Conditions: Breast Cancer Triple Negative Breast Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: no

Brief summary:
This is a 3-arm study stratified by plasma ctDNA. Patients with residual TNBC disease after pre-operative therapy will be assigned to 1 of 3 Arms based on plasma ctDNA positivity and genomic marker(s).

Detailed description:
Participants that are plasma ctDNA positive with a genomic target will be assigned to one of the three groups in Arm 1 and receive genomically directed therapy.

* Arm 1a: DNA Repair pathway = talazoparib + capecitabine (CLOSED)
* Arm 1b: Immunotherapy pathway = pembrolizumab + capecitabine (CLOSED)
* Arm 1c: PI3K Pathway = inavolisib + capecitabine ---\> +/- standard of care pembrolizumab
* Arm 1d: DNA Repair + Immunotherapy = talazoparib + capecitabine +/- standard of care pembrolizumab

Participants that are plasma ctDNA positive without a genomic target will be assigned to Arm 2 and receive capecitabine and pembrolizumab or treatment of physician's choice.

Participants that are plasma ctDNA negative will be assigned to Arm 3 and receive any of the following based on patient and physician decision: no therapy/observation, capecitabine and pembrolizumab or treatment of physician's choice.

Arms:
arm 1: Arm 1a: Patients who are ctDNA-positive and harbor a genomic target. DNA repair pathway = talazoparib + capecitabine (CLOSED)

Arm 1b: Patients who are ctDNA-positive and harbor a genomic target. Immunotherapy pathway = pembrolizumab + capecitabine (CLOSED)

Arm 1c: Patients who are ctDNA-positive and harbor a genomic target. PI3K Pathway = inavolisib + capecitabine ---\> +/- standard of care pembrolizumab

Arm 1d: Patients who are ctDNA-positive and harbor a genomic target. DNA Repair + Immunotherapy = talazoparib + capecitabine +/- standard of care pembrolizumab arm 2: Arm 2 subjects have plasma ctDNA positive but do not have a genomically driven treatment option. Treatment of physician's choice will be given with consideration for capecitabine and pembrolizumab. Dose, schedule and duration of treatment to be determined by treating physician. arm 3: Arm 3 subjects have plasma ctDNA negative. Treatment of patient and physician's choice will be given with consideration for capecitabine and pembrolizumab. Dose, schedule and duration of treatment to be determined by treating physician.

Interventions: intervention 1: Capecitabine intervention 2: Talazoparib intervention 3: Pembrolizumab intervention 4: Inavolisib
Intervention descriptions: intervention 1: Capecitabine 1000 mg/m2 BID Orally 14 days on and 7 days off Cycle = 21 days; Total of 8 cycles intervention 2: Talazoparib Cycle 1: 0.75 mg then Cycle 2-8: 1 mg Cycle = 21 days; Total of 8 cycles intervention 3: Per standard of care. intervention 4: Inavolisib Cycle 1: 6 mg then Cycle 2-8: 9mg Orally 21 days on Cycle = 21 days; Total of 8 cycles

Protocol document:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
BRE18-334 
A Phase II circulating tumor DNA enriched, genomically directed post-neoadjuvant 
trial for patients with residual triple negative breast cancer (PERSEVERE) 
HCRN BRE18-334 
 
Sponsor Investigator 
Bryan P. Schneider, MD 
Indiana University Melvin and Bren Simon Comprehensive Cancer Center 
 
Co-Investigators 
Kathy D. Miller, MD 
Tarah Ballinger, MD 
Nawal Kassem, MD 
Indiana University Melvin and Bren Simon Comprehensive Cancer Center 
 
Statistician 
Guanglong Jiang, MS 
Indiana University School of Medicine 
 
Pharmacist 
Christopher A. Fausel, PharmD 
Indiana University Melvin and Bren Simon Comprehensive Cancer Center 
 
Trial Support and Funding Provided By 
Genentech  
Pfizer 
Foundation Medicine 
Epic Sciences 
Vera Bradley Foundation for Breast Cancer Research 
Indiana University Precision Health Initiative 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
7676 interactive way, Suite 120 
Indianapolis 46278 
 
 
Investigational New Drug (IND): 151567 
 
Initial Protocol Version: 08DEC2020 
Amended Protocol Version Dates: 
12JUL2021 
11JAN2022 
10AUG2022 
14JUN2023 
 


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PROTOCOL SIGNATURE PAGE 
 
A Phase II circulating tumor DNA enriched, genomically directed post-neoadjuvant trial for patients with 
residual triple negative breast cancer (PERSEVERE) 
 
VERSION DATE: 14JUN2023 
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). 
 
COMPLETE AND EMAIL COPY TO HOOSIER CANCER RESEARCH NETWORK 
 
 
 
 
 
 
 
 
_______________________________________ 
 _________________________  
 Signature of Investigator 
 
 
 
 
Date 
 
 
_______________________________________ 
 Investigator Name (printed) 
 
 
_______________________________________ 
 Investigator Title 
 
 
_______________________________________ 
 Name of Facility 
 
 
_______________________________________ 
 Location of Facility (City and State) 
 
 
_______________________________________ 
 Not Submitting to IRB 
 Expected IRB Approval Date 
 
 


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SYNOPSIS 
TITLE
A Phase II circulating tumor DNA enriched, genomically directed post-
neoadjuvant trial for patients with residual triple negative breast cancer: 
PERSEVERE 
SHORT TITLE
Circulating tumor DNA enriched, genomically directed post-neoadjuvant 
trial for patients with residual triple negative breast cancer 
PHASE 
Phase II
OBJECTIVES
Primary Objective
 
Demonstrate a 2-year disease-free survival (DFS) of > 50% for 
participants with residual disease and ctDNA positive triple negative 
breast cancer (TNBC) treated with a genomically directed therapy 
following preoperative chemotherapy (ARM 1)  
 
Secondary Objectives 
 
Evaluate the 2-year DFS for participants with residual disease and 
ctDNA positive TNBC and no actionable genomic targets treated with a 
standard approach therapy following preoperative chemotherapy 
(ARM 2)  
 
Evaluate the 2-year DFS for participants with residual disease and 
ctDNA negative TNBC treated with a standard approach therapy 
following preoperative chemotherapy (ARM 3) 
 
Evaluate the overall DFS for ARMS 1, 2, and 3 
 
Evaluate the overall distant disease-free survival (DDFS) for ARMS 1, 2, 
and 3 
 
Evaluate 1-year DFS for ARMS 1, 2, and 3 
 
Determine 5-year overall survival (OS) for ARMS 1, 2, and 3 
 
Evaluate the DFS and OS for patients with markers associated with 
response to immune checkpoint inhibitor treatment vs. those without 
markers associated with response to immune checkpoint inhibitor 
treatment identified on residual disease. 
 
Describe the toxicities associated with genomically directed therapy in 
this population 
 
Describe patient preferences for return of ctDNA results 
 
Evaluate the impact of ctDNA status and availability of genomically 
directed therapy on fear of recurrences (FCR) and health-related 
quality of life (HRQoL) 
KEY ELIGIBILITY 
CRITERIA (See Section 
3 for full eligibility 
criteria and See 
Section 4 for 
information regarding 
eligibility review and 
registration 
procedures.) 
1. ECOG Performance Status 0 or 1 within 28 days prior to study 
registration. 
2. Must have histologically or cytologically confirmed triple negative (ER-
/PR-/HER2-) invasive breast cancer per pathology report. NOTE:  ER and 
PR will be considered negative if ≤ 10% of cells stain weakly positive. 
HER2 will be considered negative if scored 0 or 1+ by 
immunohistochemistry (IHC) or 2+ by IHC associated with a 
fluorescence in situ hybridization (FISH) ratio of < 2.0 and < 6 copies per 
cell. 


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3. Must have clinical stage I-III at diagnosis (AJCC 8th edition) based on 
initial evaluation by physical examination and/or breast imaging prior to 
neoadjuvant chemotherapy. 
4. Must have completed preoperative (neoadjuvant) chemotherapy. 
NOTE: Acceptable preoperative regimens include an anthracycline or a 
taxane, or both. Participants who received preoperative therapy as part 
of a clinical trial may enroll. Participants may not have received 
adjuvant chemotherapy after surgery prior to arm assignment. 
Bisphosphonate use is allowed. 
5. Subjects who received pembrolizumab in the neoadjuvant setting are 
eligible and may continue pembrolizumab treatment during the 
screening process.  
 
Subjects assigned to Arm 1 will require a 3 week wash out period 
prior to initiation of study treatment. Subjects may resume 
pembrolizumab to complete the planned year of therapy (17 
cycles) after completion of study therapy based on investigator 
discretion. 
 
Subjects assigned to Arm 2 and Arm 3 may continue 
pembrolizumab treatment during the study based on 
investigator discretion. Total duration of pembrolizumab 
treatment should not extend beyond 17 cycles. 
6. Must have completed definitive resection of primary tumor. 
Participants must begin assigned arm therapy no later than 96 days 
from the last local therapy (surgery or radiation). NOTE: Negative 
margins for both invasive and ductal carcinoma in situ (DCIS) are 
desirable, however participants with positive margins may enroll if the 
study site treatment team believes no further surgery is possible and 
participant has received radiotherapy. Participants with margins 
positive for lobular carcinoma in situ (LCIS) are eligible. Either 
mastectomy or breast conserving surgery (including lumpectomy or 
partial mastectomy) is acceptable. 
7. Must have significant residual invasive disease at the time of definitive 
surgery following preoperative chemotherapy.  Significant residual 
disease is defined as at least one of the following: 
 
Residual invasive disease in the breast measuring at least 1 
cm. The presence of DCIS without invasion does not qualify 
as residual disease in the breast. 
 
Any macroscopic ( > 2mm) residual lymph node involvement 
regardless of primary tumor site involvement (includes no 
residual disease in the breast). 
 
Residual cancer burden (RCB) score 2 or 3. 
8. Breast Radiotherapy 
 
Radiotherapy is required for participants who underwent breast-
conserving therapy, including lumpectomy or partial 
mastectomy unless deemed clinically inappropriate by treating 
provider.  


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 
Post mastectomy radiation is at the discretion of the treating 
physician.   
 
If radiation was given prior to surgery, additional radiation after 
surgery is allowed but not required. 
 
In all cases participants must begin arm assigned therapy no 
later than 96 days from the last local therapy (surgery or 
radiation) 
 
Any acute toxicity must have resolved to grade < 2 prior to 
starting arm specific therapy. 
9. Adequate laboratory values must be obtained within 21 days prior to 
study registration. 
 
Hemoglobin (Hgb) ≥ 9.0 g/dL 
 
Platelets ≥ 100 K/mm3 
 
Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 
 
Calculated creatinine clearance of ≥ 50 cc/min using the 
Cockcroft-Gault formula: 
o Males: (140 – Age in years) × Actual Body Weight in kg 
72 × Serum Creatinine (mg/dL) 
o Females: Estimated creatinine clearance for males × 0.85 
 Bilirubin ≤ 1.5  ULN (except in participants with documented 
Gilbert’s disease, who must have a total bilirubin ≤ 3.0 mg/dL) 
 Aspartate aminotransferase (AST, SGOT) ≤ 2.5  ULN 
 Alanine aminotransferase (ALT, SGPT) ≤ 2.5  ULN 
10. Must consent to allow submission of blood and archived tumor tissue 
sample from definitive surgery for next generation sequencing of the 
tumor. Tumor block is preferred however 14 unstained slides + 1H&E 
can be submitted if necessary. NOTE: Due to possible false positives, 
ctDNA should not be drawn before completing radiation or less than 14 
days from surgery if radiation is not required.  
11. No stage IV (metastatic) disease, however no specific staging studies are 
required in the absence of symptoms or physical exam findings that 
would suggest distant disease. 
STATISTICAL 
CONSIDERATIONS 
 
This trial is designed to test the hypothesis that genomically directed therapy 
in the plasma ctDNA positive arm results in superior outcomes compared 
with the outcomes of those in BRE12-158. We propose a three-arm 
therapeutic design with the following characteristics: 
 
ARM 1 (Patients who are ctDNA-positive and harbor a genomically directed 
target) 
 
Sample size: 90 
 
We assume a DFS probability of 50% at 24-months based on the 
historical control from BRE12-158. We also assume the DFS probability 
is at least 62.5% for patients with genomically directed therapy (ARM 
1). 
 
We will conclude that a DFS survival probability of >50% at 24-months 
in the genomically directed arm will be considered a positive trial. 
 


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If a particular study drug is on shortage (ie, not available) for Arm 1 and a 
patient is assigned to that particular Arm they will be reassigned to Arm 2. 
 
Length of the follow-up period: 24 months 
 
Alpha=0.05 for one-sided test 
 
With 90 patients in Arm 1, we will have 80% power to demonstrate 
superiority in Arm 1 vs. 50% 2-yr DFS seen in the prior trial, BRE12-
158 
 
ARM 2 (Patients who are ctDNA-positive and do not harbor a genomically 
directed target) 
Assuming 90 patients are required for the primary endpoint and assuming 
78% of those who are plasma positive will harbor a genomic target and be 
assigned to Arm 1, 25 patients will not have a genomic target and will be 
assigned to ARM 2. Prospective evaluation of capecitabine or the treatment 
of physician’s choice will serve as an informal comparator for outcomes with 
contemporaneous traditional therapy in the ctDNA positive population. 
There will be insufficient numbers for formal comparisons and thus only 
descriptive statistics and comparisons will be made, including comparison 
with patients in BRE12-158.  
 
ARM 3 (Patients who are ctDNA-negative) 
Assuming 115 ctDNA positive patients will be required to fulfill the 
primary endpoint and assuming 65% of all patients screened in this 
population will be ctDNA positive, 62 patients will be ctDNA negative and 
be assigned to ARM 3. There will be insufficient numbers for formal 
comparisons and thus only descriptive statistics and comparisons will be 
made. 
 
SCREENING 
Assuming 177 patients will require a successful ctDNA test result and 
assuming 10% ctDNA testing failure + patient dropout, 195 patients will 
be needed to screen for this trial. 
TOTAL 
NUMBER OF 
SUBJECTS 
Screen = 195 patients for ctDNA status (estimated number of subjects 
required to obtain the necessary 90 subjects in Arm 1) 
ctDNA test successful = 177 
ctDNA-positive with successful ctDNA test = 115 
 
ctDNA-positive to receive genomically directed therapy = 90 (Arm 1) 
 
ctDNA-positive without genomic target to receive treatment of 
physician’s choice= 25 (Arm 2) 
ctDNA-negative to receive treatment of physician’s choice = 62 (Arm 3) 
ESTIMATED 
ENROLLMENT 
PERIOD 
36 months 
 
 
 


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SCHEMA 
8 
1 
BACKGROUND & RATIONALE 
9 
2 
OBJECTIVES 
15 
3  
ELIGIBILITY CRITERIA 
15 
4 
PARTICIPANT REGISTRATION 
19 
5 
TREATMENT PLAN 
19 
6 
DOSE MODIFICATIONS 29 
7 
SCHEDULE OF EVENTS 35 
8 
CRITERIA FOR DISEASE EVALUATION 
49 
9 
BIOLOGICAL SAMPLES 49 
10 
DRUG INFORMATION 52 
11 
ADVERSE EVENT MANAGEMENT 
54 
12 
STATISTICAL CONSIDERATIONS 62 
13 
TRIAL MANAGEMENT 64 
14. 
Data Handling and Record Keeping 
67 
16. 
REFERENCES 
69 
APPENDIX A: MANAGEMENT OF TALAZOPARIB-SPECIFIC ADVERSE EVENTS 
71 
 
 
 


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SCHEMA 
A Phase II circulating tumor DNA enriched, genomically directed post-neoadjuvant trial for patients with 
residual triple negative breast cancer 
 (PERSEVERE) 
 
 
1: Experimental Arm (ctDNA-Positive, and harbor a genomically directed target)  
Genomically directed therapy in conjunction with capecitabine. Arm 1a CLOSED based on FDA approval of 
pembrolizumab for high-risk early-stage triple-negative breast cancer in July 2021. Arm 1b will be closed due to a 
majority of patients receiving immunotherapy as standard of care. Arm 1c and Arm 1d are amended to now include 
targeted therapy with standard of care (vs. targeted therapy with atezolizumab and capecitabine) based on results of 
Impassion030 which demonstrate no benefit to atezolizumab in the adjuvant setting compared with placebo. For the 
standard of care in arm 1c, we recommend consideration of continued pembrolizumab per the KEYNOTE 522 after 
completion of inavolisib + capecitabine. If the patient has contra-indication to immunotherapy, we recommend no 
additional therapy after completion of inavolisib + capecitabine. For the standard of care in arm 1d, we recommend 
addition of pembrolizumab (per KEYNOTE 522) in combination with the talazoparib and capecitabine. If the patient 
has a contraindication to pembrolizumab, would recommend no additional therapy to be combined with the 
talazoparib and capecitabine. Pembrolizumab should not be extended beyond 17 cycles total (neoadjuvant + 
adjuvant). 
 
2: Control Arm (ctDNA-Positive, and do not harbor a genomically directed target) 
Capecitabine and pembrolizumab are considered standard options. Other therapies are not recommended but can be 
administered at treating physician’s discretion. The use of no additional therapy is permitted if deemed appropriate by 
the treating provider, but not a recommended option. 
 
3: Control Arm (ctDNA-Negative) 
Capecitabine and pembrolizumab are considered standard options. Other therapies are not recommended but can be 
administered at treating physician’s discretion. The use of no additional therapy is permitted if deemed appropriate by 
the treating provider, but not a recommended option. 
 
If a particular study drug is on shortage for Arm 1 and a patient is assigned to that particular Arm, they will be 
reassigned to Arm 2. 
Therapy
ARM
Plasma ctDNA
TNBC
Residual
Disease
Positive
1. Genomically
directed
Negative
1c. PI3K Pathway
Inavolisib + Capecitabine ->
+/- standard of care pembrolizumab
1d. DNA Repair Pathway
Talazoparib + Capecitabine +/- standard of 
care pembrolizumab
2. Standard of Care
Capecitabine, pembro, capecitabine + 
pembro or treatment of physician’s choice
3. Standard of Care
Capecitabine, pembro, capecitabine + 
pembro or treatment of physician’s choice
2. No genomic 
target


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1 
BACKGROUND & RATIONALE 
 
1.1 
Primary (neoadjuvant) chemotherapy for breast cancer 
Neoadjuvant chemotherapy has a well-established role in the management of both early-stage and locally 
advanced breast cancer. Providing treatment prior to definitive surgery not only improves the ability to 
achieve breast conservation, but also allows determination of in vivo sensitivity to therapy and offers an 
ideal platform for clinical research. Although many will experience shrinkage in tumor volume with 
neoadjuvant therapy, at the time of surgery only about 33% of patients will experience a pathologic 
complete response (pCR) with complete lack of invasive tumor tissue in the surgical specimen. Long-term 
follow-up of neoadjuvant studies consistently demonstrates significantly improved survival in individuals 
with pCR, with comparatively inferior outcomes in those with residual disease at surgery.1-4 The impact of 
residual disease is more striking in patients with triple negative (ER-/PR-/HER2-) disease compared to 
patients with other molecular phenotypes.5 Unfortunately, patients with triple negative disease who have 
substantial (Miller-Payne classification6 1 or 2 or residual cancer burden classification II or III7) residual 
disease at the time of surgery have a dismal prognosis with only 40-50% remaining free of recurrence at 2 
years4,8. In short, the presence of viable invasive tumor after appropriate neoadjuvant chemotherapy 
reflects inherent resistance and portends an exceedingly high risk of subsequent recurrence.  
 
A phase III trial, CREATE-X9, randomized over 900 HER2-negative patients with residual disease in the 
breast or lymph node involvement after completion of standard neoadjuvant therapy of 8 cycles of 
capecitabine at 2500 mg/m2/day (2 out of 3 weeks) vs. no additional therapy. Approximately 64% of the 
population had hormone receptor positive disease and 36% had triple negative disease. The capecitabine 
arm demonstrated an improvement in DFS from 74% in the control arm to 82% in the capecitabine arm 
(HR=0.70; p=0.005).  The addition of capecitabine also improved OS from 89.2% to 94% (HR=0.60; 
p<0.01). The hazard ratios were highly significant in the triple negative subgroup (HR=0.58; 95% CI=0.39-
0.87).  Thus, capecitabine can be considered a standard option in this setting for triple negative breast 
cancer. A more recently reported meta-analysis at the 2019 San Antonio Breast Cancer Symposium 
supports the benefit for the addition of capecitabine to a standard backbone of adjuvant or pre-operative 
therapy.  
 
While improvements were seen in CREATE-X, much work remains for improving outcomes for patients in 
this setting. We recently concluded a randomized phase II trial of genomically directed therapy vs. the 
treatment of physician’s choice for this population; BRE12-158. The primary outcome is pending, but a 
preliminary assessment of DFS based on the status of circulating tumor DNA (ctDNA) performed at a 
single time point after surgery but prior to initiating post-neoadjuvant therapy was evaluated. The 
estimated 2-year DFS for those patients with plasma ctDNA negativity was approximately 76%. 
Conversely, those with ctDNA positivity had a DFS of 50%. This represents one of the most powerful 
stratification variables for patients with TNBC and residual disease after pre-operative therapy. Thus, we 
propose a novel trial to address the optimal approach for patients in this setting using plasma ctDNA 
status to stratify and high throughput genomic technology to identify and treat with highly active targeted 
agents.   
 
KEYNOTE-522 randomized 602 patients to a traditional backbone of chemotherapy with or without 
pembrolizumab (200mg every 3 weeks) followed by continued post-neoadjuvant pembrolizumab for 9 
cycles vs. placebo. The addition of pembrolizumab improved the pathological complete response from 
51.2% in the chemotherapy alone arm to 64.8% in the pembrolizumab/chemotherapy arm.27 A recent 
update has also demonstrated a statistically significant improvement in event free survival (EFS). The 36-
month EFS improved from 76.8% in the chemotherapy alone arm to 84.5% in the 
pembrolizumab/chemotherapy arm.28 In addition, there was a significant benefit seen with the addition 


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of pembrolizumab for those patients who did not achieve a pCR. Based on these data, pembrolizumab has 
now been approved by the FDA in combination with chemotherapy in the pre-operative setting with up to 
9 cycles in the post-neoadjuvant setting.  
 
1.2 
Rationale for genomically directed approach 
Currently, many of the therapies delivered in the neo-adjuvant and adjuvant setting for breast cancer are 
non-specific cytotoxic agents that are not selected based on specific characteristics from the tumor. 
Increasingly, molecular aberrancies have opened the door for potential design and use of drugs to 
capitalize on dysregulated pathways. Examples of successful drugs matched to genomic alterations 
include various categories of aberrancy.10 When considering frequency and activity some of the most 
promising mutation/drug combinations for breast cancer include: PARP inhibition, PI3K/AKT inhibition, 
and checkpoint inhibition.  
 
