Dose and Timing .................................................................... 14 
1.6 
Hypothesis..................................................................................................................... 15 
2. 
Study Objectives and Endpoints........................................................................................15 
2.1 
Objectives ..................................................................................................................... 15 
2.2 
Endpoints ...................................................................................................................... 16 
3. 
Eligibility Criteria ...............................................................................................................17 
3.1 
Inclusion Criteria .......................................................................................................... 17 
3.2 
Exclusion Criteria ......................................................................................................... 19 
4. 
Subject Registration............................................................................................................20 
5. 
Treatment Plan....................................................................................................................20 
5.1 
Study Treatment Administration................................................................................... 21 
5.2 
Safety Lead In ............................................................................................................... 23 
5.3 
Concomitant Medications ............................................................................................. 24 
5.4 
Reproductive Information ............................................................................................. 25 
6. 
Toxicities and Dose Delays/Dose Modifications ...............................................................26 
6.1 
Talazoparib Dose Modifications and Toxicity Management........................................ 26 
6.2 
Atezolizumab Dose Modification and Toxicity Management ...................................... 27 
6.3 
Radiation Therapy Dose Modification and Toxicity Management .............................. 27 
6.4 
Protocol Therapy Discontinuation ................................................................................ 27 
6.5 
Protocol Discontinuation .............................................................................................. 28 
7. 
Study Calendar & Evaluations ..........................................................................................29 
8. 
Biospecimen Studies and PATIENT REPORTED OUTCOME MEASURES .............32 
8.1 
Tissue ............................................................................................................................ 32 
8.2 
Peripheral Blood Samples ............................................................................................. 33 
8.3 
Genetic Testing ............................................................................................................. 34 
8.4 
Banking of Leftover Biospecimens .............................................................................. 34 
8.5 
Confidentiality of Biospecimens................................................................................... 34 
8.6 
Patient Reported Outcome Measures ............................................................................ 34 
9. 
Criteria for Disease Evaluation  ........................................................................................35 
9.1 
Evaluation using RECIST 1.1 ....................................................................................... 35 
9.2 
Immune-Related RECIST (irRECIST) ......................................................................... 38 
10 
Drug AND RADIATION Information ..............................................................................41 
10.1 
Talazoparib ................................................................................................................... 41 
10.2 
Atezolizumab ................................................................................................................ 42 
10.3 
Radiotherapy ................................................................................................................. 43 
11. Adverse Events ....................................................................................................................48 
11.1 
Definitions..................................................................................................................... 48 
11.2 
Reporting....................................................................................................................... 52 


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11.3 
Special Situation Reports .............................................................................................. 53 
11.4 
HCRN Requirements for Reporting SAEs to Genentech ............................................. 53 
11.5 
HCRN Requirements for Reporting SAEs to Pfizer ..................................................... 54 
11.6 
Sponsor-Investigator Responsibilities .......................................................................... 54 
11.7 
HCRN Responsibilities to FDA .................................................................................... 54 
11.8 
IND Safety Reports Unrelated to this Trial .................................................................. 54 
12 
Statistical Methods ..............................................................................................................54 
12.1 
Study Design ................................................................................................................. 54 
12.2 
Sample Size and Accrual .............................................................................................. 55 
12.3 
Endpoints ...................................................................................................................... 55 
12.4 
Assessment of Safety .................................................................................................... 56 
12.5 
Assessment of Efficacy ................................................................................................. 56 
12.6 
Data Analysis Plans ...................................................................................................... 56 
12.7 
Interim Analysis/Criteria for Stopping Study ............................................................... 58 
13 
Trial Management ..............................................................................................................59 
13.1 
Data and Safety Monitoring Plan (DSMP) ................................................................... 59 
13.2 
Emory Winship Cancer Institute Data Safety Monitoring Committee ......................... 59 
13.3 
Data Quality Oversight Activities by HCRN................................................................ 60 
13.4 
Compliance with Trial Registration and Results Posting Requirements ...................... 60 
14. Data Handling and Record Keeping .................................................................................60 
14.1 
Data Management ......................................................................................................... 60 
14.2 
Case Report Forms and Submission ............................................................................. 60 
14.3 
Record Retention .......................................................................................................... 61 
14.4 
Confidentiality .............................................................................................................. 61 
15 
Ethics ....................................................................................................................................61 
15.1 
Institutional Review Board (IRB) Approval ................................................................. 61 
15.2 
Ethical Conduct of the Study ........................................................................................ 61 
15.3 
Informed Consent Process ............................................................................................ 62 
16 
References ............................................................................................................................63 
17 
APPENDIX I: MANAGEMENT OF ATEZOLIZUMAB-SPECIFIC ADVERSE 
EVENTS........................................................................................................................................68 
19. APPENDIX II: MANAGEMENT OF RADIATION-SPECIFIC ADVERSE EVENTS
 
92 
20. APPENDIX III ....................................................................................................................94 
 
 
 


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SCHEMA 
 
 
 
 
ctDNA – circulating tumor DNA; CBC with diff – complete blood cell count with differential; 
CMP – complete metabolic panel; CTCAE – National Cancer Institute Common Terminology 
Criteria for Adverse Events version 5.0; Mets - metastasis; 
MFI – Multidimensional fatigue Inventory; EORTC QLQ-C30 - EORTC Quality of Life 
Questionnaire Core 30; gBRCA1/2 negative – germline BRCA 1/2 pathogenic variant negative, 
e.g. germline BRCA1/2 wildtype or gBRCA variants of uncertain significance; XRT- 
radiotherapy 
 
To participate on this study, patients must fulfill all eligibility criteria and must not meet any 
exclusion criteria, as well as consent to blood draws and resulting biospecimen collection and 
analysis.  Archival tissue collection for research purpose before treatment is optional but 
encouraged.  Fresh tumor tissue collection from the same non-irradiated site for research 
purposes before and after first dose of atezolizumab (prior to C1D1 and C2D1) is also optional 
but encouraged.  gBRCA and PD-L1 status must be confirmed prior to treatment.     
 
 


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Background and Rationale 
Metastatic breast cancer is an incurable disease.  While the discovery of agents which 
specifically target hormone receptor and Her2 positive tumors have significantly improved 
outcomes in patients with these breast cancer subtypes, the lack of a clearly defined therapeutic 
target in women with metastatic triple negative breast cancer (mTNBC) results in patients 
continuing to do poorly with a median survival of 18 months or less.1  A higher proportion of 
TNBCs are diagnosed in younger women, BRCA1 carriers and/or women of African or Hispanic 
ancestry.  Among all breast cancer subtypes, TNBC has the greatest potential to benefit from 
immune therapy, as it is associated with more immunogenicity than non-TNBCs.2,3  Enhanced 
immune activity characterized by tumor infiltrating lymphocytes in the biopsy and surgical 
specimens of TNBC patients is associated with overall improved prognosis.4  Therefore, 
therapies aimed at augmenting the immune response to TNBC may address the need for more 
tumor specific and less toxic treatment. 
 
Higher genetic instability, enhanced mutational load, appearance of neoantigens and the 
expression of programmed death ligand 1 (PD-L1) seen in tumor-infiltrating immune cells of 
patients with TNBC suggests that checkpoint inhibition of PD-L1 may be a beneficial treatment 
strategy in this breast cancer subtype.5,6  Atezolizumab, an antibody which specifically targets 
PD-L1 on tumor cells, was efficacious in TNBC based on results from the IMpassion 130 Phase 
III trial.  Among all patients, overall response rates (ORR) at 8 weeks were significantly higher 
in mTNBC patients treated with nab-paclitaxel and atezolizumab vs. nab-paclitaxel and placebo 
(56% vs. 49.5%, respectively, p=0.002).  In patients with PD-L1 positive tumors (41% of 
patients), the difference in ORR rates was even higher (58.9% with atezolizumab vs. 42.6% 
placebo, p=0.002) and correlated with a significantly improved median progression-free survival 
of 7.2 months vs. 5.5 months with nab-paclitaxel alone (p=0.002) and clinically, meaningful 
improvement of overall survival of 7 months.7,8  Atezolizumab, importantly, did not compromise 
patient reported health related quality of life, as assessed by EORTC QLQ-C30.7,9,10   
 
Nevertheless, in spite of these advances, prognosis for mTNBC patients treated with 
atezolizumab and nab-paclitaxel remains poor as patients ultimately progress within a relatively 
short time period.  Among gBRCA1 or gBRCA2 mutation carriers (5-10% of all breast cancer 
patients), PARP inhibitors [PARPi(s)], including talazoparib, are approved in PD-L1 negative 
mTNBC and are commonly prescribed as subsequent treatment in gBRCA positive patients with 
PD-L1 positive tumors who progress on atezolizumab and nab-paclitaxel.11 However, in PD-L1+ 
mTNBC patients who are not gBRCA carriers, median duration of response is only 8.5 months 
after treatment with atezolizumab, and cytotoxic chemotherapy, a highly indiscriminate 
treatment, remains the primary therapy for progressive disease and is associated with significant 
toxicity often without durable long-term benefit in the majority of patients.7  Indeed, among 
patients on IMpassion130 who resumed anticancer treatment after developing progressive 
disease on atezolizumab and nab-paclitaxel, over 95% were treated with other chemotherapy 
agents while less than 4% received additional immune therapy.7  A potential, alternative 
therapeutic strategy would be to introduce agents which re-sensitize the immune system to 
atezolizumab and promote a more durable tumor-specific response that spares patients from 
toxicities associated with traditional chemotherapy regimens.   


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Additionally, there remain many mTNBC patients who were treated with chemotherapeutic 
agents and/or other immune therapies (e.g. pembrolizumab) in the first line setting, and these 
patients have not received PD-L1 checkpoint blockade despite having PD-L1+ tumors.  
Therefore, it is possible that these heavily pre-treated PD-L1+ mTNBC patients who are naïve to 
atezolizumab may still benefit from an atezolizumab combination in the second line setting or 
beyond.  It is also possible that sensitivity to atezolizumab may be restored in mTNBC patients 
previously treated with this agent as noted above.  
 
PARPi(s) are one option for increasing response to atezolizumab in heavily pretreated (with or 
without previous immune therapy) mTNBC PD-L1+ patients, as preclinical models have 
demonstrated moderately enhanced antitumor activity when both agents are combined, 
irrespective of gBRCA mutation status (see below).  Among PARPi(s) used in breast cancer, 
talazoparib is the most potent in preclinical studies.  It not only has strong catalytic inhibition, 
but it also traps PARP at levels 100-fold higher than other PARPi(s).12,13  Talazoparib, therefore, 
is an attractive PARPi to be used in combination with atezolizumab, a drug with proven efficacy 
in mTNBC patients with PD-L1+ infiltrate.  Talazoparib has already been studied with 
avelumab, another PD-L1 inhibitor, in small Phase I studies, without dose reductions or 
concerning toxicities and modest to moderate activity in mTNBC patients but no study has 
examined the use of talazoparib with atezolizumab specifically.14  Moreover, PARPi(s) are 
known radiosensitizing agents even in the absence of BRCA mutations.  Therefore, it is possible 
that within the context of atezolizumab, radiation may elicit an abscopal response, particularly 
when combined with talazoparib, the most potent PARPi in its class.  We, therefore, hypothesize 
that talazoparib and radiation in combination with atezolizumab will improve upon the modest 
activity noted with talazoparib and avelumab even in patients without gBRCA pathogenic 
variants.  It is thus possible that the combination of all three agents will elicit a stronger 
antitumor response than any of these agents given alone to gBRCA1/2 negative patients.  
However, these three agents have not been tested previously in PD-L1+ mTNBC patients with or 
without gBRCA pathogenic variants.  Therefore, we propose a Phase II study evaluating the 
efficacy and safety of talazoparib given with high dose radiation and atezolizumab to restore 
sensitivity to immune therapy in, gBRCA1/2 negative mTNBC PD-L1+ patients, who develop 
progressive disease on atezolizumab or in patients who have progressed on chemotherapy with 
or without immune therapy in the first or second line.  This will allow us to not only assess the 
safety of this strategy in these patients but also assess the potential ability of talazoparib coupled 
with radiation to amplify the immune response in heavily pretreated (with or without immune 
therapy) patients with PD-L1+ mTNBC tumors.7  An advantage of this approach is the use of 
talazoparib to enhance local treatment (radiotherapy) to improve systemic response to immune 
therapy without increasing the risk for widespread side effects associated with the addition of 
other experimental or traditional systemic cytotoxic agents which circulate throughout the body.     
 
 
 


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1.2 
PARP Inhibitors and Radiotherapy 
Talazoparib is the most potent of all PARPi(s), a class of drugs which enrich unrepaired DNA 
damage, and are therefore, potential radiosensitizers that promote apoptosis.  PARPi(s) suppress 
homologous recombination and PARP-1-dependent nonhomologous end joining (NHEJ) repair 
while promoting error-prone alt-NHEJ and can induce “synthetic lethality” in cancers with 
underlying DNA damage repair abnormalities, such as patients with gBRCA1/2 mutations.  
Although PARPi (s) are approved for use in gBRCA mutation carriers, there is also noted 
activity in tumors with somatic DNA repair pathway mutations (e.g. homologous recombination 
deficiency [HRD]) which have been reported in up to 60% of TNBCs.15  In addition, previous 
pre-clinical and clinical studies have indicated that PARPi(s) are an effective radiosensitizer 
irrespective of gBRCA status, as PARP inhibition may synergize with the single- and double-
stranded DNA breaks induced by radiotherapy.16-18  Most clinical studies have given 1-2 weeks 
of induction PARPi therapy before concurrent treatment with radiation.  Studies, like ours, 
examining the use of focused high-dose radiation (as opposed to large field irradiation) with a 
PARPi have the potential to increase tumor response without exacerbating hematologic toxicities 
typically associated with PARPi alone [Grade 3 anemia (38%), neutropenia (18%), and 
thrombocytopenia (11%)].11  Pertinent to immune therapy, both PARPi(s) and radiotherapy 
upregulate the expression and secretion of chemokines such as CCL2, CCL5, CSCL-16, and 
CSCL-10 and promote intratumor infiltration by cytotoxic T lymphocytes.19,20  These two 
treatments also independently upregulate PD-L1 on the tumor cell surface.  Therefore, 
talazoparib and radiotherapy given concurrently have the potential to amplify tumor responses to 
PD-L1 immunotherapies like atezolizumab, regardless of gBRCA status.21,22  
 
1.3 
PARP Inhibitors and Immune therapy 
PARPi(s) impair repair of nucleotides and base excision which generate cytosolic DNA 
fragments that activate the DNA-sensing cGAS-STING pathway leading to production of type I 
interferon and antitumor activity regardless of BRCAness within the tumor.23   Furthermore, 
genomic instability resulting from PARPi yields many protein altering mutations that create 
immunogenic neo-antigens independent of BRCA1/2 status.21,23  Moreover, BRCA1/2 status has 
no bearing on the increased expression of PD-L1 secondary to PARPi treatment observed in 
breast cancer cell lines and animal models.21  Therefore, there is mechanistic rationale for 
combining PARPi with immune therapy in patients who are not gBRCA mutation carriers.  
Evidence in support of this treatment approach comes from single-arm Phase 1 and 2 Trials 
conducted in patients with recurrent platinum-resistant ovarian cancer.24  In these studies, the 
combination of niraparib, a PARPi, and pembrolizumab, a PD-1 inhibitor, was tolerable and 
demonstrated promising responses in patients without BRCA mutations.24   Additional studies 
exploring this combination of drugs in mTNBC patients without BRCA mutations are also 
ongoing.  In the Phase 1b/2 Javelin PARP Medley study, talazoparib (1mg PO daily) is given 
concurrently with the PD-L1 inhibitor, avelumab (800mg Q2 weeks).  This regimen has 
demonstrated a modest response rate of 18.2% with an acceptable safety profile in heavily 
chemotherapy pre-treated mTNBC patients who are naïve to PARPi and/or immune therapies.14  
Notably, higher response rates were seen in tumors with DNA damage repair pathway mutations.  
Importantly, concurrent talazoparib and avelumab had a similar safety profile to either avelumab 
or talazoparib given as monotherapies.  Treatment related Grade 3 or higher adverse events, 
predominantly anemia, thrombocytopenia, or neutropenia, were successfully managed by either 
reducing the talazoparib dose to 0.75mg daily or dose interruption of both avelumab and 


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talazaporib.14  Dose reductions were necessary in a small minority of patients, and thus provide 
support for talazoparib 1mg daily dosing with atezolizumab in our proposed study.   
 
In another single arm, Phase 2 TOPACIO/KEYNOTE-162 study, niraparib used in combination 
with pembrolizumab also showed promising response rates and an acceptable safety profile in 
patients with mTNBC.25  Among 27 patients with BRCA wild-type tumors (tBRCAwt), the ORR 
was 11%, while among 15 patients with BRCA tumor mutations, the ORR was 47%.  Among 
tBRCAwt patients (n=27), 5 with mutations in the homologous recombination repair pathway 
had a higher ORR of 20%.25  Patients with PD-L1 positive disease had an ORR of 32%, 
independent of BRCA tumor status, indicating that this particular subset of patients may be more 
responsive to the combination of PARPi and immune therapy.  It is important to note, however, 
that PD-L1 positivity was higher in the tBRCAmut population (80%) compared to the tBRCAwt 
population (56%).25  Similar to the Javelin study, the most common grade 3 or higher adverse 
events were anemia (18%), thrombocytopenia (15%) and fatigue (7%).25  Two patients 
developed Grade 3 immune-related adverse events, which resolved after treatment with 
corticosteroids and interruption of niraparib or interruption/discontinuation of pembrolizumab.25  
Findings from these studies indicate efficacy in patients with mTNBC PD-L1 positive disease 
previously treated with chemotherapy and independent of BRCA status as well as acceptable 
rates of toxicity and thus support further exploration of PARPi with immune therapy, particularly 
in the context of high dose radiotherapy.  Indeed, given that radiation was not a component of 
treatment in any of the above studies, it is possible that higher response rates may be seen by the 
addition of this local therapy (see below).  As atezolizumab has already demonstrated activity in 
mTNBC patients with PD-L1 positive infiltrate, we propose combining talazoparib with high 
dose radiation and atezolizumab, specifically, in PD-L1+, mTNBC patients without gBRCA 
pathogenic variants.  
 
