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NCT03206203 A Phase II trial of Atezolizumab (anti-PDLl) with Carboplatin in Patients with Metastatic Triple Negative Breast Cancer Protocol Number GNE ML30041 / TBCRC 043  
  
  
  
VICC BRE 15136 Protocol Chair Laboratory Correlatives:  
 Pathology:  
  
This document is confidential Do not discl.ose or use except as authorized Pagel o/103 Protocol Chair:  V. Abramson TBCRC 043 Biostatistics:  
  
  
Supporters Coordinating Center  
  
Protocol Version 11/13/2020 CONFIDENTIAL
This document is confidential Do not disclose or use except as authorized TBCRC 043 VICC BRE 15136: A Phase II trial of Atezolizumab (anti-PDL1) with Carboplatin in Patients with Metastatic Triple **Negative Breast Cancer**
- Protocol Revision Record -  
  
| Original Protocol:   | 4/4/2016   |
|----------------------|------------|
| Protocol Revision 1: | 6/22/2017  |
| Protocol Revision 2: | 8/04/2017  |
| Protocol Revision 3: | 11/19/2018 |
| Protocol Revision 4: | 04/06/2020 |
| Protocol Revision 5: | 07/30/2020 |
| Protocol Revision 6: | 11/13/2020 |
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table of contents

| 1.                                                                                                                                                               | SCHEMA .                                                                                                                                                                  |               |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|
| 2.                                                                                                                                                               | STUDY DESIGN/SUMMARY .                                                                                                                                                    |               |
| 3.                                                                                                                                                               | OBJECTIVES .                                                                                                                                                              |               |
| 3.1                                                                                                                                                              | PRIMARY OBJECTIVE                                                                                                                                                         |               |
| 3.2                                                                                                                                                              | S S ECONDARY O BJECTIVES .                                                                                                                                                |               |
| 3.3                                                                                                                                                              | E E XPLORATORY O BJECTIVES                                                                                                                                                |               |
| BACKGROUND .                                                                                                                                                     |                                                                                                                                                                           |               |
| 4.                                                                                                                                                               |                                                                                                                                                                           |               |
| 4.1                                                                                                                                                              | I I NVESTIGATIONAL A GENTS                                                                                                                                                |               |
| 4.2                                                                                                                                                              | R R ATIONALE .                                                                                                                                                            |               |
| 5.                                                                                                                                                               | PARTICIPANT SELECTION                                                                                                                                                     |               |
| 5.1                                                                                                                                                              | I I NCLUSION C RITERIA                                                                                                                                                    |               |
| 5.2                                                                                                                                                              | E E XCLUSION C RITERIA .                                                                                                                                                  |               |
| 5.3                                                                                                                                                              | INCLUSION OF UNDERREPRESENTED POPULATIONS ...........................................................................................................23                   |               |
| REGISTRATION PROCEDURES                                                                                                                                          |                                                                                                                                                                           |               |
| 6.                                                                                                                                                               |                                                                                                                                                                           |               |
| 6.1                                                                                                                                                              | GUIDELINES FOR ALL PARTICIPATING INSTITUTIONS                                                                                                                             |               |
| BIOPSY OF METASTATIC LESION                                                                                                                                      |                                                                                                                                                                           |               |
| 6.2                                                                                                                                                              |                                                                                                                                                                           |               |
| 7.                                                                                                                                                               | STUDY CALENDARS                                                                                                                                                           |               |
| STUDY CALENDAR: CARBOPLATIN +/- ATEZOLIZUMAB ..................................................................26                                                |                                                                                                                                                                           |               |
| 7.1                                                                                                                                                              |                                                                                                                                                                           |               |
| 7.2                                                                                                                                                              | STUDY CALENDAR:  ATEZOLIZUMAB (CROSSOVER) ................................................................................29                                              |               |
| 8.                                                                                                                                                               | T TREATMENT PLAN                                                                                                                                                          |               |
| 8.1                                                                                                                                                              | O VERVIEW                                                                                                                                                                 |               |
| 8.2                                                                                                                                                              | CONCOMITANT T REATMENT AND S UPPORTIVE C ARE G UIDELINES ......................................................................31                                         |               |
| A A SSESSMENTS DURING T REATMENT .............................................................................................................................32 |                                                                                                                                                                           |               |
| 8.3                                                                                                                                                              | C C ROSS - OVER POST - PROGRESSION ....................................................................................................................................32 |               |
| 8.4                                                                                                                                                              |                                                                                                                                                                           |               |
| 8.5                                                                                                                                                              | D D URATION OF T HERAPY                                                                                                                                                   |               |
| 8.6                                                                                                                                                              | D D URATION OF F OLLOW - UP  .                                                                                                                                            |               |
| 8.7                                                                                                                                                              | CRITERIA FOR REMOVAL FROM STUDY                                                                                                                                           |               |
| 9.                                                                                                                                                               | EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS                                                                                                                  |               |
| 9.1                                                                                                                                                              | A A TICIPATED T OXICITIES OF ATEZOLIZUMAB ( A TEZOLIZUMAB ) AND D OSE M ODIFICATIONS ....................35                                                               |               |
| 9.2                                                                                                                                                              | GENERAL GUIDELINES FOR DOSAGE MODIFICATION AND TREATMENT INTERRUPTION OR                                                                                                  |               |
| D DISCONTINUATION                                                                                                                                                |                                                                                                                                                                           |               |
| 9.3                                                                                                                                                              | A A TICIPATED T OXICITIES OF C ARBOPLATIN AND D OSE M ODIFICATIONS .........................................................60                                            |               |
| 9.4                                                                                                                                                              | SPECIAL CONSIDERATIONS .                                                                                                                                                  |               |
| 10. DRUG FORMULATION/STORAGE/SUPPLY .................................................................................................64                          |                                                                                                                                                                           |               |
| A A TEZOLIZUMAB (MPDL3280A)                                                                                                                                      |                                                                                                                                                                           |               |
| 10.1                                                                                                                                                             |                                                                                                                                                                           |               |
| 10.2                                                                                                                                                             | C C ARBOPLATIN .                                                                                                                                                          |               |
| 10.3                                                                                                                                                             | D DRUG A CCOUNTABILITY .                                                                                                                                                  |               |
| 1. CORRELATIVE/SPECIAL STUDIES ..............................................................................................................................67  |                                                                                                                                                                           |               |
| 1.1                                                                                                                                                              | A A RCHIVED T ISSUE S AMPLES .                                                                                                                                            |               |
| 1.2                                                                                                                                                              | B BLOOD/PLASMA COLLECTION  .                                                                                                                                              |               |
| Protocol Version 11/13/2020                                                                                                                                      | CONFIDENTIAL                                                                                                                                                              | Page 4 of 103 |  
Page 4 of 103 This document is confidential Do not disclose or use except as authorized  
  