Great activity has been demonstrated with the use of PARP inhibition for patients that harbor a germline 
pathogenic mutation in BRCA1 or BRCA 2. Both Olaparib and talazoparib are now approved for patients 
with HER2 negative metastatic breast cancer who have a germline BRCA mutation. Additionally, data 
support potential benefit for PARP inhibition in patients who harbor both somatic and germline mutations 
across the DNA repair pathway. Pi3K inhibition with alpelisib is FDA approved for patients with ER+, HER2- 
metastatic breast cancer who harbor an activating mutation in PI3K. Inhibition of the PI3K pathway has 
also been shown to improve outcomes in patients with TNBC with an activated PI3K pathway. It is known 
that patients with breast cancer who have gain-of-function mutations in PI3K-alpha (PIK3CA) respond to 
alpha-specific inhibitors. Inavolisib (GDC-0077) is a novel alpha-specific PI3K inhibitor that has 
demonstrated efficacy against PIK3CA mutated breast tumors.13.  Checkpoint inhibition with 
pembrolizumab is approved across all solid tumors with microsatellite instability and elevated tumor 
mutation burden (>10 mutations per megabase). Pembrolizumab is also FDA approved for patients with 
metastatic TNBC with PD-L1 CPS > 10% (using the Dako 22c3 antibody) and is FDA-approved in the first 
line setting in combination with chemotherapy. The use of pembrolizumab in the neoadjuvant (curative) 
setting and continuation in the post-neoadjuvant setting has shown benefit over chemotherapy alone 
based on the results from KEYNOTE 522. In KEYNOTE 522, all patients benefited from pembrolizumab 
regardless of PD-L1 status. The benefit of continued pembrolizumab in the post-neoadjuvant setting for 
those with residual disease is less clear as there was no re-randomization in the post-neoadjuvant setting. 
Further, there are no data to assess the impact of immune biomarkers from the residual disease specimen 
for post-neoadjuvant pembrolizumab (a secondary endpoint for those in arm 2 and arm 3). Atezolizumab 
was previously approved for the treatment of first line metastatic TNBC in combination with 
chemotherapy for patients with at least 1% PD- L1 positivity in immune cells infiltrating the tumor. More 
recently, however, the FDA-approval has been withdrawn due to lack of benefit in the confirmatory trial; 
Impassion131, and because of other approved options. Recent results from Impassion030 demonstrated 
no benefit for atezolizumab in the adjuvant setting, but atezolizumab continues to be tested in other 
settings with other drug partners. Its role in the neoadjuvant and post-neoadjuvant setting with other 
agents is under active investigation.  
 
In general, the therapeutic index for these targeted approaches has been exceptionally high. This proposal 
will attempt to capitalize on this basic philosophy by matching the most promising targeted agents in 
TNBC with molecular aberrancies determined through cutting edge assessment of the tumor using 
massively parallel sequencing. 
 
 
 


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1.3 
Rationale and Study Design 
This study will capitalize on an exceptional setting to test a genomic approach and will enrich for 
participants who have already been exposed to standard non-specific chemotherapy in the neoadjuvant 
setting with substantial residual disease. This patient population, by definition, is resistant to traditional 
non-specific cytotoxic chemotherapy. Also, by nature of the high risk of relapse, they are clearly in need of 
additional, and hopefully superior, targeted therapy. In addition, there will be a focus on the impact of 
drug combinations to maximize therapeutic impact. For the patients who have both DNA repair deficiency 
and markers to suggest immune avidity, we will combine PARP inhibition with capecitabine and standard 
of care therapy (pembrolizumab if deemed appropriate by the treating provider). For those with an 
activated PI3K pathway, we will combine inavolisib (an alpha-specific PI3K inhibitor) with capecitabine 
followed by standard of care therapy (pembrolizumab if deemed appropriate by the treating provider). 
From a genomic standpoint, the use of these agents in a relatively early point in the tumor’s life (i.e. 
adjuvant setting) will minimize some intrinsic concerns such as genomic drift. The premise of this trial is to 
test a personalized approach compared with historically non-personalized approach. This proposal, then, 
sets out to test the hypothesis that a genomically directed therapy will improve outcome over standard of 
care in a population that needs a better standard. The limitations of this approach include: 1. This is a 
non-randomized approach and thus, the historical value may be biased by other risk factors; and 2). This 
may have different results simply due to more contemporary treatment and managements when 
compared to the older trial, BRE12-158. That being said, these are the only preliminary data to date in this 
setting and represent the most scientifically valid assumptions. 
 
1.4 
Use of next generation sequencing to detect circulating tumor DNA (ctDNA) 
An emerging method for non-invasive cancer detection is the analysis of “liquid biopsies” – the ability to 
detect tumor characteristics from the circulation, of which the most popular to date, is circulating tumor 
DNA (ctDNA). ctDNA is released into the circulation from the apoptosis or necrosis of tumor tissue, or 
from circulating tumor cells (CTCs) present in blood14,15. It has been demonstrated that ctDNA can be 
detected in many types of cancer, including: breast16-19, prostate20, gastric21, and others14. The fraction of 
ctDNA compared to total cell-free DNA (cfDNA), can be quite small, in many cases less than 1%22-24. Highly 
sensitive next-generation sequencing techniques can be used to detect low amounts of ctDNA. Because 
somatic mutations provide intrinsic specificity for nucleic acid material derived from tumor tissue, the 
presence of ctDNA implies the presence of disease. Recently published data from our group 
demonstrated that ctDNA detected in the plasma of TNBC patients after neoadjuvant chemotherapy and 
surgery indicates rapid relapse19. A pivotal study by Garcia-Murillas et al., in a cohort of early breast 
cancer patients demonstrated that detection of ctDNA showed a similar pattern of rapid recurrence.25 A 
similar study by Olsson et al.26 showed that serial ctDNA sampling in patients with primary breast cancer 
can reach an average lead time of 11 months before the occurrence of metastatic disease. A prevailing 
theme among all these studies is that the presence of ctDNA predicts rapid relapse. 
 
Congruent with previously published data, we recently analyzed plasma samples from TNBC patients who 
have completed neoadjuvant chemotherapy and surgery as part of a randomized phase II trial of 
genomically directed therapy vs. the treatment of physician’s choice; BRE12-158 (Figure 1). The primary 
outcome is pending, but a preliminary assessment of DFS based on the status of circulating tumor DNA 
(ctDNA) performed at a single time point after surgery but prior to initiating post-neoadjuvant therapy 
was evaluated. The detection of ctDNA was significantly associated with an inferior DFS (median DFS: 22.8 
months vs. Not Reached; HR=2.67, 95% CI:1.28-5.57; p=0.0089). At 24 months, the DFS probability was 
50% in ctDNA-positive patients as compared to 76% in ctDNA-negative patients. As seen in the Kaplan-
Meier curve (Figure 2), patients who were ctDNA-positive experienced a rapid relapse of their disease. 
 
 


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More recently, tissue informed assays have improved the sensitivity for detecting minimal residual 
disease. Specifically, the FoundationOne Tracker uses a trusted and clinically relevant tissue-informed CGP 
baseline paired with personalized ctDNA -based assessment that empowers informed biomarker-guided 
treatment decisions. CtDNA-based disease monitoring with FoundationOne Tracker can serve as a 
sensitive biomarker for MRD and can accurately assess risk to support additional adjuvant or 
perioperative treatment. In a retrospective analysis of resectable bladder cancer, FoundationOne Tracker 
exhibited a positive predictive value (PPV) of 91% for determining risk of relapse based on ctDNA 
assessment post resection. Additionally, the median disease-free survival (DFS) (3 months vs. not reached, 
hazard ratio (HR)=5.8 (95% confidence interval (CI) 3.8–8.7, p<0.0001)) and overall survival (OS) (13 


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months vs. not reached, HR=5.8 (95% CI 3.4–9.9, p<0.0001)) were significantly shorter for ctDNA-positive 
patients. In a separate retrospective study evaluating MRD detection in metastatic colorectal patients 
who underwent surgical resection with curative intent, FoundationOne Tracker exhibited a 94% PPV, and 
patients ctDNA detection post-surgery had shorter median DFS (3.2 vs 3.1 months, HR 4.97( 95% CI 2.67-
9.24)) and OS (31.6 months vs not reached, HR 27.05 ( 95% CI 3.60-203.46)) compared to those who were 
ctDNA negative. These studies demonstrate that post-operative MRD detection via FoundationOne 
Tracker is a strong prognostic biomarker that correlates with DFS and OS in patients with resected early-
stage bladder cancer. Based on improved sensitivity, the FoundationOne Tracker will be used in this study 
to determine ctDNA status (positive vs. negative).  
 
1.5 
Definition of actionable mutations/pathways with recommended agent 
 
1.5.1 
Talazoparib + capecitabine (Arm 1a): patients with a deleterious somatic or germline mutation in 
BRCA1/2, PALB2, ATR, BARD1, BLM BRIP1, FANCA, FANCC, FANCD2, FANCF, MRE11A, RAD51, 
RAD51B, RAD51C, RAD51D, RAD54L, NBN, WRN, RECQL, ARID1A. This group in Arm 1 is CLOSED. 
 
1.5.2 
Atezolizumab + capecitabine (Arm 1b): patients whose tumors have PD-L1 immune cell staining 
(SP142 antibody) ≥ 1%, or a tumor mutation burden (TMB) ≥ 10 mutations/megabase, or MSI-high 
(determined by NGS). Since this arm represents therapy similar to standard of care therapy, this 
arm will CLOSE.  
 
1.5.3 
Inavolisib + capecitabine → +/- standard of care pembrolizumab (Arm 1c): patients whose 
tumors harbor gain-of-function mutations in PIK3CA.This group in Arm 1 will be updated to 
include the consideration of standard of care up to 9 cycles of pembrolizumab after completion of 
8 cycles of inavolisib and capecitabine. Pembrolizumab should not be extended beyond 17 cycles 
total (neoadjuvant + adjuvant). If pembrolizumab is contraindicated, no therapy would be the 
preferred standard of care option. Capecitabine will be supplied by the study. 
 
1.5.4 
Talazoparib + capecitabine +/- standard of care pembrolizumab (Arm 1d): patients with a 
deleterious somatic or germline mutation in BRCA1/2, PALB2, ATR, BARD1, BLM BRIP1, FANCA, 
FANCC, FANCD2, FANCF, MRE11A, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, NBN, WRN, 
RECQL, or ARID1A. Capecitabine will be administered with talazoparib. This group in Arm 1 will be 
updated to include the consideration for the addition of concurrent pembrolizumab with the 
talazoparib and capecitabine. The pembrolizumab should not be extended beyond 17 cycles total 
(neoadjuvant + adjuvant). Capecitabine and talazoparib will be supplied by the study. If 
pembrolizumab is contraindicated, the patient will receive the combination of capecitabine and 
talazoparib alone.   
 
1.6 
Protocol therapy 
Participants that are plasma ctDNA positive (65%) with a genomic target will be assigned to one of the 
groups in Arm 1 and receive genomically directed therapy in conjunction with standard of care therapy 
(n=90). There will be two groups in Arm 1. Arm 1a CLOSED based on FDA approval of pembrolizumab for 
high-risk early-stage triple-negative breast cancer in July 2021. Arm 1b will close as this arm mirrors the 
standard of care arm and based on results of IMPassion030. 
 
 
Arm 1a: DNA Repair pathway = talazoparib + capecitabine (n≈21) (CLOSED) 
 
Arm 1b: Immunotherapy pathway = pembrolizumab + capecitabine (n≈38) (to CLOSE) 
 
Arm 1c: PI3K Pathway = inavolisib + capecitabine → +/- standard of care pembrolizumab (n≈43) 
 
Arm 1d: DNA Repair  = talazoparib + capecitabine +/- standard of care pembrolizumab (n≈47)   


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Participants that are plasma ctDNA positive (n≈25) without a pre-specified genomic target will be assigned 
to Arm 2 and receive capecitabine and pembrolizumab or treatment of physician’s choice. Capecitabine 
and pembrolizumab are considered standard options. Other therapies are not recommended but can be 
administered at treating physician’s discretion. The use of no additional therapy is permitted if deemed 
appropriate by the treating provider, but not a recommended option.  
 
Participants that are plasma ctDNA negative (about 35%; n≈62) will be assigned to Arm 3 and receive 
capecitabine and pembrolizumab or treatment of physician’s choice. Capecitabine and pembrolizumab 
are considered standard options. Other therapies are not recommended but can be administered at 
treating physician’s discretion. The use of no additional therapy is permitted if deemed appropriate by the 
treating provider, but not a recommended option.  
 
For all arms, we will plan to evaluate the impact of immune avidity on outcomes. We will compare 
outcomes for those tumors have PD-L1 immune cell staining ≥ 10%, or a tumor mutation burden (TMB) 
>10 mutations/megabase, or MSI-high (determined by NGS) vs. those with no markers of immunity. 
 
1.6.1 
Resolving ctDNA-positive patients with multiple actionable genomic mutations/pathways  
Priority for the arm assignment will be given in the following order, based on known clinical evidence of 
highest likelihood of efficacy: 
1. Patient with DNA repair mutations in BRCA1, BRCA2, or PALB2 will take priority over all other 
findings. They will be assigned to arm 1d.  
2. PI3K mutations will take priority over all other DNA repair mutations (BRCA1, BRCA2, or PALB2). 
They will be assigned to arm 1c. 
 
1.7. 
Fear of recurrence and patient reported outcomes 
Fear of cancer recurrence (FCR) is a highly prevalent, persistent, and debilitating problem affecting breast 
cancer survivors. Defined as “fear, worry, or concern about cancer returning or progressing” (Lebel et al, 
Support Care Cancer, 2016), consequences of FCR include maladaptive coping skills, negative intrusive 
thoughts, and excessive distress. FCR amongst breast cancer survivors is often managed with either 
hypervigilance and excessive use of the medical system, or avoidance that becomes detrimental over time 
(Vachon et al Psycho-Oncology, 2020). Misunderstandings and unrealistic expectations for return of 
genomic sequencing in patients with metastatic cancer have been well characterized; however, 
understanding how this information is processed by patients in the curative setting is an unmet need to 
inform optimal delivery and minimize psychological distress. The PRESEVERE trial offers the opportunity 
to understand the psychological impact of additional prognostic and genomic information in a 
homogeneous population of patients who are at high risk of recurrence and are participating in a clinical 
trial.  
 
Prior studies in early-stage breast cancer have found higher FCR to be associated with younger age, lower 
education, white race, increased physical symptoms, fatigue, pain, and lower health care satisfaction (Janz 
NK, BCRT, 2011; Liu BCRT, 2011). Interestingly, several studies have shown that FCR does not seem to 
correlate with actual determinants of risk of recurrence such as tumor stage, margin status, etc. The 
theoretical model of FCR based on Leventhal’s Self Regulation Model of Illness proposes that FCR is a 
function of a) perception of personal risk for recurrence, which is influenced by cancer factors and 
treatment received, b) emotional status, in particular anxiety and excessive avoidant of reassurance- 
seeking behaviors, and c) greater perceived physical, economic, or social consequences of cancer (Lee-
Jones, 1997). It is hypothesized that knowledge of ctDNA positivity status may increase FCR through 
increased perception of personal risk; simultaneously, it is hypothesized that positive genomic testing 
results and additional systemic therapy will prolong FCR due to additional physical and social 


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consequences of cancer. It is expected that these results will inform interventions to reduce FCR in this 
population and in those receiving genomic information in the early-stage breast cancer setting. 
 
2 
OBJECTIVES 
 
2.1 
Primary Objective 
 
Demonstrate a 2-year disease-free survival (DFS) of > 50% for participants with residual disease 
and ctDNA positive triple negative breast cancer (TNBC) treated with a genomically directed 
therapy following preoperative chemotherapy (ARM 1)  
 
2.2 
Secondary Objectives 
 
Evaluate the 2-year DFS for participants with residual disease and ctDNA positive TNBC and no 
actionable genomic targets treated with a standard approach therapy following preoperative 
chemotherapy (ARM 2)  
 
Evaluate the 2-year DFS for participants with residual disease and ctDNA negative TNBC treated 
with a standard approach therapy following preoperative chemotherapy (ARM 3) 
 
Evaluate the overall DFS for ARMS 1, 2, and 3 
 
Evaluate the overall distant disease-free survival (DDFS) for ARMS 1, 2, and 3 
 
Evaluate 1-year DFS for ARMS 1, 2, and 3 
 
Determine 5-year overall survival (OS) for ARMS 1, 2, and 3 
 
Evaluate the DFS and OS for patients with markers associated with response to immune 
checkpoint inhibitor treatment vs. those without markers associated with response to immune 
checkpoint inhibitor treatment identified on residual disease. 
 
Describe the toxicities associated with genomically directed therapy in this population 
 
Describe patient preferences for return of ctDNA results 
 
Evaluate the impact of ctDNA status and availability of genomically directed therapy on FCR and 
HRQoL 
 
2.3 
Exploratory Objectives 
 
Collect archived tumor specimens, genomic DNA, and circulating tumor samples to explore 
potential correlates of recurrence and toxicity 
 
Evaluate the drug specific effect on both efficacy outcomes (DFS and OS) and toxicity. 
 
Explore modifiers of FCR and HRQoL in this population, including patient preferences for return of 
results, coping strategies, anxiety, health literacy, self- efficacy, and disease characteristics. 
 
3 
ELIGIBILITY CRITERIA 
 
3.1 
General Inclusion Criteria 
1. Written informed consent and HIPAA authorization for release of personal health information. 
NOTE:  HIPAA authorization may be included in the informed consent or may be obtained 
separately. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. ECOG Performance Status 0 or 1 within 28 days prior to study registration. 
 
4. Must have clinical stage I-III at diagnosis (AJCC 8th edition) based on initial evaluation by physical 
examination and/or breast imaging prior to neoadjuvant chemotherapy.  


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5. Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-) invasive breast 
cancer per pathology report. NOTE:  ER and PR will be considered negative if ≤ 10% of cells stain 
weakly positive. HER2 will be considered negative if scored 0 or 1+ by immunohistochemistry 
(IHC) or 2+ by IHC associated with a fluorescence in situ hybridization (FISH) ratio of < 2.0 or < 6 
copies per cell.  
 
6. Must have completed preoperative (neoadjuvant) chemotherapy. NOTE: Acceptable preoperative 
regimens include an anthracycline or a taxane, or both. Participants who received preoperative 
therapy as part of a clinical trial may enroll. Participants may not have received adjuvant 
chemotherapy after surgery prior to registration. Bisphosphonate use is allowed.  
 
7. Subjects who received pembrolizumab in the neoadjuvant setting are eligible and may continue 
treatment during the screening process. Subjects assigned to Arm 1 will require a 3 week wash 
out period prior to initiation of study treatment. Subjects may resume pembrolizumab to 
complete the planned year of therapy (17 cycles) after completion of study therapy based on 
investigator discretion. Subjects assigned to Arm 2 and Arm 3 may continue pembrolizumab 
treatment during the study based on investigator discretion. Total duration of pembrolizumab 
treatment should not extend beyond 17 cycles. 
 
8. Must have significant residual invasive disease at the time of definitive surgery following 
preoperative chemotherapy.  Significant residual disease is defined as at least one of the 
following: 
 
Residual invasive disease in the breast measuring at least 1 cm. The presence of DCIS 
without invasion does not qualify as residual disease in the breast. 
 
Any macroscopic, (> 2mm) residual, lymph node involvement regardless of primary tumor 
site involvement (includes no residual disease in the breast). 
 
Residual cancer burden (RCB) score 2 or 3. 
 
9. Must have completed definitive resection of primary tumor. Participants must begin assigned arm 
therapy no later than 96 days from the last local therapy. NOTE: Negative margins for both 
invasive and ductal carcinoma in situ (DCIS) are desirable, however participants with positive 
margins may enroll if the study site treatment team believes no further surgery is possible and 
participant has received radiotherapy. Participants with margins positive for lobular carcinoma in 
situ (LCIS) are eligible. Either mastectomy or breast conserving surgery (including lumpectomy or 
partial mastectomy) is acceptable. 
 
10. Breast Radiotherapy 
 
Radiotherapy is required for participants who underwent breast-conserving therapy, 
including lumpectomy or partial mastectomy unless deemed inappropriate by the treating 
provider.  
 
Post mastectomy radiation is at the discretion of the treating physician.   
 
If radiation was given prior to surgery, additional radiation after surgery is not required. 
 
In all cases participants must and begin arm assigned therapy no later than 96 days from 
the last local therapy  
 
Any acute toxicity must have resolved to grade < 2 prior to starting arm specific therapy. 
 
 
 


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11. Must consent to allow submission of blood and archived tumor tissue sample from definitive 
surgery for next generation sequencing of the tumor. Tumor block is preferred however 14 slides 
+ 1H&E can be submitted if necessary. NOTE: Due to possible false positives, ctDNA should not be 
drawn before completing radiation or less than 14 days from surgery if radiation is not required. 
 
13.12. 
Adequate laboratory values must be obtained within 28 days prior to study registration. 
 
Hemoglobin (Hgb) ≥ 9.0 g/dL 
 
Platelets ≥ 100 K/mm3 
 
Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 
 
Calculated creatinine clearance of ≥ 50 cc/min using the Cockcroft-Gault formula: 
o Males: (140 – Age in years) × Actual Body Weight in kg 
72 × Serum Creatinine (mg/dL) 
o Females: Estimated creatinine clearance for males × 0.85 
 
Bilirubin ≤ 1.5 ULN (except in participants with documented Gilbert’s disease, who must 
have a total bilirubin ≤ 3.0 mg/dL) 
 
Aspartate aminotransferase (AST, SGOT) ≤ 2.5 ULN 
 
Alanine aminotransferase (ALT, SGPT) ≤ 2.5 ULN 
 
14.13. 
Women of childbearing potential and their partners and male subjects and their partners 
must be willing to use effective contraception (as outlined in Section 5.6) from the time consent is 
signed until after protocol therapy discontinuation based on package insert or investigator 
brochure guidelines (See Section 5.6 for timeframes). 
 
15.14. 
Women of childbearing potential must have a negative urine or serum pregnancy test 
within 7 days prior to study registration.  Women should be counseled regarding acceptable birth 
control methods to utilize.  If prior to treatment after discussion with the subject it is felt by the 
treating physician there is a possibility the subject is pregnant a pregnancy test should be 
repeated. NOTE:  Women are considered not of childbearing potential if they are surgically sterile 
(they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or they 
are postmenopausal for at least 12 consecutive months. 
 
16.15. 
Women must not be breastfeeding from the time of treatment initiation until the number 
of days after protocol therapy discontinuation based on package insert or investigator brochure 
guidelines (See Section 5.6 for timeframes). 
 
3.1.1 
Inclusion Criteria for patients assigned to Arm 1c ONLY 
1. Adequate laboratory values must be obtained within 21 days prior to starting arm therapy. 
 