1.4 
Radiotherapy and Immune Therapy   
A number of both preclinical studies and clinical trials in a variety of cancers have shown 
promising synergism between radiotherapy and immune therapy leading to enhanced treatment 
efficacy.  Concurrent administration of anti-PD-L1 antibodies with radiotherapy in murine 
models increases CD8+ T cell responses associated with improved local tumor control.26  
Preclinical evidence indicates that at least part of the clinical effectiveness of radiation is due to 
its ability to induce local cell death with a release of immunogenic factors termed “immunogenic 
cell death.”  Ionizing radiation-mediated tumor regression is dependent on the adapter protein 
STING for type I interferon-dependent antitumor effects of radiation.27  This allows for 
mobilization of several host immune effector mechanisms that stimulate anti-tumor immune 
activity.  There are several immune effector mechanisms that have been described in the 
literature including the creation of an inflammatory microenvironment characterized by the 
release of tumor antigens and danger-associated molecular patterns including calreticulin, ATP 
and high-mobility group protein B1 (HMGB1).28,29 Increased production and recruitment of 
proinflammatory cytokines and chemokines have also been proposed to play a role in host 
response to ionizing radiation. These processes change the phenotype of tumor cells resulting in 
upregulation of cell-surface molecules that ultimately render these tumors more susceptible to T-
cell-mediated anti-tumor effects.30  
 


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Additionally, local radiotherapy may have systemic effects.  The abscopal effect has been 
described in patients treated with radiotherapy to select metastatic lesions leading to shrinkage of 
non-irradiated tumors outside of the radiation field.31  Such “bystander” effects have been seen in 
murine models and in clinical studies of patients treated with immune therapy and radiotherapy 
with augmented T cell responses in both the primary and metastatic lesions both within and 
outside of the radiation field.32,33  Radiotherapy is believed to emulate the effect of a vaccine by 
sensitizing the host immune system to recognize previously unnoticed tumor cells.  High dose 
radiotherapy has been shown to improve antitumor T-cell responses and the upregulation of 
MHC molecules on cancer cells.  However, as with PARPi, immunosuppressive pathways, such 
as PD-L1/PD-1 are also induced which inhibits the ability of radiotherapy to enhance a patient’s 
immune system against the cancer cells.  While upregulation of PD-L1 in the tumor 
microenvironment (TME) negatively impacts T-cell function and T-cell mediated anti-tumor 
activity, the combination of radiotherapy and anti-PD1 or anti-PDL1 blockade can potentiate the 
immune response of T-cells and intra-tumoral T-cell infiltration to enhance anti-tumor activity in 
these tumor cells.    Therefore, the addition of a PD-L1 inhibitor to high dose radiation has the 
potential to mitigate the immunosuppressive effects of radiotherapy, thereby enhancing anti-
tumor immune activity.  Immune therapy may also modulate the tumor microenvironment by 
normalizing tumor vessels, enhance tumor vessel perfusion, thereby reducing tumor hypoxia and 
promoting radiosensitivity.34,35   
 
A number of both preclinical studies and clinical trials in a variety of cancers have shown 
promising synergism between radiotherapy and immune therapy leading to enhanced treatment 
efficacy.  The combination of radiotherapy and PD-L1 signaling blockade has been shown to 
improve not only local control, but also long-term survival compared with radiotherapy alone in 
mice models supporting the synergistic interaction between irradiation and anti-PD-L1 
strategies.32,33, 36, 37,38  Several Phase I and Phase II studies have tested both the safety and 
efficacy of radiation in combination with immune therapies in patients with a variety of cancers 
including TNBCs.  Many have taken advantage of intensity modulated radiation therapy (IMRT) 
and stereotactic body radiation therapy (SBRT) to deliver high doses of focused radiation in a 
short period of time in order to elicit a heightened immune response.39  Importantly, no increase 
in toxicity has been demonstrated when using SBRT with immune therapy agents (e.g. 
pembrolizumab) relative to either treatment alone in women with TNBC.30,31,40   Indeed, in a 
recent Phase II trial, the combination of high dose radiotherapy to 1 to 4 lesions and 
pembrolizumab lead to a 33% overall response rate outside of the radiation field in heavily 
chemotherapy pre-treated mTNBC patients with acceptable rates of toxicity.40  The combination 
of radiotherapy and immune therapy, therefore, appears to be more potent than either treatment 
alone.32,33,41 There are several prospective trials utilizing concurrent radiotherapy with immune 
therapy particularly in lung cancer, melanoma, and head and neck malignancies and studies in 
oligometastatic breast cancer.  Given the recent approval of atezolizumab plus nab-paclitaxel in 
mTNBC and no competing trials of PARPi, radiotherapy and immune therapy in mTNBC 
patients previously treated with chemotherapy and/or immune therapy, an opportunity arises to 
study the ability of radiation in combination with talazoparib and atezolizumab to elicit 
responses in heavily pretreated patients who are naïve to atezolizumab and/or restore sensitivity 
to atezolizumab in patients previously treated with this agent.  Notably, this combination of 
treatments has not been studied in mTNBC PD-L1+ patients.  The potential for concurrent 
talazoparib and high dose radiotherapy to enhance immune response to anti-PDL1 blockade is an 


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exciting opportunity for patients with mTNBC PD-L1+ tumors regardless of gBRCA status.  
Given the limited treatment options available for these patients and the potential to upregulate 
PD-L1 with talazoparib and radiotherapy, we will enroll gBRCA1/2 negative subjects with PD-
L1 positive mTNBC to the proposed study.    
 
1.5 
Rationale for Radiation Dose and Timing  
The optimal dose and timing of radiotherapy when given with PARPi or immune therapy in 
breast cancer patients is based on preclinical and small patient studies.   Several preclinical and 
clinical studies indicate that PARPi given prior to and concurrently with radiotherapy enhances 
radiosensitivity of tumor cells.16,42-49  Murine models of breast carcinoma indicate that repeated 
radiation doses of 8Gy x 3 fractions result in priming of CD8+T cells that mediate the abscopal 
effect in the context of immune checkpoint blockade, while higher doses of 12 Gy and above in a 
single fraction attenuates immunogenicity.50  In vitro studies have also demonstrated that SBRT 
given over three daily doses of 10 Gy to breast cancer cell lines upregulates PD-L1.39  From 
these studies, moderately hypofractionated doses of 8 Gy x 3 or 6 Gy x 5 appear to be more 
effective in priming the immune system for immune therapy compared to a single high dose 
XRT treatment.51  Repeated fractions of 8 Gy have been shown to be effective at synergizing 
with CTLA-4 and PD-1 blockade.50  In one case report of a PD-L1 inhibitor given concurrently 
with conventionally fractionated radiation, there was no increase in acute toxicities.52  In studies 
of PD-1 inhibitors given with radiotherapy (30 Gy in 5 fractions) in mTNBC patients, four of 9 
women assessed 13 weeks after radiation had stable or partial responses which were durable for 
at least 22 weeks, while side effects were mild and included fatigue, myalgia, and nausea.40 The 
optimal timing of XRT with immune therapy has also been studied with CTLA-4 targeted 
therapy.  In these preclinical and clinical studies, radiotherapy administered concurrently or 
immediately before CTLA-4 blockade was associated with the best abscopal responses.51 Despite 
the excitement generated by the above studies, it is also important to acknowledge the results of 
the recent randomized, non-comparative phase 2 TONIC trial of primer treatments. In this study, 
mTNBC patients were treated with adriamycin, cyclosphosphamide, cisplatin, or 8Gy x 3 
radiation to one metastatic lesion over a two-week period prior to nivolumab, a PD-1 inhibitor.  
Among all induction therapies, radiation produced a low ORR of 8% while doxorubicin 
produced a high ORR of 35%.53  One potential reason for these disappointing results is the 
timing of the radiation.  As noted above, previous studies indicate that PD-1 blockade must be 
initiated within a week of radiation completion and preferably concurrently to maximize synergy 
between radiotherapy and immune checkpoint blockade.54   The timing of radiotherapy could 
explain the low ORR rates in the TONIC trial.  Therefore, it is possible and likely that 
radiotherapy given to 1-4 lesions concurrently with talazoparib and immune therapy, as proposed 
in the current study, may improve upon the otherwise low response rates previously observed in 
mTNBC patients.   
 
In this current study, we propose to initiate talazoparib 12 days before radiation (8Gy x 3 
fractions administered every other day to 1 to 4 extracranial metastatic lesions to minimize the 
number of days of treatment while maximizing the potential for efficacy).  Atezolizumab will be 
initiated after the first but prior to the second fraction of radiotherapy and preferably on the same 
day to elicit the highest potential response rates from the combination of these therapies.   
 
 
 


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1.6 
Hypothesis  
We hypothesize that talazoparib, high dose radiation, and atezolizumab will be effective, as 
measured by ORR, and safe in gBRCA negative mTNBC patients with PD-L1+ tumor infiltrate.  
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
Estimate objective response rate (ORR) of talazoparib, high dose radiotherapy and atezolizumab, 
eight weeks after the first dose of atezolizumab in non-irradiated lesion(s) of gBRCA1/2 
pathogenic variant negative mTNBC patients whose tumors are immune cell (IC)-positive. 
 
2.1.2 Secondary Objectives 
• Determine the frequency and severity of adverse events using CTCAE v 5.0 after 
induction talazoparib followed by concurrent talazoparib, high dose radiation, and 
atezolizumab given as second, third, or fourth-line treatment for PD-L1 positive 
metastatic triple negative breast cancer (mTNBC) (≥ 2 lesions)  
• Obtain progression free survival (PFS) data in gBRCA 1/2 negative mTNBC patients 
with PD-L1 positive infiltrate treated with talazoparib, radiation, and atezolizumab 
• Obtain overall survival (OS) data in gBRCA 1/2 negative mTNBC patients with PD-L1 
positive infiltrate treated with talazoparib, radiation, and atezolizumab 
• ORR by immune-related RECIST (irRECIST) 
• Determine duration of overall response (DOR) to talazoparib, high dose radiation, and 
atezolizumab given in the second or third-line setting to gBRCA1/2 negative mTNBC 
patients with PD-L1 positive infiltrate 
• Determine disease control rate (DCR) in gBRCA1/2 negative patients with PD-L1 
positive infiltrate treated with talazoparib, high dose radiation, and atezolizumab given in 
the second or third-line setting  
• Determine time to progression (TTP) in gBRCA1/2 negative mTNBC patients with PD-
L1 positive infiltrate treated with talazoparib, high dose radiation, and atezolizumab 
given in the second or third-line setting 
• Determine adherence to prescribed talazoparib, high dose radiation, and atezolizumab in 
the second or third-line setting among PD-L1 positive mTNBC patients 
• Determine best overall tumor response in each patient to talazoparib, high dose radiation, 
and atezolizumab in the second or third-line setting among PD-L1 positive mTNBC 
patients  
 
2.1.3 Correlative/Exploratory Objectives 
• Assess patient reported outcomes (PRO) measures of quality of life and fatigue before 
talazoparib, during and after radiation and atezolizumab in mTNBC patients with PD-L1 
positive infiltrate treated with talazoparib, radiation, and atezolizumab 
• Collect and store peripheral blood and plasma collected from gBRCA1/2 negative 
mTNBC patients with PD-L1 positive infiltrate before, during, and after treatment with 
talazoparib, radiation, and atezolizumab.  (Philanthropic institutional funds will be used 
to support such studies and additional funding sources will be identified to conduct future 


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studies that explore the relationship between ctDNA, inflammatory cytokines, and 
number and types of B cells and ORR, PFS, and OS as well as side effects of treatment 
including immune-related adverse events.)   
• Collect and store FFPE of tumor tissue from any metastatic lesion and fresh tumor tissue 
from one non-irradiated metastatic breast cancer site before and after radiotherapy in a 
subset of patients from gBRCA1/2 negative mTNBC patients (n~10 patients) for future 
analyses.  Of note, every effort should be made to biopsy the same non-irradiated site 
prior to and after radiotherapy.  (Philanthropic institutional funds will be used to support 
such studies and additional funding sources will be identified to explore the relationship 
between the number and distribution of myeloid cells and ORR, PFS, and OS. 
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
The primary endpoint of the study is the objective response rate (ORR) in non-irradiated 
lesion(s) assessed 8 weeks after the first dose of atezolizumab in gBRCA 1/2 pathogenic variant 
negative mTNBC patients with PD-L1 positive infiltrate treated with induction talazoparib and 
then concurrent high dose radiotherapy and atezolizumab in the second or third line setting. This 
measure of response and timepoint were chosen to emulate the study design of Impassion130.  
Historic control data of ORR of 10% in gBRCA1/2 negative and 45% in gBRCA1/2 patients 
with mTNBC treated with PARPi and immune therapy in the 2nd or third line setting will be 
used.11,25  The majority of patients enrolled on this study will be prescribed radiotherapy to 
palliate symptoms, prevent symptoms (e.g. bone fracture, neurological compromise, tumor 
invasion into critical structures), and prevent tumor growth in 1 to 4 metastatic lesions.  Previous 
studies of PET/CT, MRI, CT of the chest, abdomen and pelvis as well as bone scan have been 
used to evaluate breast cancer metastases and response to immune therapy and radiotherapy.7,55-
58  In one study, 96% of patients had at least a partial response to radiotherapy on PET/CT with a 
median time to first post-therapy PET of 1.2 months (range; 0.5-4.1).57  These imaging options 
are considered standard of care in patients and will be covered by insurance.    
 
2.2.2 Secondary Endpoints 
• Frequency and severity of adverse events using CTCAE v. 5.0 up to 12 weeks post first 
dose of atezolizumab will be described in patients treated with induction talazoparib 
followed by concurrent high dose radiation and atezolizumab given as second or third-
line treatment for PD-L1 positive metastatic triple negative breast cancer (mTNBC) (> 2 
lesions)  
• Progression free survival (PFS) is defined as the day of study treatment initiation until 
disease progression by RECIST 1.1 or death whichever occurs first. 
• Overall survival (OS) is defined as the day of study treatment initiation until death from 
any cause. 
• ORR by immune-related RECIST (irRECIST) which will include confirmed complete 
response (CR) + confirmed partial response (PR) determined as per irRECIST 
• Duration of overall response (DOR) is defined as the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since treatment started). 


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• Disease control rate (DCR) is defined as the percentage of patients with advanced or 
metastatic cancer who have achieved complete response, partial response and stable 
disease.  
• Time to progression (TTP) is defined as the day of study treatment initiation until disease 
progression by RECIST 1.1. 
• Adherence to prescribed talazoparib, high dose radiation, and atezolizumab in the second 
or third-line setting among PD-L1 positive mTNBC patients measured by intravenous 
infusion, oral medication, and radiation treatment compliance with prescribed systemic 
therapy and radiation dose and days of treatment. 
• Best overall tumor response is defined as the best response recorded from the start of the 
study treatment until disease progression/recurrence.   
   
3. 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Be willing and able to provide written informed consent/assent and HIPPA for the trial.  
 
2. Ages 18-75 years old at time of consent.  Female or male patients allowed. 
 
3. ECOG PS of 0-2, KPS > 60%. 
 
4. Biopsy proven metastatic triple negative breast cancer (estrogen receptor (</= 10%), 
progesterone receptor (</= 10%) and no overexpression of HER2 as evaluated by local 
institutions with at least 2 exracranial lesions of metastatic disease on imaging. 
 
5. PD-L1 positive tumor infiltrate as defined as >1% on IHC using the SP142 Ventana 
Assay. 
 
6. Known gBRCA1/2 status (gBRCA 1/2 negative [e.g. gBRCA wild-type, gBRCA variants 
of uncertain significance] are eligible]). 
 
7. Patients must have at least 1 extracranial metastatic lesion of measurable or non-
measurable disease by RECIST v1.1) that is amenable to high dose radiotherapy and at 
least one additional extracranial lesion of measurable disease by Response Evaluation 
Criteria in Solid Tumors (RECIST v1.1) that will not be treated with radiotherapy on this 
study. Of note, lesions maybe in the same organ but must be 2 cm apart and breast lesions 
may be treated. 
 
8. Patients must have received at least one and no more than three previous lines of 
systemic treatment in the advanced setting with or without immune therapy. Patients with 
disease recurrence or progression following neoadjuvant or adjuvant cytotoxic 
chemotherapy are not eligible unless they have received at least one line of chemotherapy 
with or without immune therapy in the advanced setting. NOTE: Targeted small 
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that inhibit angiogenesis (e.g. bevacizumab, afilbercept) are not counted in the number of 
lines of therapy. Cytotoxic chemotherapy with or without immune therapy for advanced 
disease prior to protocol treatment is not permitted within 2 weeks of the protocol 
treatment.  Patients may or may not have received radiotherapy or neoadjuvant or 
adjuvant chemotherapy in the treatment of their initial, non-metastatic breast cancer, but 
must be entered on study 2 weeks after their last dose of radiotherapy, last cycle of 
chemotherapy and biologic therapy (if applicable) for mTNBC and have sufficient 
resolution of side effects per physician assessment at time of talazoparib. 
 
9. Demonstrate adequate organ function as defined in the table below. All screening labs to 
be obtained within 14 days prior to registration. 
• Absolute neutrophil count > 1500/mcL 
• Platelets > 100,000 mm 
• Anemia > 9.0 g/dL (NOTE: The use of transfusion or other intervention to 
achieve Hgb > 9.0g/dl is acceptable) 
• Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or calculated creatinine 
clearance ≥ 60 mL/min using Cockcroft-Gault equation for patients with 
creatinine levels > 1.5× institutional ULN  
• Total bilirubin ≤ 1.5× ULN OR direct bilirubin ≤ 1× ULN  
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5× 
ULN unless liver metastases are present, in which case they must be ≤ 5×ULN  
• International normalized ratio (INR) or prothrombin time (PT) ≤1.5× ULN unless 
patient is receiving anticoagulant therapy as long as PT or partial thromboplastin 
time (PTT) is within therapeutic range of intended use of anticoagulants  
• Activated partial thromboplastin time (aPTT) ≤ 1.5× ULN unless patient is 
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
 
10. Patients must be eligible for radiotherapy, talazoparib, and atezolizumab. 
 
11. Females of childbearing potential must have a negative serum or urine pregnancy test 
within 14 days prior to Cycle 1 Day 1. If a urine test is done and it is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required. NOTE: Females are 
considered of child bearing potential unless they are surgically sterile (have undergone a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally 
postmenopausal for at least 12 consecutive months. 
 
12. Women of childbearing potential and males must agree to use two effective methods of 
contraception or complete abstinence, from the time of signing the informed consent 
(females) or first day of study treatment (males), during the course of the study and for 7 
months (females) and for 4 months (males) after the last dose of study drug.  
 
13. Patients must not have active wound healing issues from surgery and sufficient resolution 
of surgical side effects, per physician assessment, at time of radiotherapy. 
 


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14. During participation on this study, no other investigation or commercial agents or therapy 
for cancer other than bisphosphonate, rank ligand inhibitors, atezolizumab, radiotherapy 
and talazoparib should be administered. NOTE: Patients may have received 
bisphosphonates or rank ligand inhibitors prior to and while on enrollment on study.     
 
15. Patients must have the psychological ability and general health that permits completion of 
the study requirements and required follow up. 
 
3.2 
Exclusion Criteria  
Subjects meeting any of the criteria below may not participate in the study: 
 
1. gBRCA1/2 pathogenic variant positive 
 
2. Four or more lines of cytotoxic chemotherapy for mTNBC.  
 
3. Previous radiation to the metastases to be treated with radiation on this protocol.  
 
4. Previous PARPi treatment (e.g. talazoparib, niraparib, olazaparib). 
 
5. Progression of breast cancer within the first 3 months of prior immune therapy for non-
metastatic or metastatic breast cancer. 
 
6. Untreated CNS disease (patients with stable CNS disease for at least 28 days and 
asymptomatic treated CNS metastases are permitted). 
 
7. History of leptomeningeal disease. 
 
8. History of autoimmune disease that has required systemic treatment (i.e. with use of 
disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.  
 
9. Use of systemic glucocorticoid or immunosuppressive medications at time of enrollment. 
 
10. Severe, active co-morbidity such as CHF or unstable angina within last 6 months, 
transmural MI within the last 6 months.  
 