| Protocol Chair:  V. Abramson                                                                                                                                        |                                                                                                                                                                    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| TBCRC 043                                                                                                                                                           |                                                                                                                                                                    |
| 1.3                                                                                                                                                                 | T TISSUE SPECIMEN AND BLOOD/PLASMA LABELING AND DOCUMENTATION ..........................................................70                                         |
| PERIPHERAL BLOOD MONONUCLEAR CELL COLLECTION ......................................................................................70                               |                                                                                                                                                                    |
| 11.4                                                                                                                                                                |                                                                                                                                                                    |
| 1.5                                                                                                                                                                 | G G ENETIC T ESTING                                                                                                                                                |
| 11.6                                                                                                                                                                | S S PECIMEN B ANKING .                                                                                                                                             |
| 1.7                                                                                                                                                                 | BIOPSY QUESTIONNAIRE                                                                                                                                               |
| 1.8                                                                                                                                                                 | IMAGING CORRELATIVE STUDY  .                                                                                                                                       |
| 12. MEASUREMENT OF EFFECT                                                                                                                                           |                                                                                                                                                                    |
| 12.1                                                                                                                                                                | D DEFINITIONS                                                                                                                                                      |
| 12.2                                                                                                                                                                | D D ISEASE P ARAMETERS .                                                                                                                                           |
| 12.3                                                                                                                                                                | R R ESPONSE C RITERIA                                                                                                                                              |
| 12.4                                                                                                                                                                | D DURATION OF R ESPONSE                                                                                                                                            |
| 12.5                                                                                                                                                                | I I MMUNE -R ELATED R ESPONSE C RITERIA                                                                                                                            |
| 12.6                                                                                                                                                                | R R ESPONSE R EVIEW AND C ENTRAL T UMOR M EASUREMENTS                                                                                                              |
| 13. ASSESSMENT OF SAFETY ADVERSE EVENT REPORTING ............................................................................80                                     |                                                                                                                                                                    |
| 13.1                                                                                                                                                                | G G ENERAL .                                                                                                                                                       |
| 13.2                                                                                                                                                                | R R ISKS A SSOCIATED WITH ATEZOLIZUMAB ................................................................................................................80          |
| 13.3                                                                                                                                                                | S S AFETY P ARAMETERS AND D EFINITIONS .........................................................................................................................81 |
| 13.4                                                                                                                                                                | A A SSESSMENT OF A DVERSE E VENTS                                                                                                                                  |
| 13.5                                                                                                                                                                | R R EPORTING P ROCEDURES                                                                                                                                           |
| 13.6                                                                                                                                                                | COORDINATING CENTER REPORTING PROCEDURES ...................................................................................................91                     |
| 14. DATA SAFETY AND MONITORING .................................................................................................................................97  |                                                                                                                                                                    |
| 14.1                                                                                                                                                                | D DATA M ANAGEMENT AND R EPORTING ...................................................................................................................97            |
| 14.2                                                                                                                                                                | M M EETINGS                                                                                                                                                        |
| 14.3                                                                                                                                                                | M M ONITORING                                                                                                                                                      |
| 14.4                                                                                                                                                                | D DATA HANDLING AND R ECORD K EEPING ...............................................................................................................98             |
| 15. REGULATORY CONSIDERATIONS                                                                                                                                       |                                                                                                                                                                    |
| 15.1                                                                                                                                                                | PROTOCOL REVIEW AND AMENDMENTS ...................................................................................................................9                |
| 15.2                                                                                                                                                                | I I NFORMED C ONSENT .                                                                                                                                             |
| 15.3                                                                                                                                                                | E E THICS AND GCP                                                                                                                                                  |
| 16. MULTI-CENTER GUIDELINES                                                                                                                                         |                                                                                                                                                                    |
| 16.1                                                                                                                                                                | PROTOCOL REVIEW AND AMENDMENTS .......................................................................................................................100          |
| STUDY DOCUMENTATION                                                                                                                                                 |                                                                                                                                                                    |
| 16.2                                                                                                                                                                | R R ECORDS R ETENTION                                                                                                                                              |
| 16.3                                                                                                                                                                |                                                                                                                                                                    |
| 16.4                                                                                                                                                                | PUBLICATION                                                                                                                                                        |
| 17. STATISTICAL CONSIDERATIONS .................................................................................................................................101 |                                                                                                                                                                    |
| 17.1                                                                                                                                                                | S S TUDY D ESIGN / E NDPOINTS                                                                                                                                      |
| 17.2                                                                                                                                                                | SAMPLE SIZE/ A CCRUAL R ATE                                                                                                                                        |
| 17.3                                                                                                                                                                | I I NTERIM ANALYSIS                                                                                                                                                |
| 17.4                                                                                                                                                                | A A NALYSIS OF S ECONDARY AND E XPLORATORY E NDPOINTS ..................................................................................102                        |
| 17.5                                                                                                                                                                | STATISTICAL A NALYSIS P LAN                                                                                                                                        |
| REPORTING AND EXCLUSIONS .                                                                                                                                          |                                                                                                                                                                    |
| 17.6                                                                                                                                                                |                                                                                                                                                                    |
| REFERENCES .                                                                                                                                                        |                                                                                                                                                                    |  
Protocol Chair:  V. Abramson TBCRC 043 1.
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schema

* Optional cross-over at progression Tumor Assessment  every 9 weeks
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study design/summary

The primary objective of this phase II multiple institution trial is to evaluate the efficacy of carboplatin + atezolizumab versus carboplatin alone in patients with metastatic triple negative breast cancer. Patients with an ECOG performance status of 0-1 who have received either zero or one prior regimen for metastatic disease are eligible. Patients will be randomized to one of two arms. In arm 1, patients will receive combination therapy with carboplatin and atezolizumab and in arm 2 patients will receive carboplatin monotherapy. All patients will undergo core biopsy of a metastatic lesion (if reasonably safe) at baseline and at the time of progression. If a fresh biopsy is deemed not safe, a paraffin block from a prior biopsy or surgery must be available for enrollment. Standard staging radiology scans will be performed at baseline and every 9 weeks thereafter. Upon progression of disease (clinically or by RECIST), patients on the carboplatin alone arm may cross over to arm 1 to receive atezolizumab. All patients with progression of disease who want to cross over to receive atezolizumab are required to undergo a biopsy of a metastatic site at progression if reasonably safe. Patients who were receiving carboplatin + atezolizumab will be discontinued from study medications upon disease progression by RECIST. Patients will be screened and enrolled from the oncology practice at the Vanderbilt-Ingram Cancer Center and from participating member centers of the Translational Breast Cancer Research Consortium (TBCRC).
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objectives primary objective

- To evaluate the efficacy, as measured by median progression free survival (PFS) of carboplatin + atezolizumab (using RECIST) versus carboplatin alone (using RECIST) in patients with triple negative metastatic breast cancer
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secondary objectives exploratory objectives

- To perform the following correlative studies from biopsies taken at baseline:
a) Tumor infiltrating lymphocyte frequency and phenotype (TILs) at baseline
- To determine overall response rate (ORR)
- To evaluate the efficacy, as measured by clinical benefit rate (CBR), of carboplatin +
atezolizumab versus carboplatin alone in patients with triple negative metastatic breast cancer. CBR is defined as complete response (CR) plus partial response (PR) plus stable disease (SD) for 6 months.  
- To determine the duration of response (DOR) for patients achieving a partial or complete response
- To evaluate the overall survival (OS) of carboplatin + atezolizumab versus carboplatin alone in patients with triple negative metastatic breast cancer
- To evaluate PFS, ORR, and DOR based on irRECIST as assessed by central imaging review. b) PD-L1 expression from the baseline pre-treatment tissue and at progression lesion,  
  
performed by IHC (SP142 clone) using a facility designated by the Supporter (Genentech)
c) HER2 (IHC, FISH) and ER/PR levels (IHC) from a metastatic site d) Perform RNA-seq to determine non-synonymous mutation burden in expressed genes and gene expression to assign a triple negative subtype at baseline for correlations with clinic outcome e) Immune phenotyping (IHC) for markers of T cell subsets and activation (CD4, CD8, FoxP3, CD25, Glut1) and exhaustion (PD1, CTLA4) and test feasibility of flow cytometric analyses to include additional markers
- To assess the effect of BRCA mutations on response to the study drugs - To evaluate the effect of steroids on the efficacy of atezolizumab To assess the prognostic effects of TILs on PFS and CBR in patients receiving atezolizumab
- To determine the correlation between low muscle mass and tumor immunophenotype by PDL1 expression, TIL frequency, tumor mutation burden, T cell activation, and T cell exhaustion.  
- To determine the correlation between low muscle attenuation and tumor immunophenotype by PDL1 expression, TIL frequency, tumor mutation burden, T cell activation, and T cell exhaustion.  
- To determine the correlation between adipose mass and tumor immunophenotype by PDL1 expression, TIL frequency, tumor mutation burden, T cell activation, and T cell exhaustion.  
- To determine the prognostic impact of LMM, LMA, and adiposity on progression free survival in patients receiving atezolizumab (anti-PDL1).
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background

Over the past decade, the term "triple negative breast cancer" has been used to classify tumors that lack expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2. Triple negative breast cancers (TNBC) are generally more aggressive than their ER positive counterparts, with higher rates of relapse in the early stage and decreased overall survival in the metastatic setting. TNBC is a pathologically, molecularly and clinically heterogeneous disease and the lack of recurrent targetable alterations makes this disease particularly difficult to treat. Using gene expression analyses from 386 tumors, we recently identified six distinct TNBC subtypes, each displaying unique biologies (**Figure 1**). The TNBC molecular subtypes include two basal-like
(BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype [1]. More importantly, the inherent differences between the subtypes predict for differential responses to standard chemotherapy. In a retrospective re-analysis of pretreatment biopsies, TNBC molecular subtypes have shown clinical utility and are predictive of response to neoadjuvant anthracycline and cyclophosphamide followed by taxane (PMID:23948975)[2]. This study showed BL1 had the highest pCR rate (50%) at time of surgery and BL2 and LAR the lowest (0 and 10%, respectively), deviating from the overall response of 32% for unselected TNBC [2]. The differing biologies of TNBC subtypes, as indicated by their gene expression signatures, are providing significant insight to differential response to therapies.  
Protocol Version 11/13/2020 CONFIDENTIAL *Page 8 of 103* This document is confidential Do not disclose or use except as authorized  
  
Figure 1. IM TNBC  
  
subtype is enriched in immune genes that are involved in cytokine signaling, immune signal transduction and antigen presentation.  
Heatmap shows relative expression of immune related genes across TNBC molecular subtypes from 386 tumor gene expression arrays.  
Comparable subtyping  
 results have been obtained from two independent analyses of gene expression arrays and each have identified similar subtypes, including a immune-activated or -associated biology [3, 4]. The IM subtype is composed of immune antigens and genes involved in cytokine and core immune signal transduction pathways (**Figure 2**). The data from our work and others suggest that the IM subtype is composed of an immune-activated and associated signaling components contributed from both the tumor and the infiltrating lymphocytes. Adams and colleagues recently reported that higher levels of tumor infiltrating lymphocytes (TILs), in evaluable TNBC tumors Figure 2. Immune regulatory genes that are indicative of tumor immune cell infiltrate are enriched in the IM TNBC subtype. Heatmap shows unsupervised clustering of immune panel of genes that highly correlate with pathological evaluation of tumor infiltrating lymphocytes using RNA-seq expression from TNBC tumor samples from TCGA.  
collected from patients enrolled in an adjuvant phase III trial, were prognostic for overall and disease-free survival [5]. Similarly, the presence of TILs in pretreatment biopsies was especially predictive of response to neoadjuvant chemotherapy in the carboplatin arm of the GeparSixto trial [6]. These preliminary data suggesting that TILs are predictive markers of response, specifically to neoadjuvant platinum agent compared to liposomal-doxorubicin, suggest that cell death induced by platinum agents may "prime" or generate neoantigens to stimulate nearby lymphocytes.  
  