Fasting total glucose ≤ 126 mg/dL  
 
HbA1C ≤ 5.7% 
 
Cholesterol < 300 mg/dL; 10.34 mmol/L 
 
Triglycerides < 300 mg/dL; 3.42 mmol/L 
 
3.2 
General Exclusion Criteria 
1. Clinically significant infections as judged by the treating physician.  
 
2. Stage IV (metastatic) disease, however no specific staging studies are required in the absence of 
symptoms or physical exam findings that would suggest distant disease. 
 


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3. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 
months of registration are eligible for this trial. NOTE: Patients without a known history of being 
HIV positive do not require testing at screening. Patients who are known to be HIV positive will 
require testing as described to be eligible for this trial. Testing should be considered standard of 
care. 
 
4. Patients with evidence of chronic hepatitis B virus (HBV) infection, with undetectable HBV viral 
load within 6 months of registration are eligible for this trial. They should be on suppressive 
therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been 
treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral 
load must be undetectable within 6 months of registration to be eligible for this trial.  NOTE: 
Patients without a known history of being hepatitis positive do not require testing at screening. 
Patients who are known to be hepatitis positive will require testing as described to be eligible for 
this trial. Testing should be considered standard of care. 
 
5. Participants with unstable angina or a myocardial infarction within 12 months of study 
registration. 
 
6. Active second malignancy (except non-melanomatous skin cancer or incidental prostate cancer 
found on cystectomy): Active second malignancy is defined as a current need for cancer therapy 
or a high possibility (> 30%) of recurrence during the study.  Previous contralateral breast cancer 
is allowable unless it meets “active” criteria as stated above. 
 
7. Inability to swallow pills. 
 
8. Evidence of significant uncontrolled concomitant disease that could affect compliance with the 
protocol, safety of participation, or interpretation of results. This includes significant liver disease 
(such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome) or any 
other serious medical condition or abnormality in clinical laboratory tests that meet these criteria 
in the investigator’s opinion.  
 
9. History of severe allergic, anaphylactic, or other hypersensitivity reactions to any of the study 
medications being used in this study. 
 
10. Treatment with any investigational agent within 30 days prior to study registration. 
 
3.2.1 
Exclusion Criteria for patients assigned to Arm 1c ONLY  
1. Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) that, in the 
opinion of the investigator, would require medical or surgical intervention during the study period 
to prevent or treat vision loss that might result from that condition. 
 
2. Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of 
Type 1 diabetes. 
 
3. Active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, scleritis, or 
endophthalmitis) conditions in either eye or history of idiopathic or autoimmune-associated 
uveitis in either eye. 
 
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5. History of or active inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis). 
Patients currently receiving immunosuppressants for inflammatory bowel disease (e.g., 
sulfasalazine) are considered to have active disease and are therefore ineligible. 
 
6. Any active bowel inflammation (including diverticulitis) 
 
7. Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab therapy. 
Bisphosphonate and denosumab therapy for bone metastases or osteopenia/osteoporosis is 
allowed. 
 
4 
PARTICIPANT REGISTRATION  
Subjects will consent to participation in the trial. Sites will continue to enroll and the Foundation Medicine 
Assays will be used for both tissue and blood. Blood and tissue will be collected and submitted upon 
consent while eligibility is being determined. Once the amendment for utilization of the 
FoundationOneTracker assay is approved at the site, the FoundationOne® CDx assay for tissue will 
continue to be used and the FoundationOne Tracker assay for blood will be utilized. Tissue will be 
collected first and once a successful tissue test and the ability to select appropriate variants for tracking 
are confirmed, blood will be collected from the subject for the remainder of the required testing. NOTE: A 
successful tissue test is required to run the FoundationOneTracker. Subjects who have a tissue sample fail 
FoundationOne®CDx assay or primer design fails will not be able to have the FoundationOneTracker run 
for blood. 
 
ctDNA should not be drawn before completing radiation or less than 14 days from surgery if radiation is 
not required.  Once the sequencing results are received, subjects will be assigned to the appropriate Arm 
as described below (see registration process document provided by HCRN). An additional consent will be 
obtained for subjects assigned to Arm 1. The protocol therapy is not blinded to the participant or the 
treating investigator. All participants must be registered through HCRN’s electronic data capture (EDC) 
system and begin assigned treatment within 96 days of last local therapy. If a particular study drug is on 
shortage for Arm 1 and a patient is assigned to that particular Arm, they will be reassigned to Arm 2. 
 
NOTE: Treating investigators will receive sequencing results after completion of Arm assignment. ctDNA 
status will be discussed with the patient by the treating investigator. Genomic results will be discussed 
with the patient based on investigator discretion.  Results will be flagged if a suspected germline mutation 
is found.  It will be the responsibility of the treating investigator to follow-up with the subject regarding 
the results and need for additional genetic testing and/or genetic counseling as appropriate.  
 
5 
TREATMENT PLAN 
This is a 3-arm study stratified by plasma ctDNA. Patients with residual TNBC disease after pre-operative 
therapy will be assigned to 1 of 3 Arms based on plasma ctDNA positivity and genomic marker(s). If a 
particular study drug is on shortage for Arm 1 and a patient is assigned to that particular Arm, they will be 
reassigned to Arm 2. Assignment to Arm 1a CLOSED based on FDA approval of pembrolizumab for high-
risk early-stage triple-negative breast cancer in July 2021. Arm 1b will close due to its similarity to 
standard of care and based on results of IMPassion030. If a subject assigned to Arm 1c does not meet 
additional Arm 1c criteria, the subject will be reassigned to Arm 2. 
 
 
 


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Participants that are plasma ctDNA positive with a genomic target will be assigned to one of the 2 groups 
in Arm 1 and receive genomically directed therapy.  
 
Arm 1a: DNA Repair pathway = talazoparib + capecitabine (CLOSED) 
 
Arm 1b: Immunotherapy pathway = atezolizumab + capecitabine (to CLOSE) 
 
Arm 1c: PI3K Pathway = inavolisib + capecitabine → +/- standard of care pembrolizumab 
 
Arm 1d: DNA Repair + Immunotherapy = talazoparib + capecitabine +/- standard of care 
pembrolizumab  
 
Participants that are plasma ctDNA positive without a genomic target will be assigned to Arm 2 and 
receive pembrolizumab and/or capecitabine (preferred option is pembrolizumab with capecitabine) or 
treatment of physician’s choice. The use of no additional therapy is permitted if deemed appropriate by 
the treating provider, but not a recommended option.  
 
Participants that are plasma ctDNA negative will be assigned to Arm 3 and receive pembrolizumab and/or 
capecitabine (preferred option is pembrolizumab with capecitabine) or treatment of physician’s choice. 
The use of no additional therapy is permitted if deemed appropriate by the treating provider, but not a 
recommended option.  
 
Subjects receiving pembrolizumab are eligible and may continue treatment during the screening process. 
Subjects assigned to Arm 1 will require a 3 week wash out period prior to initiation of study treatment. 
Subjects assigned to Arm 2 and Arm 3 may continue pembrolizumab treatment during the study based on 
investigator discretion. 
 
See Appendix C for information regarding contingency plans for COVID-19. 
 
5.1 
Arm 1 Drug Administration 
Arm 1 subjects have plasma ctDNA positive (~65%) and a genomically driven treatment option. A ± 3 day 
window will be applied to all visits.  
 
Arms 1c, and 1d will have a Safety Lead In Phase. Drug interaction and increased toxicity are not 
anticipated in these arms, however, there is limited experience with these combinations. To exclude 
prohibitive toxicity, the first six patients on these arms will be treated with combined therapy as outlined 
in each table below. If a patient goes off study before completing the dose-limiting toxicity (DLT) 
observation period for reasons other than DLT, then that patient should be replaced.  
 
At pre-specified times during the safety lead in phase of Arm 1c and 1d, accrual will be paused to the 
relevant Arm for review of data by the study team. Subjects being screened during this time may be 
delayed in starting treatment due to this enrollment pause. The feasibility of this delay should be 
discussed by the site investigator with the subject to determine the subject’s willingness to delay 
treatment initiation.  
 
5.1.1 
Arm 1a Treatment; CLOSED 
Assignment to Arm 1a CLOSED based on FDA approval of pembrolizumab for high-risk early-stage triple-
negative breast cancer in July 2021. DNA Repair pathway = patients with somatic or germline mutations, 
deletions or loss by fusions in DNA repair genes that are deemed to be deleterious.  Patients are eligible 
for this arm if they have alterations in the pre-specified DNA repair genes, as follows: BRCA1/2, PALB2, 
ATR, BARD1, BLM, BRIP1, CHEK2, FANCA, FANCC, FANCD2, FANCF, MRE11A, RAD51, RAD51B, RAD51C, 
RAD51D, RAD54L, NBN, WRN, RECQL, ARID1A. 
 


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5.1.1.1 Capecitabine and Talazoparib 
 
Drug1 
Dose2 
Route 
Schedule 
Cycle Length 
Total # of 
Cycles 
Capecitabine2 
1000 mg/m2 BID 
Orally 
14 days on and 
7 days off 
3 weeks 
(21 days) 
8 
Talazoparib3 
Cycle 1: 0.75 mg 
Orally 
21 days on 
3 weeks 
(21 days) 
8 
Cycle 2-8: 1 mg 
1: Subjects will be asked to keep a diary to bring to each clinic visit in addition to all pill bottles for reconciliation. 
2: All capecitabine doses will be based on the patient’s actual weight. The actual weight at screening should be 
used for calculating body surface area (BSA). The BSA may be recalculated based on the actual weight at the 
start of each treatment cycle but recalculation is only required if a patient’s weight changes by ≥ 10%. The 
calculated total daily dose should be rounded to the nearest 500 mg so treatment can be administered using 
only the 500 mg tablets. Morning (AM) and evening (PM) doses can be different if rounding the total daily dose 
to the nearest 500 mg requires.    
3: Talazoparib dose is fixed, and as such, is not adjusted for changes in the patient’s weight. Talazoparib dose 
should be increased to 1.0 mg for Cycles 2-8 in the absence of a DLT in Cycle 1. Capsules should be swallowed 
whole and must not be opened or dissolved. If the patient vomits or misses a dose, an additional dose should 
not be taken. The next prescribed dose should be taken at the usual time. Guidelines for management of 
talazoparib-specific adverse events can be found in Appendix A.  
 
The current package insert and institutional guidelines should be utilized for capecitabine administration. 
The current investigator’s brochure and institutional guidelines should be utilized for talazoparib 
administration. There is no particular sequence of administration to these medications but the way in 
which subjects are instructed should remain consistent throughout study treatment. 
 
5.1.1.2 Safety Lead In 
Weekly reviews will occur with the study team. A representative from each enrolling institution will be 
asked to attend a conference call or communicate by email each subject’s status for appropriate 
monitoring of DLTs. Sites enrolling patients in the safety run-in must be willing to provide source 
documentation for all critical data within 5 business days of any subject visit. If at any time during 
enrollment of the first six patients, ≥ 2 patients experience a DLT, accrual will be suspended for review by 
the study team. If ≤ 1 of 6 patients experiences a DLT, a review will occur by the study team prior to Arm 
1a re-opening for additional enrollment using the identical treatment doses. If 2 or more of 6 patients 
experience a DLT, enrollment to Arm 1a will be stopped and the study amended to explore lower starting 
doses. Please see Section 13 for additional information regarding study oversight during the Phase 1 
component of the study. 
 
The DLT monitoring period is Cycle 1 and Cycle 2. DLTs are defined as: 
 
Toxicity Category 
Criteria Defining a DLT 
Hematological 
Grade 4 neutropenia lasting for ≥ 7 days 
Febrile neutropenia 
Grade ≥ 3 thrombocytopenia of any duration associated with clinically 
significant bleeding of any duration or Grade 4 thrombocytopenia of any 
duration 


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Non-hematological 
Grade  3 toxicity regardless of duration with the following exceptions: 
 
Grade ≥ 3 electrolyte abnormality that lasts > 72 hours may be an 
exception as long as the patient has no has clinical symptoms, in 
which case all grade ≥ 3 electrolyte abnormality regardless of 
duration should count as a DLT. 
 
Grade ≥ 3 fatigue that last < 1 week. 
 
Grade ≥ 3 nausea, vomiting, diarrhea that < 72 hours with the use of 
adequate/maximal medical interventions and/or prophylaxis 
 
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: 
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 
 
Any toxicity that results in a > 14 day delay in Cycle 2 Day 1 or Cycle 3 Day 1 will be considered a 
DLT.  
 
Death not clearly due to the underlying disease or extraneous causes will be considered a DLT. 
 
The need for dose modification (see Section 6) based on toxicities not meeting the definition of DLT 
during Cycle 1 or Cycle 2 will NOT be considered DLT.  
 
 
5.1.2 
Arm 1b Treatment (TO CLOSE) 
Immunotherapy pathway = patients whose tumors have PD-L1 staining (SP142 antibody) ≥ 1%, immune 
cell staining, or a tumor mutation burden (TMB) ≥ 10 mutations/megabase, or MSI-high (determined by 
NGS). 
 
5.1.2.1 Capecitabine and Atezolizumab  
 
Drug1 
Dose2 
Route 
Schedule 
Cycle Length 
Total # of 
Cycles 
Capecitabine 
1000 mg/m2 
BID 
Orally 
14 days on 
7 days off 
3 weeks 
(21 days) 
8  
Atezolizumab 
1200 mg 
IV over 1 hour3 
Every 21 days 
3 weeks 
(21 days) 
9 
1: Subjects will be asked to keep a diary to bring to each clinic visit in addition to all pill bottles for 
reconciliation. 
2: All capecitabine doses will be based on the patient’s actual weight. The actual weight at screening 
should be used for calculating body surface area (BSA). The BSA may be recalculated based on the 
actual weight at the start of each treatment cycle but recalculation is only required if a patient’s weight 
changes by ≥ 10%. The calculated total daily dose should be rounded to the nearest 500 mg so 
treatment can be administered using only the 500 mg tablets. Morning (AM) and evening (PM) doses 
can be different if rounding the total daily dose to the nearest 500 mg requires.    


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3: Atezolizumab dose is fixed and as such, doses are not adjusted for changes in the patient’s weight. 
The first dose of Atezolizumab will be delivered over 60 (± 15) minutes intravenously. Institutional 
standards will be used regarding the infusion and if the first infusion is tolerated, all subsequent 
infusions may be delivered over 30 (± 10) minutes. Guidelines for management of atezolizumab-specific 
adverse events can be found in Appendix B.  
 
The current package insert and institutional guidelines should be utilized for capecitabine administration. 
The current investigator’s brochure and institutional guidelines should be utilized for atezolizumab 
administration including premedications and infusion time windows. There is no particular sequence of 
administration to these medications but the way in which subjects are instructed should remain 
consistent throughout study treatment. 
 
5.1.3 
Arm 1c Treatment 
PI3K Pathway = patients whose tumors harbor gain-of-function mutations in PIK3CA. If a subject assigned 
to Arm 1c does not meet additional Arm 1c criteria, the subject will be reassigned to Arm 2. 
 
5.1.3.1 Capecitabine and Inavolisib followed by consideration for standard of care pembrolizumab 
 
Drug1 
Dose2 
Route 
Schedule 
Cycle Length 
Total # 
of Cycles 
Capecitabine 
1000 mg/m2  
BID 
Orally 
14 days on 
7 days off 
3 weeks 
(21 days) 
8 
Inavolisib3 
Cycle 1: 6 mg 
Cycle 2-8: 9mg 
Orally 
21 days on 
3weeks 
(21 days) 
8 
AFTER COMPLETION OF 8 CYCLES OF CAPECITABINE AND INAVOLISIB TREATMENT
Pembrolizumab4 
Pembrolizumab dose, route, schedule and cycle length per 
investigator discretion based on standard of care. 
Up to 9 
1: Subjects will be asked to keep a diary to bring to each clinic visit in addition to all pill bottles for 
reconciliation. 
2: All capecitabine doses will be based on the patient’s actual weight. The actual weight at screening 
should be used for calculating body surface area (BSA). The BSA may be recalculated based on the 
actual weight at the start of each treatment cycle but recalculation is only required if a patient’s 
weight changes by ≥ 10%. The calculated total daily dose should be rounded to the nearest 500 mg 
so treatment can be administered using only the 500 mg tablets. Morning (AM) and evening (PM) 
doses can be different if rounding the total daily dose to the nearest 500 mg requires.    
3: Inavolisib dose is fixed and as such, inavolisib dose is not adjusted for changes in the patient’s 
weight. Inavolisib dose should be increased to 9 mg for Cycles 2-8 in the absence of dose limiting 
toxicity in cycle. NOTE: Verify dosage of tablets for Cycle 2 and subsequent as the dosage of tablets 
for Cycle 1 may be different. Ensure total dose for Cycle 2+ is 9 mg. If the patient vomits or misses a 
dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual 
time. Guidelines for management of inavolisib-specific adverse events can be found in Appendix B.  
4: Cycle 9 Day 1 standard of care therapy should occur 4 weeks (± 7 days) after completion of Cycle 8 
study treatment.  
 
The current package insert and institutional guidelines should be utilized for capecitabine administration. 
The current investigator’s brochure and institutional guidelines should be utilized for inavolisib 


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administration. There is no particular sequence of administration to these medications but the way in 
which subjects are instructed should remain consistent throughout study treatment. The current package 
insert and institutional guidelines should be utilized for pembrolizumab administration including 
premedications and infusion time windows. 
 
5.1.3.2 Arm 1c Safety Lead In  
Once a subject is enrolled on Arm 1c weekly reviews will occur with the study team. A representative 
from each enrolling institution will be asked to attend a conference call or communicate by email each 
subject’s status for appropriate monitoring of DLTs. Sites enrolling patients in the safety run-in must be 
willing to provide source documentation for all critical data within 5 business days of any subject visit. If at 
any time during enrollment of the first six patients, ≥ 2 patients experience a DLT, accrual will be 
suspended for review by the study team. If ≤ 1 of 6 patients experiences a DLT, a review will occur by the 
study team prior to Arm 1c re-opening for additional enrollment using the identical treatment doses. If 2 
or more of 6 patients experience a DLT, enrollment to Arm 1c will be stopped and the study amended to 
explore lower starting doses. Please see Section for additional information regarding study oversight 
during the Phase 1 component of the study. 
 
The DLT monitoring period is Cycle 1 and Cycle 2. DLTs are defined as: 
 
Toxicity 
Category 
Criteria Defining a DLT 
Hematological 
Grade 4 neutropenia lasting for ≥ 7 days 
Febrile neutropenia 
Grade ≥ 3 thrombocytopenia of any duration associated with clinically significant 
bleeding of any duration or Grade 4 thrombocytopenia of any duration 
Non-
hematological 
Grade ≥ 3 toxicity regardless of duration with the following exceptions: 
 
Grade ≥ 3 electrolyte abnormality that lasts > 72 hours may be an exception 
as long as the patient has no has clinical symptoms, in which case all grade ≥ 3 
electrolyte abnormality regardless of duration should count as a DLT. 
 
Grade ≥ 3 fatigue that last < 1 week. 
 
Grade ≥ 3 nausea, vomiting, diarrhea that < 72 hours with the use of 
adequate/maximal medical interventions and/or prophylaxis 
 
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: 
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 
 
Grade ≥ 4 hyperglycemia (fasting) 
 
Grade ≥ 3 hyperglycemia (fasting) that does not respond to insulin therapy 
within 3 days or that requires hospitalization 
 
Any toxicity that results in a > 14 day delay in Cycle 2 Day 1 or Cycle 3 Day 1 will be considered a DLT. 


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 
Death not clearly due to the underlying disease or extraneous causes will be considered a DLT. 
 
The need for dose modification (see Section 6) based on toxicities not meeting the definition of DLT 
during Cycle 1 or Cycle 2 will NOT be considered DLT.  
 
5.1.4 
Arm 1d Treatment 
DNA Repair = patients who have genomic alterations that match to the criteria of both Arms 1a & 1b 
 
5.1.4.1 Capecitabine + Talazoparib +/- consideration for standard of care Pembrolizumab 
 
Drug1 
Dose 
Route 
Schedule 
Cycle 
Length 
Total # of 
Cycles 
Capecitabine4 
1000 mg/m2 BID 
Orally 
14 days on 
7 days off 
3 weeks 
(21 days) 
8 
Talazoparib2 
Cycle 1: 0.75 mg 
Orally 
21 days on 
3 weeks 
(21 days) 
8 
Cycle 2-8: 1 mg 
Pembrolizumab4 
Pembrolizumab dose, route, schedule and cycle length per 
investigator discretion based on standard of care. 
Up to 9 
1: Subjects will be asked to keep a diary to bring to each clinic visit in addition to all pill bottles for 
reconciliation. 
2: Talazoparib doses are fixed and as such, doses are not adjusted for changes in the patient’s weight. 
Talazoparib dose should be increased to 1.0 mg for Cycles 2-8 in the absence of DLT in Cycle 1. 
Capsules should be swallowed whole and must not be opened or dissolved. If the patient vomits or 
misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at 
the usual time. Guidelines for management of talazoparib-specific adverse events can be found in 
Appendix A. 
4: All capecitabine doses will be based on the patient’s actual weight. The actual weight at screening 
should be used for calculating body surface area (BSA). The BSA may be recalculated based on the 
actual weight at the start of each treatment cycle but recalculation is only required if a patient’s 
weight changes by ≥ 10%. The calculated total daily dose should be rounded to the nearest 500 mg so 
treatment can be administered using only the 500 mg tablets. Morning (AM) and evening (PM) doses 
can be different if rounding the total daily dose to the nearest 500 mg requires.    
 
The current package insert and institutional guidelines should be utilized for capecitabine administration. 
The current investigator’s brochure and institutional guidelines should be utilized for talazoparib 
administration. The current investigator’s brochure and institutional guidelines should be utilized for 
pembrolizumab administration including premedications and infusion time windows. There is no 
particular sequence of administration to these medications but the way in which subjects are instructed 
should remain consistent throughout study treatment. 
 
5.1.4.2 Arm 1d Safety Lead In 
Once a subject is enrolled on Arm 1d weekly reviews will occur with the study team. A representative 
from each enrolling institution will be asked to attend a conference call or communicate by email each 
subject’s status for appropriate monitoring of DLTs. Sites enrolling patients in the safety run-in must be 
willing to provide source documentation for all critical data within 5 business days of any subject visit. If at 
any time during enrollment of the first six patients, ≥ 2 patients experience a DLT, accrual will be 
suspended for review by the study team. If ≤ 1 of 6 patients experiences a DLT, a review will occur by the 


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study team prior to Arm 1d re-opening for additional enrollment using the identical treatment doses. If 2 
or more of 6 patients experience a DLT, enrollment to Arm 1d will be stopped and the study amended to 
explore lower starting doses. Please see Section for additional information regarding study oversight 
during the Phase 1 component of the study. 
 