11. Acute bacterial or fungal infection requiring IV antibiotics at time of registration. 
 
12. COPD or other respiratory illness requiring hospitalization at time of registration. 
 
13. HIV positive with CD4 count <200 cells/ microliter. 
 
14. Current hormone replacement therapy use. 
 
 
 


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15. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy. Indolent cancers (such as low risk 
prostate or in-situ cancers) that are not being treated, are acceptable. 
 
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.  
 
17. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
18. Receipt of the last dose or treatment of anti-cancer chemotherapy, radiotherapy, surgery, 
endocrine therapy, targeted therapy, biologic therapy, or tumor embolization ≤ 2 weeks 
(4 weeks for any monoclonal Antibody (mAb), 6 weeks for nitrosoureas or mitomycin C) 
prior to first dose of study treatment, or has not recovered (i.e., to ≤Grade 1 or Baseline) 
from clinically significant adverse events (AEs) due to these previously administered 
agents. 
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through HCRN’s electronic data capture (EDC) system. Subjects 
must be registered prior to starting protocol therapy.  
 
5. 
TREATMENT PLAN  
This is a Phase II study designed to assess efficacy and safety of talazoparib, high dose radiation, 
and atezolizumab in patients with metastatic TNBC that is PD-L1 positive. A total of 23 gBRCA 
pathogenic variant negative patients will be enrolled.  All patients will be treated with induction 
talazoparib of 1mg PO daily starting Day 1. Patients will then receive 8 Gy x 3 fractions to 1-4 
metastatic lesions beginning Day 12,13, or 14 and given QOD.  840 mg of atezolizumab will be 
given intravenously (IV) on Day 15 of the 1st cycle and then on Day 1 and Day 15 of the 
remaining cycles.  The sequence of administration is not specified on the days in which 
talazoparib and atezolizumab are given on the same day.  Each cycle equals 28 days. Treatment 
will continue until progression or severe toxicity.   
 
A safety lead in of up to 6 patients will be performed.  Immune-related and non-immune related 
adverse events will be tracked up to 12 weeks post initiation of atezolizumab, as the majority of 
treatment-related toxicities from talazoparib, radiation, and atezolizumab occur within this time 
period. Further details are described below. 
 
 


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5.1 
Study Treatment Administration 
 
Drug1 
Dose 
Route 
Schedule2 
Cycle 
Length 
Talazoparib 
1 mg  
Orally 
Day 1 to Day 28 
4 weeks  
(28 days) 
Atezolizumab 
840 mg  
IV over 60 
minutes  
Day 15 of Cycle 1 then 
Day 1 and Day 15 of subsequent Cycles 
Radiation 
8 Gy 
NA  
3 fractions given QOD beginning 
Day 12, 13 or 14 of Cycle 1 but  
24-72 hours prior to 1st dose of Atezolizumab 
1 A window of ± 5 days may be applied to all study visits to accommodate observed holidays, inclement 
weather, scheduling conflicts etc. Date and time of each drug administration should be clearly 
documented in subject’s chart and electronic case report forms (eCRFs). Timing of Cycle 1 treatment 
should be followed as outlined. 
 
5.1.1 Talazoparib 
Talazoparib 1 mg total dose will be taken orally once a day on Day 1 through Day 28. 
Talazoparib can be taken with or without food. If a subject misses a dose, they should take their 
next dose at the scheduled time. The capsule should be swallowed whole and must not be 
dissolved or crushed. Subjects will be asked to complete a drug diary and bring the diary in 
addition to medication for reconciliation. For patients with moderate renal impairment (CrCl ≤ 
59 mL/min) after Cycle 1, the recommended dose of Talazoparib is 0.75 mg once daily. 
 
5.1.2 Atezolizumab   
Atezolizumab 840 mg will be delivered as an IV infusion on Day 15 of Cycle 1 then Day 1 and 
15 of each cycle starting at Cycle 2 (every 2 weeks). The initial dose will be delivered over 60 
minutes (± 15). If the first infusion is tolerated, all subsequent infusions may be delivered over 
30 minutes (+10 minutes/- 5 minutes). Atezolizumab infusions instructions outlined in the Table 
below. 
 
No premedication is indicated for the administration of the first treatment of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) with the first treatment of 
atezolizumab may receive premedication with antihistamines or antipyretics/analgesics (e.g., 
acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in treating 
atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 
 
5.1.2.1 Guidelines for Medical Management of Infusion-Related Reactions (IRRs)  
Guidelines for medical management of IRRs during the first treatment are provided in the Table 
below.  For subsequent cycles, IRRs should be managed according to the package insert and 
institutional guidelines. Guidelines are provided below for reference. 
 
 
 


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5.1.2.2 Management Guidelines for Infusion-Related Reactions 
 
Event 
Management 
IRR, Grade 1  
● Reduce infusion rate to half the rate being given at the time of event onset. 
● After the event has resolved, the investigator should wait for 30 minutes while 
delivering the infusion at the reduced rate. 
● If the infusion is tolerated at the reduced rate for 30 minutes after symptoms 
have resolved, the infusion rate may be increased to the original rate. 
● Monitor vital signs as clinically indicated 
IRR, Grade 2 
● Interrupt atezolizumab infusion. 
● Administer aggressive symptomatic treatment (e.g., oral or IV antihistamine, 
anti-pyretic medication, glucocorticoids, epinephrine, bronchodilators, oxygen). 
● After symptoms have resolved to baseline, resume infusion at half the rate being 
given at the time of event onset. 
● For subsequent infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics and monitor closely for IRRs. 
● Monitor vital signs as clinically indicated 
IRR, Grade 3 or 
4 
● Stop infusion. 
● Administer aggressive symptomatic treatment (e.g., oral or IV antihistamine, 
anti-pyretic, glucocorticoids, epinephrine, bronchodilators, oxygen). 
● Monitor vital signs as clinically indicated 
● Hospitalization indicated for clinical sequelae (examples: renal impairment, 
pulmonary infiltrates) 
● Permanently discontinue atezolizumab. a 
IRR = infusion-related reaction. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate). 
 
5.1.3 Radiation Therapy 
The first dose of radiation to 1-4 extracranial metastatic lesions (breast treatment is allowed) will 
be given on Day 12, 13, or 14 of Cycle 1 and 24-72 hours prior to the first dose of atezolizumab 
(typically Day 15).  If administration of XRT is outside this window, the site will contact HCRN 
who will contact the sponsor investigator for approval.  Radiotherapy will continue for a total of 
24 Gy to each targeted metastatic lesion at 8 Gy per fraction for a total of 3 fractions given every 
other business day excluding weekends and holidays.  Delivering the first dose of atezolizumab 
just before but on the same day as the 2nd XRT fraction is preferable.  Other radiation 
fractionation schemes are not allowed.  Additional information is in Section 10.3. 
 
PTV goal coverage is at least 95% of the PTV covered by at least 95% of the prescribed dose 
with dose not exceeding 115% of the prescribed dose. 1-4 metastatic target lesions separated by 
at least 2cm may be treated. Radiation treatment to previously irradiated lesions or within 2 cm 
of previously irradiated sites is not permitted.  
 
Variation acceptable is 95% of the prescribed dose must cover >70% of the PTV (95% of the 
prescribed dose to 70-95% of the PTV is permitted.)   
 
Deviation unacceptable is < 70% coverage of the PTV by 95% of the prescribed dose.   


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Acceptable variation for radiation treatment duration is radiation treatment completion of all 
three radiation fractions in >4 but < 10 consecutive business days excluding holidays.   
 
Unacceptable Deviation for radiation treatment duration is radiation treatment completion in > 
10 consecutive business days excluding holidays. 
 
Surgery is not allowed for 30 days prior to or during radiotherapy but may be permitted after 
radiotherapy is completed.   
 
If re-irradiation of the index lesion (s) is deemed necessary after protocol treatment, it is 
preferred that re-irradiation be performed 3 months or later after initial radiation and after the last 
protocol assessment and should only be considered at least 4 weeks after initial treatment on 
protocol.  If re-irradiation of the index lesion occurs, it must be documented. 
 
5.2 
Safety Lead In 
Immune-related and non-immune related adverse events will be tracked up to 12 weeks post 
initiation of atezolizumab, as the majority of treatment-related toxicities from talazoparib, 
radiation, and atezolizumab occur within this time period.  Accrual will be halted after the 3rd 
and 6th subject until the 12-week post atezolizumab timeframe is met. 
 
The combination of talazoparib, radiation, and atezolizumab will be deemed unsafe if any of the 
following occur:  
• Two of the first 3 patients enrolled develop Grade 2 irAEs and are unable to resume 
systemic therapy within 8 weeks due to treatment-related toxicities OR 
• Two of the first 3 patients enrolled develop Grade 3 or higher irAEs OR 
• Two of the first 3 patients enrolled develop: 
o Grade 3 or higher febrile neutropenia 
o Grade 3 thrombocytopenia with bleeding event 
o Grade 4 neutropenia, anemia, or thrombocytopenia 
o Any clinically meaningful Grade 3 non-hematologic event that leads to 
hospitalization or a medical intervention other than electrolyte or IVF support as 
deemed by site investigator 
o Any Grade 4 or higher non-hematological event with the exception of Grade 4 
fatigue.   
 
If these toxicities occur in 1 or fewer of the first 3 patients enrolled, the trial will proceed to 
enroll an additional three patients.   
 
If 2 of the first 6 patients enrolled develop Grade 2 irAEs and are unable to resume systemic 
therapy within 8 weeks due to treatment-related toxicities or any of the above named Grade 3 or 
higher irAEs or non-irAEs, the study treatment will be deemed unsafe and the trial will be 
stopped.   
 
If one or fewer of the first 6 patients enrolled develop one of the above toxicities, the trial will 
continue to enroll the remaining patients unless the treatment is found to be ineffective during 
the planned interim analysis or until enrollment is complete. 


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5.3 
Concomitant Medications 
Any concomitant medications and treatment will be recorded from 30 days prior to talazoparib 
and up to the Day 30 safety visit after study treatment is discontinued whether they are breast or 
non-breast cancer related therapies.   
 
5.3.1 Allowed Concomitant Medications and Supportive Care 
The following concurrent medications are permitted and should be recorded in the source 
documents and transferred to OnCore EDC: 
• Antiemetics 
• Antidiarrheal therapy 
• Antiallergic measures, such as antihistamines, and corticosteroids 
• Bisphosphonates – patients may be on it already or may initiated treatment while on 
protocol therapy 
• Agents used to assist in management of therapy-induced side effects (NSAIDS, 
gabapentin, venlafaxine) 
• Diabetes management medication including metformin 
• Rank Ligand inhibitors 
• Pain medications 
• P-gp inhibitors are allowed but talazoparib dose will be reduced to 0.75mg once daily 
when coadministered with P-gp inhibitors including amiodarone, carvedilol, 
clarithromycin, itraconazole, and verapamil.  When the P-gp inhibitor is discontinued, 
increase talazoparib dose after 3-5 half-lives oft eh P-gp inhibitor to the dose used prior 
to the intitiation of the P-gp inhibitor. 
 
All supportive therapy will be given during the study period at the discretion of the treating 
physician(s) to optimize medical care as long as they are within the parameters of the protocol 
and documented on each site’s source documents as concomitant medication:  
• Anticonvulsants if indicated 
• Anti-emetics may be given prior to each fraction to prevent nausea 
• Antidiarrheal as indicated by symptomatic diarrhea  
• Analgesic premedication or to avoid general discomfort during simulation and treatment 
is recommended when appropriate. 
• Analgesic medications to decrease pain  
• Medications for neuropathy (e.g. gabapentin) 
• Corticosteroids if indicated 
• Herbal products are at the treating physicians’ discretion and should be captured on the 
concomitant medication forms.  
• Nutritional supplementation may be administered per standard indications and should be 
captured on the concomitant medication forms.  
• Highly active antiretroviral therapy (HAART) is permitted for HIV affected individuals 
• Medications for gastritis and esophagitis including proton pump inhibitors and magic 
mouthwash  
• G-CSF or pegylated G-CSF may be given in the rescue setting during protocol treatment 
and ANC must be recovered to entrance values for the protocol    
 


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5.3.2 Prohibited Concomitant Medications 
• Anticancer therapies such as chemotherapy other than talazoparib, immunotherapies 
other than atezolizumab, targeted therapy other than radiotherapy, etc. other than 
allowed on protocol.   
• Hormone replacement therapy (see exclusion criteria) 
• Chronic immunosuppressive therapies 
 
5.3.3 Medications not recommended 
• Herbal medicine is not recommended during the treatment phase 
 
5.4 
Reproductive Information 
Negative pregnancy test done ≤ 14 days prior to treatment, for women of childbearing potential 
only. Female subjects should be using highly effective contraceptive measures, and must have a 
negative pregnancy test or must have evidence of non-child-bearing potential by fulfilling one of 
the following criteria at screening: 
• Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 
months following cessation of all exogenous hormonal treatments. 
• Women under 50 years old would be consider postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and with LH and FSH levels in the post-menopausal range for the institution 
• Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, bilateral salpingectomy or tubal ligation 
 
Women of childbearing potential and males must agree to use one highly effective method or 
two effective methods of contraception, from the time of signing the informed consent 
(females)/first day of study treatment (males), during the course of the study and for 7 months 
(females) and 4 months (males) after the last dose of study drug. Abstaining from heterosexual 
intercourse is considered an effective method of contraception. 
 
 
5.4.1 Contraception Options 
Highly effective methods 
Other effective methods  
(barrier methods) 
Intra-uterine devices (IUD) 
Latex condom 
Diaphragm with spermicide; Cervical cap; 
Sponge 
If the highly effective method cannot be used, using two effective methods at the same time 
are recommended. 
 
 
 


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6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used to grade 
adverse events. Subjects enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and at regular intervals during their participation in this study as specified 
in Study Calendar & Evaluations. Subjects will be evaluated for adverse events (all grades), 
serious adverse events, and adverse events requiring study drug interruption or discontinuation as 
specified in Study Calendar & Evaluations.   
 
6.1 
Talazoparib Dose Modifications and Toxicity Management  
Dose or treatment modification for talazoparib are allowable and may occur as dose reductions, 
interruptions (within a cycle), or dose delays (between cycles) during the cycle or at the start of a 
new cycle.  Per package insert, the dose of the talazoparib may be reduced from 1.0 to 0.75 mg 
PO Daily.  However, talazoparib should be withheld completely for the adverse reactions listed 
in the table below until blood levels resolve. Further dose reductions are allowed to 0.5 mg and 
0.25mg PO daily per investigator’s brochure.  In general, cycles should be 28 days long unless 
the start of a new cycle is delayed.  If doses are missed within a cycle and the AE resolves before 
the end of the cycle, then the patient can resume taking the talazoparib for the remainder of the 
cycle.  The start of a new cycles should be delayed according to guidelines below if the AE 
requiring a dose hold has not resolved by Day 1 of the next planned cycle.  Talazoparib should 
be withheld in the following scenarios: 
 
Adverse Reaction 
Withhold Talazoparib 
until levels resolve to 
Resume Talazoparib 
Hemoglobin < 8g/dL 
Hemoglobin > 9g/dL 
Resume talazoparib at 
reduced dose 
Platelet Count < 50,000/uL 
Platelet Count ≥ 50,000/uL 
Neutrophil Count < 1,000/uL 
Neutrophil Count ≥1,500/uL 
Non-hematologic Grade 3 or 4 
< Grade 1 
Consider resuming 
talazoparib at reduced dose 
or discontinue 
 
For patients with moderate renal impairment (CrcL 30 – 59 mL/min), the recommended dose of 
Talazoparib is 0.75 mg once daily.  For patients with severe renal impairment (15mL/min 
<crCL<30mL/min), the recommended dose of talazoparib is 0.5mg once daily.  Talazoparib has 
not been studied in patients requiring hemodialysis.   
 
Talazoparib dose will be reduced to 0.75mg once daily when coadministered with P-gp inhibitors 
including amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil.  When the P-gp 
inhibitor is discontinued, increase talazoparib dose after 3-5 half-lives of the P-gp inhibitor to the 
dose used prior to the initiation of the P-gp inhibitor. 
 
Investigators should manage their patients according to medical judgment and specific dose 
delays or interruptions recommended by the talazoparib investigator’s brochure (see Additional 
Information) 
 
 
 


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6.2 
Atezolizumab Dose Modification and Toxicity Management 
Treatment modification for atezolizumab is allowable and may occur as dose interruptions 
(within a cycle) or dose delays (between cycles).  The dose of the atezolizumab should not be 
reduced.  In general, cycles should be 28 days long unless the start of a new cycle is delayed.  If 
doses are missed within a cycle and the AE resolves before the end of the cycle, then the patient 
can resume taking the atezolizumab for the remainder of the cycle but should still stop on Day 15 
to maintain the 13-day break.  The start of a new cycle should be delayed according to guidelines      
in Appendix I if the AE requiring a dose hold has not resolved by Day 1 of the next planned 
cycle.   
 
Investigators should manage their patients according to medical judgment and specific dose 
delays or interruptions recommended by the atezolizumab investigator’s brochure. See Appendix 
I for toxicity management guidelines. Atezolizumab is not withheld for hematologic adverse 
reactions.   
 
6.3 
Radiation Therapy Dose Modification and Toxicity Management 
One to four extra-cranial metastatic lesions (breast treatment is allowed) will be each treated to a 
dose of 24 Gy at 8 Gy per fraction.  The irradiated lesions may be measurable or non-measurable 
by RECIST v 1.1. criteria.  The non-irradiated lesion must be measurable disease by RECIST v 
1.1 criteria.  Treatments should be given every other business day, excluding weekends and 
holidays.  No dose reduction in radiation is permitted, but dose interruptions are allowed.  
Radiation treatment breaks for up to 3 consecutive business days (excluding planned holidays) 
for radiotherapy-related toxicities or personal reasons are allowed as per the investigator’s best 
medical judgment.  
 
6.4 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined in section 6.1, a 
subject will also be discontinued from protocol therapy and followed per protocol under the 
following circumstances outlined below.  The reason for discontinuation of protocol therapy will 
be documented on the electronic case report form (eCRF)   
• Documented disease progression per RECIST 1.1 (NOTE: a follow-up scan 4 weeks 
after disease progression may be obtained at the discretion of the investigator to confirm 
disease progression if the clinician suspects pseudoprogression on imaging and feels the 
patient is deriving clinical benefit from the study treatment) 
o Local recurrence – defined as disease progression in sites treated with 
radiotherapy on this protocol.  Radiologists will take care to differentiate treated, 
sclerotic reactions from true progression of disease.   
o Distant disease progression – defined as radiological evidence of disease 
progression or recurrence in location (s) other than those treated with 
radiotherapy on this protocol 
• Site investigator determines a change of therapy would be in the best interest of the 
subject 
• Subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or 
for other reasons. NOTE: If a subject decides to prematurely discontinue protocol 
therapy (“refuses treatment”), the subject should be asked if he or she may still be 


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contacted for further scheduled study assessments. The outcome of that discussion should 
be documented in both the medical records and in the eCRF. 
• Female subject becomes pregnant  
• Protocol therapy is interrupted for ≥ 64 days.  
 
6.5 
Protocol Discontinuation  
If a subject decides to discontinue from the protocol (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as possible. A 
complete final evaluation at the time of the subject’s protocol withdrawal should be made with 
an explanation of why the subject is withdrawing from the protocol. If the reason for removal of 
a subject from the study is an adverse event, it will be recorded on the eCRF. 