Analysis of the gene expression data from the IM subtype and identification of transcripts associated with lymphocytes further supports that the IM tumor samples contain tumor-infiltrating lymphocytes (TILs). This is illustrated by observed enrichment of immune markers in the RNAseq data from TNBC samples in The Cancer Genome Atlas (TCGA) [6]. Unsupervised hierarchical clustering showed a strong correlation of TIL-associated immune signatures in TNBC tumors of the IM subtype compared to all other TNBC tumors (Figure 3). Given the recent efficacy of anti-PDL1 compounds in TNBC [7], we examined the levels of known  
 immune checkpoint regulatory genes (PDL1, PD1 and CTLA4) to determine if these targets are differentially expressed in TNBC subtypes. Breast cancer RNA-seq data (RSEM) was downloaded (Broad Firehose) and TNBC samples subtyped as previously described [1, 8]. PDL1, PD1 and CTLA4 expression were significantly higher in the IM TNBC subtype (4437.4 vs. 784.1, p=0.0001; 144.3 vs. 31.4, p=0.001 and 167.8 v. 39.5, p=0.0001, respectively) compared to all other breast cancers (**Figure 3A-3C**). These data demonstrate that the IM TNBC subtype is significantly enriched in the expression of genes involved in immune checkpoint signaling. Assessment of the IM signature in relation to spatial localization of T cells may identify a subset of TNBC in which immune cells may be present and checkpoint inhibitors have efficacy.  
Figure 3. Expression of immune signaling components is **enriched in immunomodulatory (IM) TNBC.**
Boxplots show mRNA expression (RSEM counts) for **(A)** PD-L1, (B) PD1 and **(C)** CTLA4 across TNBC
molecular subtypes (BL1, BL2, IM, M, MSL and LAR) or ER-positive (ER) and HER2-amplified (HER2) breast.  
cancer from TGCA.  
Since there has been a strong correlation between non-synonymous mutation burden and response to anti PD-1 therapy in non–small cell lung cancer (NSCLC), and anti-PD-L1 antibodies have efficacy in TNBC, we examined non-synonymous mutation burden in TNBC and non-TNBC tumors from the TCGA [9]. The number of non-synonymous mutations per sample was higher for TNBC (n=69) than non-TNBC (n=38), suggesting the possibility that TNBC tumors may be more immunogenic and express more neoantigens (**Figure 4B**). In addition, the mutational burden was differential among TNBC molecular subtypes, with significantly more amino acid coding mutations in the BL1 (138.2 vs. 70.0, p=0.0093) and M subtypes (133.9 vs. 70.0, p=0.036) compared to all other subtypes (Figure 4 B).  
  
  
A better understanding of the clinical and pathologic factors associated with benefit to immunotherapy in metastatic breast cancer could improve personalized therapy and provide insight into mechanisms of resistance. One such factor may be the body composition of the host. Obesity is associated with systemic inflammation and suppression of adaptive immunity, yet augmented T cell responses after PD1/PDL1 blockade11; lower muscle mass is associated with pro-inflammatory cytokines that may promote tumor growth and impair response to immune checkpoint blockade12,13. Low muscle mass (LMM), or sarcopenia, is associated with poorer outcome and increased toxicity in advanced cancer14. Low muscle attenuation (LMA), reflecting muscle "quality" and intramuscular fat infiltration, is also associated with poor outcome and reflects physical functioning15. To date, there has been no evaluation of how muscle or adiposity impact immune phenotype and outcome in patients with metastatic breast cancer receiving immunotherapy. TBCRC043 offers a homogeneous population of patients with metastatic TNBC with baseline biopsies for immunophenotyping, centrally collected body imaging, and outcome follow up to investigate this question. Using transverse cuts at the third lumbar vertebrae on abdominal CT scans as a reflection of total body composition16,17, we will quantify muscle mass, muscle attenuation, and adiposity. Low muscle mass is defined as skeletal muscle index (SMI,
lean muscle area/height, cm2/m2) less than 41 and low muscle attenuation will be defined as average muscle density less than 25 HU, or less than 33 HU if the patient is overweight/obese by BMI18. Total adiposity will be defined as the sum of visceral adipose tissue, subcutaneous adipose tissue, and intramuscular adipose tissue and evaluated by tertiles. Regarding the impact of body composition on immune phenotype and prognosis in patients receiving PDL1 blockade for metastatic triple negative breast cancer in TBCRC-043, our primary hypothesis is that LMM
Protocol Version 11/13/2020 CONFIDENTIAL Page 11 *of 103* This document is confidential Do not disclose or use except as authorized
(sarcopenia) is associated with T cell exhaustion (PD1 and CTLA4 expression) and worse progression free survival in patients with metastatic breast cancer receiving anti-PDL1 therapy, attenuating the prognostic effect of tumor infiltrating lymphocytes.
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investigational agents

4.1.1 Atezolizumab (Atezolizumab)  
Atezolizumab is a human immunoglobulin (Ig) G1 monoclonal antibody consisting of two heavy chains (448 amino acids) and two light chains (214 amino acids) and is produced in Chinese hamster ovary cells. Atezolizumab was engineered to eliminate Fc-effector function via a single amino acid substitution (asparagine to alanine) at position 298 on the heavy chain, which results in a non-glycosylated antibody that has minimal binding to Fc receptors and prevents Fc-effector function at expected concentrations in humans. Atezolizumab targets human programmed deathligand 1 (PD-L1) and inhibits its interaction with its receptor, programmed death-1 (PD-1).  
Atezolizumab also blocks the binding of PD-L1 to B7.1, an interaction that is reported to provide additional inhibitory signals to T cells. Atezolizumab is being investigated as a potential therapy against solid tumors and hematologic malignancies in humans.
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4.1.1.1 summary of nonclinical experience

The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and in vivo activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an acceptable safety profile, and to identify a Phase I starting dose. Comprehensive pharmacology, PK, and toxicology evaluations were thus undertaken with atezolizumab. The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in mice and cynomolgus monkeys to support intravenous (IV) administration and to aid in projecting the appropriate starting dose in humans. Given the similar binding of atezolizumab for cynomolgus monkey and human PD-L1, the cynomolgus monkey was selected as the primary and relevant nonclinical model for understanding the safety, pharmacokinetics, and toxicokinetics of atezolizumab. Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab supported entry into clinical studies, including providing adequate safety factors for the proposed Phase I starting doses. The results of the toxicology program were consistent with the anticipated pharmacologic activity of down-modulating the PD-L1/PD-1 pathway and supported entry into clinical trials in patients. Refer to the atezolizumab Investigator's Brochure for details on the nonclinical studies.  
4.1.1.2 Clinical Experience with atezolizumab 4.1.1.2.1 Onoging Clinical Studies  
  
Current studies of atezolizumab include one ongoing Phase Ia monotherapy study, three ongoing combination studies, five Phase II studies, and one Phase III study. Details of all ongoing studies can be found in the atezolizumab Investigator's Brochure.
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phase ia study pcd4989g

Study PCD4989g is a multicenter, first-in-human, open-label, dose-escalation study evaluating the safety, tolerability, immunogenicity, pharmacokinetics, exploratory pharmacodynamics, and preliminary evidence of biologic activity of atezolizumab administered as a single agent by IV infusion every 3 weeks to patients with locally advanced or metastatic solid malignancies or hematologic malignancies. Ongoing expansion cohorts are studying the efficacy in patients with pancreatic cancer, bladder cancer, breast cancer, esophageal cancer, prostate cancer, small-cell lung cancer, malignant lymphoma, multiple myeloma, and other less common tumor types.
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phase ib study gp28328

Ongoing Phase Ib Study GP28328 is evaluating the safety and pharmacology of atezolizumab administered with bevacizumab alone (Arm A) or with bevacizumab plus leucovorin, 5fluorouracil, and oxaliplatin (FOLFOX; Arm B) in patients with advanced solid tumors. Additional cohorts have been included to investigate atezolizumab in combination with carboplatin plus paclitaxel, in combination with carboplatin plus pemetrexed, and in combination with carboplatin plus nab paclitaxel, pemetrexed, and cisplatin in patients with advanced or metastatic non-small cell lung cancer (NSCLC).
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phase ib study gp28384

Ongoing Phase Ib Study GP28384 is evaluating the safety and pharmacology of atezolizumab administered in combination with vemurafenib in patients with previously untreated BRAFV600mutation−positive metastatic melanoma.
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phase ib study gp28363

Ongoing Phase Ib Study GP28363 is evaluating the safety and pharmacology of atezolizumab administered in combination with cobimetinib (MEK inhibitor) in locally advanced or metastatic solid tumors.
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phase ii study go28625 (fir)

Ongoing, single-arm, Phase II Study GO28625 is evaluating the safety and efficacy of atezolizumab monotherapy in PD-L1−positive patients with NSCLC. In particular, this study is evaluating whether archival or fresh tumor tissue is more predictive of response to atezolizumab. Safety and efficacy data are not yet available for this study.
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phase ii study go28753 (poplar)

Study GO28753 is a randomized, open-label, phase II study in patients with locally advanced or metastatic NSCLC who have failed a prior platinum-containing regimen. Patients in the control arm of Study GO28753 will receive docetaxel alone. Eligible patients will be enrolled regardless of PD-L1 status and will be stratified by PD-L1 expression. The primary endpoint is overall survival (OS) for both the PD-L1−positive population and the overall study population.
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phase ii study go28754 (birch)