The DLT monitoring period is Cycle 1 and Cycle 2. DLTs are defined as: 
 
Toxicity Category 
Criteria Defining a DLT 
Hematological 
Grade 4 neutropenia lasting for ≥ 7 days 
Febrile neutropenia 
Grade ≥ 3 thrombocytopenia of any duration associated with clinically 
significant bleeding of any duration or Grade 4 thrombocytopenia of any 
duration 
Non-hematological 
Grade  3 toxicity regardless of duration with the following exceptions: 
 
Grade ≥ 3 electrolyte abnormality that lasts > 72 hours may be an 
exception as long as the patient has no has clinical symptoms, in 
which case all grade ≥ 3 electrolyte abnormality regardless of 
duration should count as a DLT. 
 
Grade ≥ 3 fatigue that last < 1 week. 
 
Grade ≥ 3 nausea, vomiting, diarrhea that < 72 hours with the use of 
adequate/maximal medical interventions and/or prophylaxis 
 
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: 
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 
 
Any toxicity that results in a > 14 day delay in Cycle 2 Day 1 or Cycle 3 Day 1 will be considered a 
DLT.  
 
Death not clearly due to the underlying disease or extraneous causes will be considered a DLT. 
 
The need for dose modification (see Section 6) based on toxicities not meeting the definition of DLT 
during Cycle 1 or Cycle 2 will NOT be considered DLT.  
 
 
 


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5.2 
Arm 2 Drug Administration 
Arm 2 subjects have plasma ctDNA positive but do not have a genomically driven treatment option 
(~22%). Treatment of physician’s choice will be given with consideration for capecitabine and/or 
pembrolizumab given the data from CREATE-X and KEYNOTE 522. Dose, schedule and duration of 
treatment to be determined by treating physician. Administration and management of side effects will be 
handled as standard of care per institutional guidelines. Information regarding treatment administration 
will be entered into the EDC system. The site investigator will be notified of the results to facilitate 
discussion of treatment options with the patient. If a particular study drug is on shortage for Arm 1 and a 
patient is assigned to that particular Arm, they will be reassigned to Arm 2. If a subject assigned to Arm 1c 
does not meet additional Arm 1c criteria, the subject will be reassigned to Arm 2. 
 
5.3 
Arm 3 Drug Administration 
Arm 3 subjects have plasma ctDNA negative (~35%). Treatment of patient and physician’s choice will be 
given with consideration for capecitabine and/or pembrolizumab given the data from CREATE-X and 
KEYNOTE 522. Dose, schedule and duration of treatment to be determined by treating physician. 
Administration and management of side effects will be handled as standard of care per institutional 
guidelines. Information regarding treatment administration will be entered into the EDC system. The site 
investigator will be notified of the results to facilitate discussion of treatment options with the patient. 
Consideration for no treatment can also be entertained if the patient and treating physician prefer.  
 
5.4 
Supportive Care 
The use of supportive care including antibiotics, blood transfusions, etc. will be permitted as clinically 
indicated and according to institutional guidelines. Prophylactic use of white blood cell growth factors (i.e. 
Neulasta, Neupogen, Leukine, or biosimilar filgrastim or Pegfilgrastim agents) is not allowed.  However, 
white blood cell growth factors may be used in accordance with ASCO guidelines if neutropenic fever 
occurs. Recombinant erythropoietin or similar compound may NOT be administered for anemia due to 
restrictions on their use in patients being treated with curative intent. 
 
Arm 1c: Patients can receive loperamide (2 mg oral twice a day or 4 mg once a day) as anti diarrheal 
rescue if allowed by local guidance.  
 
5.5 
Concomitant Medications 
The current package Insert should be utilized to determine use of concomitant medications for 
capecitabine and pembrolizumab. The current investigator’s brochure should be utilized to determine use 
of concomitant medications for inavolisib and talazoparib. Bisphosphonate use is allowed.  
 
5.6 
Contraception Guidelines 
Women of childbearing potential and their partners or male subjects and their partners, who are sexually 
active, must agree to the use of TWO highly effective forms of contraception in combination [as listed 
below], throughout the period of taking study treatment and for a designated time after last dose of study 
treatment based on the study treatment. Abstinence is considered an acceptable form of contraception if 
the subject totally/truly abstains from any form of sexual intercourse. This information is also applicable 
to breastfeeding. 
 
 
 


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Acceptable non-hormonal birth control methods: 
 
Total sexual abstinence ie, refrain from any form of sexual intercourse in line with the patients’ 
usual and/or preferred lifestyle. Periodic abstinence (eg, calendar ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
 
Vasectomised sexual partner PLUS male condom. With participant assurance that partner 
received post-vasectomy confirmation of azoospermia. 
 
Tubal occlusion PLUS male condom 
 
Intrauterine Device PLUS male condom. Provided coils are copper-banded. 
 
Acceptable hormonal methods: 
 
Etonogestrel implants (eg, Implanon®, Nexplanon®) PLUS male condom 
 
Normal and low dose combined oral pills PLUS male condom 
 
Hormonal shot or injection (eg, Depo-Provera) PLUS male condom 
 
Intrauterine system device (eg, levonorgestrel-releasing intrauterine system - Mirena®) PLUS male 
condom 
 
Timeframe after treatment discontinuation for continued contraception as described above: 
 
Inavolisib:  60 days (females) and 120 days (males) 
 
Atezolizumab: 5 months 
 
Capecitabine: 6 months 
 
Talazoparib: 7 months (females) and 4 months (males) 
 
Pembrolizumab: 4 months 
 
5.7 
Questionnaires 
Patient reported outcome (PRO) measures will describe patient preferences for return of ctDNA results, 
and will quantify the impact of ctDNA status on fear of recurrence (FCR) and health- related quality of life 
(HRQoL).  We will also characterize phenotypic modifiers of changes in FCR and HRQoL in this patient 
population.  PRO measures to be administered are detailed in Appendix D.   
 
PROs will be administered at screening, return of results, end of treatment, and at approximately 
6 months surveillance follow up.  These will be administered via a REDcap database. This study 
will utilize the secure, web-based, Research Electronic Data Capture (REDCap) system for PRO 
data input. The servers hosting REDCap are administered and supported by Indiana University’s 
University Information Technology Services (UITS) and are physically located in IU’s secured and 
environmentally structured data center on the IU Bloomington campus. To comply with HIPAA 
guidelines, physical, administrative, and technical safeguards and on ongoing risk management 
framework have been implemented and documented (NIST 800-53) to ensure the security and 
protection of the study data within the data center, the servers, and the database. REDCap is a 
software toolset developed by Vanderbilt University, with collaboration from a consortium of 
institutional partners, for electronic collection and management of research and clinical trial 
data. Indiana University has joined this consortium and has implemented REDCap within the 
Indiana University’s central Information Technology Services (UITS) technical environment to 
enable rapid development and deployment of electronic data capture and reporting to support 
specific clinical and translational research projects. The implementation of these projects within 
REDCap depends on a thorough study-specific data dictionary that is defined in an iterative 
process by all members of the research team. The iterative development and testing process 
results in a well-defined data collection strategy for individual studies. The REDCap software 


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toolset provides a secure, web-based environment that is flexible enough to be used for a variety 
of types of research, provides an intuitive interface for users to enter data and have real time 
validation rules (with automated data type and range checks) at the time of entry. The system 
offers easy data manipulation with logged auditing, functionality for reporting, monitoring and 
querying patient records, and an automated export mechanism to common statistical packages 
such as SPSS, SAS, Stata, and R/S-Plus. REDCap App is a component of the overall REDCap 
platform that can be used for offline data capture and is synchronized with the primary REDCap 
database. It is available for download to iOS and Android devices and the REDCap App encrypts 
the data on the device.  
 
6 
DOSE MODIFICATIONS  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5 will be used to grade adverse 
events. Participants 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 section 7 Schedule of 
Events.  
 
6.1 
Dose Level Reduction/Modification Tables  
Arms 1a (CLOSED), 1b (TO CLOSE), 1c, and 1d will have a lower starting dose at Cycle 1 to ensure 
tolerability.  Increased toxicities are not anticipated in these arms, however, there is limited experience 
with these combinations. 
 
Arm 1a: (21 day Cycle); CLOSED 
Dose level 
Capecitabine 
Talazoparib 
1 
1000 mg/m2 BID  
for 14 days  
1mg QD  
for 21 days  
0 
(Starting dose Cycle 1) 
1000 mg/m2 BID  
for 14 days  
0.75 mg QD  
for 21 days 
-1 
750 mg/m2 BID  
for 14 days  
0.5 mg QD  
for 21 days 
-2 
500 mg/m2 BID  
for 14 days  
0.25 mg QD  
for 21 days 
 
Arm 1b: (21 day Cycle) TO CLOSE 
Dose level 
Capecitabine 
Atezolizumab 
0 (Starting dose) 
1000 mg/m2 BID 
for 14 days  
1200 mg IV every 21 days 
-1 
1000 mg/m2 BID 
for 14 days  
Discontinue  
-2 
750 mg/m2 BID 
for 14 days  
Discontinue  
-3 
500 mg/m2 BID 
for 14 days  
Discontinue  


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Arm 1c: (21 day Cycle) 
Dose level 
Capecitabine 
Inavolisib 
1 
1000 mg/m2 BID for 14 days   
9 mg for 21 days 
0 
(Starting dose Cycle 1) 
1000 mg/m2 BID for 14 days   
6 mg for 21 days 
-1 
750 mg/m2 BID for 14 days  
3 mg for 21 days 
-2 
500 mg/m2 BID for 14 days  
Discontinue 
 
 
Arm 1d: (21 day Cycle) 
Dose level 
Capecitabine 
Talazoparib 
1 
1000 mg/m2 BID for 14 days  
1mg QD for 21 days  
0 
(Starting dose Cycle 1) 
1000 mg/m2 BID for 14 days  
0.75 mg QD for 21 days 
-1 
750 mg/m2 BID for 14 days  
0.5 mg QD for 21 days 
-2 
500 mg/m2 BID for 14 days  
0.25 mg QD for 21 days 
 
6.2 
General Delays and Dose Modifications 
 
Dose interruption and/or modification may be implemented due to hematologic or 
nonhematologic toxicities per dose modification tables after completion of Cycle 2 for safety lead 
in patients and as needed for all others.  
 
If toxicity causes treatment to be delayed, clinic visits (and study procedures) associated with 
each cycle of therapy, as defined by the administration of any of the Arm 1 investigational agents, 
will also be delayed (e.g., from Day 14 to Day 21). However, laboratory assessments and clinical 
visits shall be scheduled as needed for adverse events follow up. Once the toxicity has resolved to 
the required level, study treatment and study procedures will be resumed, according to the study 
cycle day count.  
 
If any observed toxicity is attributable to only one drug as assessed by the investigator, the dose 
of the other drug(s) may not require modification. 
 
Dose modifications for isolated abnormal hematologic laboratory values will be based on 
hematologic parameters at the start of a treatment cycle. 
 
Treatment may be delayed to manage toxicity. Delays up to 3 weeks (21 days) are permitted. A 
delay of longer than 3 weeks for an adverse event will require permanent discontinuation of the 
investigational agent but the patient may continue the capecitabine after discussion with the 
sponsor-investigator. 


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 
No more than 2 total dose reductions will be permitted for any agent. If the patient has had two 
dose reductions and another toxicity requiring reduction is experienced, that agent will be 
permanently discontinued. For inavolisib in Arm 1c, there is only 1 total dose reduction in cycle 1. 
 
Special interest events are known toxicities attributable to specific drugs and will require 
customized dose modifications.  
o The non-hematologic toxicities listed in the special interest event dose modification table 
below should follow specified modifications.   
 
6.2.1 
Event Dose Modification Table 
 
Event 
Capecitabine 
Talazoparib 
Inavolisib 
Hematologic Event Grade 3 
Hold then,  
reduce to -1 dose level   
(750 mg/m2 BID) 
Hold then,  
reduce dose  
one level 
Hold then, 
 reduce dose one 
level 
Hematologic Event Grade 4 
Hold then, 
 Reduce to -2 dose level  
 (500 mg/m2 BID) 
Hold then,  
reduce dose  
one level 
Hold then, 
reduce dose  
one level 
Non-hematologic Event Grade 3** 
Hold then,  
continue dose  
Hold then, 
reduce dose  
one level 
Hold then,  
reduce dose  
one level 
Non-hematologic Event Grade 4** 
Hold then,  
reduce to -1 dose level  
(750 mg/m2 BID) 
Hold then,  
reduce dose  
one level 
Hold then,  
reduce dose  
one level 
**See special interest event modifications are listed in the table below. 
 
6.2.2 
Special Interest Event Dose Modification Table 
 
*Special Interest Events 
Capecitabine 
Talazoparib 
Inavolisib 
Adrenal insufficiency 
Grade 2−4 
Hold then,  
continue dose 
Hold then, 
 reduce dose  
one level 
Hold then,  
reduce dose  
one level 
Hyperglycemia Grade 2 or Fasting 
blood glucose values 160 to 250 
mg/dL or 8.9-13.9 mmol/L) 
Continue dose 
Continue dose 
Hold then,  
continue dose 
Hyperglycemia Grade 3 or 4 
Fasting blood glucose values > 250 
mg/dL or > 13.9mmol/L) 
Hold then,  
continue dose 
Hold then,  
reduce dose  
one level 
Hold then,  
reduce dose  
one level 
Hyperthyroidism Asymptomatic 
Hold then,  
continue dose 
Hold then,  
reduce dose  
one level 
Hold then,  
reduce dose  
one level 
Hyperthyroidism 
Symptomatic 
Hold then,  
continue dose 
Hold then,  
reduce dose  
one level 
Hold then,  
reduce dose one 
level 
Hypophysitis  
(pan-hypopituitarism) 
Grade 2 or 3 
Hold then,  
continue dose 
Hold then,  
reduce dose  
one level 
Hold then,  
reduce dose  
one level 
Hypophysitis  
(pan-hypopituitarism) 
Grade 4 
Hold then,  
continue dose 
Hold then,  
reduce dose  
one level 
Hold then,  
reduce dose  
one level 


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*Special Interest Events 
Capecitabine 
Talazoparib 
Inavolisib 
Hypothyroidism Asymptomatic 
Hold then, 
 continue dose 
Hold then,  
reduce dose  
one level 
Hold then,  
reduce dose  
one level 
Hypothyroidism Symptomatic 
Hold then,  
continue dose 
Hold then,  
reduce dose  
one level 
Hold then,  
reduce dose  
one level 
Diarrhea 
Grade 2 
Continue 
Continue 
Hold then, continue 
dose 
Diarrhea  
Grade 3 
Hold then, 
 reduce to -2 dose 
level  (500 mg/m2 BID) 
Hold then, 
reduce dose 
one level 
Hold then,  
reduce dose  
one level 
Diarrhea  
Grade 4 
Hold then,  
reduce to -2 dose 
level  (500 mg/m2 BID) 
Hold then, 
reduce dose 
one level 
Hold then,  
reduce dose  
one level 
Nausea/Vomiting 
Grade 3 
Hold then, 
 reduce to -2 dose 
level  (500 mg/m2 BID) 
Hold then, 
reduce dose 
one level 
Hold then,  
reduce dose  
one level 
Nausea/Vomiting  
Grade 4 
Hold then,  
reduce to -2 dose 
level  (500 mg/m2 BID) 
Hold then, 
reduce dose 
one level 
Hold then, 
 reduce dose  
one level 
Mucositis 
Grade 2 
Continue 
Continue 
Hold then, continue 
dose 
Mucositis  
Grade 3  
Hold then, 
reduce to -2 dose 
level  (500 mg/m2 BID) 
Hold then, 
reduce dose 
one level 
Hold then,  
reduce dose  
one level 
Mucositis 
Grade 4 
Hold then, 
reduce to -2 dose 
level (500 mg/m2 BID) 
Hold then, 
reduce dose 
one level 
Discontinue 
Colitis, Grade 2 
Continue 
Continue 
Hold then, reduce 
dose or continue 
same dose 
Colitis, Grade 3 
Hold then,  
reduce to -2 dose 
level  (500 mg/m2 BID) 
Hold then,  
reduce dose  
one level 
Hold then,  
reduce dose  
one level 
Colitis, Grade 4 
Hold then,  
reduce to -2 dose 
level (500 mg/m2 BID) 
Hold then,  
reduce dose  
one level 
Hold then,  
reduce dose  
one level 
Major Organ Event 
Grade 3-4 
Hold then,  
continue dose 
Hold then,  
reduce dose  
one level 
Hold then,  
reduce dose  
one level 
Myocarditis 
Grade 2-4 
Hold then, 
 Reduce to -1  dose 
level (750 mg/m2 BID) 
Hold then,  
reduce dose  
one level 
Hold then,  
reduce dose  
one level 
Pneumonitis 
Grade 2-3 
Hold then,  
continue dose 
Hold then,  
reduce dose  
one level 
Hold then, 
reduce dose  
one level 
Pneumonitis 
Grade 4 
Hold then,  
continue dose 
Hold then,  
reduce dose  
one level 
Discontinue 
 
 


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*Special Interest Events 
Capecitabine 
Talazoparib 
Inavolisib 
Skin/Dermatologic Event, 
Grade 2 
Continue 
Continue 
Hold then, reduce 
dose or continue 
same dose 
Skin/Dermatologic Event, Grade 3 
Hold then,  
continue dose 
Hold then,  
reduce dose  
one level 
Hold then, 
 reduce dose  
one level 
Skin/Dermatologic Event, Grade 4 
Hold then,  
continue dose 
Hold then,  
reduce dose  
one level 
Hold then,  
reduce dose  
one level 
Skin-Palmar-plantar 
erythrodysesthesia syndrome  
(Hand Foot Syndrome) 
Grade 3 
Hold then,  
reduce to -2 dose 
level  (500 mg/m2 BID) 
Hold then,  
continue dose 
Hold then, continue 
dose 
 
Hold all investigational agents until event resolves to 1 grade above baseline or better. 
 
Continue Dose-Continue agent listed at current dosing, consider management per institutional 
guidelines and/or Appendix A and B. 
 
Discontinue- Stop agent listed. 
 
6.3 
Dose Modifications for Capecitabine 
Dose modifications for capecitabine will be made per package insert guidelines with site investigator 
discretion. 
 
6.4 
Dose Modifications for talazoparib 
See section above for specific dose modifications.  
 
6.4.1 
Management of Talazoparib Specific Adverse Events 
Toxicities related or possibly related with talazoparib treatment should be managed according to 
guidelines provided in the current investigator’s brochure and standard medical practice. Management of 
talazoparib-specific adverse events can be found in Appendix A. If a diagnosis of Myelodysplastic 
Syndrome (MDS) or Acute Myeloid Leukemia (AML) is confirmed by a hematologist, the patient must 
permanently discontinue study treatment. 
 
6.5 
Dose Modifications for Inavolisib 
See section 6 above for specific dose modifications.  No more than two total dose reductions of 
inavolisib per patient (i.e., doses below 3 mg/day of inavolisib) will be allowed, and dose re-escalation of 
inavolisib may be permitted in the study after discussion with the sponsor-investigator. There is only 1 
total dose reduction in cycle 1. 
 
6.5.1 
Management of Inavolisib-Specific Adverse Events 
Toxicities related or possibly related with inavolisib treatment should be managed according to guidelines 
provided in the current investigator’s brochure and standard medical practice. Management of inavolisib-
specific adverse events can be found in Appendix B. 
 
6.6 
Discontinuation from Protocol Therapy 
In addition to discontinuation from therapy related to toxicities as outlined in section above, 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).   


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 
Documented disease progression: (local, regional and/or distant), invasive contralateral breast 
cancer 
 
Site investigator determines a change of therapy would be in the best interest of the subject 
 
Subject requests to discontinue protocol therapy for any reason 
o In a subject decides to prematurely discontinue protocol therapy (“refuses treatment”), the 
subject should be asked if he or she may still be 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 > 21 days from the expected day of the next treatment.  
 
6.7 
Discontinuation from Protocol Activities 
If a subject decides to discontinue from all protocol activities and not just from protocol therapy, a final 
evaluation should be completed at the time of the subject’s protocol withdrawal. An explanation of why 
the subject is withdrawing from the protocol will be recorded on the eCRF. A final assessment of adverse 
events will be recorded on the eCRF.  
 
 
 
 


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7 
SCHEDULE OF EVENTS 
NOTE: Please see Appendix C for additional information regarding protocol specific contingency plans for COVID 19 
 
7.1 
All Arms 
 
 
Screening8 
Return of Results/Treatment Planning10 
-42 days- 
28 days 
REQUIRED ASSESSMENTS 
 
 
 
Informed consent1 
X 
 
Arm 1 ONLY 
Complete medical history and height 
X 
 
 
Diagnosis and Staging2 
X 
 
 
Complete physical examination 
X 
 
 
Arm 1c only: Ophthalmic examination9 
 
 
X9 
Weight, BP and ECOG performance status 
X 
ECOG PS 
 
Adverse event & con med assessment 
X 
 
 
LABORATORY ASSESSMENTS 
 
 
 
CBC with differential3 
 
X 
 
CMP3 
 
X 
 
Arm 1c only: HgBA1c, Fasting glucose, and Fasting Lipid Panel9 
 
 
X9 
Calculated creatinine clearance 
 
X 
 
Urine pregnancy or serum HCG3 
 
X 
 
CORRELATIVE SAMPLES 
 
 
 
Tumor from definitive surgery – Mandatory4 
X 
 
 
Whole blood for genomic DNA – Mandatory5 
X 
 
 
Whole blood for Plasma ctDNA – Mandatory6 
X 
 
 
QUESTIONNAIRES7
 
 
Preference for ctDNA results
X 
 
X 
Fear of cancer recurrence index (FCRI)
X
 
X 
Assessment of survivor concerns (ACS)
X
 
X 
Impact of Events scale (IES)
X
 
X 
PROMIS-29 HRQoL
X
 
X 
PROMIS Anxiety short form
X
 
X 
Breast cancer self- efficacy scale
X 
 
 
Health literacy scale
X
 
 
CDC BRFSS – physical activity, smoking, alcohol
X
 
 
 
 
 


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1: Subjects will consent to participation in the trial and proceed to formal study registration providing ALL of the eligibility criteria is met. Consent for Arm 1 
specific treatment may be obtained prior to treatment C1D1 of the assigned Arm.  
 
2: Diagnosis and staging information to include: confirmation of TNBC per pathology report (ER, PR and HER2 negative) Precise ER and PR status should be 
provided if available. Confirmation of clinical stage TNBC 1-3 per AJCC 8th edition. 
 
3: CBC with platelet and differential (white blood cell count, absolute neutrophil count, hemoglobin and platelet count). Serum chemistries (creatinine, 
glucose, total bilirubin, aspartate transaminase [AST] and alanine transaminase [ALT]). Complete pregnancy testing only in women of childbearing potential. 
Urine pregnancy or serum HCG to be done 7 days prior registration. Women should be counseled regarding acceptable birth control methods to utilize from 
the time of screening, during treatment and after treatment completion. NOTE: If prior to treatment after discussion with the subject it is felt by the treating 
physician there is a possibility the subject is pregnant a pregnancy test should be repeated. 
 