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7. 
STUDY CALENDAR & EVALUATIONS  
 
Study Evaluation 
Cycle = 28 days 
Screening 
On Treatment 
Safety follow 
up visit9 
Long-term 
Follow 
up10 
Cycle 1 
Cycle 2 
Cycle 3+ 
-30 
days 
-14 
days 
Day 1  
Day 13 
± 1 day  
Day 15 
± 2 days 
Day 17 
± 3 days 
Day 1 
± 5 days 
Day 15 
± 5 days 
Day 1 
± 5 days 
Day 15 
± 5 days 
30 days post 
last dose 
+ 7 days 
Every 4 
months  
(±30 days) 
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History1 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Vital signs and ECOG Performance Status2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient Reported Outcomes3 
 
 
 X3 
 
 
X 
 X3 
 
 
 X3 
 
 
AEs & concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LABORATORY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Blood Cell Count with diff 
(CBC)4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Metabolic Profile (CMP)4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid Function Testing4 
 
 
 
X4 
 
 
 
 
X4 
 
 
 
Pregnancy test (serum or urine) (WOCBP)4 
 
X4 
 
 
 
 
 
 
 
 
 
 
DISEASE ASSESSMENT 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI of chest, abdomen and pelvis5 
X 
 
 
 
 
 
 
 
 
X5 
 
X5 
Bone Scan5 
X 
 
 
 
 
 
 
 
 
X5 
 
X5 
PET Scan5 
X 
 
 
 
 
 
 
 
 
X5 
 
X5 
TREATMENT EXPOSURE 
 
 
 
 
 
 
 
 
 
 
 
 
Talazoparib6 
 
 
Daily 
Daily 
Daily 
 
 
Radiotherapy6 
 
 
 
X6 
X6 
X6 
 
 
 
 
 
 
Atezolizumab6 
 
 
 
 
X6 
 
X 
X 
X 
X 
 
 
SPECIMEN COLLECTION  
 
 
 
 
 
 
 
 
 
 
 
 
Archival Tumor Tissue7 
X7 
 
 
 
 
 
 
 
 
 
 
 
Fresh Tumor Tissue7 
 
X7 
 
 
 
 
X7 
 
 
 
 
 
Blood Samples8 
 
 
X8 
X8 
X8 
 
X8 
 
 
X8 
 
 
FOLLOW-UP 
 
 
 
 
 
 
 
 
 
 
 
 
Survival Status, Subsequent Therapy 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CBC with differential and platelet to include: WBC, ANC, Hgb, Hct, PLT. CMP to include sodium, potassium, chloride, creatinine, blood urea nitrogen; 
liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline phosphatase  
 
 


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Key to Footnotes   
 
1: Medical History; other data to be obtained during this assessment includes a trial awareness question.  In addition, the following will be 
captured:  self-reported race, gBRCA status, PD-L1 status based on the Ventana PD-L1 (SP142) assay, tumor mutation testing results if performed 
(such as FoundationOne or Guardant360), prior anti-cancer treatment including medications (chemotherapy, checkpoint inhibitors, etc) radiation 
(dose and sites treated) and/or surgery.  Diagnosis and staging to include pathology report and TNM staging documentation. AJCC manual Ed 8 
will be utilized.  For subjects with known CNS metastases, a brain scan report showing stable CNS disease within 30 days prior to start of protocol 
is required. 
 
2: Vital signs to include temperature, pulse, respirations, blood pressure, weight, and height (screening only) and ECOG performance status.   
 
3: Patient reported outcomes to include: Multidimensional Fatigue Inventory (MFI-20) and EORTC QLQ-30. Baseline assessments will be 
performed (1) prior to treatment Cycle 1 Day 1, (2) on the last day of radiotherapy (3) prior to Cycle 2 Day 1 (about 2 weeks after 1st dose of 
atezolizumab) (4) prior to treatment Cycle 3 Day 15 (about 8 weeks after the 1st dose of atezolizumab), and (5) prior to treatment Cycle 4 Day 15 
(about 12 weeks after 1st dose of atezolizumab). 
 
4: If screening (baseline) CBC and CMP were performed within 7 days of Cycle 1 Day 1 of treatment, these do not need to be repeated.  Research 
blood samples for baseline specimen collection may be drawn up to 7 days prior to Cycle 1 Day 1.  All laboratory assessments should be done 
prior to treatment. Thyroid Function testing should be performed just prior to first dose of atezolizumab and then every 2 cycles. TSH and T4 will 
be obtained.  T3 including free versus total testing is at the discretion of the site investigator. For women of childbearing potential (WOCBP): 
urine or serum βhCG if clinically appropriate. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.  Testing is required within 14 days prior to initiation of study treatment.  
 
5: Tumor response assessment will consist of evaluation by CT or MRI scans of chest, abdomen and pelvis and a bone scan or whole body PET 
CT with/without MRI at screening then every odd numbered cycle starting Day 15 of Cycle 3 (8 weeks post first dose of atezolizumab and then 
about every 8 weeks).  Imaging selected for each subject should remain the same throughout the study. If the site investigator suspects 
pseudoprogression on imaging and feels that the patient is deriving clinical benefit from study treatment, a follow-up scan 4 weeks later may be 
obtained at the discretion of the investigator.  Tumor imaging to be done at D30 safety visit/treatment discontinuation is at discretion of site 
investigator.  If tumor assessments are available for subjects who have not yet experienced progressive disease (PD) at the time treatment is 
discontinued, the follow-up tumor evaluations will be documented in the eCRF until PD or death is confirmed, or until another treatment is 
initiated.  MRI of the brain should be performed at screening only if suspected brain metastases or to evaluate known and treated brain metastases 
per standard of care.  A window of ± 7 days may be applied to all radiology imaging. Both patient imaging and radiotherapy data from 
participating institutions will be exported from the institution's diagnostic imaging department and radiation treatment planning system in DICOM 
format, and subsequently anonymized using the Velocity Anonymize software from Varian Medical Systems, a software that anonymize images, 
contours, plan and dose data without compromising the essential links between these radiotherapy objects and thus preserving their ability to be 
imported in a different treatment planning system at another institution. This vendor-neutral data on patients analyzed in this proposal will be 


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collected on a dedicated research server already available at Emory. Research coordinators or assistants are able to submit standard of care 
imaging through the same method. (See Appendix III for detailed instructions).  
 
6: See Section 5 for complete details regarding treatment administration. Each cycle = 28 days. Talazoparib will be given orally daily starting 
Cycle 1 Day 1. Subjects will receive a total of 3 fractions of radiation and the first dose of radiation therapy can be given on Day 12, Day 13 or 
Day 14. The first dose of atezolizumab will be given 24 to 72 hours after the first dose of radiation intravenously but prior to the 2nd dose of 
radiation and preferably same day.  Atezolizumab will continue every 2 weeks (should align to Day 1 and Day 15 for subsequent cycles).  For 
example, Talazoparib will start on Day 1 and continue daily. If radiation starts on Day 13, atezolizumab could be given on Day 15 just prior to the 
second dose of radiation also given Day 15.  Then the last dose of radiation can be given on Day 17.  
      
7: See Section 8 for details regarding correlative samples. If prior Ventana PD-L1 (SP142) Assay, results are not available, archival tissue should 
be sent for testing as this is considered standard of care.  Archival tissue for research purposes will also be collected if available and stored for 
correlative analysis once funding is available.  Archival tissue for correlative analysis should be requested at screening and shipped post-
registration by C2D1.  A biopsy may be performed from a metastatic lesion that will not be treated with radiation prior to talazoparib treatment on 
Cycle 1 Day 1 and again prior to treatment on Cycle 2 Day 1. Biopsy sample collections are optional and are limited to 10 subjects (total 20 
biopsies) at the Emory site ONLY. Every attempt should be made to biopsy the same metastatic lesion in each consenting patient at each time 
point. If the baseline sample is not collected, a Cycle 2 sample should not be collected. Please see the Correlative Laboratory Manual (CLM) for 
details regarding collection, processing and shipping of these samples.  
 
8: See Section 8 for complete details regarding correlative samples. Blood for correlative samples will be collected prior to treatment Cycle 1 Day 
1 then prior to first dose of radiation (Cycle 1 Day 12, 13 or 14), prior to first dose of atezolizumab (around Cycle 1 Day 15), prior to Cycle 2 Day 
1 (about 2 weeks after 1st dose of atezolizumab) and prior to Cycle 3 Day 15 (about 8 weeks after the 1st dose of atezolizumab). These samples 
are required. Please see the Correlative Laboratory Manual (CLM) for details regarding collection, processing and shipping of these samples.  
 
9: Safety Follow Up: The safety follow-up visit should only occur when subjects permanently stop study treatment for whatever reasons (toxicity, 
progression, or other reason) and should be performed 30 days (+ 7 days) after the last dose of treatment. Subjects who have an ongoing Grade ≥ 2 
or serious AE (SAE) at this visit will continue to be monitored by a member of the study team until the event is resolved, stabilized, determined to 
be irreversible by the site investigator or a new anti-cancer treatment starts, whichever occurs earlier.  
 
10: Long Term Follow Up: For subjects who discontinue for reasons other than progressive disease, radiographic disease assessment should be 
performed per standard of care. This imaging may be done locally. Follow up will occur every 4 months up to 2 years after treatment 
discontinuation     . Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate. A window of ± 30 days will be 
applied. 
 


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8. 
BIOSPECIMEN STUDIES AND PATIENT REPORTED OUTCOME MEASURES 
Please see the Correlative Laboratory Manual for details regarding collection, processing and 
shipping of the samples described below. 
 
Sample Type 
Prior to 
Cycle 1 
Day 1 
Prior to 
1st dose 
of XRT 
Cycle 1 
~Day 13 
Prior to 1st 
dose of 
Atezolizumab 
Cycle 1 
~Day 15 
Prior to 
Cycle 2 
Day 1 
Prior to 
Cycle 3 
Day 15 
Plasma for circulating tumor 
DNA (ctDNA) 
X 
X 
X 
X 
X 
Plasma & Buffy Coat for 
Inflammatory 
Markers/Cytokines 
X 
X 
X 
X 
X 
Whole blood for B Cell 
Correlates & RNA  
X 
X 
X 
X 
X 
Archival Tissue 
X 
 
 
 
 
Optional Fresh Tumor Tissue 
for mass cytometry and RNA-
seq* 
X 
 
 
X 
 
 
Collection of longitudinal blood and tumor tissue samples will be stored to conduct future 
biomarker studies of response to talazoparib, high dose radiotherapy, and atezolizumab, disease 
progression both locally and systemically, as well as side effects of treatment including fatigue 
and hematologic and pulmonary toxicities.  These samples will be stored until additional 
extramural funding is identified above pre-existing philanthropic institutional and investigator 
sources to support these correlative studies. 
 
8.1 
Tissue 
 
8.1.1 Archival Tissue 
If prior PD-L1 results are available and the testing was performed with the Ventana Assay, they 
are required. If prior results are not available, archival tissue should be sent for Ventana PD-L1 
(SP142) Assay      as this testing is considered standard of care.   
 
Archival tissue for research purposes will also be collected and is required if available and 
patient consents to providing this tissue.  SAMHD1 is recognized for its deoxynucleoside 
triphosphate (dNTP) triphosphohydrolase activity, which restricts HIV-1 and other viral 
infections, and for mutations associated with Aicardi Goutières syndrome (AGS), an 
autoimmune disorder. SAMHD1 is also dysregulated in human cancers, including 
overexpression in 27% of breast cancers.  Importantly SAMHD1 deficiency in breast cancer 
cells caused PARPi hypersensitivity, suggesting that SAMHD1 levels may function as a 
biomarker for response to PARPi.  Our plan is to use philanthropic institutional and investigator 
funds and seek extramural funding to perform immunohistochemistry (IHC) on preoperative 
breast cancer tumor samples from this study to determine the significance of SAMHD1 levels 


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on predicting response to PARPi, radiation, and atezolizumab. We have anti-SAMHD1 
antibodies that specifically recognize SAMHD1 in breast cancer tumor samples by IHC. 
 
8.1.2 Fresh Tissue 
Optional fresh tissue will be collected prior to starting treatment Cycle 1 Day 1 and prior to 
treatment Cycle 2 Day 1. A sample from the same non-irradiated site should be collected at both 
time points. A maximum of 10 paired samples will be collected from the Emory site ONLY.  If 
the baseline sample is not collected, a Cycle 2 sample should not be collected. 
 
8.2 
Peripheral Blood Samples 
Blood for correlative samples will be collected prior to treatment Cycle 1 Day 1 then prior to 
first dose of radiation, first dose of atezolizumab, Cycle 2 Day 1 (about 2 weeks after 1st dose of 
atezolizumab), and Cycle 3 Day 15 (about 8 weeks after the 1st dose of atezolizumab). These 
samples are required. 
 
8.2.1 Circulating Tumor DNA  
Plasma levels of ctDNA identified by tp53 mutations, brca1 and/or med12 are found in up to 
88% of TNBC tumors.3,4 ctDNA will be measured using targeted assays to detect point 
mutations in tp53, brca1 and/or med12 that may provide insight into response or lack of response 
to proposed therapy. Plasma can be frozen for future ctDNA extraction, an advantage for this 
study given the number of proposed enrollment centers and the fact that we will use pre-existing 
philanthropic, institutional funds and seek additional funding to support these investigations.   
 
8.2.2 B Cell Correlates and RNA 
In previous work published by Dr. Kavita Dhodapkar (co-investigator on future study of 
translational endpoints), her group demonstrated changes in the number and types of B cells 
following once cycle of combination checkpoint blockade with either anti-CTLA4 and/or anti-
PD1 immune therapy in melanoma patients.5 An early decline in the number of circulating B 
cells correlated with both the timing and severity of immune-related adverse events (irAES).  
Immune therapy led to changes in circulating B cells shortly after initiation of treatment, 
including a decline in circulating B cells and an increase in CD21l B cells and plasma blasts. 
There was also greater clonality with B cell receptor sequencing and a higher frequency of 
clones compared with CD21 high cells.  At least a 70% decline in circulating B cells and a 2-fold 
increase in circulating CD21lo B cells and plasma blasts following combined checkpoint 
blockade associated with irAEs, and these changes in B cell distribution preceded irAEs by a 
median of 3 weeks (0-10 weeks).  Treatment-induced changes in b cells were correlated with 
both the frequency and timing of irAEs such that patients with early B cell changes experienced 
higher rates of grade 3 or higher irAEs 6 months after immune checkpoint blockade.5 Based on 
this preliminary data, early changes in B cells may help identify patients at increased risk of 
irAEs. This data supports the exploration of B cell changes in response to the combination of 
talazoparib, radiotherapy and immune therapy and to examine whether Bcell changes predict 
treatment-related irAEs.  
 
8.2.3 Inflammatory Markers/Cytokines  
Plasma concentrations of sTNFR2 and IL-6 will be determined as previously described using 
sandwich ELISA according to manufacturer’s protocol (R & D Systems, Minneapolis, MN).  


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High sensitivity CRP will be measured using a standard turbidimetric assay.  These 
inflammatory markers have been associated with of depression and fatigue in our previous 
studies of breast cancer patients 6-8, as well as other studies of pain in breast cancer patients.9,10  
These samples will be shipped to Dr. Andrew Miller’s laboratory at Emory University.  
Philanthropic institutional funding is secured to run biomarkers studies of symptoms related to 
treatment, concentrations of sTNFR2, IL-1ra, and IL-6 will be determined using sandwich 
ELISA according to manufacturer’s protocol (R & D Systems, Minneapolis, MN).  We will also 
seek additional extramural funding to support this research.  Each determination (excluding the 
soluble cytokine receptors which require less sample) requires 100-150 ul of sample; all samples 
will be assayed in duplicate. Quality control plasma of both low and high cytokine 
concentrations will be included with every assay.  The mean inter- and intra-assay coefficients of 
variation for control samples are reliably 10% or less.  Dr. Miller is a Professor in the Emory 
Department of Psychiatry and Behavioral Sciences and has extensive experience conducting 
these assays and performing studies on the impact of inflammation on the brain and behavior in 
cancer patients.  CRP will be measured in the CLIA certified laboratory of the Emory University 
Hospital using a standard turbidimetric assay.  RNA will also be collected from PBMCs to 
explore biomarkers of outcome.     
 
8.3 
Genetic Testing 
Participants will be given information as part of the informed consent process that samples will 
be used for research purposes that will include genetic testing. The intent is not to give 
participants (or his/her medical providers) the results of any testing done for research purposes; 
however, incidental germline (heritable) mutations may be identified of which a participant may 
or may not already be aware. In the case where an incidental genetic finding is identified, the 
sponsor investigator of this project will be notified. Possible decisions for handling incidental 
findings may include notification of the participant (and provider); recommendation for genetic 
counseling, which may or may not include genetic testing (e.g., if the finding was not done in a 
CLIA certified laboratory); or, neither. In general, a member of the participant’s treating team 
will be given the information to help with notification. In all cases, the current policy of Emory 
University and local/participating site IRBs, as applicable, will be followed. Any additional 
approvals that may be required prior to participant notification will be secured in advance. 
 
8.4 
Banking of Leftover Biospecimens 
Subject consent will be obtained to bank any leftover samples      after study-specific correlative 
research has been completed. Hoosier Cancer Research Network (HCRN) will manage the 
banked samples. Samples will be coded and banked indefinitely in the Hoosier Cancer Research 
Network Biorepository.  
 
8.5 
Confidentiality of Biospecimens 
Samples will be identified by the subject’s study number assigned at the time of registration to 
the trial. Any material issued to collaborating researchers will be anonymized and only identified 
by the subject’s study number. 
 
8.6 
Patient Reported Outcome Measures 
Completion of Patient Reported Outcomes instruments is critical for understanding the impact of 
talazoparib, high dose radiotherapy, and atezolizumab given for metastases in TNBC patients.  


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Quality of life (EORTC QLQ-C30) and fatigue (MFI-20) will be evaluated as secondary 
endpoints.  The bodily domain of the EORTC QLQ-C30 will allow for assessment of patients 
who present for symptoms other than pain.59 
 
Both instruments are of minimal burden to patients and take approximately 20 minutes to 
complete.  At Emory, ongoing longitudinal studies of patients receiving radiotherapy in the 
definitive and metastatic setting have used an overlapping set of instruments and established 
feasibility with over 95% compliance with completing these forms. 
 
8.6.1 European Organization for Research and Treatment Quality of Life Questionnaire 
Core-C30 (EORTC QLQ-C30)  
EORTC QLQ-C30 is one of the most widely used general health-related quality of life 
questionnaires in oncology for patients with metastatic disease and palliative care research.  This 
30-item questionnaire contains items/scales pertaining to pain, physical function, emotional 
function, fatigue, global health status/quality of life, nausea/vomiting, appetite, dyspnea, 
constipation and sleep.60 The instrument has been validated in multiple cancer patient 
populations with metastatic disease and has been used in trials of mTNBC patients including 
IMpassion130.7,61 
 
8.6.2 Multidimensional Fatigue Inventory (MFI-20)  
MFI-20 will be used to evaluate the presence and severity of fatigue among subjects by self-
report.62  The MFI-20 assesses 5 dimensions of fatigue, including general fatigue, physical 
fatigue, mental fatigue, reduced activity, and reduced motivation.63,64  The MFI has been used to 
quantify fatigue in cancer patients, and a minimal clinically important difference of 10 points has 
been established.65 Fatigue is one of the more common patient reported symptoms from PARPi 
and immune therapies and may severely impact QOL.  Therefore, a separate instrument 
specifically devoted to accurately measuring this important symptom will be employed.    
 