Ongoing, single-arm, Phase II Study GO28754 is evaluating the safety and efficacy of atezolizumab monotherapy in PD-L1−positive patients with NSCLC. Safety and efficacy data are not yet available for this study.
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phase ii study wo29074

Ongoing Phase II Study WO29074 is evaluating the safety and efficacy of atezolizumab monotherapy or the combination of atezolizumab and bevacizumab versus sunitinib in treatmentnaïve patients with renal cell carcinoma (RCC). As of the clinical cutoff date (CCOD) of 17 October 2016, safety data was available from 304 patients in the safety-evaluable population, of whom 101 were treated with ATZ+BEV, 103 with atezolizumab alone, and 100 with sunitinib. The safety of atezolizumab in combination with bevacizumab was consistent with the known safety profile of individual treatment components; no new safety signals were identified. Safety of atezolizumab monotherapy was also consistent with the known profile of atezolizumab. The safety data demonstrated a more favorable safety profile for atezolizumab monotherapy compared to sunitinib. No new safety signals were identified.
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phase ii study go29293

Ongoing Study GO29293 is a single-arm, open label, Phase II study to assess the clinical benefit of atezolizumab as a single agent in patients with locally advanced or metastatic UBC. The co-primary endpoints of this study are independent review facility (IRF)−assessed objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) and investigator-assessed ORR according to modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
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phase iii study go28915 (oak)

Study GO28915 is a randomized, open-label, Phase III study in patients with locally advanced or metastatic NSCLC who have failed a prior platinum-containing regimen. Patients in the control arm of Study GO28915 will receive docetaxel alone. Eligible patients will be enrolled regardless of PD-L1 status and will be stratified by PD-L1 expression. The primary endpoint is OS for both the PD-L1−positive population and the overall study population.  
For further details, see the atezolizumab Investigator's Brochure.
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4.1.1.2.2 clinical safety

As of the clinical cutoff date (CCOD) of 17 May 2019 > 21,000 patients with solid tumors or hematologic malignancies have received atezolizumab as a single agent or in combination with cytotoxic chemotherapy and/or targeted therapy through participation in a clinical trial. Safety findings of single-agent atezolizumab across multiple tumor types in the clinical development program are consistent with the known mechanism of action of atezolizumab and the underlying disease. Overall, treatment with atezolizumab is well tolerated with a manageable adverse event profile. Currently, no maximum tolerated dose, no dose-limiting toxicities (DLTs), and no clear dose-related trends in the incidence of adverse events (AEs) have been determined. Among 3178 patients treated with single-agent atezolizumab for whom pooled safety data are available, the most commonly reported AEs (≥ 10%) include fatigue, decreased appetite, nausea, Protocol Version 11/13/2020 CONFIDENTIAL Page 14 *of 103* This document is confidential Do not disclose or use except as authorized  
  
cough, dyspnea, constipation, pyrexia, diarrhea, anemia, back pain, vomiting, asthenia, arthralgia, pruritus, rash, headache, urinary tract infection, and peripheral edema. The AEs observed with atezolizumab in combination with chemotherapy and/or targeted therapies are consistent with the known risks of the individual study treatment. Atezolizumab-related AEs were comparable between patients who received atezolizumab monotherapy and those who were treated with atezolizumab in combination with targeted therapy and/or chemotherapy.
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adverse events

The following adverse events are considered known risks of atezolizumab treatment:  
| -                                            | Fatigue                                  |                       |                         |
|----------------------------------------------|------------------------------------------|-----------------------|-------------------------|
| -                                            | Arthralgia                               |                       |                         |
| -                                            | Asthenia                                 |                       |                         |
| -                                            | Decreased appetite                       |                       |                         |
| -                                            | Diarrhea                                 |                       |                         |
| -                                            | Dyspnea                                  |                       |                         |
| -                                            | Urinary tract infection                  |                       |                         |
| -                                            | Cough                                    | -                     | Pruritus                |
| -                                            | Nausea                                   |                       |                         |
| -                                            | Fever                                    |                       |                         |
| -                                            | Rash                                     |                       |                         |
| -                                            | Vomiting                                 |                       |                         |
| -                                            | Musculoskeletal pain                     |                       |                         |
| Very Common  (occurs in  > 10%  of patients) | -                                        | Chills                |                         |
| -                                            | Dysphagia                                |                       |                         |
| -                                            | Increase in liver enzymes                |                       |                         |
| -                                            | Hypersensitivity                         |                       |                         |
| -                                            | Hypokalemia                              |                       |                         |
| -                                            | Hyponatremia                             |                       |                         |
| -                                            | Hypotension                              |                       |                         |
| -                                            | Hypothyroidism                           |                       |                         |
| -                                            | Nasal congestion                         | -                     | Colitis                 |
| -                                            | Hypoxia                                  |                       |                         |
| -                                            | Flu-like symptoms                        |                       |                         |
| -                                            | Infusion-related reaction                |                       |                         |
| -                                            | Pneumonitis                              |                       |                         |
| -                                            | Thrombocytopenia                         |                       |                         |
| -                                            | Hepatitis                                |                       |                         |
| -                                            | Abdominal pain                           |                       |                         |
| Common  (occurs in  1% - 10%  of patients)   |                                          |                       |                         |
| Less Common but important                    | -                                        | Adrenal insufficiency |                         |
| -                                            | Diabetes                                 |                       |                         |
| -                                            | Hyperthyroidism                          |                       |                         |
| -                                            | Meningoencephalitis                      |                       |                         |
| -                                            | Hypophysitis                             |                       |                         |
| -                                            | Myocarditis                              |                       |                         |
| -                                            | Nephritis                                | -                     | Guillain-Barré syndrome |
| -                                            | Myasthenic syndrome /  myasthenia gravis |                       |                         |
| -                                            | Pancreatitis                             |                       |                         |
| -                                            | Increase in amylase and lipase           |                       |                         |
| -                                            | Diabetic ketoacidosis                    |                       |                         |
| -                                            | Myositis                                 |                       |                         |
| (occurs in  < 1%  of patients)               |                                          |                       |                         |
| Protocol Version 11/13/2020                  | CONFIDENTIAL                             | Page 15 of 103        |                         |  
Protocol Version 11/13/2020 CONFIDENTIAL Page 15 *of 103*  
This document is confidential  
Do not disclose or use except as authorized  
- Severe Cutaneous Adverse  
  
  
  
  
Reactions (SCARs)(erythema
- multiforme, acute generalised exanthematous pustulosis, Stevens-Johnson syndrome
- (SJS), Toxic Epidermal Necrolysis (TEN) and drug rash with eosinophilia and systemic
- symptoms (DRESS).
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immune-mediated adverse events

Immune-mediated AEs are consistent with the role of the PD-L1/PD-1 pathway in regulating peripheral tolerance. Given the mechanism of action of atezolizumab, events associated with inflammation and/or immune-mediated AEs have been closely monitored during the atezolizumab clinical program. As of investigator's brochure document date 15 July 2019 (clinical cutoff date 17 May 2019), based on pooled data from 3178 monotherapy patients with multiple tumor types, with supporting data from the estimated cumulative exposure in > 21,000 patients across all clinical trials, the overall immune-mediated adverse drug reaction (ADR) monotherapy rate for atezolizumab is 12.7%, the majority of which were Grade 1- 2 immune-mediated ADRs. In addition to infusion-related reactions, expected immune-mediated adverse drug reactions associated with atezolizumab include pneumonitis, hepatitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome/myasthenia gravis, meningoencephalitis, myocarditis, nephritis, and myositis, severe cutaneous adverse reactions (erythema multiforme, acute generalised exanthematous pustulosis, Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and drug rash with eosinophilia and systemic symptoms (DRESS).
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for further details see the

As of the clinical cutoff date (CCOD) 17 May 2019, efficacy data are most extensive for patients with non-small cell lung cancer (NSCLC; 1636 atezolizumab treated patients enrolled in BIRCH, POPLAR, OAK, IMpower150, IMpower131, GO28625, and the NSCLC cohort of PCD4989g) and patients with metastatic urothelial carcinoma (mUC; 983 atezolizumabtreated efficacy-evaluable patients in studies PCD4989g, IMvigor210, and IMvigor211) who were administered atezolizumab. Results from studies evaluating atezolizumab as monotherapy in patients with locally advanced or metastatic NSCLC (PCD4989g, FIR, OAK, POPLAR, and BIRCH) single-agent treatment with atezolizumab indicated clinically meaningful overall survival (OS) improvement in the 2L/3L NSCLC intent to treat (ITT) population, in comparison with standard of care, in both non-squamous and squamous histologies, and across all PD-L1  
 expression subgroups. Atezolizumab in combination with chemotherapy and other therapeutic agents was demonstrated to have benefit in the settings of small cell lung cancer (SCLC; IMpower133) and NSCLC (IMpower132). Clinical benefit was observed in patients with renal cell carcinoma (RCC) with the combination of atezolizumab and bevacizumab in IMmotion151. Additionally, in IMmotion150, a clinically meaningful improvement in IRC-assessed progression-free survival (PFS) was observed with atezolizumab and bevacizumab compared with sunitinib in the IC1/2/3 population, and no difference in treatment effect was observed with atezolizumab monotherapy compared with sunitinib in either the IC1/2/3 or ITT populations. The study IMpassion130 (WO29522) demonstrated improved OS and PFS in patients with triple-negative breast cancer (TNBC) who were treated with atezolizumab and nabpaclitaxel. Updated PFS analysis results were consistent with the primary analysis, confirming long-term benefit. However, study GO30182 (IMblaze370) did not meet its objectives of improved in OS or PFS versus regorafenib in patients with colorectal cancer (CRC) who were treated with atezolizumab and cobimetinib. Other available efficacy data suggested that treatment with atezolizumab as a single agent or in combination with other therapeutic agents resulted in anti-tumor activity across a range of other tumor types and hematologic malignancies (including pediatric-type tumors), across lines of therapy, and across PD-L1 expression subgroups. For further details, see the atezolizumab Investigator's Brochure.
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4.1.1.2.4 clinical pharmacokinetics and immunogenicity