4: Mandatory collection of tumor tissue from definitive surgery to be identified at screening and shipped immediately after consent. This sample will be used 
to confirm the patient’s triple negative breast cancer diagnosis. Also, extracted nucleic acids from this tumor sample will be used to perform next generation 
sequencing testing. Required for eligibility. Tissue can be collected and submitted upon consent while eligibility is being determined. Unused samples after 
protocol specific testing is complete will be stored for future research in minimal residual disease and cancer biomarkers.   
 
5: Mandatory 8.5 mL whole blood for genomic DNA will be collected at screening after consent obtained. Unused samples after protocol specific testing is 
complete will be stored for future research in minimal residual disease and cancer biomarkers.   
 
6: Mandatory: 17 mL whole blood for plasma ctDNA will be collected after a successful tissue test and the ability to select appropriate variants for tracking are 
confirmed. ctDNA should not be drawn before completing radiation or less than 14 days from surgery if radiation is not required. Required for eligibility. 
Unused samples after protocol specific testing is complete will be stored for future research in minimal residual disease and cancer biomarkers.   
 
7: Questionnaires may be administered electronically or by paper. No protocol deviation will be incurred if patients do not return a response to the 
questionnaires.  Patients must be made aware of their ctDNA results and assigned to a treatment arm BEFORE completing the questionnaires at “Return of 
Results/Treatment Planning” timepoint. Questionnaires completed during the screening period do not need to be repeated if they fall outside of the screening 
window. 
 
8: Participants must register and begin assigned treatment no later than 96 days from the last local therapy. For those that do not require radiotherapy, the 
most recent surgery for breast cancer must have been completed no more than 96 days prior to study treatment initiation. A 42 day window may be applied 
from the time of screening to registration for required assessments, correlative specimen collection (unless otherwise specified) and questionnaire completion. 
A 28 day window may be applied from the time of screening to registration for laboratory assessments. See Section 4 for additional detail regarding 
FoundationOne assay use. 
 
9: Ophthalmic examinations during study treatment and at treatment discontinuation are performed as clinically indicated per investigator discretion based on 
patient clinical status. If an ophthalmic exam is required during study treatment or study treatment discontinuation, the exam should consist of a full 
ophthalmic exam with dilation and refraction with specific attention paid to lens examination and detailed documentation. This exam may be performed after 


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assignment to Arm 1c and prior to treatment initiation on C1D1 but confirmation that there is no concurrent ocular or intraocular condition (e.g., cataract or 
diabetic retinopathy) that, in the opinion of the investigator, would require medical or surgical intervention during the study period to prevent or treat vision 
loss that might result from that condition is required for eligibility. HgBA1c, Fasting glucose, and Fasting Lipid Panel testing is required for eligibility for patients 
assigned to Arm 1c. Fasting means not having anything to eat or drink (except water) for 8-12 hours before the test. 
 
10:  Once the sequencing results are received, subjects will be assigned to the appropriate Arm and an additional consent will be obtained if the subject is 
assigned to Arm 1. The protocol therapy is not blinded to the participant or the treating investigator. NOTE: Treating investigators will receive sequencing 
results after arm assignment. ctDNA status (positive or negative) will be shared with subjects. Sequencing results will be shared with subjects at the treating 
investigator’s discretion. Sequencing results will be flagged if a suspected germline mutation is found.  It will be the responsibility of the treating investigator to 
follow-up with additional genetic testing and/or genetic counseling as appropriate. Subjects will be given the opportunity to ask questions regarding Arm 
assignment. A physician exam is not required during Return of Results/Treatment Planning. If a particular study drug is on shortage for Arm 1 and a patient is 
assigned to that particular Arm, they will be reassigned to Arm 2. If a subject assigned to Arm 1c does not meet additional Arm 1c criteria, the subject will be 
reassigned to Arm 2.  
 
 
 
 


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7.2 
Arm 1 a: DNA Repair pathway = talazoparib + capecitabine  
Assignment to Arm 1a CLOSED based on FDA approval of pembrolizumab for high-risk early-stage triple-negative breast cancer in July 2021. No 
patients were assigned to this Arm and the calendar was deleted. 
 
7.3 
Arm 1b: Immunotherapy pathway = atezolizumab + capecitabine (TO CLOSE)  
 
Cycle = 3 weeks 
Cycles 1-91 
Safety Visit2 
Surveillance3 
D1 of each cycle 
(±7 days) 
30/90 days  
(±7) after last dose 
±1 month 
REQUIRED ASSESSMENTS 
 
 
 
Informed consent for Assigned Arm 
X4 
 
 
Complete physical examination 
X 
D30 
X 
Weight, BP and ECOG performance status 
X 
D30 
X 
Adverse event & con med assessment 
X 
X 
 
LABORATORY ASSESSMENTS 
 
 
 
CBC with differential5 
X 
D30 
 
CMP5 
X 
D30 
 
Calculated creatinine clearance 
X 
 
 
Thyroid Function Testing5 
X5 
D30 
 
Urine pregnancy or serum HCG5 
X5 
 
 
RADIOLOGY IMAGING  
 
 
 
Breast imaging (remaining native breast tissue only) 
X3 
 
Yearly  
TREATMENT EXPOSURE 
 
 
 
Genomically directed atezolizumab + capecitabine10 
X 
 
 
CORRELATIVE AND BANKING SAMPLES 
 
 
 
Tumor from initial diagnosis – Optional6 
X6 
 
 
Tumor from progression – Optional6 
 
@progression 
Whole blood for Plasma ctDNA – Mandatory7 
X7 
D30 
X7 
Whole blood for CTCs – Mandatory8 
X8 
D30 
 
QUESTIONNAIRES9
 
Preference for ctDNA results
D30 
X 
Fear of cancer recurrence index (FCRI)
D30 
X 
Assessment of survivor concerns (ACS)
D30 
X 
Impact of Events scale (IES)
D30 
X 
PROMIS-29 HRQoL
D30 
X 
PROMIS Anxiety short form
D30 
X 
 
 
 


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1: Cycle 1 Day 1 testing need not be repeated if obtained within 14 days of starting protocol therapy. 
 
2: Participants in Arm 1 discontinued from the treatment phase of the study for any reason will have a safety visit 30 days (±7) after the last dose of protocol 
therapy. Subjects will also have an assessment of adverse events 90 days (±7) after the last dose of study treatment. This assessment may be accomplished via 
email, phone call or other avenues as appropriate.   
 
3: Radiology imaging performed is per standard of care based on investigator discretion. If at any time during treatment, recurrence is suspected, imaging 
should be performed based on investigator’s discretion. During surveillance, monitoring for the development of either local (chest wall, axillary, or 
supraclavicular nodes) or distant recurrent disease, is based on investigator’s discretion. Complete physical exam including weight, and BP should be 
performed at least once every 3 months for the first two years, then at least every 6 months during years 3-5 after Treatment Discontinuation.  At disease 
progression, participant should be followed for survival only. If there are concerns for recurrence upon physical exam, imaging should be performed to confirm 
per investigator’s discretion. Surveillance visits are calculated from the last visit. 
 
4: Participants will complete a treatment specific consent prior to Cycle 1 Day 1 based on the Arm they are assigned.  
 
5: CBC with platelet and differential (white blood cell count, absolute neutrophil count, hemoglobin and platelet count). Serum chemistries (creatinine, 
glucose, total bilirubin, and aspartate transaminase [AST] and alanine transaminase [ALT]). 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. WOCBP 
should be counseled regarding acceptable birth control methods to utilize during treatment and after treatment completion.  If prior to treatment after 
discussion with the subject it is felt by the treating physician there is a possibility the subject is pregnant a urine or serum pregnancy test should be repeated. 
 
6: Optional collection of tumor tissue from initial diagnosis to be shipped prior to D30 safety visit. Optional collection of tissue for subjects undergoing a 
standard of care biopsy at progression. Subjects will be asked to consent to these collections. 
 
7: Mandatory: 34 mL whole blood for plasma ctDNA will be collected prior to treatment on Cycles 1-8, Safety Visit, every 3 months for up to 2 years after 
treatment discontinuation and at progression. 
 
8: Mandatory 20 mL whole blood for CTC will be collected at screening prior to C2D1 and C4D1 then at the Safety Visit. 
 
9: Questionnaires may be administered electronically or by paper. No protocol deviation will be incurred if patients do not return a response to the 
questionnaires. Questionnaires will be completed at the safety visit and at +6 months surveillance visit, ± 1 month. 
 
10: Participants will receive genomically directed therapy. Atezolizumab and capecitabine will be administered in combination for 8 cycles. Atezolizumab will 
be given alone on Cycle 9. 
 
 


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7.4 
Arm 1c: PI3K Pathway = inavolisib + capecitabine → +/- standard of care pembrolizumab  
 
Cycle = 3 weeks 
Cycle 11 
Cycles 2-8 
Cycles 9-171 
Safety Visit2 
Surveillance3 
D1 
(±3 days) 
D1 of each 
cycle 
(±3 days) 
Day 1 of each 
cycle 
(±3 days) 
30/90 days 
(±7) after last 
dose 
±1 month 
REQUIRED ASSESSMENTS 
 
 
 
 
 
Informed consent for Assigned Arm4 
X4 
 
 
 
 
Complete physical examination 
X 
X 
X 
D30 
X 
Ophthalmic examination8 
X8 
 
Weight, BP and ECOG performance status 
X 
X 
X 
D30 
X 
Adverse event & con med assessment 
X 
X 
X 
X 
 
LABORATORY ASSESSMENTS 
 
 
 
 
 
CBC with differential5 
X 
X 
X 
D30 
 
CMP5 
X 
X 
X 
D30 
 
HgBA1c5 
X 
X5 
 
 
 
Fasting Glucose5 
X 
X5 
 
 
 
Calculated creatinine clearance 
X 
 
 
 
 
Thyroid Function Testing5 
 
 
X5 
D30 
 
Urine pregnancy or serum HCG5 
X5 
 
 
RADIOLOGY IMAGING  
 
 
 
 
 
Breast imaging (remaining native breast tissue only)3 
X3 
X3 
X3 
 
Yearly  
TREATMENT EXPOSURE 
 
 
 
 
 
Genomically directed inavolisib + capecitabine10 
X 
X 
 
 
 
+/- Pembrolizumab10 
 
 
X 
 
 
CORRELATIVE SAMPLES 
 
 
 
 
 
Tumor from initial diagnosis – Optional6 
X6 
X6 
 
 
 
Tumor from progression – Optional6 
 
 
 
X6 
Whole blood for Plasma ctDNA – Mandatory7 
X7 
X7 
X7 
D30 
X7 
QUESTIONNAIRES9
 
 
 
 
Preference for ctDNA results
 
 
D30 
X 
Fear of cancer recurrence index (FCRI)
 
 
D30 
X 
Assessment of survivor concerns (ACS)
 
 
D30 
X 
Impact of Events scale (IES)
 
 
D30 
X 
PROMIS-29 HRQoL
 
 
D30 
X 
PROMIS Anxiety short form
 
 
D30 
X 
 
 


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1: Cycle 1 Day 1 and Cycle 9 Day 1 testing need not be repeated if obtained within 14 days of starting protocol therapy. 
 
2: Participants in Arm 1 will have a safety visit 30 days (±7) after the last dose of protocol therapy. A safety follow up visit is not required for participants who 
complete the planned 8 cycles of inavolisib/capecitabine and proceed to standard of care treatment with pembrolizumab (preferred option) and no therapy is 
the preferred option if contraindication to pembrolizumab. Patients will have a Day 30 safety follow up visit after completion of standard of care treatment in 
addition to an assessment of adverse events 90 days (±7) after the last dose of standard of care therapy. The 90 day assessment may be accomplished via 
email, phone call or other avenues as appropriate.   
 
3: Radiology imaging performed is per standard of care based on investigator discretion. If at any time during treatment, recurrence is suspected, imaging 
should be performed at investigator’s discretion. During surveillance, monitoring for the development of either local (chest wall, axillary, or supraclavicular 
nodes) or distant recurrent disease is based on investigator’s discretion. Complete physical exam including weight, and BP should be performed at least once 
every 3 months for the first two years, then at least every 6 months during years 3-5 after Treatment Discontinuation.  At disease progression, participant 
should be followed for survival only. If there are concerns for recurrence upon physical exam, imaging should be performed to confirm per investigator’s 
discretion. Surveillance visits are calculated from the last visit, not treatment discontinuation. 
 
4: Participants will complete a treatment specific consent prior to Cycle 1 Day 1 based on the Arm they are assigned.  
 
5: CBC with platelet and differential (white blood cell count, absolute neutrophil count, hemoglobin and platelet count). Serum chemistries (creatinine, 
glucose, total bilirubin, aspartate transaminase [AST] and alanine transaminase [ALT]). HgBA1c to be performed at screening, every 3 months during treatment 
and after completion of inavolisib. During inavolisib and capecitabine treatment fasting glucose monitoring is based on site investigator discretion and subject 
clinical status. Additional glucose monitoring may be required during Cycle 1 specifically around Day 4 and Day 15 and should be initiated based on investigator 
discretion. Fasting glucose monitoring is not required during pembrolizumab treatment. Thyroid Function testing should be performed just prior to first dose of 
pembrolizumab and then every 2 cycles. TSH and T4 will be obtained.  Additional thyroid testing (such as T3 including free versus total testing) is at the 
discretion of the site investigator. WOCBP should be counseled regarding acceptable birth control methods to utilize during treatment and after treatment 
completion.  If prior to treatment after discussion with the subject it is felt by the treating physician there is a possibility the subject is pregnant a urine or 
serum pregnancy test should be repeated. 
 
6.Optional collection of tumor tissue from initial diagnosis to be shipped prior to D30 safety visit. Optional collection of tissue for subjects undergoing a 
standard of care biopsy at progression. Subjects will be asked to consent to these collections. Unused samples after protocol specific testing is complete will be 
stored for future research in minimal residual disease and cancer biomarkers.   
 
7: Mandatory: 34 mL whole blood for plasma ctDNA will be collected prior to treatment on Cycles 1-8, Day 30 Safety Visit, every 3 months for up to 2 years 
after treatment discontinuation and at progression. Subjects that proceed to pembrolizumab after completion of capecitabine/inavolisib will have an 
additional sample drawn prior to treatment on Cycle 9 Day 1. Unused samples after protocol specific testing is complete will be stored for future research in 
minimal residual disease and cancer biomarkers.   
 
 
 


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8: Patients will undergo ophthalmic examinations during the study treatment period and at study treatment discontinuation as clinically indicated per 
investigator discretion based on patient clinical status.  The ophthalmic examination should consist of a full ophthalmic exam with dilation and refraction with 
specific attention paid to lens examination and detailed documentation.  In addition, patients will be asked if they have experienced any significant visual 
changes, pain, or sensitivity to light at each clinic visit.  Any new eye-related symptoms including significant change in vision, eye pain, or photophobia will be 
evaluated by an ophthalmologist. 
 
9: Questionnaires may be administered electronically or by paper. No protocol deviation will be incurred if patients do not return a response to the 
questionnaires. Questionnaires will be completed at the Day 30 safety visit then at +6 months surveillance visit, ± 1 month. 
 
10: Participants will receive genomically directed therapy. Inavolisib and capecitabine will be administered Cycles 1-8. After completion of inavolisib and 
capecitabine, standard of care with pembrolizumab will be considered for Cycles 9-17 (Total of 9 cycles). Cycle 9 Day 1 study treatment should occur 4 weeks ± 
7 days after completion of Cycle 8 study treatment. If a subject assigned to Arm 1c does not meet additional Arm 1c criteria, the subject will be reassigned to 
Arm 2. 
 
 


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7.5 
Arm 1d: DNA Repair + Immunotherapy = talazoparib + capecitabine +/- standard of care pembrolizumab 
 
 
Cycles 1-91 
Safety Visit2 
Surveillance3 
D1 of each cycle 
(±3 days) 
30/90 days  
(±7) after last dose 
±1 month 
REQUIRED ASSESSMENTS 
 
 
 
Informed consent for Arm assignment4 
X4 
 
 
Complete physical examination 
X 
D30 
X 
Weight, BP and ECOG performance status 
X 
D30 
X 
Adverse event & con med assessment 
X 
X 
 
LABORATORY ASSESSMENTS 
 
 
 
CBC with differential5 
X 
D30 
 
CMP5 
X 
D30 
 
Calculated creatinine clearance 
X 
 
 
Thyroid Function Testing5 
X5 
D30 
 
Urine pregnancy or serum HCG5 
X5 
 
 
RADIOLOGY IMAGING  
 
 
 
Breast imaging (remaining native breast tissue only)3 
X3 
 
Yearly  
TREATMENT EXPOSURE 
 
 
 
Genomically directed talazoparib+ capecitabine +/-pembrolizumab9 
X 
 
 
CORRELATIVE SAMPLES 
 
 
 
Tumor from initial diagnosis – Optional6 
X6 
 
 
Tumor from progression – Optional6 
 
@progression 
Whole blood for Plasma ctDNA – Mandatory7 
X7 
D30 
X7 
QUESTIONNAIRES8
 
Preference for ctDNA results
D30 
X 
Fear of cancer recurrence index (FCRI)
D30 
X 
Assessment of survivor concerns (ACS)
D30 
X 
Impact of Events scale (IES)
D30 
X 
PROMIS-29 HRQoL
D30 
X 
PROMIS Anxiety short form
D30 
X 
 
 
 


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1: Cycle 1 Day 1 testing need not be repeated if obtained within 14 days of starting protocol therapy. 
 
2: Participants in Arm 1 will have a safety visit 30 days (±7) after the last dose of protocol therapy. Subjects on Arm 1d will also have an assessment of adverse 
events 90 days (±7) after the last dose of study treatment. This assessment may be accomplished via email, phone call or other avenues as appropriate.   
 
3: Radiology imaging performed is per standard of care based on investigator discretion. If at any time during treatment, recurrence is suspected, imaging 
should be performed based on investigator’s discretion. During surveillance, monitoring for the development of either local (chest wall, axillary, or 
supraclavicular nodes) or distant recurrent disease is based on investigator’s discretion. Complete physical exam including weight, and BP should be performed 
at least once every 3 months for the first two years, then at least every 6 months during years 3-5 after Treatment Discontinuation.  At disease progression, 
participant should be followed for survival only. If there are concerns for recurrence upon physical exam, imaging should be performed to confirm. Surveillance 
visits are calculated from the last visit, not treatment discontinuation. 
 
4: Participants will complete a treatment specific consent prior to Cycle 1 Day 1 based on the Arm they are assigned.  
 
5: CBC with platelet and differential (white blood cell count, absolute neutrophil count, hemoglobin and platelet count). Serum chemistries (creatinine, 
glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total bilirubin, alkaline phosphatase, and aspartate transaminase [AST] 
and alanine transaminase [ALT]) and electrolytes (total calcium, chloride, potassium, sodium). Thyroid Function testing should be performed just prior to first 
dose of pembrolizumab and then every 2 cycles. TSH and T4 will be obtained.  Additional thyroid testing (such as T3 including free versus total testing) is at the 
discretion of the site investigator. WOCBP should be counseled regarding acceptable birth control methods to utilize during treatment and after treatment 
completion.  If prior to treatment after discussion with the subject it is felt by the treating physician there is a possibility the subject is pregnant a urine or 
serum pregnancy test should be repeated. 
 
6: Optional collection of tumor tissue from initial diagnosis to be shipped prior to D30 safety visit. Optional collection of tissue for subjects undergoing a 
standard of care biopsy at progression. Subjects will be asked to consent to these collections. Unused samples after protocol specific testing is complete will be 
stored for future research in minimal residual disease and cancer biomarkers.   
 
7: Mandatory: 34 mL whole blood for plasma ctDNA will be collected prior to treatment on Cycles 1-8, Treatment Discontinuation (Safety Visit), every 3 months 
for up to 2 years after treatment discontinuation and at progression. Unused samples after protocol specific testing is complete will be stored for future 
research in minimal residual disease and cancer biomarkers.   
 
8: Questionnaires may be administered electronically or by paper. No protocol deviation will be incurred if patients do not return a response to the 
questionnaires. Questionnaires will be completed at treatment discontinuation at +6 months surveillance visit, ± 1 month. 
 
9: Participants will receive genomically directed therapy. Talazoparib and capecitabine and standard of care pembrolizumab will be administered Cycles 1-8. An 
additional dose of standard of care pembrolizumab alone is permitted on Cycle 9 (per KEYNOTE 522) if deemed appropriate by treating provider. 
 
 


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7.6 
Arm 2 
 
 
On Study1 
Treatment Discontinuation 
Surveillance2 
D1 
30 days  
(±7) after last dose 
±1 month 
REQUIRED ASSESSMENTS 
 
 
 
Complete physical examination 
Repeat as needed based 
on FDA label and standard 
practice 
 
X 
Weight and BP  
 
X 
Adverse event & concomitant medication assessment6 
 
 
LABORATORY ASSESSMENTS 
 
 
 
CBC with differential 
Repeat as needed based 
on FDA label and standard 
practice 
 
 
CMP 
 
 
Calculated creatinine clearance 
 
 
RADIOLOGY IMAGING  
 
 
 
Breast imaging (remaining native breast tissue only)2 
X2 
 
Yearly  
TREATMENT EXPOSURE 
 
 
 
Capecitabine or treatment of physician’s choice1  
X 
 
 
CORRELATIVE SAMPLES 
 
 
 
Tumor from initial diagnosis – Optional3 
X3 
 
 
Tumor from progression – Optional3 
 
@progression 
Whole blood for Plasma ctDNA – Mandatory4 
X4 
X4 
X4 
QUESTIONNAIRES5
 
 
Preference for ctDNA results
 
X
X 
Fear of cancer recurrence index (FCRI)
 
X
X 
Assessment of survivor concerns (ACS)
 
X
X 
Impact of Events scale (IES)
 
X
X 
PROMIS-29 HRQoL
 
X
X 
PROMIS Anxiety short form
 
X
X 
 
 


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1: Arm 2 subjects have plasma ctDNA positive but do not have a genomically driven treatment option. Pembrolizumab and/or capecitabine, or treatment of 
physician’s choice will be given. Dose, schedule and duration of treatment to be determined by treating physician. Administration and management of side 
effects will be handled as standard of care per institutional guidelines. Information regarding treatment administration and laboratory data will be entered into 
the EDC system.   
 
2: Radiology imaging performed is per standard of care based on investigator discretion. If at any time during treatment, recurrence is suspected, imaging 
should be performed based on investigator’s discretion. During surveillance, monitoring for the development of either local (chest wall, axillary, or 
supraclavicular nodes) or distant recurrent disease is based on investigator’s discretion. Complete physical exam including weight and BP completed at least 
once every 3 months for the first two years, then at least every 6 months during years 3-5 after Treatment Discontinuation. This information is required if 
available but if not collected does not constitute a deviation.  At disease progression, participant should be followed for survival only. Surveillance visits are 
standard of care and are calculated from the last visit, not treatment discontinuation (with the exception of M3).  
 
