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meetings

This trial will be monitored by the VICC Breast Cancer Research Team. The Breast Cancer Research Team is composed of the Clinical Core Director of the Breast Cancer Program and Team Leader, Surgical Oncologists, Radiation Oncologists, Medical Oncologists, Research Nurses, the Data Manager, and our Regulatory Specialist. The Breast Cancer Research Team meets on a monthly basis to discuss all AEs/SAEs, accrual, compliance, safety issues, adherence to protocol,  
 reviews, etc. pertaining to all breast cancer studies. This particular study will be thoroughly reviewed during these meetings. These monthly meetings have minutes recorded each time and those are also reviewed on a monthly basis by the Breast Cancer Research Team Physician Leader.
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monitoring

This trial will be monitored continuously by the study's Protocol Chair and by the Breast Cancer Research Team at VUMC. The Vanderbilt-Ingram Cancer Center (VICC) oversees patient safety and data monitoring for its investigator-initiated and NIH-NCI funded clinical trials through its Data and Safety Monitoring Committee (DSMC). The purpose of the DSMC is to ensure the efficient implementation and management of the VICC Data and Safety Monitoring Plan (DSMP). The Committee maintains authority to intervene in the conduct of studies as necessary to ensure clinical research performed at VICC achieves the highest quality standards. The VICC DSMC meets on a quarterly basis and ad hoc to discuss data and safety monitoring of clinical trials and to oversee the VICC DSMP. Internal audits for compliance with adverse event reporting, regulatory and study requirements, and data accuracy and completion are conducted according to the VICC DSMP according to study phase and risk. The committee reviews all serious adverse events (SAE) on Vanderbilt sponsored investigator-initiated studies on a quarterly basis and provides DSMC SAE review reports to the Vanderbilt IRB. Additionally, regular interim monitoring will be conducted by the Coordinating Center remotely.
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data handling and record keeping

An electronic case report form (eCRF) is required and must be completed for each included participant. The completed dataset should not be made available in any form to third parties, except for authorized representatives of appropriate Health/Regulatory Authorities, without written permission from Vanderbilt.
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14.4.2 record retention

To enable evaluations and/or audits from Health Authorities and Vanderbilt, each site investigator agrees to keep records including: The identity of all participants (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. To comply with international regulations, the records should be retained by the investigator in compliance with regulations. During data entry, range and missing data checks will be performed on-line. The checks to be performed will be documented in the Data Monitoring Plan for the study. A summary report (QC Report) of these checks together with any queries resulting from manual review of the eCRF's will be generated for each site and transmitted to the site and the site monitor. Corrections will be made by the study site personnel. This will be done on an ongoing basis.
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regulatory considerations

Protocol Review And Amendments  
Information regarding study conduct and progress will be reported to the Institutional Review Board (IRB) per the current institutional standards of each participating center. Any changes to the protocol will be made in the form of an amendment and must be approved by the IRB of each institution prior to local implementation. The Protocol Chair (or her designee) is responsible for the coordination and development of all protocol amendments, and will disseminate this information to the participating centers.
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informed consent

The investigator (or his/her designee) will explain to each subject the nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits involved and any discomfort it may entail. Each subject will be informed that participation in the study is voluntary, that s/he may withdraw from the study at any time, and that withdrawal of consent will not affect her subsequent medical treatment or relationship with the treating physician(s) or institution. The informed consent will be given by means of a standard written statement, written in non-technical language, which will be IRB approved. The subject should read and consider the statement before signing and dating it, and will be given a copy of the signed document. No subject will enter the study or have study-specific procedures done before his/her informed consent has been obtained. Confidentiality and security will be maintained for the tissue collection within this study. All tissue samples obtained for this study will be assigned a code and this code used to identify the sample. The samples will not be labeled with the patient's name, address or other information that would identify them. All information will be coded to maintain privacy. Research data, including the data collected from the medical charts will be entered into a password-protected database. The database (Breast Cancer Program Database) in which this study data is going to be stored has a firewall (in addition to the institutional firewall) with the highest level of protection, i.e. the same level of protection as the on-line hospital information system at Vanderbilt. This means that users must log on to a web server that sits between the institutional firewall and the firewall to the database, and only this application server is allowed to query the database. Information, including the identifier and password for the authorized users, is transmitted via a secure shell protocol using 128k encryption. Only Dr. Vandana Abramson, the PI, and the Breast Team Data Manager, approved through our institutional review board will be allowed access to patient identifiers. Other levels of authorization may exist for approved users, e.g. access to de-identified data. This database will store a de-identified link to the patient data and will not otherwise store patient data, even de-identified. The safety monitoring will be performed by the groups deemed appropriate by the Vanderbilt University Medical Center Institutional Review Board for reviewing the clinical trials procedure. Safety monitoring for the database is also performed by the Networking and Security Services of the Vanderbilt University Medical Center. Audit trails for access to the web server and the databases behind the dual firewall system are maintained in accordance with the practices of the Networking and Security Services of the Vanderbilt University Medical Center. In accordance with the Health Information Portability and Accountability Act (HIPAA), the written  
 informed consent document (or a separate document to be given in conjunction with the consent document) will include a subject authorization to release medical information to the study sponsor and supporting agencies and/or allow these bodies, a regulatory authority, or Institutional Review Board access to subjects' medical information that includes all hospital records relevant to the study, including subjects' medical history.
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ethics and gcp