On the basis of available preliminary PK data (0.03−20 mg/kg), atezolizumab appeared to show linear pharmacokinetics at doses ≥ 1 mg/kg. For the 1-mg/kg and 20-mg/kg dose groups, the mean clearance (CL) and the mean volume at steady state (Vss) had a range of 3.20−4.43 mL/kg and 48.1−64.1 mL/kg, respectively, which is consistent with the expected profile of an IgG1 antibody in humans. The development of ATAs has been observed in patients in all dose cohorts and was associated with changes in pharmacokinetics for some patients in the lower dose cohorts (0.3, 1, and 3 mg/kg). The development of detectable ATAs has not had a significant impact on pharmacokinetics for doses from 10−20 mg/kg. Patients dosed at the 10-, 15-, and 20-mg/kg dose levels have maintained the expected target trough levels of drug despite the detection of ATAs. To date, no clear relationship between detection of ATAs and AEs or IRRs has been observed.
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rationale

Therapies for breast cancer should be guided by biologic features of the tumor, such as expression of steroid hormone receptors and hormone dependence and/or HER2/neu overexpression. Notable examples are the successful use of hormonal therapy (e.g. tamoxifen or aromatase inhibitors) for patients with hormone-sensitive (estrogen receptor [ER] and/or progesterone receptor [PR] expressing) tumors32, and the use of trastuzumab (Herceptin™), a monoclonal antibody against HER2/neu, for patients with overexpression of the aforementioned protein33. These are excellent examples of where appropriate patient selection is instrumental on the success of these therapies. An issue with triple negative breast cancer is that the key drivers of this disease are not well understood, and thus molecular targets for therapeutic intervention have not been identified. We have identified distinct subtypes of triple negative breast cancer to better understand potential drivers of disease progression and to help identify potential therapeutic targets. The presence of immune cells and expression of immune checkpoint genes in the IM subtype may identify patient populations that benefit from immune checkpoint inhibitors. In addition, carboplatin may induce an increase in mutational burden, which may increase response to immunotherapy. Considering all of our preclinical data, in this study patients with metastatic TNBC will be randomized to carboplatin with or without atezolizumab. We hypothesize that the combination of carboplatin and atezolizumab will be superior to carboplatin alone in efficacy, as measured by median progression free survival. We anticipate that high levels of pretreatment TILs or the IM subtype will correlate with better outcomes. In addition we hypothesize that the mutational burden in non-synonymous coding mutations will be predictive of response to anti-PD-L1 therapy.
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participant selection inclusion criteria

- Patients must provide informed written consent. - Patients must be ≥18 years of age. - ECOG performance status 0-1. - Clinical stage IV (metastatic) ER, PR, HER2 negative invasive mammary carcinoma, previously documented by histological analysis and that meets the following criteria:
o HER2 negativity is defined as any of the following by local laboratory assessment: In-situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe average HER2 gene copy number < 4 signals/cell), or IHC 0 or IHC 1+ (if more than one test result is available and not all results meet the inclusion criterion definition, all results should be discussed with the Protocol Chair to establish eligibility of the patient)
o ER and PR negativity are defined as < 10% of cells expressing hormonal  
  
receptors via IHC analysis.  
- Willing to undergo biopsy of a metastatic lesion (in patients with reasonably accessible metastatic lesions such aschest wall, skin, subcutaneous tissue, lymph nodes, bones, peripheral lung, and liver metastases).  
- Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension by RECIST criteria v1.1.  
- Zero or one prior chemotherapy regimens for metastatic disease.  
- No prior treatment with carboplatin in the metastatic setting. Carboplatin in neoadjuvant/adjuvant setting may be allowed if prior treatment with carboplatin was completed at least one year prior to initiation of this study and after discussion with the study chair.  
- Patients must have adequate hematologic, hepatic, and renal function. All tests must be obtained less than 28 days from initiation of study drug (C1D1). This includes:
o ANC ≥1000/mm3 o Platelet count ≥100,000/mm3 o Calculated creatinine clearance > 30 mL/min using the Cockcroft and Gault Formula (see Section 10.2)
o Bilirubin, SGOT, SGPT, alkaline phosphatase ≤ 2.5x upper limits of normal if no liver metastases present. Serum total bilirubin must be < 3x upper limits of normal for patients with Gilbert disease. Total bilirubin, SGOT, SGPT ≤ 5x upper limits of normal if liver metastases present.  
- For patients who are not postmenopausal (women) or surgically sterile (absence of ovaries and/or uterus or vasectomy), agreement to remain abstinent or to use two adequate methods of contraception (e.g., condoms, diaphragm, vasectomy/vasectomized partner, tubal ligation), during the treatment period and for at least 30 days after the last dose of study treatment. Hormone based oral contraceptives are not allowed on study. Postmenopausal is defined as:
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o age >= 55 years

o Age ≤ 55 years and amenorrheic for 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression; or follicle stimulating hormone and estradiol in the postmenopausal range
- Subjects must complete all baseline screening assessments. The biopsy may be obtained before or after the patient is deemed eligible by administrative review, but must be before administration of study drugs on cycle 1, day 1.
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exclusion criteria

Patients who meet any of the following criteria will be excluded from registration:
Cancer-Specific Exclusion Criteria  
- Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to randomization
- Known CNS disease, except for treated asymptomatic CNS metastases, provided all of the following criteria are met: measurable disease outside the CNS, only supratentorial and cerebellar metastases are allowed (i.e., no metastases to midbrain, pons, medulla, or spinal cord), no evidence of progression or hemorrhage after completion of CNS-directed therapy, no ongoing requirement for dexamethasone as therapy for CNS disease (anticonvulsants at a stable dose are allowed), no stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to randomization.
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- leptomeningeal disease

- Uncontrolled tumor-related pain: patients requiring narcotic pain medication must be on a stable regimen at registration. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to randomization. Patients should be recovered from the effects of radiation. There is no required minimum recovery period. Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not presently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to randomization.  
- Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL
or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy. Patients who are receiving denosumab must discontinue denosumab use and replace it with a bisphosphonate instead while on study. Patients receiving a bisphosphonate for skeletal metastases are not excluded and can continue treatment.  
- Malignancies other than TNBC within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer).  
- Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, biological therapy) other than the ones specified
in the protocol. Any standard or investigational drugs should be discontinued 2  
 weeks prior to the first dose of study medication.  
General Medical Exclusion Criteria
- Women only: pregnancy or lactation  
- Evidence of significant uncontrolled concomitant disease that in the opinion of the investigator could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome)
- Significant cardiovascular disease, such as New York Heart Association (NYHA)
cardiac disease (Class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina. Patients with a known left ventricular ejection fraction (LVEF) < 40% will be excluded. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.  
- Severe infection requiring systemic treatment within 4 weeks prior to randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
- Major surgical procedure within 4 weeks prior to randomization or anticipation of the need for a major surgical procedure during the course of the study other than for diagnosis. Placement of central venous access catheter(s) (e.g., port or similar) is not considered a major surgical procedure and is therefore permitted.  
- History of severe reactions (e.g. allergic, anaphylactic, or other hypersensitivity) to chimeric or humanized antibodies or fusion proteins  
- Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation  
- History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study. Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible for this study.  
- Prior allogeneic stem cell or solid organ transplantation  
  
- History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.  
- Positive test for HIV (testing required prior to registration)  
- Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]
test at screening) or hepatitis C
- Patients with past hepatitis B virus (HBV) infection or resolved HBV infection
(defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible.  
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
- Active tuberculosis  
- Receipt of a live, attenuated vaccine within 4 weeks prior to initiation of study drug
(C1D1) or anticipation that such a live, attenuated vaccine will be required during the study  
- Prior treatment with CD137 agonists, anti−PD-1, or anti−PD-L1 therapeutic antibody or pathway-targeting agents  
- Treatment with systemic immunostimulatory agents (including but not limited to interferons or IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to randomization  
- Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [TNF] agents) within 2 weeks prior to cycle 1, day 1, or anticipated requirement for systemic immunosuppressive medications during the trial. Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study. Patients on a stable low dose (< 10 mg) daily prednisone or equivalent are allowed on study.  
Patients with a history of allergic reaction to IV contrast requiring steroid pretreatment should have baseline and subsequent tumor assessments performed using MRI. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are  
Psychiatric illness/social situations that would compromise patient safety or limit
.  
compliance with study requirements
5.3
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inclusion of underrepresented populations

Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards age or race in the clinical trial outlined. This trial is open to the accrual of mn and women.
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6. registration procedures

All patients MUST be registered with the Vanderbilt-Ingram Cancer Center (VICC) prior to the start of protocol treatment.  Each participating site must also be registered with their own institution according to their institutional guidelines prior to start of protocol treatment.
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6.1 guidelines for all participating

Prior to registration, a copy of the IRB approval at the site will be requested and kept on file at the Vanderbilt-Ingram Cancer Center (VICC) Coordinating Center. Eligible participants will be entered on study centrally at the to  
  
verify slot availability prior to enrollment.  
All patients MUST be registered with the VICC prior to the start of protocol treatment. Registration can only be conducted during the business hours of 8M - 5PM Central Standard Time Monday through Friday.
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all sites must email the

to notify of upcoming registration and ensure slot availability. The following information should be included in your email:
o Study number o  
Patient initials
o  
Disease type o Anticipated consent date o Anticipated start date 2) To request a subject ID number, the site must submit the following documents with
their email notification to the Coordinating Center:  
Copy of the patient's signed and dated Informed Consent including
.  
documentation of the consent process.  
HIPAA authorization form (if separate from the main consent form)
.
Protocol Version 11/13/2020
- VICC Patient Enrollment Form  
  
The Coordinating Center will then provide a subject ID number via email.  
3) Once the patient has been deemed eligible by the site, an email with the following documents must be sent to the Coordinating Center for eligibility review and patient enrollment :
- Copy of the patient's signed and dated Informed Consent, including documentation of the consent process.  
- HIPAA authorization form (if separate from the main consent form) - VICC Patient Enrollment Form
- Eligibility supporting documents such as pathology reports, laboratory tests, etc. or EMR access. Note: all source documents should be deidentified and screening/subject ID number added prior to sending.  
- Tissue Block Registration Form (see the **Lab Manual**)
- Signed and completed Eligibility Checklist. **To be eligible for registration to**
the study, the participant must meet each inclusion and exclusion criterion listed in the eligibility checklist.
Note: All study documents should be received 24-48 hours prior to the patient's anticipated start date. Same day treatment registrations will only be accepted with prior notice and discussion with the Coordinating Center. Please email the Coordinating Center if enrollment is needed sooner.  
Upon satisfactory review of eligibility documents submitted, the Coordinating Center will approve enrollment and issue a subject ID number if one was not issued at screening. Once registration/enrollment confirmation from Coordinating Center is received, the site may proceed with protocol procedures. Please contact the assigned Study Contact with any questions regarding this process. You can also reach out to your assigned CRA once the study is activated. The VICC Coordinating Center will assign sequence numbers to all patients in screening. Only patients deemed eligible will be randomized to a treatment arm. Sequence numbers will only be re-used if a patient screen fails and then re-screens. The Coordinating Center will randomize eligible patients to carboplatin + atezolizumab or carboplatin alone. Following registration and randomization, eligible participants should begin protocol treatment within 1 week. Issues that would cause treatment delays should be discussed with the Protocol Chair. If a participant does not receive protocol therapy following randomization within allowed time period, the participant will become ineligible and will not be enrolled on study. Such patients will have to undergo screening again to participate in the study in the future. Any requests for eligibility exceptions and/or deviations must be approved in writing by the Protocol Chair, as well as any committees required by local Protocol Chair:  V. Abramson TBCRC 043 institutional policies. As is generally accepted, standard of care procedures performed prior to consent, but within the protocol defined screening window for each assessment can be used for study purposes. All research only procedures must be performed after the consent date.
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biopsy of metastatic lesion

6.2  
After signing informed consent for the research biopsy, potential participants should have a biopsy of a metastatic lesion as per Section 11 below.  Tissue from the metastatic biopsy neds to be available, but not required to have been evaluated centrally, prior to beginning treatment on study.  
Outside sites should ship specimens along with the Tissue Registration Form (located in the lab manual) directly to:  
  
Ship ALL paraffin material, RNAlater tubes or slides as detailed in the lab manual.  
*Specimens should be mailed to arrive at VUMC from Monday 8AM through Friday 1PM**
TBCRC 043
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study calendars study calendar carboplatin

| Screening                                                   |                    |                             |        |    |    |
|-------------------------------------------------------------|--------------------|-----------------------------|--------|----|----|
| Procedure                                                   | Day -28 to  Day 1b | Cycle 1  (21-days) Day 1a,b | 30 day |    |    |
| Additional cyclesa                                          | End-oftreatmentd                    | (+/- 3 days)                |        |    |    |
| Day 1                                                       | follow-upd         | 1, 2 & 3 year follow-upn    |        |    |    |
| Informed consent                                            | X                  |                             |        |    |    |
| Inclusion/exclusion criteria                                | X                  |                             |        |    |    |
| Demographics/ medical history (SOC)                         | X                  |                             |        |    |    |
| Physical exam/signs/symptomse (SOC)                         | X                  | X                           | X      | X  |    |
| Vital signs (including oxygen sat)c (SOC)                   | X                  | X                           | X      | X  |    |
| Single 12-lead ECG                                          | X                  |                             |        |    |    |
| ECOG Performance Status (SOC)                               | X                  | X                           | X      | X  |    |
| Clinical laboratory testsf (SOC)                            | X                  | X                           | X      | X  |    |
| Serum pregnancy test (SOC)f                                 | X                  |                             |        |    |    |
| TSH, free T3, T4g (After screening,  atezolizumab arm only) | X                  | X (every 4th cycle)         | X      |    |    |
| Blood  collection PT (or INR) and PTT                       | X                  |                             |        |    |    |
| HIV, HBV, HCV serologyh                                     | X                  |                             |        |    |    |
| Circulating tumor DNA                                       | X                  | X (Cycle 2 only)            | X      |    |    |
| Mononuclear Cell Collection                                 | X                  | X (Cycle 2 only)            | X      |    |    |
| Tumor assessment CTs, bone scani (SOC)                      | X                  | X (every 3 cycles)          |        |    |    |
| Archived tumor blocks/slidesj                               | X                  |                             |        |    |    |
| Tumor biopsy (metastatic site)k                             | X                  | X                           |        |    |    |
| Carboplatin administration (IV) (SOC)                       | X                  | Xl                          |        |    |    |
| Atezolizumab administration (IV): if on  atezolizumab arm   | X                  | X                           |        |    |    |
| Concomitant medicationsm                                    | X                  | X                           | X      |    |    |
| Adverse events                                              | X                  | X                           | X      | X  | Xn |
| Biopsy questionnaireo                                       | X (cycle 2, day 1) |                             |        |    |    |
| BRCA 1 and 2 testingp (SOC)                                 | X                  |                             |        |    |    |  
Protocol Version 11/13/2020 CONFIDENTIAL Page 26 *of 103* This document is confidential Do not disclose or use except as authorized TBCRC 043 AE = adverse event; BSA = body surface area; CX = Cycle X, where X is the cycle number; DLT = dose-limiting toxicity; ECG = electrocardiogram; **ECOG** = Eastern  
 Cooperative Oncology Group; **HbA1C** = glycosylated hemoglobin; IMP = investigational medicinal product; INR = international normalized ratio; PT = prothrombin time; PTT = partial prothrombin time; SAE = serious adverse event SOC = Standard of Care; all tests not indicated as SOC are research-related.  
a Evaluation assessments should be performed prior to administration of IMP unless otherwise indicated. Results should be reviewed by the Investigator prior to the administration of the next dose. All visits must occur within + 3 days from the **scheduled date unless otherwise noted**. Delays up to 7 days will be considered by Study Chair.  
b Screening must occur within 28days of dosing. The following procedures must be repeated at the day 1 visit if they were previously done >7 days prior to study treatment administration: Medical and cancer history, physical examination, weight measurement, vital signs, hematology, serum chemistry panel. Tumor assessments must be repeated at the baseline visit only if determined to be changed by clinical exam or other clinical observations. SOC procedures performed prior to consent but within the protocol defined screening window for each assessment can be used for study purposes. All research only procedures must be performed after the consent date.  
c See section 10.1.2 for vital sign information during atezolizumab infusion. d The 30-day follow-up assessments should be done 30 (±3 days) days after the last dose of study drugs. 30 day follow-up can be done by phone or by a clinic visit. Any ongoing toxicities should be documented. Any ongoing serious adverse events will be followed every 3 months (in person or by phone) until resolution. Any AEs or SAEs considered possibly or probably related to IMP that have not stabilized, returned to baseline, or are considered irreversible will continue to be monitored as per the protocol .  
e The physical examination will include measurements of height and weight at screening. Weight will be measured on day 1 of each cycle and at the End-of-treatment visit. Dosing changes are only required if the weight changes 10% or more. Physical examination will include examination of major body systems including neurologic, cardiac, respiratory, gastrointestinal, and skin. Clinically relevant signs and symptoms will be reported as AEs.  
f Clinical laboratory tests will include hematology and serum chemistry panel including white blood cell count, differential, hemoglobin, platelet count, sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, and magnesium, AST (SGOT), ALT (SGPT), and total serum bilirubin, albumin, and total protein. Additional tests will be performed when clinically appropriate. In case of Grade 3 or higher AST/ALT, additional testing will be done weekly until recovery to baseline value (see protocol section 9.1.2 and 9.2.2.1). Labs do not have to be repeated on cycle 1, day 1 if they were done up to 7 days prior to day 1. For all other timepoints, labs can be performed up to 3 days prior to each timepoint indicated in the study calendar. Results from labs obtained on C1D1 (up to -7 days) must meet eligibility criteria. At the start of each cycle, the ANC must be ≥1000/mm3 and the platelet count must be ≥ 80,000/mm3 (see section 9.2.1) **for carboplatin to be administered.**
Atezolizumab may be administered if these criteria are not met at the discretion of the treating physician. Serum pregnancy test does not need to be performed for patients > 55 years old, those who are known to be post-menopausal, or who have had a hysterectomy.  
g Thyroid function studies: see section 9.1.4 for abnormal results h All patients will be tested for HIV and HIV-positive patients will be excluded from the clinical trial. Please note that this result must be back by the time patient starts study so it is advised this be drawn prior to day 1 if the result may take some time to obtain. HBV serology includes Hepatitis B surface antigen, anti-HBc, and anti-HBs. As above, it is advised the HBV serology be obtained in advance if results may be delayed. Hepatitis B virus (HBV) DNA must be collected on or before Cycle 1, Day 1 in patients who have negative serology for hepatitis B surface antigen and positive serology for anti-HBc.  
i Tumor assessment should be performed approximately every 3 cycles (up to -5 days) while on study treatment (i.e. on or up to 5 days prior to Day 1 of Cycles 4, 7, 10 etc) and at End-of-treatment visit if not obtained within the past 6 weeks. Scans should consist of CT scan of the chest, abdomen, and pelvis and a bone scan at baseline. Of note, if the prior bone scan did not show metastases, it does not need to be repeated if the bone scan was obtained within 8 weeks of C1D1. Subsequent scans should consist of CT chest, abdomen and pelvis, and bone scan if bone metastases were present on the baseline studies. MRI is also an acceptable form of imaging. At the end of treatment, all scans (baseline and through disease progression) should be sent on a CD to the Vanderbilt Cancer Imaging Support Laboratory for central review and assessment. See Section 12.6 for details and address. j Archived tumor biopsy specimen: Archived biopsy block (unstained slides) will be requested at the time of registration prior to initiation of treatment. See Section 11.1 for details. If archived tissue is not available, the VICC coordinating center should be contacted.  
k After signing consent, a fresh tumor biopsy from a metastatic site amenable to a reasonably safe biopsy will be obtained prior to day 1 and upon progression of disease
(see Section 11). The second biopsy will not be required for patients who are removed from study for reasons other than disease progression. A patient who undergoes a research biopsy procedure for the purpose of this protocol, in whom inadequate tissue is obtained, is not obligated to undergo a repeat biopsy.  
TBCRC 043 l After cycle 6, at the discretion of the treating physician, carboplatin can be stopped and atezolizumab can be continued as a single agent.  
 m The dose of steroids before each carboplatin injection should be recorded. Prohibited medications (section 8) must be discontinued at least 7 days prior to initiation of study drug (C1D1).  
n 1, 2, and 3 year follow-up can be done by phone or chart review to document survival status, and if applicate, the date of death and cause of death. Surveillance for Adverse Events of Special Interest (AESIs) (see section 13.5.12) should be included.  
o Biopsy questionnaire should be filled out by the patient on C2D1. Form can be found in the packet of supplemental forms.  
BRCA 1/2 testing and results are not required prior to enrollment. However, all patients in whom BRCA status is unknown must be referred for testing during the screening period. Testing must be sent for analysis prior to C3D1, although results need not be available. This is a standard procedure as per NCCN guidelines. The VICC coordinating center should be contacted if a patient's insurance will not pay for testing and an exception my be granted.  
TBCRC 043
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study calendar atezolizumab (crossover)