3: Optional collection of tumor tissue from initial diagnosis to be shipped prior to D30 safety visit.  Optional collection of tissue for subjects undergoing a 
standard of care biopsy at progression. Subjects will be asked to consent to these collections. Unused samples after protocol specific testing is complete will be 
stored for future research in minimal residual disease and cancer biomarkers.   
 
4: Mandatory 34 mL whole blood for plasma ctDNA will be collected at the 1st routine care visit, 3 month visit, 6 month visit, Treatment Discontinuation, and 
every 3 months for up to 2 years after treatment discontinuation. While ideally, all timepoints should be collected it will not be considered a deviation if the 1st 
routine care visit, 3 month visit, 6 month visit, Treatment Discontinuation and post-treatment samples are not drawn. Unused samples after protocol specific 
testing is complete will be stored for future research in minimal residual disease and cancer biomarkers.   
 
5: Questionnaires may be administered electronically or by paper. No protocol deviation will be incurred if patients do not return a response to the 
questionnaires. Questionnaires will be completed at treatment discontinuation and at +6 months surveillance visit, ± 1 month. 
 
6: Arm 2 subjects are undergoing treatment that is considered standard of care, recording and reporting of adverse events and concomitant medications will 
only be done when the AE requires dose modification of the standard of care drug.   
 
 


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7.7 
Arm 3 
 
 
On Study1 
Treatment Discontinuation 
Surveillance2 
D1 
30 days  
(±7) after last dose 
±1 month 
REQUIRED ASSESSMENTS 
 
 
 
Complete physical examination 
Repeat as needed based 
on FDA labels and 
standard practice 
 
X 
Weight and BP  
 
X 
Adverse event & concomitant medication assessment6 
 
 
LABORATORY ASSESSMENTS 
 
 
 
CBC with differential 
Repeat as needed based 
on FDA label and 
standard practice 
 
 
CMP 
 
 
Calculated creatinine clearance 
 
 
RADIOLOGY IMAGING  
 
 
 
Breast imaging (remaining native breast tissue only)2 
X2 
 
Yearly  
TREATMENT EXPOSURE 
 
 
 
Observation, capecitabine or treatment of physician’s choice1  
X 
 
 
CORRELATIVE SAMPLES 
 
 
 
Tumor from initial diagnosis – Optional3 
X3 
X3 
 
Tumor from progression – Optional3 
 
@progression 
Whole blood for Plasma ctDNA – Mandatory4 
X4 
X4 
X4 
QUESTIONNAIRES5
 
 
Preference for ctDNA results
 
X
X 
Fear of cancer recurrence index (FCRI)
 
X
X 
Assessment of survivor concerns (ACS)
 
X
X 
Impact of Events scale (IES)
 
X
X 
PROMIS-29 HRQoL
 
X
X 
PROMIS Anxiety short form
 
X
X 
 
 
 


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1: Arm 3 subjects have plasma ctDNA negative. Pembrolizumab and/or capecitabine, or treatment of physician’s choice will be given. Dose, schedule and 
duration of treatment to be determined by treating physician. Administration and management of side effects will be handled as standard of care per 
institutional guidelines. Information regarding treatment administration and laboratory data will be entered into the EDC system.   
 
2: Radiology imaging performed is per standard of care based on investigator discretion. If at any time during treatment, recurrence is suspected, imaging 
should be performed at investigator’s discretion. During surveillance, monitoring for the development of either local (chest wall, axillary, or supraclavicular 
nodes) or distant recurrent disease is based on investigator’s discretion. Complete physical exam including weight and BP should be performed at least once 
every 3 months for the first two years, then at least every 6 months during years 3-5 after Treatment Discontinuation. This information is required if available 
but if not collected does not constitute a deviation.  At disease progression, participant should be followed for survival only. Surveillance visits are standard of 
care and are calculated from the last visit, not treatment discontinuation (with the exception of M3).  
 
3: Optional collection of tumor tissue from initial diagnosis to be shipped prior to D30 safety visit. Optional collection of tissue for subjects undergoing a 
standard of care biopsy at progression.  Subjects will be asked to consent to these collections. Unused samples after protocol specific testing is complete will 
be stored for future research in minimal residual disease and cancer biomarkers.    
 
4: Mandatory 34 mL whole blood for plasma ctDNA will be collected at 1st routine care visit, 3 month visit, 6 month visit, Treatment Discontinuation, and every 
3 months for up to 2 years after treatment discontinuation and progression. While ideally, all timepoints should be collected it will not be considered a 
deviation if the 1st routine care visit, 3 month visit, 6 month visit, Treatment Discontinuation and post-treatment samples are not drawn. Unused samples after 
protocol specific testing is complete will be stored for future research in minimal residual disease and cancer biomarkers.   
 
5: Questionnaires may be administered electronically or by paper. No protocol deviation will be incurred if patients do not return a response to the 
questionnaires. Questionnaires will be completed at treatment discontinuation at +6 months surveillance visit, ± 1 month. 
 
6: Arm 3 subjects are undergoing observation or treatment that is considered standard of care, recording and reporting of adverse events and concomitant 
medications will only be done when the AE requires dose modification of the standard of care drug. 
 
 


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8 
CRITERIA FOR DISEASE EVALUATION 
DFS is defined as the duration of time from assignment to an Arm to time of a DFS event, defined as local 
failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or 
death from any cause. The diagnosis of local or distant recurrence should ideally be pathologically 
confirmed, however if biopsy if not possible, radiology confirmation by CT, MRI, or PET scan is acceptable. 
 
9 
BIOLOGICAL SAMPLES 
HCRN will provide sample collection kits and shipping supplies for tissue sample submissions and for 
blood samples collected for genomic and correlative studies. All sample labels will only include the HCRN 
participant study ID#, date/time of collection and sample type. No personal identifiers will be included. 
Refer to the clinical laboratory manual (CLM) associated with this protocol for collection, processing, 
labeling, and shipping instructions. 
 
9.1 
Plasma for ctDNA Sequencing (Required) 
Information for both Foundation One testing assays is included in this section. The original assay 
(FoundationOne® Liquid CDx) will be utilized by a site until IRB approval is obtained by that site for the 
protocol amendment in which the new assay is described. 
 
9.1.1 
FoundationOne® Liquid CDx assay; Plasma for ctDNA sequencing  
ctDNA sequencing of plasma will be performed using the FoundationOne® Liquid CDx assay. This assay 
interrogates over 300 cancer genes as well as microsatellite instability (MSI) and tumor mutation (TMB). 
The presence or absence of somatic mutation in the results will be used to assign patients to the ctDNA 
positive or ctDNA negative arm.  
 
9.1.1.1 To determine ctDNA-positivity when using this assay, the following rules will be applied: 
The patient will be considered ctDNA-positive if any apply: 
1. Detection of a circulating tumor fraction > 0% as determined by the FoundationOne® Liquid CDx 
tumor fraction algorithm. 
2. Detection of point mutation(s) or insertion/deletion(s) present at a variant allele frequency (< 
40% or > 60%). 
3. Detection of point mutation(s) or insertion/deletion(s) present at a variant allele frequency 
between 40-60% if the mutation is not present in ClinVar or dbSNP as a known germline 
alteration. 
4. Detection of copy number amplifications or deletions 
5. Detection of a genomic rearrangement event 
6. Detection of ctDNA as determined by aneuploidy model 
7. The above will confer the status of ctDNA positive unless the ctDNA positivity call is uniformly felt 
to be the result of clonal hematopoiesis of indeterminate potential (CHIP); (See #9 below for 
definition of call for CHIP).  
8. The co-occurrence of CHIP with other findings supporting ctDNA positivity, will retain a call of 
ctDNA positive.   
9. A panel of experts lead by co-investigators will ultimately adjudicate the call of ctDNA positivity or 
negativity based on the above criteria. Confounding variables, such as the presence of these 
findings representing CHIP, will be considered by the expert panel and may result in a call of 
ctDNA negative. 
 
 
 
 
 


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9.1.2 
FoundationOne Tracker Assay; Plasma for ctDNA sequencing 
ctDNA sequencing of plasma will be performed using the FoundationOneTracker. The presence or 
absence of somatic mutation in the results will be used to assign patients to the ctDNA positive or ctDNA 
negative arm.  
 
9.1.2.1 To determine ctDNA-positivity, the following rules will be applied: 
The patient will be considered ctDNA-positive if any apply: 
1. ctDNA status (detected/not detected) as determined by FoundationOne Tracker. 
2. Detection of point mutation(s) or insertion/deletion(s) present at a variant allele frequency (< 
40% or > 60%). 
3. Detection of point mutation(s) or insertion/deletion(s) present at a variant allele frequency 
between 40-60% if the mutation is not present in ClinVar or dbSNP as a known germline 
alteration. 
4. The above will confer the status of ctDNA positive unless the ctDNA positivity call is uniformly felt 
to be the result of clonal hematopoiesis of indeterminate potential (CHIP); (See #6 below for 
definition of call for CHIP).  
5. The co-occurrence of CHIP with other findings supporting ctDNA positivity, will retain a call of 
ctDNA positive.   
6. A panel of experts lead by co-investigators will ultimately adjudicate the call of ctDNA positivity or 
negativity based on the above criteria. Confounding variables, such as the presence of these 
findings representing CHIP, will be considered by the expert panel and may result in a call of 
ctDNA negative. 
 
9.2 
Tumor from Definitive Surgery for Next Generation Sequencing (Required) 
 
9.2.1 
Tumor tissue for NGS will be obtained as outlined in Section 7. 
The patient’s residual tumor at time of definitive surgery will undergo NGS using the FoundationOne®CDx 
test. This assay interrogates over 300 cancer genes, MSI, TMB, as well as immunohistochemistry for PD-L1 
(F1CDx + Ventana SP142 + F1LCDx OR F1CDx + Dako 22C3 + F1Tracker monitoring test depending upon 
change in assay). PD-L1 CPS using the Dako 22c3 antibody. Results from this will be used to assign patients 
to genomically directed therapy in conjunction with the ctDNA results.  
 
Subjects must consent to allow submission of archived tumor tissue sample from definitive surgery for 
next generation sequencing of the tumor. Tumor block is preferred however 14 unstained slides + 1H&E 
can be submitted if necessary. 
 
9.3 
FoundationOne Assays 
 
9.3.1 
FoundationOneLiquidCDx 
The FoundationOneLiquid®CDx test is a liquid biopsy test for solid tumors that analyzes ctDNA in a 
CAP/CLIA laboratory. It uses a hybrid-capture, NGS test method combined with proprietary computational 
algorithms that enable accurate variant calls by discriminating sequencing artifacts from bona fide 
mutations. It identifies four classes of genomic alterations (base substitution, insertions and deletions, 
copy number alterations, and rearrangements) in over 300 commonly altered oncogenes along with the 
detection of MSI and TMB. The assay has robust clinical performance for sensitivity and positive predictive 
value (PPV) and will be used to determine whether a patient is ctDNA+ or ctDNA- and also to assign 
patients to a genomic targeted therapy (along with the FoundationOne®CDx test).   
 
 
 


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9.3.2 
FoundationOne Tracker 
With advances in platform, we plan to move to a more sensitive ctDNA assay, the FoundationOne Tracker. 
The FoundationOne Tracker is a tissue informed assay that has improved the sensitivity for detecting 
minimal residual disease. Specifically, the FoundationOne Tracker uses a trusted and clinically relevant 
tissue-informed CGP baseline paired with personalized ctDNA -based assessment that empowers 
informed biomarker-guided treatment decisions. CtDNA-based disease monitoring with FoundationOne 
Tracker can serve as a sensitive biomarker for MRD and can accurately assess risk to support additional 
adjuvant or perioperative treatment. The FoundationOne Tracker is performed exclusively as a laboratory 
service as a custom-built, patient-specific assay for oncology that is based on patient-specific somatic 
variants (PSVs; substitutions and select indels) identified from tumor tissue testing and used to 
longitudinally track plasma circulating tumor DNA (ctDNA) abundance as a biomarker for tumor burden 
dynamics. Subjects eligible for FoundationOne Tracker have received a separate baseline NGS assay that 
tests a patient’s formalin-fixed, paraffin-embedded (FFPE) tumor tissue. DNA is extracted from formalin-
fixed, paraffin-embedded (FFPE) tumor tissue is sequenced using a tumor-tissue next-generation 
sequencing (NGS) assay targeting a cancer-related gene panel to identify somatic variants specific to the 
patient’s tumor. These PSVs are used to design a patient-variant-specific multiplex PCR NGS assay. Whole 
blood samples from the patient are collected at certain timed intervals for plasma ctDNA measurement. 
Cell free DNA is extracted and sequenced using the patient-specific FoundationOne Tracker for ctDNA 
measurement. ctDNA sequencing data are analyzed and results are reported, including detection of 
mutations in ctDNA and mean tumor molecules per mL of plasma.  
 
9.4 
Samples for future research in minimal residual disease and cancer biomarkers 
Participant consent will be obtained for additional samples for future research in minimal residual disease 
and cancer biomarkers.  These samples and any unused samples after protocol specific testing is complete 
will be stored until the research analysis can be performed. NOTE: Participants will be asked to consent to 
allow storage of their DNA and RNA for future studies. 
 
This includes: 
 
Tumor from initial diagnosis (sample collected prior to neoadjuvant chemotherapy): Optional  
o Formalin-fixed paraffin embedded tissue will be obtained after the participant is formally 
registered to the trial.  
 
Tumor from definitive surgery:  
Required for all Arms 
o Formalin-fixed paraffin embedded tissue will be obtained after the participant is formally 
registered to the trial.  
 
Tumor from progression:  
Optional 
o Formalin-fixed paraffin embedded tissue will be obtained a standard of care biopsy is 
performed at progression.  
 
Whole blood for genomic DNA:  
Required for all Arms 
o Whole blood will be collected at screening after consent is signed for Arm 2 and Arm 3 
participants.  
 
Whole blood for plasma ctDNA:  
Required for all Arms 
o Whole blood will be collected at Screening after consent, Day 1 of Cycles 1-8, D30 safety 
visit, every 3 months up to 2 years after treatment discontinuation visit and progression 
for Arm 1. For Arm 2 and Arm 3, samples will be collected after arm assignment at their 
next routine care visit (Day 1) and at the 3 month visit, 6 month visit and Treatment 


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Discontinuation. While ideally, all timepoints should be collected it will not be considered 
a deviation if the 3 month visit, 6 month visit or Treatment Discontinuation samples are 
missed for Arm 2 and Arm 3 subjects. 
 
Refer to the CLM associated with this protocol for collection, processing, labeling, and shipping 
instructions. 
 
10 
DRUG 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.  
 
10.1.2 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 0.25 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 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. 
 
10.1.3 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).  
 
10.1.4 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. 
 
 
 


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10.2 Inavolisib 
See the current investigator’s brochure for complete details regarding this medication. 
 
Inavolisib (GDC-0077) is a potent selective inhibitor of the Class I PI3K α isoform (p110α) and a specific 
degrader of mutant p110α, as an anti-cancer agent. Nonclinical studies demonstrate that GDC-0077 
specifically degrades mutant p110α, inhibits proliferation and induces apoptosis of PIK3CA-mutant breast 
cancer cell lines, inhibits tumor growth in human breast cancer xenograft models harboring PIK3CA 
mutations, and reduces downstream PI3K pathway markers, including phosphorylated form of protein 
kinase B (pAKT), PRAS40 phosphorylated at Threonine 246 (pPRAS40), and S6RP phosphorylated at Serine 
235/236 (pS6RP). Efficacy was improved when GDC-0077 was used in combination with standard-of-care 
therapies for hormone receptor positive (HR+) breast cancer, including fulvestrant (endocrine therapy) or 
palbociclib (CDK4/6 inhibitor), in a PIK3CA-mutant human breast cancer xenograft model. Together, these 
data provide rationale for evaluating GDC-0077 as a single agent and in combination with standard-of-
care endocrine and targeted therapies that may provide additional benefit to patients with locally 
advanced or metastatic, PIK3CA-mutant cancer, including HR+breast cancer. 
 
10.2.1 Supplier/How Supplied  
Genentech will supply inavolisib at no charge to subjects participating in this clinical trial as described in 
Section 5. 
 
Inavolisib (GDC-0077) drug product is intended for oral administration and will be supplied as film-coated 
tablets in two strengths (3 mg and 9 mg). 
 
The investigator 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 Storage and Stability 
Recommended storage configuration at or below 86F (30C) when protected from light. For batch-specific 
instructions and information on shelf life, refer to the packaging. 
 
10.2.3 Adverse Events 
See the current investigator’s brochure for complete details regarding adverse events related to this 
medication. The most common side effects of inavolisib occurring in more than 20% of patients are: 
gastrointestinal toxicity (nausea, vomiting, diarrhea, stomatitis/mucositis), hyperglycemia, decreased 
appetite, fatigue, neutropenia, dysgeusia, anemia, constipation and headache. Please see current IB for a 
detailed list of side effects. 
 
10.3 Capecitabine 
See the current package insert for complete details regarding this medication. 
 
Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. Both normal and tumor cells metabolize 5-
FU to 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These 
metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-
methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary 
complex. This binding inhibits the formation of thymidylate from 2’-deoxyuridylate. Thymidylate is the 
necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a 
deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can 


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mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This 
metabolic error can interfere with RNA processing and protein synthesis. 
 
10.3.1 Supplier/How Supplied  
Genentech will supply capecitabine at no charge to subjects participating in this clinical trial who are 
ctDNA positive and assigned to the genomically directed arm (Arm 1). Patients in Arm 2 (ctDNA positive 
but no actionable target) and Arm 3 (ctDNA negative) will receive the treatment of physician’s choice and 
this will be considered standard of care; thus capecitabine will not be supplied. See Section 5 for 
additional details. 
 
Tablets: 500 mg Color: Peach Engraving: XELODA on one side and 500 on the other 500 mg tablets are 
packaged in bottles of 120 (NDC 0004-1101-50).  Only 500mg tablets will be used for this trial. 
 
The investigator 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. 
 
10.3.2 Storage and Stability 
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). KEEP TIGHTLY CLOSED. Care should 
be exercised in the handling of capecitabine. Capecitabine tablets should not be cut or crushed. 
Procedures for the proper handling and disposal of anticancer drugs should be considered. Any unused 
product should be disposed of in accordance with local requirements, or drug take back programs. Several 
guidelines on the subject have been published see package insert. 
 
10.3.3 Adverse Events 
See the current package insert for complete details regarding adverse events related to this medication. 
Most common adverse reactions (≥30%) were diarrhea, hand and foot syndrome, nausea, vomiting, 
abdominal pain, fatigue/weakness, and hyperbilirubinemia.  Please see package insert for a detailed list of 
side effects. 
 
10.4 Pembrolizumab 
Pembrolizumab is standard of care and thus will not be supplied to patients on this study.  
 
11 
ADVERSE EVENT MANAGEMENT 
Adverse events will be collected and reported as described below for the experimental Arm 1 only. The 
descriptions and grading scales found in the NCI CTCAE v5 will be utilized for AE assessment. Arm 2 
subjects are undergoing treatment that is considered standard of care, recording and reporting of adverse 
events will only be done when the AE requires dose modification of the standard of care drug. Arm 3 
subjects are undergoing observation or treatment that is considered standard of care, recording and 
reporting of adverse events will only be done when the AE requires dose modification of the standard of 
care drug.  
 
11.1 
Definitions 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious adverse 
events (SAEs) per protocol. This includes all events of death, and any study specific issue of concern. The 
investigator is responsible for ensuring that all AEs and SAEs are observed or reported during the study 
are collected and reported to the FD, appropriate IRB(s), and Genentech, Inc. in accordance with CFR 
312.32 (IND Safety Reports). 
 


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11.1.1 Adverse Event (AE) 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding),  
symptom, or disease temporally associated with the use of an investigational medicinal product  
(IMP) or other protocol-imposed intervention, regardless of attribution. 
 
This includes the following: 
 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with TNBC that were not present 
prior to the AE reporting period. 
 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 
 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
 
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. 
 
11.1.2 Definition of Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence resulting in one or more of the following: 
 
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 participant 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 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. 
 
Results in persistent or significant disability/incapacity. 
 
Is a congenital anomaly or birth defect. 
 
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant 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; 
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 
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 
 
11.1.3 Adverse Events of Special Interest (AESIs)  
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the 
product, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor is 
required. Such an event might require further investigation in order to characterize and understand it. 
Depending on the nature of the event, rapid communication by the trial Sponsor to other parties (e.g., 
Regulatory Authorities) may also be warranted. 
 
Subjects will be monitored for AESIs from the time of signed informed consent until 90 days after 
discontinuation of inavolisib and/or atezolizumab. The following AEs are considered of special interest 
and must be reported to the Genentech Drug Safety utilizing the timeframe outlined in the SAE reporting 
section, irrespective of regulatory seriousness criteria: 
 
Adverse events of special interest for this study include the following: 
 
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: 
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 
 
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. 
 
The Inavolisib Events of Special Interest are: 
● 
Grade ≥ 3 fasting hyperglycemia 
● 
Grade ≥ 3 ALT/AST elevations 
● 
Grade ≥ 2 colitis or enterocolitis 
● 
Grade ≥ 3 diarrhea 
● 
Grade ≥ 3 rash 
● 
Grade ≥ 2 pneumonitis 
● 
Grade ≥ 3 stomatitis or mucosal inflammation 


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11.1.4 Expectedness of Adverse Events 
An adverse event not mentioned in the investigator’s brochure or package insert or the specificity or 
severity of which is not consistent with the investigator’s brochure or package insert is considered. 
Expected adverse events are those adverse events that are listed or characterized in the Package Insert 
(P.I) or current Investigator Brochure (I.B). Unexpected adverse events are those not listed in the P.I or 
current I.B or not identified. This includes adverse events for which the specificity or severity is not 
consistent with the description in the P.I. or I.B. For example, under this definition, hepatic necrosis would 
be unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
 
11.1.5 Relatedness and Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during questioning, 
or detected through physical examination, laboratory test, or other means will be reported 
appropriately. Each reported AE or SAE will be described by its duration (i.e., start and end dates), 
regulatory seriousness criteria if applicable, suspected relationship to inavolisib, talazoparib or 
capecitabine and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the following 
general guideline: 
 
Yes: There is a plausible temporal relationship between the onset of the AE and administration of the 
inavolisib, talazoparib or capecitabine, and the AE cannot be readily explained by the subject’s clinical 
state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response 
to the inavolisib, talazoparib or capecitabine or with similar treatments; and/or the AE abates or resolves 
upon discontinuation of the inavolisib, talazoparib or capecitabine or dose reduction and, if applicable, 
reappears upon re- challenge. 
 