This study will be carried out in compliance with the protocol and Good Clinical Practice, as described in: 1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 concerning informed consent and IRB regulations).  
3. Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996).  
The investigator agrees to adhere to the instructions and procedures described in it and thereby to adhere to the principles of Good Clinical Practice that it conforms to.
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multi-center guidelines protocol review and

Information regarding study conduct and progress will be reported to the Institutional Review Board (IRB) per the current institutional standards of each participating center. Any changes to the protocol will be made in the form of an amendment and must be approved by the IRB of each institution prior to local implementation. The Protocol Chair (or her designee) is responsible for the coordination and development of all protocol amendments. Once approved by the Protocol Chair, Vanderbilt will disseminate this information to the participating centers.
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study documentation

Each participating site is responsible for submitting copies of all relevant regulatory documentation to the Coordinating Center. The required documents include, but are not limited to the following: local IRB approvals (i.e., protocol, consent form, amendments, patient brochures and recruitment material, etc.), IRB membership rosters, summary of unanticipated problems or protocol deviations, and documentation of expertise of the investigators. The Coordinating Center will provide each participating site with a comprehensive list of the necessary documents. It is the responsibility of the participating sites to maintain copies of all documentation submitted to the Coordinating Center. The requirements for data management, submissions, and monitoring are outlined below. The  
 participating sites will submit all the research related information (source documents and research records - IRB approval documents, patient registration list, CRF info, toxicity assessments, tumor measurements/ responses, etc.) to the Coordinating Center.Personnel from the VICC Clinical Trial Shared Resource will monitor the trial remotely and may periodically visit the investigative site to assure proper conduct of the trial and proper collection of the data. The investigators at other sites will allow the monitor to review all source documents used in the preparation of the case reports, whether it be in person or remotely.
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records retention

U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the conduct of this study and the distribution of investigational drug, including CRFs, consent forms, laboratory test results, and medication inventory records, must be retained by each Principal Investigator for 2 years after marketing application approval. If no application is filed, these records must be kept 2 years after the study is discontinued and the U.S. FDA and the applicable national and local health authorities are notified. Following closure of the study, each participating center will maintain a copy of all site study records in a safe and secure location. The Coordinating Center will inform the investigator at each site at such time that the records may be destroyed.
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publication

It is understood that any manuscript or releases resulting from the collaborative research must be approved by the Protocol Chair and will be circulated to both Genentech and applicable participating sites/investigators prior to submission for publication or presentation. Additionally, any publication of study data and results must conform to the publications policy as stated the Translational Breast Cancer Research Consortium's (TBCRC) "Policies and Procedures".
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statistical considerations study design/ endpoints

The primary endpoint of this trial is the median PFS of carboplatin + atezolizumab versus carboplatin alone in patients with metastatic triple negative (ER/PR/HER2 negative) breast cancer. Prior studies have shown a median progression free survival of 2.9 months in patients with triple negative breast cancer receiving cisplatin or carboplatin who have received up to one prior chemotherapy regimen and a stable disease rate of approximately 5% at 6 months. We therefore propose that an improvement in median PFS of 2.9 months for single agent carboplatin to 4.4 months for the combination of carboplatin with atezolizumab would render this therapy worthy of further study. The overall PFS data will be estimated using the Kaplan-Meier method with 95%
confidence intervals.
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sample size/ accrual rate

The sample size estimation was completed using the log-rank test. A total sample size of 106 (n=53 in each arm) provides 80% power to detect a 1.5 month improvement in the median PFS, i.e. 2.9 months vs. 4.4 months, with a one-sided significance level equal to .10 (type I error). This estimation is based on the assumptions that accrual time is 24 months, additional follow-up time is 12 months, , and the ratio randomization is 1:1.
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analysis of secondary and exploratory