Crossover therapy (atezolizumab) must begin no later than 21 days after the clinic visit at which progression is determined.  
| Cycle 1 a (21-days)                          | Additional cyclesa   | End-oftreatmentc                     | 30 day   | 1, 2, 3 year   |
|----------------------------------------------|----------------------|---------------------|----------|----------------|
| follow-upb                                   | follow-upi           |                     |          |                |
| Day 1                                        | Day 1                |                     |          |                |
| Procedure Physical exam/signs and symptomsc  | X                    | X                   | X        |                |
| Vital signs (including oxygen sat)           | X                    | X                   | X        |                |
| ECOG Performance Status                      | X                    | X                   | X        |                |
| Clinical laboratory testsd                   | X                    | X                   | X        |                |
| Blood collection TSH, free T3, T4e           | X                    | X (every 4th cycle) |          |                |
| Circulating tumor DNA                        | X                    | X (Cycle 2 only)    | X        |                |
| Mononuclear Cell Collection                  | X                    | X (Cycle 2 only)    | X        |                |
| Tumor assessment CTs, bone scanf             | X (every 3 cycles)   |                     |          |                |
| Tumor biopsy (metastatic site) at crossoverg | X                    |                     |          |                |
| Atezolizumab administration (IV)             | X                    | X                   |          |                |
| Concomitant medicationsh                     | X                    | X                   |          |                |
| Adverse events                               | X                    | X                   | X        | Xi             |  
a Evaluation assessments should be performed prior to administration of IMP unless otherwise indicated. Results should be reviewed by the Investigator prior to the administration of the next dose. All visits should occur within 3 days of scheduled visit unless otherwise noted. Delays up to 7 days will be considered by study chair. Crossover therapy (atezolizumab) must begin no later than 21 days after the clinic visit at which progression is determined. Exceptions must be discussed with the Protocol Chair.  
b The 30-day follow-up assessments should be done 30 (±3 days) days after the last dose of study drugs. 30 day follow-up can be done by phone or by a clinic visit. Any ongoing toxicities should be documented. Any ongoing serious adverse events will be followed every 3 months until resolution. Any AEs or SAEs considered possibly or probably related to IMP that have not stabilized, returned to baseline, or are considered irreversible will continue to be monitored as per the protocol.  
c The physical examination will include measurements of height and weight at screening. Weight will be measured on day 1 of each cycle and at the End-of-treatment visit. Physical examination will include examination of major body systems including neurologic, cardiac, respiratory, gastrointestinal, and skin. Clinically relevant signs and symptoms will be reported as AEs.  
d Clinical laboratory tests will include hematology and serum chemistry panel including white blood cell count, differential, hemoglobin, platelet count, sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, and magnesium, AST (SGOT), ALT (SGPT), and total serum bilirubin, albumin, and total protein. Additional tests will be performed when clinically appropriate. In case of Grade 3 or higher abnormal AST/ALT, additional testing will be done weekly until recovery to baseline value. Labs can be performed up to 3 days prior to each timepoint indicated in the study calendar.  
e See section 9.1.4 for abnormal results TBCRC 043 f Tumor assessment should be performed approximately every 3 cycles (up to -5 days) while on study treatment and at End-of-treatment visit if not obtained within the past  
  
6 weeks. Scans should consist of CT scan of the chest, abdomen, and pelvis and a bone scan at baseline. Subsequent scans should consist of CT chest, abdomen and pelvis, and bone scan if bone metastases were present on the baseline studies. At the end of treatment, all scans (baseline and through disease progression) should be sent on a CD to the Vanderbilt Cancer Imaging Support Laboratory for central review and assessment. See Section 12 for details and address. g Tumor biopsies from a metastatic site will be obtained from patients prior to day 1 (this will be the biopsy obtained at disease progression on the carboplatin only arm).  
h The dose of steroids before each carboplatin injection should be recorded. See protocol for concomitant medications that are prohibited (section 8). i 1, 2, and 3 year follow-up can be done by phone or chart review to document survival status, and if applicate, the date of death and cause of death. Surveillance for Adverse Events of Special Interest (AESIs) - see section 13.5.12 should be included.  
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treatment plan

Overview  
This is an open-label phase II multi-institution trial that evaluates the safety profile and antitumor activity of carboplatin +/- atezolizumab in patients with metastatic triple negative (ER
negative, PR negative, HER2neu negative by IHC or FISH) breast cancer. Patients will be treated with carboplatin AUC 6 IV on day 1 and atezolizumab 1200 mg IV on day 1 of a 21 day cycle or carboplatin AUC 6 IV on day 1 of a 21 day cycle For patients on the combination arm, atezolizumab is to be administered prior to carboplatin. For patients on the combination arm, carboplatin can be stopped after cycle 6 and atezolizumab can be continued as a single-agent at the discretion of the treating physician.
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concomitant treatment and supportive care

8.2.1 Concomitant Therapy Concomitant therapy includes any prescription medications or over-the-counter preparations used by a patient between the 7 days preceding Cycle 1, day 1 and the treatment discontinuation visit. Neulasta (pegfilgrastim) may be given prophylactically per treating investigator discretion. Patients who experience infusion-associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or cimetidine or another H2 receptor antagonist, as per standard practice. Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be managed with supportive therapies as clinically indicated
(e.g., supplemental oxygen and β2-adrenergic agonists). Systemic corticosteroids and TNFα inhibitors may attenuate potential beneficial immunologic effects of treatment with atezolizumab but may be administered at the discretion of the treating physician. If feasible, alternatives to corticosteroids should be considered. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed. Megastrol administered as appetite stimulant is acceptable while the patient is enrolled in the study.  
Patients who use prophylactic or therapeutic anticoagulation therapy (such as low-molecularweight heparin or warfarin at a stable dose level), or other allowed maintenance therapy can continue their use. Males and females of reproductive potential should use highly effective means of contraception.
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8.2.2 excluded therapy