No: Evidence exists that the AE has an etiology other than the inavolisib, talazoparib or capecitabine 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to inavolisib, talazoparib or 
capecitabine administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for each protocol-
mandated therapy. 
 
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)  
 
 
 


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11.1.6 Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE v5.0 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 
 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
 
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. 
 
If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event  
 
Grade 4 and 5 events must be reported as serious adverse events  
 
11.2 
Reporting 
 
11.2.1 Adverse Event (AE) Reporting 
 
AEs will be recorded from time of initiation of study drug until 30 days after discontinuation of 
study drug(s) or until a new anti-cancer treatment starts, whichever occurs first. For subjects on 
Treatment Arm 1d the timeframe is 90 days. 
 
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 Event (SAE) Reporting 
 
11.2.2.1 Study Center (Site) Requirements for Reporting SAEs 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. For subjects on 
Treatment Arm 1d, the timeframe is 90 days. 
 
SAEs will be reported on the SAE Submission Form within 1 business day of discovery of the 
event.   


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 
SAEs include events related and unrelated to the study drug(s).  
 
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.   
 
11.2.2.2 HCRN Requirements for Reporting SAEs to Genentech (GNE)  
HCRN will report all SAEs to GNE within 1 business day of receipt of the SAE Submission Form from a site. 
Follow-up information will be provided to GNE as it is received from site. Genentech/Roche Drug Safety: 
Fax: (650) 225-4682 or (650) 225-4630 or email: usds_aereporting-d@gene.com. 
 
11.2.2.3 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 
 
11.2.3 
Reporting AEs and SAEs in relation to COVID-19 
For any study participants exhibiting symptoms consistent with COVID-19, these need to be captured as 
adverse events according to the established safety reporting system specified. Please consult with HCRN 
for questions related to the reporting of COVID-19 symptoms. In the event a participant tests positive for 
COVID-19, or if no testing is available, ensure appropriate documentation of the AE and/or SAE of COVID-
19 is reflected in the eCRF. 
 
11.3 
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.   
 
11.4 
Procedures for Eliciting and Recording Adverse Events 
 
11.4.1 Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be adopted. 
Examples of non-directive questions include: 
● “How have you felt since your last clinical visit?” 
● “Have you had any new or changed health problems since you were last here?” 
 
11.4.2 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
 


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11.4.2.1 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 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. 
 
11.4.2.2 
Post-Study Adverse Events 
For studies involving collection of survival data/ follow up until progression free period/ Extended follow 
up period (2-years) the investigator after the end of the adverse event reporting period (defined as 30 
days after the last dose of study drug) should report all deaths, (regardless of cause), and any serious 
adverse event including development of cancer or a congenital anomaly in a subsequently conceived 
offspring of a female subject [add if applicable-including pregnancy occurring in the partner of a male 
study subject] who participated in the study that is believed to be related to prior exposure to study drug. 
 
11.5 
Case Transmission Verification of Single Case Reports 
Case Transmission Verification will be performed by both parties during this period to ensure successful 
transmission of Single case reports. 
 
HCRN and the sponsor-investigator agrees to conduct the Case Transmission verification to ensure that all 
single case reports have been adequately received by Genentech via HCRN emailing Genentech a 
Quarterly line-listing documenting single case reports sent by HCRN to Genentech in the preceding time 
period. The periodic line-listing will be exchanged within seven (7) calendar days of the end of the agreed 
time period. Confirmation of receipt should be received within the time period mutually agreed upon. If 
discrepancies are identified, the sponsor-investigator, HCRN and Genentech will cooperate in resolving 
the discrepancies. The responsible individuals for each party shall handle the matter on a case-by-case 
basis until satisfactory resolution.   
 
Following Case Transmission Verification, single case reports which have not been received by Genentech 
shall be forwarded by HCRN to Genentech within five (5) calendar days from request by Genentech. At 
the end of the study, a final cumulative Case Transmission Verification report will be sent to Genentech 
 
11.6 
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 Genentech within 
thirty (30) calendar days for Capecitabine and one (1) business day for Inavolisib: 
 
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 
 
11.6.1 Pregnancy 
If a female subject becomes pregnant while receiving the study drug or within 5 months after the last 
dose of study drug, or if the female partner of a male study subject becomes pregnant while the study 
subject is receiving the study drug or within 5 months after the last dose of study drug, or lactation 
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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.  
 
Any reports of pregnancy (including pregnancy occurring in the partner of a male study subject), where 
the fetus may have been exposed to the Product, shall be transmitted to Genentech and Pfizer 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. 
 
11.6.2 Medication Overdose 
Any overdose, or study drug administration error that results in an AE, even if it does not meet the 
definition of serious, requires reporting within one 1 business day to both Funders. 
 
11.6.3 Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to Genentech within thirty (30) 
calendar days for Capecitabine and one (1) business day for Inavolisib 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. 
 
11.7 
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 Genentech and Pfizer’s parent 
INDs at the time of submission. Additionally, all written IND Safety Reports submitted to the FDA by HCRN 
on behalf of the sponsor-investigator must also be faxed to Genentech/Roche Drug Safety: Fax: (650) 225-
4682 or (650) 225-4630 and/or Pfizer Drug Safety: Fax: Pfizer U.S. Clinical Trial Department 1-866-997-
8322 or email: USA.AEReporting@pfizer.com 
 
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 and/or Pfizer upon request. 
 
11.8 
IND Safety Reports Unrelated to this Trial 
Genentech and Pfizer 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. 
 
 
 


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12 
STATISTICAL CONSIDERATIONS 
 
12.1 
Sample Size Justification 
This trial was designed to demonstrate that genomically directed therapy in the plasma ctDNA positive 
arm results in superior outcomes compared with the outcomes of those in BRE12-158. We propose a 
three arm therapeutic design with the following characteristics to demonstrate superior outcome in the 
genomically directed arm as the primary endpoint. The sample size of 90 was calculated using the One-
Arm Survival tool from SWOG based on survival probability. We took a conservative sample size from 
those two methods, to ensure we have enough power to reach our conclusion. Either the one-sample log-
rank test or the same method (Brookmeyer-Crowley one-sample test) used in power calculation can be 
used in the statistical test. The assumptions underlying the power calculation are uniform accrual over 
time, no loss to follow-up and exponential distribution of event times. 
 
ARM 1 
 
Sample size: 90 
 
We assume a DFS probability of 50% at 24-months in the historical control from BRE12-158. We 
also assume the DFS probability is at least 62.5% for patients with genomically directed therapy 
(ARM 1). 
 
We will conclude that a survival probability of >50% at 24-months in the genomically directed arm 
will be considered a positive trial. 
 
Length of the accrual period: 36 months 
 
Length of the follow-up period for the primary endpoint: 24 months 
 
Alpha=0.05 for one-sided test 
 
With 90 patients in Arm 1, we will have 80% power to demonstrate superiority in Arm 1 vs. 50% 2-
yr DFS seen in the prior trial, BRE12-158 
 
ARM 2 
Assuming 90 patients are required for the primary endpoint and assuming 78% of those who are ctDNA 
positive will fit into a genomic basket, 25 patients will not fit into a basket and be placed into ARM 2. 
Prospective evaluation of the treatment of physician’s choice will serve as an informal comparator for 
outcomes with traditional therapy in the plasma positive population. There will be insufficient numbers 
for formal comparisons and thus only descriptive statistics and comparisons will be made.  
 
ARM 3 
Assuming 115 ctDNA positive patients will be required to fulfill the primary endpoint and assuming 35% of 
all patients screened in this population will be ctDNA positive, 62 patients will be ctDNA negative and fall 
into ARM 3. There will be insufficient numbers for formal comparisons and thus only descriptive statistics 
and comparisons will be made. 
 
SCREENING 
Assuming 177 patients will require a successful ctDNA test result and assuming 10% ctDNA testing failure 
+ patient dropout, 195 patients will be needed to screen for this trial. 
 
12.2 
Participant Characteristics 
Participant characteristics will be summarized by treatment arms for demographics, baseline disease 
characteristics, and medical history.  The three treatment arms will be compared using standard methods 
such as t-tests and chi-square tests. 


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12.3 
Analysis of Primary Objective 
 
Demonstrate a 2-year disease-free survival (DFS) of > 50% for participants with residual disease 
and ctDNA positive triple negative breast cancer (TNBC) treated with a genomically directed 
therapy following preoperative chemotherapy (ARM 1).  DFS is defined as the duration of time 
from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, 
distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause. 
The assumption from this trial is that a personalized approach will beat a historically non-
personalized approach and we are powered to test that assumption. Thus, we will assume we 
have selected agents that will all have similar degree of effectiveness to support our hypothesis. 
We recognize the overt failure of any one arm may result in rejection of the hypothesis. We 
obviously will not have power to study the success or failure of each arm but will look at each in 
descriptive fashion for future hypothesis generation. Based on the preliminary data from our prior 
trial BRE12-158, the DFS probability at 24-month for ctDNA positive patients was 50.0% with a 
95% confidence interval of 37.4% ~ 66.7%. The goal of this current trial is to demonstrate that we 
will beat a 50% 2-year DFS with genomically directed therapy. We will assume that the 
genomically directed therapy will improve the 24-month DFS probability from 50% to 62.5% in 
ctDNA positive patients. With 90 patients in Arm 1, we will have 80% power (alpha=0.05; one-
sided test) to demonstrate superiority in Arm 1 vs. 50% 2-yr DFS seen in the prior trial, BRE12-158. 
o One-sample log-rank test will be used to determine significance of 2-year DFS >50% in 
Arm 1. 
 
12.4 
Analysis of Secondary Objectives 
 
Evaluate the 2-year DFS for participants with residual disease and ctDNA positive TNBC and no 
actionable genomic targets treated with a standard approach therapy following preoperative 
chemotherapy (ARM 2)  
o Kaplan-Meier curve will be used to evaluate the 2-year DFS in Arm 2. 
 
Evaluate the 2-year DFS for participants with residual disease and ctDNA negative triple negative 
breast cancer (TNBC) treated with a standard approach therapy following preoperative 
chemotherapy (ARM 3) 
o Kaplan-Meier curve will be used to evaluate the 2-year DFS in Arm 3. 
 
Evaluate the overall DFS for ARMS 1, 2, and 3 
o Kaplan-Meier curve will be used to evaluate the overall DFS in Arms 1,2,3. 
 
Evaluate the overall DDFS for ARMS 1, 2, and 3. DDFS is defined as the duration of time from 
registration to time of recurrence of breast cancer outside the breast and/or death from any 
cause. The diagnosis of local or distant recurrence should ideally be pathologically confirmed, 
however if biopsy is not possible, radiology confirmation by CT, MRI, or PET scan is acceptable. 
o Kaplan-Meier curve will be used to evaluate the overall DDFS in Arms 1,2,3. 
 
Evaluate 1-year DFS for ARMS 1, 2, and 3 
o Kaplan-Meier curve will be used to evaluate the 1-year DFS in Arms 1,2,3. 
 
Determine 5-year overall survival (OS) for ARMS 1, 2, and 3. Overall survival is defined as the time 
from date of treatment start until death from any cause. 
o Kaplan-Meier curve will be used to evaluate the 5-year OS in Arms 1,2,3. 
 
Evaluate the DFS and OS for patients with markers associated with response to immune 
checkpoint inhibitor treatment vs. those without markers associated with response to immune 
checkpoint inhibitor treatment identified on residual disease. 
o Kaplan-Meier curve will be used to evaluate 
 
Describe the toxicities associated with genomically directed therapy in this population 
o Safety and toxicity data will be tabulated and reported using CTCAE criteria v5. 


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 
Describe patient preferences for return of ctDNA results 
o Patient preferences at ctDNA testing will be characterized using descriptive statistics and 
the trajectory of change in preferences following return of results and at treatment 
discontinuation will be descriptively summarized. 
 
Evaluate the impact of ctDNA status and availability of genomically directed therapy on FCR and 
HRQoL 
o Mixed effects model with a random subject effect will be used to model the PRO of 
interest by time and by study arm and their interaction. Each PRO will be described at 
each time point and by arm using least squares means, and linear contrasts will be used 
to describe changes over time and within or between arms. 
 
12.5 
Analysis of Exploratory Objectives 
 
Collect archived tumor specimens, genomic DNA, and circulating tumor samples to explore 
potential correlates of recurrence and toxicity 
o Correlative analyses that associate clinical or genomic data with survival outcomes will 
use the appropriate time-to-event analysis (including, Cox Proportional Hazards or Log-
Rank Test). Correlative analysis that associate clinical or genomic data with categorical 
variables will use Chi-square or Fisher’s exact test, as appropriate. 
 
Evaluate the drug specific effect on both efficacy outcomes (DFS and OS) and toxicity. 
o Drug-specific associations with survival outcomes will use the appropriate time-to-event 
analysis (including, Cox Proportional Hazards or Log-Rank Test). Drug-specific associations 
with toxicity variables will use Chi-square or Fisher’s exact test, as appropriate. 
 
Explore modifiers of FCR and HRQoL in this population, including coping strategies, anxiety, health 
literacy, self- efficacy, and disease characteristics. 
o Mixed effects models will be adjusted for factors that may impact FCR and HRQoL 
 
12.6 
Assessment of Safety 
All subjects who have received at least one dose of study treatment will be evaluable for safety. The 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used 
for toxicity assessment  
 
12.7 
Assessment of Efficacy 
All subjects who have received at least one cycle of study treatment and have had at least one post 
baseline disease assessment or die of any cause before the first post baseline disease assessment will be 
evaluable for assessment of efficacy.  
13 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted in accordance with the IU Simon Cancer Center’s (IUSCC) DSMP for High Risk 
Safety Lead-In/Phase II Trials.  
 
 
 


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13.1.1 HCRN facilitated oversight activities for High Risk Safety Lead-In/Phase II Trials include: 
 
Review and processing of all AEs requiring expedited reporting as defined in the protocol 
 
Provide trial accrual progress, safety information, and data summary reports to the 
sponsor-investigator. For any increase in frequency of grade 3 or above adverse events 
(above the rate reported in the Investigator Brochure or package insert), the sponsor 
investigator will notify HCRN who will notify the DSMC Chair and Compliance Officer 
immediately. The notification will include the incidence of study adverse events, grades, 
and attributions, as well as investigator statements regarding comparison with risks per 
the IB/package insert. 
 
Notify participating sites of adverse events potentially requiring expedited reporting and 
subsequent DSMC recommendations for study modifications. 
 
Investigators will conduct continuous review of data and patient safety 
 
Coordinate, during safety lead-in, weekly (Phase I) meetings (Safety Calls), and subsequently, 
during the phase II portion, monthly (Phase II) meetings which will include representation from 
each accruing site. 
o These meetings should include review of data, the number of subjects and 
significant toxicities as described in the protocol. HCRN should maintain meeting 
minutes and attendance for submission to the DSMC upon request. 
 
Conduct the trial across all participating sites in accordance with the requirements set forth in the 
IUSCC DSMP. 
 
13.2 
IUSCC Data Safety Monitoring Committee Oversight 
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of subject safety, 
regulatory compliance, and data integrity for this trial. The DSMC will review this study to assess toxicity, 
compliance, data integrity, and accrual per the Institutional DSMP. Trials managed by HCRN are not 
routinely audited or monitored by IUSCC; however, the IUSCC DSMC retains the right to audit HCRN trials 
on a for cause basis.  
 
13.2.1 IUSCC DSMC Review 
The IUSCC DSMC will review study data twice annually per the IUSCC DSMP. In preparation for the IUSCC 
DSMC review, HCRN will provide the following: 
 
Monthly Summary Reports 
 
Reports of the following, if not already included in the Monthly Summary Report: 
o Adverse event summary report (including serious adverse events) 
o Study accrual patterns 
o Protocol deviations 
 
Audit and/or monitoring results, if applicable 
 
Data related to stopping/ dose decision rules described in study design 
 
HCRN weekly (Phase I) or monthly (Phase II) study update meeting minutes/ attendance  
 
Documentation of DSMC reviews will be provided to sponsor-investigator (SI) and HCRN. The IUSCC 
DSMC will notify the sponsor-investigator and other regulatory bodies, as appropriate, for issues of 
immediate concern. The sponsor-investigator will work with HCRN to address the DSMC’s concerns as 
appropriate. 
 
At any time during the conduct of the trial, if it is the opinion of the sponsor-investigator that the risks 
(or benefits) to the patient warrant early closure of the study, this recommendation should be made in 


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writing to the DSMC Chair and Compliance Officer. Alternatively, the DSMC may initiate suspension or 
early closure of the study at any time based on its review of the study reports. 
 
13.2.2 DSMC DLT Review  
Prior to making dose escalation/expansion/de-escalation decisions, the SI and the study team will 
officially review all toxicity events for each subject for confirming treatment-related DLT. The study 
statistician will assist the determination of DLT and the interpretation of the statistical rule for dose 
escalation. Once a decision has been reached by the investigator, the official decision and toxicity data 
will be submitted to the DSMC via email (IUSCC-DLT-Review-L@list.iupui.edu). Treating additional subjects 
may not proceed until official DSMC correspondence confirms approval of dosing decisions for the next 
stage.  
 
13.2.3 IND Information Review 
For trials with an IND held locally by the IU principal investigator, the IND Annual Report will be prepared 
and submitted to the Compliance Team. This report will be reviewed by the DSMC at the time of FDA 
submission. 
 
13.3 
Data Quality Oversight Activities 
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.  
 
13.3.1 Onsite Monitoring 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects of the 
protocol are followed. For cause visits may occur as necessary. Selected 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. 
 
Participating sites may also be subject to quality assurance audits by Genentech and/or 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.   
 
 


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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.  
 
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, 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.   
 


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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. 
 
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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16. 
REFERENCES 
 
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to preoperative doxorubicin plus cyclophosphamide for operable breast cancer:National Surgical 
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3. Klauber-DeMore N, Ollila DW, Moore DT, et al: Size of residual lymph node metastasis after 
neoadjuvant chemotherapy in locally advanced breast cancer patients is prognostic. Ann Surg 
Oncol 13:685-91, 2006 
4. von Minckwitz G, Untch M, Blohmer JU, et al: Definition and impact of pathologic complete 
response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer 
subtypes. J Clin Oncol 30:1796-804, 2012 
5. Carey LA, Dees EC, Sawyer L, et al: The triple negative paradox: primary tumor chemosensitivity of 
breast cancer subtypes. Clin Cancer Res 13:2329-34, 2007 
6. Ogston KN, Miller ID, Payne S, et al: A new histological grading system to assess response of 
breast cancers to primary chemotherapy: prognostic significance and survival. Breast 12:320-7, 
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7. Symmans WF, Peintinger F, Hatzis C, et al: Measurement of residual breast cancer burden to 
predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414-22, 2007 
8. Liedtke C, Mazouni C, Hess KR, et al: Response to neoadjuvant therapy and long-term survival in 
patients with triple-negative breast cancer. J Clin Oncol 26:1275-81, 2008 
9. Masuda N, Lee SJ, Ohtani S, et al: Adjuvant Capecitabine for Breast Cancer after Preoperative 
Chemotherapy. N Engl J Med 376:2147-2159, 2017 
10. McNeil C: NCI-MATCH launch highlights new trial design in precision-medicine era. J Natl Cancer 
Inst 107, 2015 
11. Schmid P, Adams S, Rugo HS, et al: Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative 
Breast Cancer. N Engl J Med 379:2108-2121, 2018 
12. Schmid P, Rugo HS, Adams S, et al: Atezolizumab plus nab-paclitaxel as first-line treatment for 
unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): 
updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. 
Lancet Oncol 21:44-59, 2020 
13. Gambardella V et al: PI3K pathway biomarkers and clinical response in a phase I/Ib study of GDC-
0077 in hormone receptor-positive/HER2-negative breast cancer (HR+/HER2– BC). Poster 336P 
ESMO 2020 https://www.annalsofoncology.org/article/S0923-7534(20)40434-X/fulltext 
14. Crowley E, Di Nicolantonio F, Loupakis F, et al: Liquid biopsy: monitoring cancer-genetics in the 
blood. Nat Rev Clin Oncol 10:472-84, 2013 
15. Diaz LA, Jr., Bardelli A: Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 32:579-86, 
2014 
16. Heidary M, Auer M, Ulz P, et al: The dynamic range of circulating tumor DNA in metastatic breast 
cancer. Breast Cancer Res 16:421, 2014 
17. Dawson SJ, Rosenfeld N, Caldas C: Circulating tumor DNA to monitor metastatic breast cancer. N 
Engl J Med 369:93-4, 2013 
18. Garcia-Murillas I, Schiavon G, Weigelt B, et al: Mutation tracking in circulating tumor DNA predicts 
relapse in early breast cancer. Sci Transl Med 7:302ra133, 2015 
19. Chen YH, Hancock BA, Solzak JP, et al: Next-generation sequencing of circulating tumor DNA to 
predict recurrence in triple-negative breast cancer patients with residual disease after 
neoadjuvant chemotherapy. NPJ Breast Cancer 3:24, 2017 


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20. Schutz E, Akbari MR, Beck J, et al: Chromosomal instability in cell-free DNA is a serum biomarker 
for prostate cancer. Clin Chem 61:239-48, 2015 
21. Hamakawa T, Kukita Y, Kurokawa Y, et al: Monitoring gastric cancer progression with circulating 
tumour DNA. Br J Cancer 112:352-6, 2015 
22. Diehl F, Li M, Dressman D, et al: Detection and quantification of mutations in the plasma of 
patients with colorectal tumors. Proc Natl Acad Sci U S A 102:16368-73, 2005 
23. Diehl F, Schmidt K, Choti MA, et al: Circulating mutant DNA to assess tumor dynamics. Nat Med 
14:985-90, 2008 
24. Holdhoff M, Schmidt K, Donehower R, et al: Analysis of circulating tumor DNA to confirm somatic 
KRAS mutations. J Natl Cancer Inst 101:1284-5, 2009 
25. Garcia-Murillas I, Chopra N, Comino-Mendez I, et al: Assessment of Molecular Relapse Detection 
in Early-Stage Breast Cancer. JAMA Oncol, 2019 
26. Olsson E, Winter C, George A, et al: Serial monitoring of circulating tumor DNA in patients with 
primary breast cancer for detection of occult metastatic disease. EMBO Mol Med 7:1034-47, 2015 
27. Schmid P, Cortes J, Pusztai L, et al: Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl 
J Med 382: 810-821, 2020 
28. Schmid P, Cortes J, Dent R, et al: VP7-2021: KEYNOTE-522: Phase III study of neoadjuvant 
pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant 
pembrolizumab vs. placebo for early-stage TNBC. ESMO Virtual Plenary Abstracts 21 (9): 1198-
1200, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX A: MANAGEMENT OF TALAZOPARIB-SPECIFIC ADVERSE EVENTS 
Toxicities associated or possibly associated with talazoparib treatment should be managed according to 
standard medical practice. 
 