We will calculate the ORR, CBR, DOR, and OS and corresponding 95% confidence intervals. PFS, ORR, and DOR will also be analyzed using irRECIST.  
RNA-seq will be performed on all biopsies to assign a triple negative subtype, to determine baseline and treatment-induced changes in GE after therapy and define mutations present in the tumors both at baseline and upon progression of the disease. We expect an enrichment of drug resistanceassociated mutations/gene amplifications particularly in tumors that regress and later recur while on therapy. Somatic SNPs and structural variants will be validated by whole exome sequencing (WES) of genomic DNA from the tumor and matched blood. We will validate mutations by targeted capture approaches that allow high-level coverage (greater than 200X) and analysis of clonality. The status of p53, BRCA1/2, PIK3CA, PTEN, INPP4B and other mutations associated with TNBC, along with PDL1 expression and TILs in the tumor tissue is critical for testing our hypothesis. We anticipate significant opportunity for discovery of novel mutations as well as those arising from selection during resistance to the therapies under investigation. Statistics on the correlative endpoints
(tissue assays) will be primarily descriptive. Therefore, these studies are considered to be exploratory and potentially hypothesis-generating.  
Regarding the impact of body composition on immune phenotype and prognosis in patients receiving PDL1 blockade for metastatic triple negative breast cancer in this study, data analysis will be primarily exploratory. Pearson's rho will be used to estimate the correlation between low muscle mass (sarcopenia) and T cell exhaustion (PD1 and CTLA4 expression). Additional exploratory analysis will include the linear regression model to adjust for the potential confounders such as age and gender. It is anticipated this sudy would provide data from 106 patients. Assuming about 10%
may not be able to provide evaluable data, we will have the complete data from 95 patients. A sample size of 95 would have 84.7% power to detect a true correlation rho=0.3 versus the null hypothesis rho=0, with a type-I error of 0.05. To evaluate the impact of body composition on prognosis by progression free survival in patients receiving immunotherapy, we will evaluate only the study cohort receiving atezolizumab (n = 53). A Cox regression will be used to investigate the association between low muscle mass and PFS, while including T cell exhaustion (PD1 and CTLA4 expression) as the additional covariates as well as other potential confounders.
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statistical analysis plan

Demographic information, such as age and race, will be tabulated. Descriptive statistics, including means, standard deviations, and ranges for continuous parameters, as well as percents and frequencies for categorical parameters, will be presented. Investigation for outliers and assumptions for statistical analysis, e.g., normality and homoscedasticity, will be made. If necessary, data will be transformed by utilizing appropriate transformations such as log or square root. Adverse medical  
 events will be tabulated. NCI toxicity Grade 3 and Grade 4, and laboratory abnormalities will be listed.
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reporting and exclusions

All patients included in the study must be assessed for safety, tolerability, and response to treatment, even if there are major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). All of the patients who met the eligibility criteria and received study drugs for 4 weeks should be included in the main analysis of the clinical benefit rate. Patients in response categories 4-9 should be considered to have a treatment failure (disease progression). Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the analysis of the response and clinical benefit rate.
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references

1. Lehmann, B.D., et al., *Identification of human triple-negative breast cancer subtypes and* preclinical models for selection of targeted therapies. J Clin Invest, 2011. 121(7): p. 275067.  
2. Masuda, H., et al., *Differential response to neoadjuvant chemotherapy among 7 triplenegative breast cancer molecular subtypes.* Clin Cancer Res, 2013. 19(19): p. 5533-40.  
3. Jezequel, P., et al., *Gene-expression molecular subtyping of triple-negative breast cancer* tumours: importance of immune response. Breast Cancer Res, 2015. 17(1): p. 43.  
4. Burstein, M.D., et al., *Comprehensive genomic analysis identifies novel subtypes and targets* of triple-negative breast cancer. Clin Cancer Res, 2015. 21(7): p. 1688-98.  
5. Adams, S., et al., *Prognostic value of tumor-infiltrating lymphocytes in triple-negative* breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol, 2014. 32(27): p. 2959-66.  
6. Denkert, C., et al., Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2positive and triple-negative primary breast cancers. J Clin Oncol, 2015. 33(9): p. 983-91.  
7. *Pembrolizumab shows potential in breast cancer.* Cancer Discov, 2015. 5(2): p. 100-1.  
8. Chen, X., et al., *TNBCtype: A Subtyping Tool for Triple-Negative Breast Cancer.* Cancer Inform, 2012. 11: p. 147-56.  
9. Rizvi, N.A., et al., *Cancer immunology. Mutational landscape determines sensitivity to PD1 blockade in non-small cell lung cancer.* Science, 2015. 348(6230): p. 124-8.  
10. Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Can Res 2009;15:7412−20.  
11. Wang Z, Aguilar EG, Luna JI, et al: Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med 25:141-151, 2019 12. Mariathasan S, Turley SJ, Nickles D, et al: TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554:544-548, 2018