9. 
CRITERIA FOR DISEASE EVALUATION  
All subjects should be assessed for response using both RECIST 1.1 and irRECIST criteria at 
each timepoint.  Once a subject progresses per RECIST 1.1, disease evaluation per irRECIST 
will continue and RECIST 1.1 response is no longer required. 
 
9.1 
Evaluation using RECIST 1.1 
 
9.1.1 Measurable Disease  
Measurable disease is defined as the presence of at least one measurable lesion. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
9.1.2 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 


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9.1.3 Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
 
9.1.4 Target Lesions 
All measurable non-irradiated lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
9.1.5 Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
 
 


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9.1.6 Evaluation of Target Lesions 
NOTE: In addition to the information below, also see the international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 
45;2009:228-247) for special notes on the assessment of target lesions.  
 
Complete Response (CR) 
Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis 
to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as 
reference the baseline sum diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study). In addition to the relative 
increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 
mm. (Note:  the appearance of one or more 
new lesions is also considered progressions). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, 
taking as reference the smallest sum 
diameters while on study 
 
 
9.1.7 Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All 
lymph nodes must be non-pathological in size 
(<10 mm short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
subject to be considered in complete clinical 
response. 
Non-CR/ Non-PD 
Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor marker 
level above the normal limits 
Progressive Disease (PD) 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target lesions. Unequivocal progression 
should not normally trump target lesion 
status. It must be representative of overall 


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disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor investigator. 
 
 
9.1.8 Evaluation of Best Overall Response 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/ or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all 
evaluated 
Non-PD 
No 
Non-evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
In some circumstances, investigators may suspect pseudoprogression but the clinician feels the 
patient is deriving clinical benefit from study treatment. A follow-up scan 4 weeks later may be 
obtained at the discretion of the investigator in these cases to evaluate disease status.   
 
9.2 
Immune-Related RECIST (irRECIST) 
 
9.2.1 Measurable Lesion Definitions and Target Lesion Selection 
Follow the definitions from RECIST 1.1. Measurable lesions must be accurately measured in at 
least one dimension with a minimum size of: 


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• 10 mm in the longest diameter by CT or MRI scan (or no less than double the slice 
thickness) for non-nodal lesions and ≥15 mm in short axis for nodal lesions 
• 10 mm caliper measurement by clinical exam 
• 20 mm by chest X-ray 
• At the baseline tumor assessment, the sum of the products of the two largest 
perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 
visceral lesions and five cutaneous index lesions) is calculated. 
                     
9.2.2 Non-measurable Lesion Definitions 
Follow definitions from RECIST 1.1. 
 
9.2.3 Non-target lesions will include 
• Measurable lesions not selected as target lesions 
• All sites of non-measurable disease, such as neoplastic masses that are too small to 
measure because their longest uninterrupted diameter is < 10 mm (or < two times the 
axial slice thickness), ie. the longest perpendicular diameter is ≥10 and < 15 mm. 
• Other types of lesions that are confidently felt to represent neoplastic tissue, but are 
difficult to measure in a reproducible manner.  These include bone metastases, 
leptomeningeal metastases, malignant ascites, pleural or pericardial effusions, ascites, 
inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, ill-defined 
abdominal masses, skin lesions, etc. 
 
9.2.4 Target and Non-Target Lymph Node Lesion Definitions 
Follow definitions from RECIST 1.1 
 
9.2.5 Non-Target Lesion Selection 
All lesions or sites of disease not recorded as target lesions should be recorded as non-target 
lesions at baseline. There is no limit to the number of non-target lesions that can be recorded at 
baseline. 
 
9.2.6 Bone Lesions 
Follow definitions from RECIST 1.1 
 
Regardless of the imaging modality blastic bone lesions will not be selected as target lesions. 
Lytic or mixed lytic-blastic lesions with a measurable soft tissue component ≥10 mm can be 
selected as target lesions. 
 
9.2.7 Cystic and Necrotic Lesions as Target Lesions 
Lesions that are partially cystic or necrotic can be selected as target lesions. The longest diameter 
of such a lesion will be added to the Total Measured Tumor Burden (TMTB) of all target lesions 
at baseline. If other lesions with a non-liquid/non-necrotic component are present, those should 
be preferred. 
 
9.2.8 Lesions with Prior Local Treatment 
During target lesion selection the radiologist will consider information on the anatomical sites of 
previous intervention (e.g. previous irradiation, RF-ablation, TACE, surgery, etc.). Lesions 


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undergoing prior intervention will not be selected as target lesions unless there has been a 
demonstration of progress in the lesion. 
 
9.2.9 Baseline 
• The longest diameters of non-nodal target and short axes of nodal target measurable 
lesions will be recorded. Together they determine the Baseline Total Measured Tumor 
Burden (TMTB). 
 
9.2.10 Follow-up 
•      The longest diameters of non-nodal target and new non-nodal measurable lesions, and 
short axes of nodal target and new nodal measurable lesions will be recorded. Together 
they determine the Total Measured Tumor Burden (TMTB) at follow-up. 
• Definition of Measurable New Lesions: In order to be selected as new measurable lesions 
(≤ 2 lesions per organ, ≤ 5 lesions total, per timepoint), new lesions must meet criteria as 
defined for baseline target lesion selection and meet the same minimum size requirements 
of 10 mm in long diameter and minimum 15 mm in short axis for new measurable lymph 
nodes. New measurable lesions shall be prioritized according to size, and the largest 
lesions shall be selected as new measured lesions. 
• Non-Target Lesion Assessment- The RECIST 1.1 definitions for the assessment of non-
target lesions apply. The response of non-target lesions primarily contributes to the 
overall response assessments of irCR and irNon-CR/Non-PD (irNN). Non-target lesions 
do not affect irPR and irSD assessments. Only a massive and unequivocal worsening of 
non-target lesions alone, even without progress in the TMTB is indicative of irPD. 
• New Non-Measurable Lesions Definition and Assessment: All new lesions not selected 
as new measurable lesions are considered new non-measurable lesions and are followed 
qualitatively. Only a massive and unequivocal progression of new non-measurable 
lesions leads to an overall assessment of irPD for the timepoint. Persisting new non-
measurable lesions prevent irCR 
 
9.2.11 Evaluation of Best Overall Response per irRECIST 
 
% Change in Sum 
of the Diameters 
Target 
Lesion 
Definitio
n 
Non-Target 
Lesion 
Definition 
New 
Measurabl
e Lesions 
New 
Unmeasurabl
e Lesions 
Overall     
Immune 
Related 
RECIST 
Timepoint 
Response 
100% decrease 
from baselinea 
CR 
CR 
No 
No 
CR 
100% decrease 
from baselinea 
CR 
Non-CR or not 
all evaluated 
No 
No 
PR 


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≥ 30% decrease to 
<100% decrease 
from baseline 
PR 
Any 
Yes or no 
Yes or no 
PR 
< 30% decrease 
from baseline to 
< 20% increase 
from nadir 
SD 
Any 
Yes or no 
Yes or no 
SD 
Not all evaluated 
Not 
evaluated 
Any 
Yes or no 
Yes or no 
NE 
≥ 20% increase 
from nadir 
PD 
Any 
Yes or no 
Yes or no 
PD 
CR =complete response; NE= not evaluable; PD=progressive disease; PR =partial response; 
RECIST =Response Evaluation Criteria in Solid Tumors; SD= stable disease. 
a When lymph nodes are included as target lesions, the % change in the sum of the diameters 
may not be 100% even if complete response criteria are met since a normal lymph node is 
defined as having a short axis of < 10 mm. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm in order to meet the definition of 
CR.  
 
10 DRUG AND RADIATION INFORMATION 
 
10.1 
Talazoparib 
See the investigator’s brochure for complete details regarding this medication.  
 
Talazoparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1 
and PARP2, which play a role in DNA repair. In vitro studies with cancer cell lines that harbored 
defects in DNA repair genes, including BRCA 1 and 2, have shown that talazoparib-induced 
cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of 
PARP-DNA complexes resulting in DNA damage, decreased cell proliferation, and apoptosis. 
Talazoparib anti-tumor activity was observed in human patient-derived xenograft breast cancer 
tumor models that expressed mutated or wild-type BRCA 1 and 2.   
 
10.1.1 Supplier/How Supplied 
Talazoparib capsules are supplied by Pfizer, Inc at no charge to subjects participating in this 
clinical trial as described in Section 5. 
 
The drug product is a capsule formulation composed of a blend of talazoparib tosylate drug 
substance and silicified microcrystalline cellulose filled into a hypromellose capsule. The 
capsules are presented in strengths of 0.10 mg, 0.25 mg, and 1.0 mg (free base equivalent), 
distinguished by capsule color and described in milligrams per capsule. Capsules are provided in 
high-density polyethylene (HDPE) bottles, with induction-sealed closures, containing 30 drug 
product capsules of a single strength.  
 
The investigator and      each participating site shall take responsibility for and shall take all steps 
to maintain appropriate records and ensure appropriate supply, storage, handling, distribution, 


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and usage of investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
10.1.2 Storage  
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 
86°F).  
 
10.1.3 Adverse Events 
See the current investigator’s brochure for complete details regarding adverse events related to 
this medication. Most common adverse reactions (≥10%) were alopecia, diarrhea, dizziness, 
dysguesia, dyspepsia, fatigue, headache, hyperglycemia, increase liver function tests, 
hypocalcemia, loss of appetite, myelosuppression, nausea, vomiting, abdominal pain, and 
hyperbilirubinemia.  Please see package insert for a detailed list of side effects. Cases of MDS 
and AML have been reported in patients treated with talazoparib. 
 
10.2 
Atezolizumab 
See the investigator’s brochure for complete details regarding this medication. 
 
Atezolizumab lacks the N-linked oligosaccharides typically observed on other CHO-derived 
monoclonal antibodies because it incorporates an amino acid substitution (asparagine to alanine) 
at position 298 in the CH2 domain of each heavy chain, resulting in a non-glycosylated antibody. 
This non-glycosylated antibody has minimal binding to Fcγ receptors and, consequently, 
prevents Fc-effector function and depletion of cells expressing PD-L1 at expected concentrations 
in humans. 
 
10.2.1 Supplier/How Supplied 
Genentech will supply atezolizumab at no charge to subjects participating in this clinical trial as 
described in Section 5. 
 
Atezolizumab Injection, 840/14 mL (60 mg/mL). The atezolizumab Drug Product in Formulation 
F03 (late Phase I/II and Phase III clinical studies) is provided in a single-use, 14-mL 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 14 mL (840 mg) of 
atezolizumab solution but may contain more than the stated volume to enable delivery of the 
entire 14 mL volume. The atezolizumab Drug Product is formulated as 60 mg/mL atezolizumab 
in a solution containing histidine acetate, sucrose, and polysorbate 20 at pH 5.8. 
 
The investigator and      each participating site shall take responsibility for and shall take all steps 
to maintain appropriate records and ensure appropriate supply, storage, handling, distribution, 
and usage of investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
10.2.2 Preparation  
Atezolizumab Injection, 840 mg/14 mL (60 mg/mL) 
Atezolizumab in Formulation F05 (840 mg per vial) will be administered in 0.9% NaCl IV 
infusion bags and infusion lines equipped with 0.2 or 0.22 μm in-line filters. Atezolizumab 


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should only be diluted with 0.9% sodium chloride injection USP.  The IV bag may be 
constructed of polyvinyl chloride or polyolefin, the IV infusion line may be constructed of 
polyvinyl chloride or polyethylene, and the in-line filter may be constructed of polyethersulfone. 
The use of administration supplies composed of materials other than those listed should be 
avoided if possible. Atezolizumab must be prepared/diluted to concentrations between 3.2 
mg/mL and 16.8 mg/mL under appropriate aseptic conditions as it does not contain antimicrobial 
preservatives. The prepared solution for infusion should be used immediately to limit microbial 
growth in case of potential accidental contamination. If not used immediately, in-use storage 
time and conditions prior to use are the responsibility of the user.  
 
10.2.3 Storage and Stability 
Atezolizumab Injection, 840 mg/14 mL (60 mg/mL)  
Atezolizumab (F05) and the diluent must be refrigerated at 2°C−8°C (36°F−46°F) upon receipt 
for up to 24 hours or at ambient temperature ≤ 25°C (77°F) for 8 hours. This time includes 
storage and time for administration for infusion. If the dose solution is stored at 2°C−8°C 
(36°F−46°F), it should be removed from refrigeration and allowed to reach room temperature 
prior to administration. Do not shake or freeze infusion bags containing the dose solution. 
 
This time Atezolizumab and the diluent vials should not be used beyond the expiration date 
provided by the manufacturer. No preservative is used in the atezolizumab Drug Product or the 
diluent; therefore, the vial is intended for single use only. Discard any unused portion of drug 
remaining in a vial. Vial contents should not be frozen or shaken and should be protected from 
light.  
 
10.2.4 Adverse Events 
See the current investigator’s brochure for complete details regarding adverse events related to 
this medication. 
 
The most common side effects of atezolizumab are: Fatigue, decreased appetite, diarrhea, 
vomiting, arthralgia, asthenia, dyspnea, urinary tract infection, cough, pruritis, rash, nausea, fever 
and musculoskeletal pain.  
 
Given the mechanism of action of atezolizumab, events associated with inflammation and/or 
immune-mediated adverse events have been closely monitored during the atezolizumab clinical 
program. These include potential dermatologic, hepatic, endocrine, and respiratory events, as 
well as events of hepatitis/elevated liver function tests (LFTs) and influenza-like illness that are 
considered potential adverse drug reactions associated with atezolizumab. There is also a 
potential for immune activation being associated with generalized systemic features (e.g., 
hypotension, respiratory failure, and other organ impairment). 
 
10.3 
Radiotherapy  
The Radiotherapy Treatment Phase is the time period between and including the first and last 
day of radiotherapy.  Enrolled patients will be treated with induction talazoparib (C1D1).  The 
first dose of radiation will be given on Days 12, 13, 14 of the first cycle of talazoparib.  Patients 
will be treated with atezolizumab (C1D15) 24-72 hours after the first dose radiotherapy and prior 
to and preferably on the same day as the 2nd dose of radiotherapy.  High dose radiotherapy will 


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be given to as many as 1-4 extracranial metastatic lesions (measurable or non-measurable by 
RECIST v 1.1 criteria) 24-72 hours prior to the first dose atezolizumab (i.e. Day 13, 14, 15, 16 or 
17 of Cycle 1) and every other day (e.g. XRT Fraction 2 - Day 14, 15, or 16 and XRT Fraction 3 
- Day 16, 17, or 18) for a total of 3 fractions (8 Gy each). 
 
Patients will undergo CT simulation in preparation for radiation planning. 4-dimensional CT will 
be used for tumors in the lungs or liver at the discretion of the treating physician.  Axial CT 
images will be obtained throughout the target lesion(s).  The gross tumor volume (GTV) will be 
defined as the visible tumor on CT and/or MRI imaging +/- PET or if 4DCT is used, an internal 
target volume (ITV) will be defined using all phases of the 4DCT simulation and the diagnostic 
CT and/or MRI and/or PET/CT as reference.  No additional margin will be added for 
microscopic spread of disease.  Clinical target volume will equal GTV or ITV based on     CT or 
4DCT simulation images and provider discretion     .  A planning target volume (PTV) margin of 
2-5mm will be added to the GTV or ITV depending on site of disease, immobilization, and 
institutional set-up accuracy:  2mm for spinal treatments and 5mm for other sites are generally 
recommended.  For vertebral lesions, the entire vertebral body may be considered the GTV/CTV, 
as per institutional practice.   
 
Patients can be treated with 3-D, intensity modulated radiation therapy (IMRT), SBRT, and/or 
Volumetric Arc Therapy (VMAT).  6-20 MV photon beams or proton treatment is allowed.   
Cobalt-60 and electron treatment is not allowed.    
 
1-4 extracranial metastatic target lesions separated by at least 2cm may be treated on protocol.  
Radiation treatment to previously irradiated sites or within 2cm of previously irradiated sites is 
not permitted.   
 
10.3.1 Dose Fractionation 
24 Gy at 8 Gy per fraction given every other business day excluding weekends and holidays are 
allowed on this protocol.  Other radiation fractionation schemes are not allowed.    
 
95% of the prescribed dose must cover >95% of the PTV (95% of the prescribed dose to 70-95% 
of the PTV is permitted and is considered Variation Acceptable).  Deviation unacceptable is < 
70% coverage of the PTV.  Dmax should not exceed > 115% and is not permitted on this study.  
These criteria should be evaluated for each metastasis independently not including dose in the 
treatment of all other metastases.  Unacceptable Deviation is treatment completion in >10 
consecutive business days excluding holidays. 
   
All institutions must use heterogeneity correction dose calculation algorithms.   
 
10.3.2 Isocenter Placement 
It is best to place isocenter near the center of the target lesion.  If there are multiple lesions that 
cannot be treated in a single field, multiple isocenters should be placed with each centered in a 
separate target lesion. 
 


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10.3.3 Patient Immobilization, Simulation, and Localization  
Participating subjects will be positioned in a reproducible, comfortable, and stable pose to allow 
for both reliable and accurate target position during treatment.  The immobilization and pose 
must be reliable enough to ensure that the GTV does not deviate beyond the confines of the PTV.  
Ideally, multiple metastases treated on this study would be treated in one treatment position.  
However, more treatment positions can be used at the discretion of the treating radiation 
oncologist.    
 
CT-based treatment planning and image guided radiotherapy (IGRT) is required for all patients.   
The CT scan must encompass the target metastases, as well as the following necessary organs at 
risk (OAR) when included in the radiation field: 
• Heart 
• Organ 
• Lungs 
• Liver 
• Kidneys 
• Spinal Cord 
• Brain 
• Brainstem 
• Lens 
• Bowel Bag 
• Brachial plexus 
 
CT scans should have uniform slice thickness of <5mm.  The use of IV contrast is left to the 
discretion of the treating radiation oncologist but is not required.   
 
On board imaging (OBI) using KV, MV x-rays, cone beam CT or CT every fraction is required. 
(IGRT is required).  
 
10.3.4 Target Volumes 
The treating radiation oncologist will contour the gross tumor volume (GTV) and planning target 
volume (PTV), as well as relevant normal structures within 2cm of the radiation field (e.g. spinal 
cord, kidneys, lung, bowel bag, and heart). 
 
10.3.5 Planning priorities for Organs at Risk 
An unacceptable deviation will be assigned to radiation plans which exceed the absolute limits of 
the spinal cord, cauda equina, sacral plexus, or brachial plexus (See below). 
 
Every effort will be made to cover 100% of the PTV with 100% of the prescribed dose.  
Ultimately, at least      95% of the PTV must be covered by at least      70% of the prescribed 
dose or the plan will be considered deviation unacceptable.  Radiation plans will be considered 
unacceptable if any of the criteria below in the table “CRITICAL ORGAN DOSES” are not 
fulfilled.  
 