Hematologic Toxicity 
Monitor complete blood counts monthly and as clinically indicated. Anemia (low hemoglobin), 
thrombocytopenia (low platelet count), neutropenia (low neutrophil count) and other hematologic events 
have been reported with talazoparib. 
 
Management Guidelines for Blood/Investigation Events 
 
Event
Management
Anemia event, Grade 1 or 2
● Hemoglobin ≥ 9 g/dL 
● Continue talazoparib and monitor closely. 
● Continue capecitabine 
Anemia event, Grade 3
● Hemoglobin < 8 g/dL 
● Hold talazoparib until Hemoglobin level resolves to grade 1 or 
less, then resume a reduced dose 
● Hold capecitabine until Hemoglobin level resolves to grade 1 or 
less then resume at reduced dose 75% 
Anemia event, Grade 4
● Hold talazoparib until Hemoglobin level resolves to grade 1 or 
less, then resume a reduced dose 
● Hold capecitabine until Hemoglobin level resolves to grade 1 or 
less, then resume at reduced dose 50% dose reduction 
Platelet count decrease 
event, Grade 1 or 2 
● Platelet count ≥75,000/μL 
● Continue talazoparib and monitor closely. 
● Continue capecitabine 
Platelet count decrease 
event, Grade 3 
● Platelet count <50,000/μL 
● Hold talazoparib until platelet level resolves to grade 1 or less, 
then resume a reduced dose 
● Hold capecitabine until platelet level resolves to grade 1 or less, 
then resume at reduced dose 75% 
Platelet count decrease 
event, Grade 4 
● Hold talazoparib until platelet level resolves to grade 1 or less, 
then resume a reduced dose 
● Hold capecitabine until platelet level resolves to grade 1 or less, 
then resume at reduced dose 50% dose reduction 
Neutrophil count decrease 
event, Grade 1 or 2 
● Neutrophil count ≥1500/µL 
● Continue talazoparib and monitor closely. 
● Continue capecitabine 
Neutrophil count decrease 
event, Grade 3 
● Neutrophil count <1,000/μL 
● Hold talazoparib until neutrophil level resolves to grade 1 or less, 
then resume a reduced dose 
● Hold capecitabine until neutrophil level resolves to grade 1 or 
less, then resume at reduced dose 75% 


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Neutrophil count decrease 
event, Grade 3 or 4 
● Hold talazoparib until neutrophil level resolves to grade 1 or less, 
then resume a reduced dose 
● Hold capecitabine until neutrophil level resolves to grade 1 or 
less, then resume at reduced dose 50% dose reduction 
Other hematologic event, 
Grade 1 or 2 
● Continue talazoparib and monitor closely. 
● Continue capecitabine 
Other hematologic event, 
Grade 3 
● Hold talazoparib until event resolves to Grade 1 or less, then 
resume a reduced dose 
● Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 75% 
Other hematologic event, 
Grade 4 
● Hold talazoparib until event resolves to Grade 1 or less, then 
resume a reduced dose 
● Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 50% 
 
Myelodysplasia/Acute Myeloid Leukemia 
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) have been reported in patients who 
received talazoparib. Overall, MDS/AML has been reported in 2 out of 584 (0.3%) solid tumor patients 
treated with talazoparib in clinical studies. The duration of talazoparib treatment in these two patients 
prior to developing MDS/AML was 4 months and 24 months, respectively. Both patients had received 
previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. 
 
Do not start talazoparib until patients have adequately recovered from hematological toxicity caused by 
previous chemotherapy. Monitor complete blood counts for cytopenia at baseline and monthly 
thereafter. 
 
For prolonged hematological toxicities, interrupt talazoparib and monitor blood counts weekly until 
recovery. If the levels have not recovered after 3 weeks, refer the patient to a hematologist for further 
investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is 
confirmed, discontinue talazoparib. Capecitabine should continue. 
 
Non-hematologic Toxicity 
Fatigue, increased blood glucose, nausea, vomiting, diarrhea, and headache have all been reported with 
talazoparib. 
 
 
 


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Management Guidelines for Gastrointestinal Events 
 
Event
Management
Diarrhea event, Grade 1 or 2
● Continue talazoparib and monitor closely. 
● Continue capecitabine 
Diarrhea event, Grade 3
● Hold talazoparib until event resolves to ≤Grade 1 or baseline, 
then resume a reduced dose 
● Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 50% 
Diarrhea event, Grade 4
● Hold talazoparib until event resolves to Grade 1 or less, then 
resume a reduced dose 
● Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 25% 
Nausea/Vomiting event, 
Grade 1 or 2 
● Continue talazoparib and monitor closely. 
● Continue capecitabine 
Nausea/Vomiting event, 
Grade 3 
● Hold talazoparib until event resolves to ≤Grade 1 or baseline, 
then resume a reduced dose 
● Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 50% 
Nausea/Vomiting event, 
Grade 4 
● Hold talazoparib until event resolves to Grade 1 or less, then 
resume a reduced dose 
● Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 25% 
 
 
Management Guidelines for Any Non-hematologic Events 
 
Event
Management
Non-hematologic event, 
Grade 1 or 2 
● Continue talazoparib and monitor closely. 
● Continue capecitabine 
Non-hematologic event, 
Grade 3 
● Hold talazoparib until event resolves to ≤Grade 1 or baseline, 
then resume a reduced dose 
● Continue capecitabine  
Non-hematologic event, 
Grade 4 
● Hold talazoparib until event resolves to Grade 1 or less, then 
resume a reduced dose 
● Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 75% 
 
 
 
 


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APPENDIX B: MANAGEMENT OF INAVOLISIB-SPECIFIC ADVERSE EVENTS 
 
FASTING HYPERGLYCEMIA 
In general, patients with diabetes either requiring insulin therapy or with a baseline fasting glucose 
>126 mg/dL (7.0 mmol/L) or high HbA1c, suggesting poorly controlled diabetes, should be excluded 
from studies with inavolisib. Fasting is defined as abstaining from food and drink (with the exception 
of water) for at least 4 hours. Dosage modification guidelines for fasting hyperglycemia attributable to 
inavolisib are outlined below: 
 
Event 
Management 
Hyperglycemia, Grade 1  
> ULN to 160 mg/dL 
(8.9 mmol/L) 
 
Continue inavolisib. 
 
Continue capecitabine 
 
Encourage patients to adopt a diabetic diet 
 
Initiate treatment with insulin if needed. 
 
Monitor for glucose control. 
 
Recheck in 3 days and adjust medications as needed 
Hyperglycemia, Grade 2
> 160 to 250 mg/dL 
(> 8.9-13.9 mmol/L) 
 
Hold inavolisib, resume inavolisib when symptoms resolve to 
grade 1 or less and glucose levels are stable. 
o If fasting blood glucose persists > 200-250 mg/dL or > 
13.9-27.8 mmol/L for 7 days despite above interventions, 
discuss with study PI. 
 
Continue capecitabine 
 
Encourage patients to adopt a diabetic diet 
 
Initiate treatment with insulin. 
 
Monitor for glucose control. 
 
Recheck in 3 days and adjust medications as needed 
Hyperglycemia, Grade 3
250 to 500 mg/dL 
(13.9-27.8 mmol/L) 
 
Hold inavolisib, resume inavolisib when symptoms resolve to:  
 
If hyperglycemia resolves to Grade 1, >160 mg/dL or 8.9 mmol/L 
within 7 days, may resume at current dose level of inavolisib 
 
If hyperglycemia resolves to Grade 1, >160 mg/dL or 8.9 mmol/L 
in ≥ 8 days, reduce inavolisib dose by one dose level when 
treatment resumes  
 
If hyperglycemia > 250-500 mg/dL or > 13.9-27.8 mmol/L recurs 
within 30 days, reduce inavolisib dose by one dose level 
 
Continue capecitabine 
 
Manage hyperglycemia as per standard of care 
 
Initiate or increase treatment with insulin. 
 
Monitor for glucose control. 
 
Recheck in 3 days and adjust medications as needed  
 
Encourage patients to adopt a diabetic diet 
 
Consider consultation with endocrinologist or diabetologist. 
Initiate fasting home glucose monitoring 


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Hyperglycemia, Grade 4
> 500 mg/dL  
(> 27.8 mmol/L) 
 
Hold inavolisib, resume inavolisib when:  
o When hyperglycemia resolves to Grade 1, > 160 mg/dL or 
8.9 mmol/L, reduce inavolisib dose by one dose level 
when treatment resumes. If hyperglycemia > 500 mg/dL 
or > 27.8 mmol/L recurs within 30 days, permanently 
discontinue inavolisib 
 
Manage hyperglycemia as per standard of care  
 
Assess for volume depletion and ketosis and administer 
appropriate intravenous or oral hydration 
 
Initiate or increase treatment with insulin. 
 
Monitor for glucose control. 
 
Recheck in 3 days and adjust medications as needed  
 
Encourage patients to adopt a diabetic diet 
 
Consider consultation with endocrinologist or diabetologist 
 
Fasting glucose should be checked by finger stick or lab value (if patient has scheduled appointment) 
PRIOR to dosing.  Oral anti-diabetic medications should be titrated to the maximum allowed dosages to 
achieve control of blood glucose to < 160 mg/dL or 8.9 mmol/L.  For example, metformin may be 
administered to a maximum dose allowed as per local prescribing information, given in divided doses, as 
tolerated.  Please see local prescribing information of individual oral anti-diabetic agent for dosing 
guidelines.  
 
There is a risk of hypoglycemia if insulin or sulfonylureas are used, particularly if these agents are started 
during periods of inavolisib exposure and doses are not adjusted appropriately during periods of 
treatment interruption, during which patients’ insulin sensitivity may increase rapidly.  Short-term insulin 
is allowed to control blood glucose levels, but goal should be to maintain on oral agents once acute 
episode resolves. 
 
In order to diminish the risk of hypoglycemia, insulin should not be administered for 
asymptomatic hyperglycemia of any grade. Patients should be educated on the symptoms of 
hyperglycemia, so that patients can be promptly and appropriately managed. 
 
 
 


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GASTROINTESTINAL TOXICITY 
Dose reductions for gastrointestinal toxicity should occur only if the symptoms persist despite adequate 
(combination) anti-emetic treatment(s), including ondansetron (or equivalent anti-emetic). For persistent 
nausea and/or vomiting attributable to the inavolisib and/or capecitabine, dosage modification guidelines 
for inavolisib, and/or capecitabine are outlined below: 
 
Event
Management
Diarrhea event, Grade 1
 
Continue inavolisib and monitor closely 
 
Continue capecitabine 
 
Adequate treatment with anti-diarrheals and maximum 
supportive care per institutional care 
Diarrhea event, Grade 2
 
Hold inavolisib and resume inavolisib when symptoms resolve to 
grade 1 or less 
 
Continue capecitabine 
 
Adequate treatment with anti-diarrheals and maximum 
supportive care per institutional care 
 
If recurs within 30 days, reduce inavolisib by one dose level 
Diarrhea event, Grade 3
 
Hold inavolisib until event resolves to ≤Grade 1 or baseline, then 
resume a reduced dose 
 
Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 50% 
 
If recurs within 30 days after initiation of the first dose 
reduction, reduce inavolisib by one dose level.  If recurs within 
30 days from the second dose reduction, permanently 
discontinue inavolisib 
Diarrhea event, Grade 4
 
Permanently discontinue inavolisib until event resolves to Grade 
1 or less, then resume a reduced dose 
 
Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 25% 
Nausea/Vomiting event, 
Grade 1 or 2 
 
Continue inavolisib and monitor closely 
 
Continue capecitabine 
Nausea/Vomiting event, 
Grade 3 
 
Hold inavolisib until event resolves to ≤Grade 1 or baseline, then 
resume a reduced dose 
 
Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 50% 
 
Dose re-escalation of the inavolisib and/or capecitabine may be 
permitted in subsequent cycles for patients who exhibit Grade < 
1 nausea/vomiting through at least one cycle. 
Nausea/Vomiting event, 
Grade 4 
 
Hold inavolisib until event resolves to Grade 1 or less, then 
resume a reduced dose 
 
Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 25% 
 
Dose re-escalation of the inavolisib and/or capecitabine may be 
permitted in subsequent cycles for patients who exhibit Grade < 
1 nausea/vomiting through at least one cycle. 


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Any grade mucositis 
 
Intervene early 
 
Initiate aggressive mouth care that includes dexamethasone (0.1 
mg per mL) alcohol-free mouthwash.  If that is not available, 
consider other mouthwash formulations (e.g., combinations of 
local anesthetic, antihistamine, corticosteroid, antacid, 
antifungal and/or antibiotics) 
 
Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme-
containing products, as they may exacerbate the condition.  
Avoid harsh mouthwashes (e.g., Listerine®) 
 
Diet should be modified (e.g., avoidance of spicy foods) 
Mucositis event, Grade 1; 
asymptomatic or mild 
symptoms; intervention not 
indicated 
 
Continue inavolisib and monitor closely 
 
Continue capecitabine 
 
Maximum supportive care should be administered as needed at 
the discretion of the investigator 
Mucositis event, Grade 2; 
Moderate pain or ulcer that 
does not interfere with oral 
intake; modified diet 
indicated 
 
Hold inavolisib until event resolves to ≤ Grade 1 or baseline, 
then resume at same dose 
 
For recurrent Grade 2 stomatitis or oral mucositis within 30 
days, reduce inavolisib dose by one dose level 
 
Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 50% 
Grade 3: Severe pain; 
interfering with oral intake 
 
Interrupt inavolisib until Grade ≤ 1 and reduce inavolisib dose by 
one dose level when dosing is resumed 
 
Interrupt capecitabine until recovery to Grade ≤ 2; then may 
resume capecitabine as per local prescribing information  
Grade 4: Life-threatening 
consequences; urgent 
intervention indicated 
 
Permanently discontinue inavolisib 
 
Manage capecitabine as per local prescribing information  
Grade 1; Inflammatory 
Colitis 
 
Close monitoring and treat as appropriate 
Grade 2; Inflammatory 
Colitis 
 
If colitis-related symptoms do not improve to Grade ≤ 1 after 
48 hours of anti-diarrheals, start treatment with oral 
corticosteroid a 
 
Interrupt inavolisib until recovery to Grade ≤ 1, then may 
resume at the same dose or one dose level lower per 
investigator evaluation 
 
If recurs within 30 days, reduce inavolisib by one dose level 


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Grade 3; Inflammatory 
Colitis 
 
Treat with high dose corticosteroids (IV solumedrol or PO 
prednisone) b 
 
Interrupt inavolisib until recovery to Grade ≤ 1, then reduce by 
one dose level 
 
Hold capecitabine until recovery to Grade ≤ 1 and manage as 
per local prescribing information  
 
Consider colonoscopy 
 
If Grade 3 recurs, permanently discontinue inavolisib 
Grade 4; Inflammatory 
Colitis 
 
Permanently discontinue inavolisib 
 
Manage capecitabine as per local prescribing information  
 
 
 
 
 


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SKIN TOXICITY 
Dosage modification guidelines for skin toxicity attributable to the inavolisib and/or capecitabine are 
outlined below: 
 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic event, Grade 1  
 
Continue inavolisib 
 
Continue capecitabine 
 
Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic event, Grade 2  
 
Interrupt inavolisib treatment 
 
Treat rash per standard of care, including topical and/or oral 
corticosteroids, and/or antihistamines 
 
When rash resolves to Grade ≤ 1, resume inavolisib at the 
same dose or one dose level lower per investigator evaluation 
 
If Grade 2 rash recurs within 30 days, reduce inavolisib by one 
dose level when treatment resumes 
 
Continue capecitabine 
Dermatologic event, Grade 3 
 
Hold inavolisib  
 
Interrupt capecitabine treatment until recovery to Grade ≤ 2 
and manage as per local prescribing information 
 
Treat rash with topical and/or systemic corticosteroids (oral or 
IV) and antihistamines 
 
If rash resolves to Grade ≤ 1 within 30 days, reduce inavolisib 
by one dose level when treatment resumes 
 
If rash does not resolve to Grade ≤ 1 within 30 days, 
discontinue inavolisib 
 
Refer to dermatologist for consultation and skin biopsy 
Palmar-plantar 
erythrodysesthesia 
syndrome (Hand Foot 
Syndrome), Grade 2 
 
Continue inavolisib. 
 
Continue capecitabine 
Palmar-plantar 
erythrodysesthesia 
syndrome (Hand Foot 
Syndrome), Grade 3-4 
 
Continue inavolisib. 
 
Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 50% 
 
Dose re-escalation of the inavolisib, and/or capecitabine may be permitted in subsequent cycles for 
patients who exhibit Grade ≤ 1 skin toxicity for at least one cycle after discussion with the sponsor-
investigator. The inavolisib and/or capecitabine should be permanently discontinued for rash due to 
Stevens-Johnson syndrome, toxic epidermal necrolysis, or other suspected severe hypersensitivity or 
allergic reaction that is related to inavolisib and/or capecitabine. 
 
 
 


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Clinical Study Protocol 
Version Date: 14JUN2023 
 
 
 
 
 
 
 
Page 80 of 83 
Management of Pneumonitis 
 
Grade 1
 No specific therapy 
required 
 Chest CT scan 
 Repeat CT at least every 
8 weeks until return to 
baseline 
 Consider pulmonologist/ 
respirologist consult 
 Advise patient to promptly 
report new or worsening 
respiratory symptoms 
 No action 
Grade 2
 Prescribe 
corticosteroids if 
infectious etiology 
is ruled out 
 Taper as clinically 
indicated 
 Chest CT scan 
 Repeat CT at least every 
8 weeks until return to 
baseline 
 Consider PFTs 
 Obtain 
pulmonologist/respirologis
t consult 
 Hold inavolisib and 
capecitabine as long as 
corticosteroids are being 
given. When pneumonitis 
improves to Grade  1 and 
upon completion of any 
corticosteroid treatment, 
resume inavolisib and 
capecitabine dosing at the 
same dose or one dose level 
lower per investigator 
evaluation.  For recurrent 
Grade 2 event, resume 
inavolisib and capecitabine 
dosing at one dose level 
lower 
Grade 3
 Prescribe 
corticosteroids if 
infectious etiology 
is ruled out   
 Taper as clinically 
indicated 
 Chest CT scan 
 Repeat CT at least every 
8 weeks until return to 
baseline 
 Consider PFTs and 
bronchoscopy 
 Obtain pulmonologist/ 
respirologist consult 
 Hold inavolisib and 
capecitabine as long as 
corticosteroids are being 
given. When pneumonitis 
improves to Grade  1 and 
upon completion of any 
corticosteroid treatment, 
resume inavolisib and 
capecitabine dosing at one 
dose level lower 
Grade 4
 Prescribe 
corticosteroids if 
infectious etiology 
is ruled out   
 Taper as clinically 
indicated 
 Chest CT scan 
 Repeat CT at least every 
8 weeks until return to 
baseline 
 Consider PFTs 
 Obtain pulmonologist/ 
respirologist consult 
 Bronchoscopy is 
recommended 
 Permanently discontinue 
inavolisib 
 Permanently discontinue 
capecitabine 
CT  computed tomography (scan); PFTs  pulmonary function tests. 
 


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Page 81 of 83 
Management Guidelines for Any Non-hematologic Events  
 
Event
Management
Non-hematologic event, 
Grade 1 or 2 
 
Continue inavolisib and monitor closely. 
 
Continue capecitabine 
Non-hematologic event, 
Grade 3 
 
Hold inavolisib until event resolves to ≤ Grade 1 or baseline, 
then resume a reduced dose 
 
Continue capecitabine  
Non-hematologic event, 
Grade 4 
 
Hold inavolisib until event resolves to Grade 1 or less, then 
resume a reduced dose 
 
Hold capecitabine until event resolves to Grade 1 or less, then 
resume at reduced dose 75% 
 
For Grade≤ 3 toxicities associated primarily with laboratory abnormalities only 
(e.g., elevation of ALT, AST, lipase, or amylase, or decreases in phosphorus without clinical or other 
evidence of pancreatitis or other hepatic dysfunction), study treatment may continue without 
interruption and/or dose-reduction at the discretion of the investigator per institutional practice. 
 
 


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Clinical Study Protocol 
Version Date: 14JUN2023 
 
 
 
 
 
 
 
Page 82 of 83 
APPENDIX C 
 
COVID-19 Contingency Plans  
 
New participant enrollment – HCRN and the study team are supportive of new patient enrollment if your 
site is confident that you will be able to conduct the protocol specified safety and efficacy monitoring 
required for the study. We recommend that investigators ensure the appropriate monitoring and follow-
up of currently enrolled participants before considering recruitment of new participants.  
 
Study participant site visits - For ongoing participants, where possible, and safe to do, please continue to 
prioritize scheduled study visits in order to keep the participants on the protocol defined regimen and 
facilitate full safety and efficacy monitoring. For ongoing participants who are unable to attend protocol-
specified trial visits and procedures, please continue to assess adverse events/safety remotely (e.g., 
phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers) 
and document all deviations to the study conduct, noting specifically if it is a result of COVID-19 control 
measures.  
 
Anticipated Problem for 
Sites and Patients 
Recommended Contingency Plan or Alternative Procedure(s) 
Missed Protocol required 
physical exam(s)/ 
assessments 
Exams and assessments unable to be conducted by a healthcare provider 
can be delayed or conducted remotely until it is deemed safe for patients 
to return to clinic.  
Missed treatment Cycles 
Missed treatments can be made up when it is safe for patients to return to 
clinic/infusion. Patients may have their oral medications mailed if feasible 
to maintain treatment cycle schedule.  
Missed required 
specimen collections 
Every effort should be made to collect specimens when patients return to 
clinic. Our team is working closely with sites to provide flexible shipment 
options to reduce patient appointments. 
Missed PRO assessments 
PRO questionnaires can be sent home with patients, e-mailed, or mailed 
and returned at the next safe timepoint.  
Delays/Disruptions in 
Supply Chain 
There may be unforeseen delays or disruptions in the supply chain related 
to the conduct of this trial as a result of COVID-19. If and when these 
instances arise, they will each be addressed on an individual basis. 
 
 
 
 


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Page 83 of 83 
APPENDIX D: Patient Reported Outcomes (PRO) Instructions 
 
Patient Reported Outcomes (PRO) Instructions 
 
In effort to reduce burden on sites and trial costs the Indiana University (IU) PERSEVERE Team will be 
managing the PRO questionnaires for BRE18-334 through RedCap. 
 
1. Sites should ask patients their preference for paper or electronic surveys via email (preferred 
method) 
a. Electronic: Sites should complete or have patients complete the demographic information 
to initiate questionnaires for upon screening/enrollment  
i. https://redcap.link/PERSEVERE  
ii. The postcard below can be given to patients who are comfortable initiating the 
survey on their own. 
iii. IU PERSEVERE team will send patient automated emails to the patient to 
complete surveys 
iv. If a patient does not receive this email, please contact the IU team 
 
b. Paper: Sites should provide patient questionnaires at specified protocol timepoints. 
i. Patient should complete paper questionnaires 
ii. Site should fax questionnaires using the coversheet below.