 
 


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CRITICAL ORGAN DOSES 
Structure 
Volume 
Dose/Volume 
Spinal Cord 
<0.03cc 
21.9 Gy 
 
<1.2cc 
13 Gy 
Brachial plexus 
<0.03cc 
24 Gy  
 
<3 cc 
22 Gy 
Cauda equina 
<0.03cc 
24 Gy 
 
<5 cc 
21.9 Gy 
Sacral plexus 
<0.03cc 
24 Gy 
 
<5 cc 
22.5 Gy 
Trachea and Ipsilateral 
Bronchus 
<0.03 cc 
30 Gy 
 
<5cc 
25.8 Gy 
Small Bowel 
<0.03cc 
25.2 Gy 
Large Bowel 
<0.03cc 
28.2 Gy 
Total Lungs 
V20 
<15%  
 
V11 
<37% 
 
V10.5 
<1500 cc 
 
V11.4 
<1000 cc 
Esophagus 
<0.03cc 
25.2 Gy 
 
<5 cc 
17.7Gy 
Kidney, bilateral  
V15 
<200cc 
Kidney, bilateral  
V12 
<55% 
Heart 
Mean 
<20 Gy 
 
<0.03cc 
30 Gy 
 
<15 cc 
24 Gy 
Brain, brainstem 
<0.03cc 
23.1 Gy 
Liver (Normal liver-gross 
tumor volume if within liver) 
>700cc 
<15Gy 
Duodenum 
D1cm3 
<30 Gy 
 
<0.03 cc 
22.2 Gy 
 
<10 cc 
15 Gy 
Small bowel 
D2cm3 
<21 Gy 
Small bowel 
D5cm3 
<30 Gy 
Large bowel 
<0.03 cc 
34.5 Gy 
 
<3.5cc 
24 Gy 
Rectum 
<0.03cc 
28.2 Gy 
 
<20 cc 
24.0 Gy 
Bladder 
0.03 cc 
28.2 Gy 
 
<15 cc 
16.8 Gy 
Ureter 
<0.03cc 
40 Gy 
Penile Bulb 
<3cc 
25 Gy 
Great vessels 
<0.03cc 
45 Gy 
 
<10 cc 
39 Gy 
Skin 
<0.03cc 
33 Gy 


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<10cc 
31 Gy 
Stomach 
<0.03cc 
22.2 Gy 
Femoral heads 
<10 cc 
21.9 Gy 
Bile duct 
<0.03 cc 
36 Gy 
Renal hilum/vascular trunk 
<15 cc 
19.5 Gy 
Rib 
<0.03 cc 
36.9 Gy 
 
<5cc 
40 Gy 
 
 
10.3.6 Composite Dose Calculations 
When more than one radiation field is used to treat multiple metastases, composite plans which 
include total dose summation from the multiple treatment sites on a single CT scan that 
encompasses relevant anatomy, must be generated to incorporate dose to surrounding normal 
tissues. These composite plans must include a planning CT dataset that incorporates all targets 
and relevant critical structures.  When more than one field is used to treat multiple metastases, it 
is advisable to treat all lesions with the patient in the same position.  Contact HCRN who will 
contact the sponsor-investigator, Dr. Mylin Torres, if there are technical challenges in summing 
dose and generating composite plans. 
 
Composite dose plans including all treated metastases and OARs must be submitted.  To 
facilitate composite planning, dose to all metastases should be calculated on a single CT scan.  If 
this is not possible, dose from each separate metastasis treatment plan should be generated and 
incorporated on the composite plan.   
 
10.3.7 Documentation Requirements 
Treatment interruptions, including reasons for treatment breaks, must be clearly documented in 
the treatment record.  However, treatment interruptions should be avoided generally. 
 
Sites will record radiation dose-volume values for all required structures on a datasheet which 
will be submitted with the digital radiation data to Emory University for review. 
 
If re-irradiation of the index lesion is deemed necessary after protocol treatment, it is preferred 
that re-irradiation be performed 3 months or later after initial radiation and after the last protocol 
assessment and should only be considered at least 4 weeks after initial treatment on protocol.  If 
re-irradiation of the index lesion occurs, it must be documented. 
 
 
 


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11. 
ADVERSE EVENTS  
The descriptions and grading scales found in the NCI CTCAE v5 will be utilized for AE 
assessment. A copy of the CTCAE v5 can be downloaded from the CTEP website at 
http://ctep.cancer.gov. All forms for AE/SAE recording and reporting can be found in the EDC 
system (Documents and Information Tab). 
 
11.1 
Definitions 
 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
• Unintended or unfavorable sign or symptom 
• A disease temporally associated with participation in the protocol 
• An intercurrent illness or injury that impairs the well-being of the subject 
• AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with Hepatocellular Carcinoma 
that were not present prior to the AE reporting period. 
• Preexisting medical conditions - A preexisting medical condition is one that is present at 
the start of the study. Such conditions should be reported as medical and surgical history. 
A preexisting 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 preexisting condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”). 
• If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
• Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 
• Diagnosis vs. Signs and Symptoms: NOTE: 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 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. 
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
 
 
 


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11.1.2 Serious Adverse Event (SAE) 
A SAE is an adverse event that: 
• Results in death. All deaths that occur during the protocol-specified AE reporting period, 
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”.  NOTE: Death due to 
disease progression should not be reported as a SAE, unless it is attributable by the site 
investigator to the study drug(s) 
• Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events. 
• If a subject 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 subject is hospitalized to undergo coronary bypass surgery, 
record the heart condition that necessitated the bypass as the SAE. 
o Hospitalizations for the following reasons do not require reporting: 
o Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
o Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
o Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study 
• Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
• Is a congenital anomaly or birth defect in a neonate/infant born to a mother exposed to 
the IMP. 
• Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
 
11.1.3 Adverse Events of Special Interest (AESI) 
The following AEs are considered of special interest:  
• Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law 
and based on the following observations: 


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o Treatment-emergent ALT or AST > 3 × ULN (or > 3 × baseline value in disease 
states where LFTs may be elevated at baseline) in combination with total bilirubin > 2 
× ULN (of which ≥ 35% is direct bilirubin) 
o Treatment-emergent ALT or AST > 3 × ULN (or > 3 × baseline value in disease 
states where LFTs may be elevated at baseline) in combination with clinical jaundice 
• Suspected transmission of an infectious agent by the study treatment, as defined below 
o 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 study treatment is suspected. 
 
11.1.3.1 
Atezolizumab AESIs 
• Systemic lupus erythematosus 
• Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, macrophage activating syndrome and hemophagocytic lymphohistiocytosis  
• Nephritis 
• Ocular toxicities (e.g. uveitis, retinitis, optic neuritis) 
• Grade ≥ 2 cardiac disorders (e.g. atrial fibrillation, myocarditis, pericarditis) 
• Vasculitis 
• Autoimmune hemolytic anemia 
• Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
 
11.1.4 Expected/Unexpected Adverse Event 
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert (P.I) or current Investigator Brochure (I.B). 
 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, prescribing information or when it is not included in 
the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.   
 
For patients receiving combination therapy, causality will be assessed individually for 
atezolizumab and talazoparib per each protocol-mandated therapy. 
 
 
 


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11.1.5 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  
 
11.1.6 Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (V5 .0 Update current versions) 
will be used for assessing adverse event severity. Below Table should be used for assessing 
severity for adverse events that are not specifically listed in the NCI CTCAE. 
 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 
 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events. 
Note:  Based on the most recent version of NCI CTCAE (V5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. Instrumental activities of daily living refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
b. Examples of self-care activities of daily living include bathing, dressing and 
undressing, feeding oneself, using the toilet, and taking medications, as performed 
by patients who are not bedridden. 
c. If an event is assessed as a "significant medical event," it must be reported as a 
serious adverse event  
d. Grade 4 and 5 events must be reported as serious adverse events  
 
 
 


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11.2 
Reporting 
 
11.2.1 Adverse Events  
• AEs will be recorded from time of signed informed consent until 30 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
• AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
• All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
 
11.2.2 Serious Adverse Events (SAEs) 
 
11.2.2.1 
Site Requirements for Reporting SAEs or irAEs to HCRN 
• SAEs will be reported from time of signed informed consent until 30 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
• SAEs include events related and unrelated to the study drug(s).  
• SAEs will be reported on the SAE Submission Form within 1 business day of discovery 
of the event.   
• All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
 
The site will submit the completed SAE Submission Form to HCRN within 1 business day of 
discovery of the event. The form will be submitted to HCRN electronically to 
safety@hoosiercancer.org. The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies as per local requirements.   
 
The original copy of the SAE Submission Form and the email correspondence must be kept 
within the study file at the study site. 
 
Once the SAE has resolved (see resolution guidelines listed above), sites must submit a follow-
up SAE Submission Form within a reasonable timeframe to HCRN electronically to 
safety@hoosiercancer.org.   
 
11.2.3 Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior Atezolizumab and talazoparib exposure. If 
the investigator should become aware of the development of cancer or a congenital anomaly in a 
subsequently conceived offspring of a female subject who participated in the study, this should 
be reported as an SAE adequately to Genentech drug Safety during follow up period. 
 
 
 


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11.3 
Special Situation Reports 
 
11.3.1 Pregnancy reports 
If a female subject or female partner of a male study subject becomes pregnant while receiving 
the study drug or within 7 months after the last dose of study drug, a report should be completed 
and expeditiously submitted to Genentech, Inc. Follow-up to obtain the outcome of the 
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 drug should be 
reported as an SAE to HCRN within thirty (30) calendar days of the awareness date. 
Pregnancies will be followed up until the outcome of the pregnancy is known, whenever 
possible, based upon due diligence taken to obtain the follow-up information. 
 
11.3.2 Other Special Situation Reports 
In addition to all SAEs, pregnancy reports and AESIs, the following other Special Situations 
Reports should be collected even in the absence of an Adverse Event and transmitted to HCRN 
within thirty (30) calendar days. 
● Data related to the Product usage during breastfeeding 
● Data related to overdose, abuse, misuse or medication error (including potentially 
exposed or intercepted medication errors) 
● In addition, reasonable attempts should be made to obtain and submit the age or age 
group of the patient, in order to be able to identify potential safety signals specific to a 
particular population 
 
11.3.3 Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to HCRN within fifteen (15) 
calendar days of the awareness date. A Product Complaint is defined as any written or oral 
information received from a complainant 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.  
 
11.4 HCRN Requirements for Reporting SAEs to Genentech 
HCRN will report all protocol-defined Adverse Events (AEs)/SAEs, AEs of Special Interest 
(AESIs), Special Situation Reports (including pregnancy reports) and Product Complaints (with 
or without an AE) originating from the Study for the Product to Genentech within 1 business 
day of receipt of the SAE Submission Form from a site. Follow-up information will be provided 
to Genentech as it is received from site.   
 
Genentech Drug Safety at: 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
All Product Complaints without an AE should be sent to: 
Email: kaiseraugst.global_impcomplaint_management@roche.com 
 


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11.5 
HCRN Requirements for Reporting SAEs to Pfizer 
HCRN will report all SAEs to Pfizer within 1 business day of receipt of the SAE Submission 
Form from a site. Follow-up information will be provided to Pfizer as it is received from site. 
Pfizer Drug Safety: Via fax: Pfizer U.S. Clinical Trial Department 1-866-997-8322 or email: 
USA.AEReporting@pfizer.com 
 
11.6 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.  The IND sponsor will also make an 
assessment of whether the event constitutes an unanticipated problem posing risks to subjects or 
others (UP). This assessment will be provided to the Emory University IRB, which, in turn will 
make a final determination.  If the Emory IRB determines an event is a UP it will notify the 
appropriate regulatory agencies and institutional officials. 
 
11.7 
HCRN Responsibilities to FDA 
HCRN will manage the Investigational New Drug Application (IND) associated with this 
protocol on behalf of the sponsor-investigator. HCRN will cross-reference this submission to the 
Genentech’s parent IND at the time of submission. All written IND Safety Reports submitted to 
the FDA by HCRN on behalf of the sponsor-investigator must also be faxed to Genentech Drug 
Safety: Fax: (650) 225-4682 or (650) 225-4630. 
 
HCRN will be responsible for all communication with the FDA in accordance with 21CFR312 
including but not limited to the 7 and 15 Day Reports, as well as an Annual Progress Report. A 
copy of these documents will be available to Genentech upon request. 
 
11.8 
IND Safety Reports Unrelated to this Trial 
Genentech will provide to HCRN IND safety reports from external studies that involve the study 
drug(s) per their guidelines.  HCRN will forward safety reports to the sponsor-investigator who 
will review these reports and determine if revisions are needed to the protocol or consent. HCRN 
will forward these reports to participating sites within 1 business day of receiving the sponsor-
investigator’s review.  Based on the sponsor-investigator’s review, applicable changes will be 
made to the protocol and informed consent document (if required).  All IND safety reports will 
also be made available to sites via the EDC system.    
 
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
12 
STATISTICAL METHODS 
 
12.1 
Study Design 
This is a Phase II unblinded single arm study designed to determine the efficacy and safety of 
talazoparib, high dose radiation, and atezolizumab given as second or third-line treatment to 
gBRCA pathogenic variant negative mTNBC (≥ 2 lesions) patients with PD-L1 positive tumors 
who have progressed on one to three lines of prior chemotherapy with or without immune 
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12.2 
Sample Size and Accrual 
Sample size is determined using Simon’s 2-stage Minimax design to detect a 20% increase in 
objective response rate (ORR). The null hypothesis that the true response rate among gBRCA1/2 
negative patients of 10%, based on the TOPACIO study25, will be tested against a one-sided 
alternative.  In the first stage, 7 patients will be accrued.  If there are 0 responses in these 7 
gBRCA1/2 negative patients, the study will be stopped.  Otherwise, 11 additional patients will be 
accrued for a total of 18 evaluable patients.  This design yields a Type I error rate of 0.1 for one 
sided test and power of 80% when the true response rate is 30% in the gBRCA pathogenic 
variant negative patients.  Assuming an attrition rate of 20%, we will enroll 23 total gBRCA 1/2 
negative patients.  
 
12.3 
Endpoints 
 
12.3.1 Definition of Primary Endpoint 
The objective response rate is the proportion of all subjects with confirmed PR or CR in non-
irradiated lesions according to RECIST v.1.1.  Response will be assessed by the Investigator 8 
weeks after the first dose of atezolizumab as was previously done on the Impassion130 Trial.7   
 
12.3.2 Definition of Secondary Endpoints 
• Frequency and severity of adverse events scored according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 up to 12 weeks post 1st 
dose of atezolizumab will be described. The adverse events will be summarized 
descriptively using frequencies and percentages of all captured toxicities and grades 
using CTCAE v.5 criteria.  We will determine whether talazoparib and targeted, high 
dose radiotherapy to 1-4 lesions in combination with atezolizumab in mTNBC patients (≥ 
2 lesions) adversely increases the frequency and severity of toxicities associated with any 
of these agents alone when given in isolation, including Grade 2 or higher irAEs, 
hematologic toxicities, pneumonia, pneumonitis and fatigue. 
• Progression Free Survival is a measurement from Cycle 1 Day 1 until the criteria for 
disease progression is met as defined by RECIST 1.1 or death occurs. Subjects who have 
not progressed will be right-censored at the date of the last disease evaluation. 
• Overall Survival is defined by the date of Cycle 1 Day 1 to date of death from any cause. 
• ORR by immune-related RECIST (irRECIST) which will include confirmed complete 
response (CR) + confirmed partial response (PR) determined as per irRECIST 
• Duration of Overall Response is the period measured from the time that measurement 
criteria are met for complete or partial response (whichever status is recorded first) until 
the date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since treatment 
started). 
• Disease Control Rate is the proportion of all subjects with stable disease (SD), or partial 
response (PR), or complete response (CR) according to RECIST 1.1, for 8 weeks from 
the start of talazoparib until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the start of treatment).  
• Time to Progression is measurement from the date of Cycle 1 Day 1 until the criteria for 
disease progression is met as defined by RECIST 1.1. Subjects who have not progressed 
or have died due to any cause will be right-censored at the date of the last disease 


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evaluation or date of death. 
• Adherence, measured by intravenous infusion, oral medication, and radiation treatment 
compliance with prescribed systemic therapy and radiation dose and days of treatment.  
• Patient-reported outcomes (PROs) include 1) Fatigue, as measured by MFI, actual scores 
and change from baseline; 2) Health Related Quality of Life, as measured by EORTC 
QLQ-C30, actual scores and change from baseline. 
• Best overall tumor response is defined as the best response recorded from the start of the 
study treatment until disease progression/recurrence.   
 
12.4 
Assessment of Safety 
All patients who receive at least one dose of talazoparib will be evaluable for toxicity.  The 
adverse events will be summarized descriptively using frequencies and percentages of all 
captured toxicities and grades using CTCAE v.5 criteria.  We will determine whether talazoparib 
and targeted, high dose radiotherapy to 1-4 lesions in combination with atezolizumab in mTNBC 
(≥ 2 lesions) patients adversely increases the frequency and severity of toxicities associated with 
any of these agents alone when given in isolation, including Grade 2 or higher irAEs, 
hematologic toxicities, pneumonia, pneumonitis and fatigue.  Please refer to the Study Calendar 
for the schedule of toxicity assessments. 
 
12.5 
Assessment of Efficacy 
All subjects with measurable disease who have received at least one cycle of treatment and have 
their disease re-evaluated will be evaluable for assessment of response.  The ORR is the primary 
assessment of response and is the proportion of all subjects with confirmed PR or CR in non-
irradiated sites according to RECIST 1.1 and will be assessed 8 weeks after the first dose of 
atezolizumab.  ORR by irRECIST will also be measured.  We will perform this analysis with and 
without patients who received at least one cycle of treatment and have their disease re-evaluated.  
In addition, progression free survival, as well as duration of overall response, disease control 
rate, and time to progression will be measured according to RECIST 1.1 and irRECIST.  Overall 
survival will also be measured. 
 
12.6 
Data Analysis Plans 
All analyses will include summary statistics, including number and percentage for categorical 
variables and number of patients, mean, standard deviation, median, minimum, and maximum 
for continuous variables. Two-sided 95% confidence intervals (CIs) will be provided where 
appropriate. Time-to-event analyses will be performed using Kaplan-Meier methods.  Any 
statistical analysis to be performed among subgroups is for descriptive and future study purposes. 
 
12.6.1 Analysis Plans for Primary Objective 
Overall response rate (ORR) in non-irradiated lesions 8 weeks post-atezolizumab.  ORR rate is 
defined as the number of patients who develop a partial response (PR) or complete response 
(CR) divided by the total number of patients.  The ORR will be estimated, and a 95     % 
confidence interval will be reported using Wilson interval (Wallis, SA. Binomial confidence 
intervals and contingency tests: mathematical fundamentals and the evaluation of alternative 
methods. Journal of Quantitative Linguistics 2013. 20 (3): 178–208).   
 


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12.6.2 Analysis Plans for Secondary Objectives 
Adverse events will be summarized descriptively using frequencies and percentages of all 
captured toxicities and grades using CTCAE v.5 criteria.  Adverse events leading to 
discontinuation of talazoparib, radiation, and/or atezolizumab will be recorded.  Rates of side 
effects, and by location and site, will be reported, and will be compared across location or site 
type using chi-square tests or Fisher’s exact tests, where appropriate.  Progression-free survival, 
overall survival, duration of response, disease control rate, and time to progression will be 
estimated using the Kaplan-Meier method.  DCR will be estimated as the proportion of all 
subjects with stable disease (SD), or partial response (PR), or complete response (CR) 8 weeks 
from the start of talazoparib until disease progression/recurrence out of the total number of 
patients. PFS, ORR, DOR, and DCR will be defined by both RECIST v1.1 and irRECIST 
criteria, based on the date of PD that will be used to determine duration, and will be analyzed 
separately by both criteria.   
 
Progression-free survival is defined as length of time from start of talazoparib for the breast 
cancer metastases that a patient lives with the disease, but it does not get worse.  Overall survival 
is defined as length of time from the start of talazoparib for the breast cancer metastases that 
patients diagnosed with the disease are still alive.  Adherence will be measured by oral pill, 
intravenous infusion and radiation treatment compliance with prescribed systemic therapy and 
radiation dose and days of treatment.  Patient-reported outcomes (PROs) including 1) Fatigue, as 
measured by MFI, actual scores and change from baseline; 2) Health Related Quality of Life, as 
measured by EORTC QLQ-C30, actual scores and change from baseline; 3) PROs and change in 
values over time will be summarized descriptively, using frequencies and percentages for 
categorical variables, and mean, median, standard deviation, interquartile range, and 
minimum/maximum for continuous variables.  Best overall tumor response will be summarized 
by number and percentage of patients.   
 
12.6.3 Analysis Plans for Exploratory Objectives 
The influence of race on all above endpoints will be explored, as we anticipate at least 30% of 
our enrolled patients being African American based upon the patient demographics of the 
participating institutions.  Additionally, we will explore the influence of BRCA and HRD status 
as well as previous lines of cytotoxic chemotherapy with or without immune therapy on response 
will be explored.    
 
The incidence of biomarkers will be summarized using descriptive statistics. Comparisons of 
efficacy and safety endpoints between biomarker subpopulations may be performed.    For each 
patient in the study, blood samples will be prospectively collected, evaluated and archived to 
support exploratory biomarker analysis. Exploratory biomarkers will be correlated with response. 
ctDNA will be measured pre- and 8 weeks post-atezolizumab, and B cell amount and type will 
be measured pre- and 2 weeks post-atezolizumab.  ctDNA will be correlated with ORR using 
chi-squared tests (if ctDNA is dichotomized using cut points) or ANOVA, and will be correlated 
with PFS/OS using Cox regression and log-rank tests (if ctDNA is dichotomized using cut 
points).  The proportional hazards assumption will be verified.  Inflammatory cytokine 
measurements will be correlated with PROs using chi-squared tests, ANOVA, t-tests, and/or 
non-parametric equivalents such as Fisher’s exact tests, Kruskal-Wallis, or Mann Whitney U 
tests, where appropriate.  Longitudinal assessments will be modeled using generalized estimating 


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equations (GEE) or mixed modeling approaches, or withed paired approaches such as paired t-
tests or McNemar’s tests. The number and distribution of myeloid cells and IHC staining for 
SAMHD1 will be compared to ORR, PFS, and OS using chi-squared tests, ANOVA, t-tests, and 
log-rank tests.  Cox regression will be considered.  The number and types of B cells will be 
evaluated before and after radiotherapy using paired tests, such as paired t-tests and McNemar’s 
tests.  B cell distributions will be compared between patients who develop Grade 3 or higher 
toxicities an those who do not.  Gene expression will also be compared between those who 
develop toxicities vs. those that do not, as well as responders vs. non-responders using chi-
squared tests, ANOVA, and/or non-parametric equivalents, where appropriate. 
 
12.6.4 Subgroup Analyses 
Per-Protocol Population - All patients who receive and complete the first cycle of study 
treatment, have protocol-required post-baseline disease assessments and have no major protocol 
violations that would impact efficacy evaluations. Supportive analyses of efficacy endpoints will 
be performed on the per-protocol population. 
 
12.7 
Interim Analysis/Criteria for Stopping Study 
Safety will be summarized using descriptive statistics.  Atezolizumab will be held for most grade 
2 irAEs per investigator’s brochure and re-started after resolution of symptoms to grade 1 or 
better.  However, we will stop the trial and deem the combination of talazoparib, radiation, and 
atezolizumab unsafe if any of the following occur:  
1) Two of the first 3 patients enrolled develop grade 2 irAEs and are unable to resume 
systemic therapy within 8 weeks due to treatment-related toxicities OR  
2) Two of the first 3 patients enrolled develop grade 3 or higher irAEs.   
 
Additionally, the study will be stopped if 2 of the first 3 patients enrolled develop any one of the 
following: 
1) Grade 3 or higher febrile neutropenia 
2) Grade 3 thrombocytopenia with bleeding event 
3) Grade 4 neutropenia, anemia, or thrombocytopenia  
4) Any clinically meaningful Grade 3 non-hematologic event that leads to hospitalization or 
a medical intervention other than electrolyte or IVF support as deemed by the site 
investigator  
5) Any grade 4 or higher non-hematological event with the exception of Grade 4 fatigue.   
 
If these toxicities occur in 1 or fewer of the first 3 patients enrolled, the trial will proceed to 
assess an additional three patients.  If 2 of the first 6 patients enrolled develop any of the above 
grade 2 irAEs and/or other Grade 3 or higher toxicities, the study combination of treatments will 
be deemed unsafe and the trial will be stopped.  If one or fewer of the first 6 patients enrolled 
develop one of the above toxicities, the trial will continue to enroll the remaining patients until 
enrollment is complete.  
 
12.7.1 Pre-Determined Criteria for Safety Concerns (n=18 gBRCA1/2 negative) 
After all evaluable patients have been enrolled (18 gBRCA1/2 negative), we will deem the 
combination of talazoparib, radiation, and atezolizumab as unsafe if any of the following rates of 
toxicities are exceeded:  


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1) ≥ 40% of patients develop grade 3 or higher febrile neutropenia 
2) > 40% of patients develop grade 4 neutropenia  
3) > 40% of patients develop grade 4 leukopenia  
4) > 30% of patients develop thrombocytopenia with bleeding event  
5) > 20% of patients develop bone fracture following radiotherapy to the bone 
6) > 35% of patients develop pneumonia 
7) > 25% of patients develop Grade 3 or higher pneumonitis 
8) > 5% of patients develop Grade 3 brachial plexopathy (assessed by LENT/SOMA or 
RTOG criteria) or Grade 3 spinal cord injury assessed by CTCAE version 5 due to 
radiation treatment to these areas 
9) > 30% of patients develop other clinically meaningful non-hematologic Grade 3 toxicities 
(excluding neutropenia and leukopenia) that leads to hospitalization or a medical 
intervention other than electrolyte or IVF support not mentioned above and/or  
10) > 40% of patients develop Grade 4 neutropenia, anemia, or thrombocytopenia or any 
grade 4 or higher non-hematological event with the exception of Grade 4 fatigue.   
 
13 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted with guidance from the Emory Winship Cancer Institute’s DSMP.  
 
HCRN oversight activities include: 
• Review and process all adverse events requiring expedited reporting as defined in the 
protocol 
• Provide trial accrual progress, safety information and data summary reports to the 
sponsor-investigator  
• Submit data summary reports to the lead institution Data Safety Monitoring Committee 
according to Emory Winship Cancer Institute DSMP. 
 
13.2 
Emory Winship Cancer Institute Data Safety Monitoring Committee 
HCRN will provide the following for the Winship Cancer Institute DSMC to review: 
• Adverse event summary report 
• Audit results if applicable 
• Data related to stopping/decision rules described in study design 
• Study accrual patterns  
• Protocol deviations 
 
The Winship Cancer Institute DSMC will review study data annually.  Documentation of DSMC 
reviews will be provided to sponsor-investigator and HCRN.  Issues of immediate concern by the 
DSMC will be brought to the attention of the sponsor-investigator and other regulatory bodies as 
appropriate.  The sponsor-investigator will work with HCRN to address the DSMC’s concerns.   
 
 
 


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13.3 
Data Quality Oversight Activities by HCRN 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study.  Automated edit check listings will be used to generate queries in the EDC 
system and transmitted to the site to address in a timely fashion. Corrections will be made by the 
study site personnel. 
 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. For cause audits may be performed as necessary. During onsite 
monitoring visits, source documents will be reviewed for verification of agreement with data 
entered into the EDC system.  It is important for the site investigator and their relevant personnel 
to be available for a sufficient amount of time during the monitoring visits or audit, if applicable. 
The site investigator and institution guarantee access to source documents by HCRN or its 
designee. 
 
The trial site may also be subject to quality assurance audit by Genentech, Pfizer or its designee 
as well as inspection by appropriate regulatory agencies.  
 
13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information.   
 
14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform (EDC system), a system compliant with Good 
Clinical Practices and Federal Rules and Regulations.  HCRN personnel will coordinate and 
manage data for quality control assurance and integrity. Select data will be collected and entered 
into the EDC system by study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in EDC system or other secure database(s). If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives.  
 


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The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, Genentech, IRB, or government agencies, like the FDA, 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
15 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB to HCRN 
before he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require.  
 
Progress reports and notifications of serious and unexpected adverse events will be provided to 
the IRB according to local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 


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15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject.  
 
 
 


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69. Smith AK, Conneely KN, Pace TW, et al: Epigenetic changes associated with 
inflammation in breast cancer patients treated with chemotherapy. Brain Behav Immun 
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70. Torres MA, Pace TW, Liu T, et al: Predictors of depression in breast cancer patients 
treated with radiation: role of prior chemotherapy and nuclear factor kappa B. Cancer 
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independent risk factors of fatigue in breast cancer survivors. Psychol Med 47:1733-
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72. Panis C, Pavanelli WR: Cytokines as Mediators of Pain-Related Process in Breast 
Cancer. Mediators Inflamm 2015:129034, 2015 
73. Iakovou I, Doumas A, Badiavas K, et al: Pain palliative therapy in women with breast 
cancer osseous metastatic disease and the role of specific serum cytokines as prognostic 
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74. Daddacha W, Koyen AE, Bastien AJ, et al: SAMHD1 Promotes DNA End Resection to 
Facilitate DNA Repair by Homologous Recombination. Cell Rep 20:1921-1935, 2017 
75. Galon J, Pages F, Marincola FM, et al: The immune score as a new possible approach for 
the classification of cancer. J Transl Med 10:1, 2012 
76. Fridman WH, Teillaud JL, Sautes-Fridman C, et al: The ultimate goal of curative anti-
cancer therapies: inducing an adaptive anti-tumor immune response. Front Immunol 2:66, 
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77. Sharma P, Allison JP: The future of immune checkpoint therapy. Science 348:56-61, 
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78. Melosky B, Juergens R, McLeod D, et al: Immune checkpoint-inhibitors and 
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trial for a continuous outcome variable. Stat Methods Med Res 25:1057-73, 2016 
 
 


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17 
APPENDIX I: MANAGEMENT OF ATEZOLIZUMAB-SPECIFIC ADVERSE 
EVENTS 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice.  Additional tests, such as autoimmune serology or 
biopsies, should be used to evaluate for a possible immunogenic etiology. 
 
PULMONARY EVENTS 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab.  Patients will be assessed for pulmonary signs and 
symptoms throughout the study and will also have computed tomography (CT) scans of the chest 
performed at every tumor assessment.  All pulmonary events should be thoroughly evaluated for 
other commonly reported etiologies such as pneumonia or other infection, lymphangitic 
carcinomatosis, pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or 
pulmonary hypertension.   
 
Management Guidelines for Pulmonary Events, Including Pneumonitis 
Event 
Management 
Pulmonary 
event, Grade 1 
● Continue atezolizumab and monitor closely. 
● Re-evaluate on serial imaging. 
● Consider patient referral to pulmonary specialist. 
Pulmonary 
event, Grade 2 
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Refer patient to pulmonary and infectious disease 
specialists and consider bronchoscopy or BAL. 
● Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day oral prednisone. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
● For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
● Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
● Bronchoscopy or BAL is recommended. 
● Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day oral prednisone. 
● If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
● If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. 
BAL= bronchoscopic alveolar lavage. 
a: Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 


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mg/day oral prednisone. The acceptable length of the extended period of time must be 
agreed upon by the site investigator and sponsor-investigator. 
b: If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c: Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the site investigator (or an 
appropriate delegate) and the sponsor-investigator. 
 
 


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HEPATIC EVENTS 
Immune-related hepatitis has been associated with the administration of atezolizumab.  Eligible 
patients must have adequate liver function, as manifested by measurements of total bilirubin and 
hepatic transaminases, and liver function will be monitored throughout study treatment.   
 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should 
have liver function tests (LFTs) performed immediately and reviewed before administration of 
the next dose of study drug. 
 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate. 
 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
• Continue atezolizumab. 
• Monitor LFTs until values resolve to within normal limits.  
Hepatic event, 
Grade 2 
• All events 
• Monitor LFTs more frequently until return to baseline values.  
 
Events of > 5 days’ duration 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Hepatic event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab. c 
• Consider patient referral to gastrointestinal specialist for evaluation and 
liver biopsy to establish etiology of hepatic injury.  
• Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 
month. 
LFT = liver function tests. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone 
or equivalent.  The acceptable length of the extended period of time will be determined by 
the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an appropriate 
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GASTROINTESTINAL EVENTS 
Immune-related colitis has been associated with the administration of atezolizumab.  All events 
of diarrhea or colitis should be thoroughly evaluated for other more common etiologies.  For 
events of significant duration or magnitude or associated with signs of systemic inflammation or 
acute-phase reactants (e.g., increased C-reactive protein, platelet count, or bandemia):  Perform 
sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with three to five specimens 
for standard paraffin block to check for inflammation and lymphocytic infiltrates to confirm 
colitis diagnosis.  
 
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 
1 
• Continue atezolizumab. 
• Initiate symptomatic treatment. 
• Endoscopy is recommended if symptoms persist for > 7 days. 
• Monitor closely. 
Diarrhea or 
colitis, Grade 
2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Initiate symptomatic treatment. 
• Patient referral to GI specialist is recommended. 
• For recurrent events or events that persist >5 days, initiate treatment with 
1−2 mg/kg/day oral prednisone or equivalent.  
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Diarrhea or 
colitis, Grade 
3 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab c 
Diarrhea or 
colitis, Grade 
4 
• Permanently discontinue atezolizumab. c 
• Refer patient to GI specialist for evaluation and confirmation biopsy. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
GI=gastrointestinal. 
a: Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time will be 


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determined by the investigator. 
b: If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed. 
c: Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate).  
 
 
 


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ENDOCRINE EVENTS 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab. Patients with unexplained symptoms such as 
headache, fatigue, myalgias, impotence, constipation, or mental status changes should be 
investigated for the presence of thyroid, pituitary, or adrenal endocrinopathies.  The patient 
should be referred to an endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating 
hormone (TSH) and free triiodothyronine and thyroxine levels should be measured to determine 
whether thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., 
TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may help to 
differentiate primary pituitary insufficiency from primary adrenal insufficiency. 
 
Management Guidelines for Endocrine Events 
Event 
Management 
Asymptomatic 
hypothyroidism 
• Continue atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH weekly. 
Symptomatic 
hypothyroidism 
• Withhold atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH weekly. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
Asymptomatic 
hyperthyroidism 
TSH ≥ 0.1 mU/L and < 0.5 mU/L: 
• Continue atezolizumab. 
• Monitor TSH every 4 weeks. 
 
TSH < 0.1 mU/L: 
• Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
hyperthyroidism 
• Withhold atezolizumab. 
• Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
• Permanently discontinue atezolizumab. c 
Symptomatic 
adrenal 
insufficiency, 
Grade 2−4  
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to endocrinologist. 
• Perform appropriate imaging. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
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replacement therapy, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Hyperglycemia, 
Grade 1 or 2  
• Continue atezolizumab. 
• Initiate treatment with insulin if needed. 
• Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
• Withhold atezolizumab. 
• Initiate treatment with insulin. 
• Monitor for glucose control. 
• Resume atezolizumab when symptoms resolve and glucose 
levels are stable. 
Hypophysitis (pan-
hypopituitarism), 
Grade 2 or 3 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• Initiate hormone replacement if clinically indicated. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab. c 
• For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis  
(pan-
hypopituitarism), 
Grade 4 
• Permanently discontinue atezolizumab c 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• Initiate hormone replacement if clinically indicated. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate).  
 
 
 


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OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).   
 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, Grade 1  
• Continue atezolizumab. 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy. 
• If symptoms persist, treat as a Grade 2 event. 
Ocular event, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. 
a 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy. 
• If event resolves to Grade 1 or better, resume 
atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab c 
Ocular event, Grade 3 or 
4 
• Permanently discontinue atezolizumab. c 
• Refer patient to ophthalmologist. 
• Initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent.   
• If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate).  
 
 
 


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IMMUNE-RELATED MYOCARDITIS 
Immune-related myocarditis has been associated with the administration of atezolizumab.  
Immune-related myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope.  Immune-related myocarditis 
needs to be distinguished from myocarditis resulting from infection (commonly viral, e.g., in a 
patient who reports a recent history of GI illness), ischemic events, underlying arrhythmias, 
exacerbation of preexisting cardiac conditions, or progression of malignancy.   
 
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An endomyocardial 
biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if clinically 
indicated. Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines below. 
 
Management Guidelines for Immune-Related Myocarditis 
Event 
Management 
Immune-related 
myocarditis, Grade  
     2-4 
• Permanently discontinue atezolizumab and contact sponsor-
investigator.      a 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement.       
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
a                Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-related event.  The decision to re-
challenge patients should be based on the investigator’s assessment of benefit-risk and      
documented by the investigator (or an appropriate delegate). Sponsor-investigator is 
available to advise as needed. 
 
 
 


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Infusion-Related Reactions       
No premedication is indicated for the administration of Cycle 1 of atezolizumab. However, 
patients who experience an infusion-related reaction (IRR) or cytokine-release syndrome (CRS) 
with atezolizumab may receive premedication with antihistamines, antipyretics, and/or 
analgesics (e.g., acetaminophen) for subsequent infusions. Metamizole (dipyrone) is prohibited 
in treating atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 
 
     Management Guidelines for Infusion-Related Reactions       
 
Event 
Management 
IRR, Grade 1  
• Reduce infusion rate to half the rate being given at the time of 
event onset. 
• After the event has resolved, the investigator should wait for 30 
minutes while delivering the infusion at the reduced rate. 
• If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to the 
original rate. 
IRR, Grade 2 
• Interrupt atezolizumab infusion. 
• Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, 
epinephrine, bronchodilators, oxygen). 
• After symptoms have resolved to baseline, resume infusion at half 
the rate being given at the time of event onset. 
• For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or analgesics 
and monitor closely for IRRs. 
IRR, Grade 3 or 4 
• Stop infusion. 
• Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
• Permanently discontinue atezolizumab and contact Medical 
Monitor. a 
IRR  =  infusion-related reaction. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab according to institutional guidelines and the above table.  In the case of 
Grade 3 or 4 IRRs, guidance from the Medical Monitor is highly recommended. 
 
 
 
 


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PANCREATIC EVENTS 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab.  The differential 
diagnosis of acute abdominal pain should include pancreatitis.  Appropriate work-up should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests.   
 
Management Guidelines for Pancreatic Events, Including Pancreatitis  
Event 
Management 
Amylase and/or 
lipase elevation, 
Grade 2 
• Continue atezolizumab. 
• Monitor amylase and lipase weekly. 
• For prolonged elevation (e.g.,> 3 weeks), consider treatment with 
corticosteroids equivalent to 10 mg/day oral prednisone.           
Amylase and/or 
lipase elevation, 
Grade 3 or 4 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Monitor amylase and lipase every other day. 
• If no improvement, consider treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
• For recurrent events, permanently discontinue atezolizumab. c 
Immune-related 
pancreatitis, Grade 
2 or 3 
 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
• For recurrent events, permanently discontinue atezolizumab. c 
Immune-related 
pancreatitis, Grade 
4 
• Permanently discontinue atezolizumab. c 
• Refer patient to GI specialist. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 
month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone 
or equivalent.  The acceptable length of the extended period of time must be determined by 
the investigator. 
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oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate).  
 
 
 
 


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DERMATOLOGIC EVENTS 
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of rash 
were mild in severity and self-limited, with or without pruritus.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  A biopsy should be considered unless contraindicated.   
 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic event, Grade 1  
• Continue atezolizumab. 
• Consider treatment with topical corticosteroids and/or 
other symptomatic therapy (e.g., antihistamines). 
Dermatologic event, Grade 2  
• Continue atezolizumab. 
• Consider patient referral to dermatologist. 
• Initiate treatment with topical corticosteroids. 
• Consider treatment with higher-potency topical 
corticosteroids if event does not improve. 
Dermatologic event, Grade 3  
• Withhold atezolizumab for up to 12 weeks after event 
onset. a 
• Refer patient to dermatologist for evaluation and, if 
indicated, biopsy. 
• Initiate treatment with 10 mg/day oral prednisone or 
equivalent, increasing dose to 1−2 mg/kg/day if event 
does not improve within 48−72 hours. 
• If event resolves to Grade 1 or better, resume 
atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab. c 
Dermatologic event, Grade 4 
• Permanently discontinue atezolizumab. c 
Stevens Johnson syndrome or 
toxic epidermal necrolysis, (any 
grade) 
Additional guidance for Stevens Johnson syndrome or 
toxic epidermal necrolysis: 
Withhold atezolizumab for suspected Stevens Johnson 
syndrome or toxic epidermal necrolysis. 
Confirm diagnosis by referring patient to a specialist 
(dermatologist, ophthalmologist, or urologist as relevant) 
for evaluation and, if indicated, biopsy. 
Follow the applicable treatment and management 
guidelines above. 
• If Stevens Johnson syndrome or toxic epidermal 
necrolysis is confirmed, permanently discontinue 
atezolizumab. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone 
or equivalent.  The acceptable length of the extended period of time will be determined by 
the investigator. 
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oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate).  
 
 
 
 


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NEUROLOGIC DISORDERS 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to differentiate 
between alternative etiologies.   
 
Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-related 
neuropathy, Grade 1 
• Continue atezolizumab. 
• Investigate etiology. 
Immune-related 
neuropathy, Grade 2  
• Withhold atezolizumab for up to 12 weeks after event onset. 
a 
• Investigate etiology. 
• Initiate treatment as per institutional guidelines. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab. c 
Immune-related 
neuropathy, Grade 3 or 4 
• Permanently discontinue atezolizumab. c  
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis and 
Guillain-Barré syndrome 
(any grade) 
• Permanently discontinue atezolizumab. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of 1−2 mg/kg/day oral or IV prednisone 
or equivalent. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone 
or equivalent.  The acceptable length of the extended period of time must be determined by 
the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate).  
 
 
 


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IMMUNE-RELATED MENINGOENCEPHALITIS 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab.  Immune-related meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness.  Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process.   
 
All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema.  If deemed 
safe by the treating physician, a lumbar puncture should be performed and a neurologist should 
be consulted. Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines below. 
 
Management Guidelines for Immune-Related Meningoencephalitis 
Event 
Management 
Immune-related 
meningoencephalitis, all 
grades 
• Permanently discontinue atezolizumab. a 
• Refer patient to neurologist. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an 
appropriate delegate). 
 
 
 


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IMMUNE-RELATED NEPHRITIS 
Immune-related nephritis has been associated with the administration of atezolizumab. Eligible 
patients must have adequate renal function, and renal function, including serum creatinine, 
should be monitored throughout study treatment. Patients with abnormal renal function should be 
evaluated and treated for other more common etiologies (including prerenal and postrenal 
causes, and concomitant medications such as nonsteroidal anti-inflammatory drugs). Refer the 
patient to a renal specialist if clinically indicated. A renal biopsy may be required to enable a 
definitive diagnosis and appropriate treatment. If no alternative cause of acute kidney injury is 
identified, patients with signs and symptoms of acute kidney injury, in the absence of an 
identified alternate etiology, should be treated according to the management guidelines for 
immune-related renal events in the table below. 
 
Management Guidelines for Renal Events 
 
Event 
Management 
Renal event, 
Grade 1 
• Continue atezolizumab. 
• Monitor kidney function, including creatinine, closely until values resolve 
to within normal limits or to baseline values. 
Renal event, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to renal specialist. 
• Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Renal event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab. 
• Refer patient to renal specialist and consider renal biopsy. 
• Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
• If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 
month. 
 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE and 
are applicable to both CTCAE Version 4.0 and CTCAE Version 5.  
a. Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be agreed upon by the 
investigator and the sponsor-investigator. 
b. If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent 
of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 


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c. Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the sponsor-investigator. 
 
 


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IMMUNE-RELATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are amongst the most common 
disorders. Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 
dermatomyositis), biochemical (serum creatinine-kinase increase), and imaging 
(electromyography/MRI) features, and is confirmed with a muscle-biopsy. One etiology of 
myositis is immune-mediated, which is the current concern with atezolizumab. 
  
It is recommended that atezolizumab should be withheld for moderate or severe (Grade 2 or 3) 
immune-related myositis and permanently discontinued for recurrent severe or life-threatening 
myositis (recurrent Grade 3 and Grade 4). Please refer the patient to rheumatologist and/or 
neurologist and consider muscle biopsy and supportive measures as clinically indicated. 
Corticosteroids treatment with 1-2 mg/kg/day IV methylprednisolone or higher-dose bolus if 
severely compromised (weakness severely limiting mobility, cardiac function, respiratory 
function, dysphagia) and/or additional immunosuppressive agents should be administered for ≥ 
Grade 2 events or if the event does not improve after initial corticosteroids. Please refer to the 
table below for detailed management guidelines for immune-mediated myositis. 
  
Management Guidelines for Immune-Related Myositis  
Event 
Management 
Immune-related myositis, Grade 1 
• Continue atezolizumab 
• Refer subject to rheumatologist or neurologist 
• Initiate treatment as per institutional guidelines 
Immune-related myositis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after 
event onseta and contact site investigator. 
• Refer subject to rheumatologist or neurologist 
• Initiate treatment as per institutional guidelines 
• Consider treatment with corticosteroid equivalent 
to 1-2 mg/kg/day IV methylprednisolone and 
convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If corticosteroids are initiated and event does not 
improve within 48 hours after initiating 
corticosteroids, consider adding an 
immunosuppressive agent 
• If event resolves to Grade 1 or better, resume 
atezolizumab.b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently 
discontinue atezolizumab and contact the sponsor-
investigator. c 
Immune-related myositis, Grade 3 
• Withhold atezolizumab for up to 12 weeks after 
event onseta and contact site investigator. 
• Refer subject to rheumatologist or neurologist 
• Initiate treatment as per institutional guidelines 


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• Respiratory support may be required in more 
severe cases 
• Initiate treatment with corticosteroid equivalent to 
1-2 mg/kg/day IV methylprednisolone or higher 
dose bolus if subject is severely compromised (eg, 
cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 
1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume 
atezolizumab.b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently 
discontinue atezolizumab and contact HCRN. c 
• For recurrent events, treat as a Grade 4 event 
Immune-related myositis, Grade 4 
• Permanently discontinue atezolizumab and contact 
site investigator.c 
• Refer subject to rheumatologist or neurologist 
• Initiate treatment as per institutional guidelines.  
• Respiratory support may be required in more 
severe cases 
• Initiate treatment with corticosteroid equivalent to 
1-2 mg/kg/day IV methylprednisolone or higher 
dose bolus if subject is severely compromised (eg, 
cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 
1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper 
corticosteroids over ≥ 1 month. 
IV, intravenous 
a Atezolizumab may be withheld for a period of time (ie, > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
sponsor-investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have 
fully recovered from the immune-related event. Subjects can be rechallenged with atezolizumab 


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only after approval has been documented by both the investigator (or an appropriate delegate) 
and the sponsor-investigator. 
 
 


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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE ACTIVATION SYNDROME 
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).   
 
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.   
 
Patients with suspected HLH should be diagnosed according to published criteria by McClain 
and Eckstein (2014).  A patient should be classified as having HLH if five of the following eight 
criteria are met: 
      
• Fever ≥ 38.5°C 
• Splenomegaly 
• Peripheral blood cytopenia consisting of at least two of the following: 
o Hemoglobin < 90 g/L (9 g/dL) (< 100 g/L [10 g/dL] for infants < 4 weeks old) 
o Platelet count < 100 × 109/L (100,000/μL) 
o ANC < 1.0 × 109/L (1000/μL) 
• Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen < 1.5 g/L (150 mg/dL) 
• Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
• Low or absent natural killer cell activity 
• Ferritin > 500 mg/L (500 ng/mL) 
• Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated ≥ 2 standard deviations above 
age-adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be classified as 
having MAS if the following criteria are met: 
• Ferritin > 684 mg/L (684 ng/mL) 
• At least two of the following: 
o Platelet count ≤ 181 × 109/L (181,000/μL) 
o AST ≥ 48 U/L 
o Triglycerides > 1.761 mmol/L (156 mg/dL) 
o Fibrinogen ≤ 3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in Table 14. 


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Table 14 
Management Guidelines for Suspected Hemophagocytic Lymphohistiocytosis or 
Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
• Permanently sponsor-investigator. 
• Consider patient referral to hematologist. 
• Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
• Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy. 
• If event does not respond to treatment within 24 hours, contact 
sponsor-investigator and initiate treatment as appropriate according 
to published guidelines (La Rosée 2015; Schram and Berliner 
2015; La Rosée et al. 2019). 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome. 
 
IMMUNE-MEDIATED PERICARDIAL DISORDERS 
The following recommendations will be included in the updated atezolizumab Investigator’s 
Brochure (IB) and study protocols for immune-mediated pericardial disorders: 
• 
The diagnosis of immune-mediated pericarditis should be considered in all patients 
presenting with chest pain. 
• 
The diagnosis of immune-mediated pericardial effusion and cardiac tamponade should be 
considered in all patients presenting with chest pain associated with dyspnea or 
hemodynamic instability. 
• 
Cardiac tamponade should be treated as a medical emergency and consultation with a 
cardiologist should be sought for further management. 
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
o If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• 
Atezolizumab should be withheld for patients with suspected immune-mediated 
pericardial disorders. 
• 
Atezolizumab should be permanently withdrawn for any grade confirmed immune-
mediated pericardial disorders. 
• 
Caution should be used when considering the use of atezolizumab in a patient 
experienced a pericardial disorder on prior treatment with other immune-stimulatory 
anticancer agents. 
 
 


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REFERENCES 
• Adashek ML, Feldman M. Cytokine release syndrome resulting from anti−programmed 
death-1 antibody: raising awareness among community oncologist. J Oncol Practice 
2019;15:502−4. 
• La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:190−6. 
• La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:2465−77. 
• McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 29 October 
2018; cited: 17 May 2019]. Available from: https://www.uptodate.com/contents/clinical-
features-and-diagnosis-of-hemophagocytic-lymphohistiocytosis. 
• Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League Against 
Rheumatism/American College of Rheumatology/Paediatric Rheumatology International 
Trials Organisation Collaborative Initiative. Ann Rheum Dis 2016;75:481−9. 
• Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk 
Manag 2019;15:323−35. 
• Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient receiving 
PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
• Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:2908−14. 
 
 
 


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19. 
APPENDIX II: MANAGEMENT OF RADIATION-SPECIFIC ADVERSE 
EVENTS 
Toxicities associated or possibly associated with radiation treatment should be managed 
according to standard medical practice.   
 
Lung Injury 
Pneumonitis due to radiation may occur weeks to months after treatment and is caused by 
inflammation of the end bronchioles and alveoli.  Radiation oncologists will be expected to 
participate in the care and monitoring of enrolled patients for this symptom per standard of care.  
Patients reporting fever, shortness of breath, dry cough, and/or chest pain should be immediately 
evaluated and treated.  Mild radiation pneumonitis may be treated with nonsteroidal anti-
inflammatory agents or steroid inhalers.  For severe cases, systemic steroids, bronchodilators, 
and pulmonary hygiene may be prescribed.  Concurrent infections should be treated with 
antibiotics.  Radiation fibrosis is a late manifestation of radiation lung injury. 
 
For patients with lung (central or peripheral) and/or mediastinal/cervical lymph node metastases 
to be treated with radiation, corticosteroid premedication can be used at the discretion of the 
treating oncologist (in which case, its use needs to be reported. 
 
Gastrointestinal/Esophageal Injury 
Radiation may cause esophagitis or dysphagia, gastritis, enteritis, or colitis which typically 
resolves within a few weeks of radiation.  It may also cause permanent injury, although 
infrequent at the proposed radiation treatment doses, which manifests as dysphagia with stenosis 
or esophageal, gastric, or intestinal ulceration with perforation in the extreme cases.  Any of 
these toxicities must be clearly documented.     
 
For patients with liver and/or abdominal-pelvic metastases (as well as any other patient at the 
discretion of the treating oncologist) anti-emetics may be given prior to each fraction of SBRT to 
prevent nausea. 
 
Analgesics may be given to help with esophagitis.   
 
Antidiarrheal medication as indicated may be used for symptomatic diarrhea. 
 
Cardiac and pericardial Injury 
Although uncommon at the proposed radiation doses on this protocol, radiation treatment to the 
heart has been associated with pericarditis, endocarditis, coronary artery disease, hypertension, 
myocardial infarction, and heart failure. 
 
Assessments of heart function (e.g. Echo or MUGA) may be helpful prior to radiation to lesions 
within 2cm of the heart to determine impact of radiation on heart function.  Referral to a 
cardiologist can help manage potential risk factors for heart disease.   
 


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Kidney Injury 
Radiation may cause kidney injury but not typically at the doses prescribed on this protocol.   
Assessments of kidney function prior to radiation may be used to monitor for early signs of renal 
injury.  Referrals to a nephrologist to help with the management of renal injury may be indicated.  
 
Spinal injury  
Radiation can cause myelitis which manifests as paresthesia, sensory changes, and motor 
weakness including paralysis.  Because there is no effective treatment for myelitis, it is critical to 
prevent and avoid injury to the spinal cord.  Corticosteroids may help with symptoms.   
 
Osseous injury 
Pathologic fractures and vertebral body compression fractures are extremely uncommon (<15%) 
at the proposed radiation doses of this protocol.  Fractures of bones treated on this protocol will 
be reported immediately to the study monitor and study PI, Dr. Mylin Torres. 
 
Pathologic fractures may be treated by vertebroplasty, kyphoplasty or surgical intervention.   
 
Alopecia, erythema, desquamation are common side effects from radiation for osseous 
metastasis.  Edema, pain, and neuralgia may be additional side effects of the treatment.   
 
Erythema/desquamation may be managed with emollients, lotions/creams and/or silvadene 
cream.   
 
Pain 
Analgesic premedication to avoid general discomfort during simulation and treatment is 
recommended when appropriate. 
 
 
 
 
 


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20. 
APPENDIX III 
For patient images stored on a PACS system at the participating institution or site, these images 
can be sent to Velocity in DICOM format where a research database will be used that does not 
contain any PHI, only the subject identifier number.  Images from the clinical database will be 
saved to a directory, anonymized using a commercial anonymizer available in the Emory 
Department of Radiation Oncology (Velocity Anonymize, Varian Medical Solutions), and then 
uploaded in the research system. The anonymization procedure takes about 10 minutes to 
complete.  
 
The research server is ideally suited for such projects as it replicates the clinical software 
environment but has its own database holding project-specific datasets. In addition, the research 
station has installed the Eclipse Advanced Scripting Programming Language (ESAPI) where 
researchers can write code in C# to create customized software scripts to extract and analyze 
patient data according to a project's design. For analysis, we will re-use a script created in the 
frame of previous research to automatically output plan quality measures to an Excel file for 
statistical processing. Extracted measures are plan indices such as the conformity, homogeneity 
and gradient indexes, dose statistics inside targets and critical structures, complete dose-volume 
histogram graphs, standard constraints values as well as any user-defined DVH points in any 
either absolute or relative formats for the dose or volume. With an extended version of the script, 
we can extract radiomics measures such as image features, statistics, and textures. These 
radiomics features can be extracted from either the patient's CT dataset or the plan's dose 
distribution. Extracted features also include segmentation characteristics such as the volume, 
area and tortuosity of each structure in the plan. Once imported in the research database, data 
received from the participating institutions will be processed with scripts to generate measures 
for statistical analysis.   
 
If there are any questions regarding this process, please contact Edi Schreibmann, 
eschre2@emory.edu, 404-778-5667. 
 
References 
 
1. Hammond ME, Hayes DF, Wolff AC, Mangu PB, Temin S. American society of clinical 
oncology/college of american pathologists guideline recommendations for 
immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J 
Oncol Pract 2010;6:195-7. 
2. Wolff AC, Hammond MEH, Allison KH, et al. Human Epidermal Growth Factor Receptor 2 
Testing in Breast Cancer: American Society of Clinical Oncology/College of American 
Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 2018;36:2105-22. 
3. Madic J, Kiialainen A, Bidard FC, et al. Circulating tumor DNA and circulating tumor cells 
in metastatic triple negative breast cancer patients. Int J Cancer 2015;136:2158-65. 
4. Hu ZY, Xie N, Tian C, et al. Identifying Circulating Tumor DNA Mutation Profiles in 
Metastatic Breast Cancer Patients with Multiline Resistance. EBioMedicine 2018;32:111-8. 
5. Das R, Bar N, Ferreira M, et al. Early B cell changes predict autoimmunity following 
combination immune checkpoint blockade. J Clin Invest 2018;128:715-20. 
6. Smith AK, Conneely KN, Pace TW, et al. Epigenetic changes associated with inflammation 
in breast cancer patients treated with chemotherapy. Brain Behav Immun 2014;38:227-36. 


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7. Torres MA, Pace TW, Liu T, et al. Predictors of depression in breast cancer patients treated 
with radiation: role of prior chemotherapy and nuclear factor kappa B. Cancer 
2013;119:1951-9. 
8. Xiao C, Miller AH, Felger J, Mister D, Liu T, Torres MA. Depressive symptoms and 
inflammation are independent risk factors of fatigue in breast cancer survivors. Psychol Med 
2017;47:1733-43. 
9. Panis C, Pavanelli WR. Cytokines as Mediators of Pain-Related Process in Breast Cancer. 
Mediators of inflammation 2015;2015:129034. 
10. Iakovou I, Doumas A, Badiavas K, Mpalaris V, Frangos S, Farmakis G. Pain palliative 
therapy in women with breast cancer osseous metastatic disease and the role of specific 
serum cytokines as prognostic factors. Cancer biotherapy & radiopharmaceuticals 
2014;29:116-23.