Any concomitant therapy intended for the treatment of cancer, whether health authority-approved or experimental, is prohibited. This includes but is not limited to the following:  
- Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational agents, or herbal therapy
- After Cycle 1, certain forms of radiotherapy may be considered for pain palliation if patients are deriving benefit (e.g., treatment of known bony metastases); atezolizumab administration may be suspended during radiotherapy.  
Patients must discontinue:
- Traditional herbal medicines because the ingredients of many herbal medicines are not fully studied and their use may result in unanticipated drug-drug interactions that may cause, or confound assessment of, toxicity
- The use of a RANKL inhibitor (denosumab); this agent could potentially alter the activity and the safety of atezolizumab. Bisphophonates may be used in lieu of RANKL inhibitors.
Patients are not allowed to receive immunostimulatory agents, including but not limited to IFN-α, IFN-γ, or IL-2, during the entire study. These agents, in combination with atezolizumab, could potentially increase the risk for autoimmune conditions. Patients should also not be receiving immunosuppressive medications, including but not limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide. These agents could potentially alter the activity and the safety of atezolizumab. Systemic corticosteroids and anti-TNFα agents may attenuate potential beneficial immunologic effects of treatment with atezolizumab but may be administered during the course of treatment at the discretion of the treating physician after discussion with the Protocol Chair. If feasible, alternatives to these agents should be considered. In addition, all patients (including those who discontinue the study early) should not receive other immunostimulatory agents for 10 weeks after the last dose of atezolizumab.
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assessments during treatment

All visits must occur within ± 3 days from the scheduled date, unless otherwise noted. Please see the Study Calendar at the beginning of this protocol for the schedule of treatment period assessments.
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cross-over post-progression

Patients who are randomized to carboplatin alone can cross over to receive atezolizumab upon disease progression based on clinical progression or radiographic progression. Patients who are randomized to carboplatin alone and who discontinue carboplatin for toxicity cannot cross over to receive single agent atezolizumab. There may be exceptions to this based on discussion with the Protocol Chair. However, patients on the carboplatin + atezolizumab arm can continue to receive single agent atezolizumab if they discontinue carboplatin due to toxicity. Patients who cross over to receive atezolizumab will follow the assessments and procedures as outlined in the study calendar. The duration of each cycle will continue to be 21 Protocol Version 11/13/2020 CONFIDENTIAL Page 32 *of 103* This document is confidential Do not disclose or use except as authorized days and the cycle numbers will "reset" to 1 and will be followed by the "X" suffix (e.g.,  
 Cycles 1X, 2X, etc.). Crossover therapy (atezolizumab) must begin no later than 21 days after the clinic visit at which progression is determined. Patients must have labs and procedures performed as outlined in the cross-over study calendar and must meet the values as described in the Inclusion Criteria, prior to receiving atezolizumab based on assessments and procedures performed within 21 days prior to Day 1 of Cycle 1X. Labs and procedures not included in the cross-over study calendar do not have to be repeated. Patients must also agree to a tumor biopsy, as outlined in the eligibility criteria, prior to initiating atezolizumab. Patients will receive crossover treatment until progression, intolerable toxicity, or elective withdrawal from the study. Patients who cross over will be evaluated with radiologic assessments every 3 cycles until disease progression.
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duration of therapy

Duration of therapy will depend on individual response, evidence of disease progression and tolerance. In the absence of treatment delays due to adverse events, treatment may continue until one of criteria in Section 8.7 applies.
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duration of follow-up

Participants will be followed for 30 days for toxicity after the final dose of study drug. The 30 day follow-up can be done by phone or through a clinic visit. Patients who at the treatment completion visit have an ongoing serious adverse event or an adverse event leading to treatment discontinuation will be followed every 3 months until the event resolves, the investigator assesses the event as stable, or the patient is lost to follow-up. Participants will also be followed for disease progression by chart review yearly for 3 years from the date of last study drug administration. If the patient is no longer coming to the institution for care, then the patient may be called as needed for follow-up.
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criteria for removal from study

Patients will be removed from study when any of the criteria listed below apply. All patients who initiate protocol treatment will be included in the overall evaluation of response (intentto-treat analysis). All reasons for discontinuation of therapy should be documented clearly in the medical record. If a subject discontinues or withdraws from the study, every reasonable attempt will be made to get a tissue/tumor biopsy, along with blood, at the end of treatment, if the subject is able and willing.  
Patients may be withdrawn from the study if they experience any of the following:
- Disease progression, per investigator assessment by RECIST (or irRECIST for atezolizumab arm) - Intolerable toxicity to atezolizumab or carboplatin. Patients assigned to carboplatin +
atezolizumab who experience toxicity to atezolizumab or carboplatin can continue on study with single agent carboplatin or atezolizumab, respectively, at the discretion of the treating physician. Patients will be followed for disease progression and should continue radiologic assessments every 3 cycles as per the study.
Other reasons for patient discontinuation may include, but are not limited to, the following:
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- Non-compliance with the study protocol, including, but not limited to not attending the  
  
majority of scheduled visits. The Protocol Chair will determine when non-compliance should lead to removal from study. Note: The patients will still be included in the overall evaluation of response (intent-to-treat analysis).  
- Patient personal decision. The reason for discontinuation from the study must be documented. The patients will be included in the overall evaluation of response (intentto-treat analysis) if any protocol therapy was administered prior to withdrawal.  
- If the patient becomes pregnant - Patient is lost to follow-up - Study is terminated for any reason
The investigator has the right to discontinue a patient from the study for any medical condition that the investigator determines may jeopardize the patient's safety if he or she continues in the study; for reasons of noncompliance (e.g., missed doses, visits); or if the investigator determines it is in the best interest of the patient. The Protocol Chair should be notified in such cases.
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expected toxicities and dosing delays/dose

Anticipated Toxicities **Of Atezolizumab (Atezolizumab) And Dose Modifications**  
Toxicities associated or possibly associated with atezolizumab treatment should be managed according to standard medical practice. Additional tests, such as autoimmune serology or biopsies, should be used to evaluate for a possible immunogenic etiology, when clinically indicated. Although most immune-mediated adverse events observed with atezolizumab have been mild and self-limiting, such events should be recognized early and treated promptly to avoid potential major complications. Discontinuation of atezolizumab may not have an immediate therapeutic effect, and in severe cases, immune-mediated toxicities may require acute management with topical corticosteroids, systemic corticosteroids, or other immunosuppressive agents. The investigator should consider the benefitrisk balance for a given patient prior to further administration of atezolizumab. In patients who have met the criteria for permanent iscontinuation, resumption of atezolizumab may be considered if the patient is deriving benefit and has fully recovered from the immune-mediated event. Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Medical Monitor. Guidelines for managing patients who experience selected adverse events are provided in the following sections. Management guidelines are presented by adverse event severity based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) and in some instances may vary by CTCAE version (4.0 vs. 5.0).  
| Management Guidelines for Renal Events  Event Management Renal  event,  Grade 1 - Continue atezolizumab. - Monitor kidney function, including creatinine,  closely until values resolve to within normal limits or  to baseline values. Renal  event,  Grade 2 - Withhold atezolizumab for up to 12 weeks after event  onset. a - Refer patient to renal specialist. - Initiate treatment with corticosteroids  equivalent to 1-2 mg/kg/day oral prednisone.  - If event resolves to Grade 1 or better, resume atezolizumab. b - If event does not resolve to Grade 1 or better while  withholding atezolizumab, permanently discontinue  atezolizumab and contact Study Chair. c   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
- Permanently discontinue atezolizumab and contact  
  
Study Chair.  
- Refer patient to renal specialist and consider renal biopsy. - Initiate treatment with corticosteroids  
equivalent to 1-2 mg/kg/day oral prednisone.  
- If event does not improve within 48 hours after initiating  
corticosteroids, consider adding an immunosuppressive agent.  
- If event resolves to Grade 1 or better, taper corticosteroids  
over ≥ 1 month.  
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after  
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone. The acceptable length of the extended period of time must be agreed upon by the investigator and the Study Chair.  
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the  
equivalent of ≤10 mg/day oral prednisone before atezolizumab can be resumed.  
c Resumption of atezolizumab may be considered in patients who are deriving benefit  
and have fully recovered from the immune-mediated event. Patients can be rechallenged with atezolizumab only after approval has been documented by both the  
investigator (or an appropriate delegate) and the Study Chair.  
| Renal  event,  Grade 3 or  4                                                       | -                                                                                                                         | Permanently discontinue atezolizumab and contact Study Chair.   |
|------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|
| -                                                                                  | Refer patient to renal specialist and consider renal biopsy.                                                              |                                                                 |
| -                                                                                  | Initiate treatment with corticosteroids  equivalent to 1-2 mg/kg/day oral prednisone.                                     |                                                                 |
| -                                                                                  | If event does not improve within 48 hours after initiating  corticosteroids, consider adding an immunosuppressive  agent. |                                                                 |
| -                                                                                  | If event resolves to Grade 1 or better, taper corticosteroids over  ≥ 1 month.                                            |                                                                 |
| a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after |                                                                                                                           |                                                                 |
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general guidelines for dosage modification

Atezolizumab treatment will be given as long as the patient continues to experience clinical benefit in the opinion of the investigator until the earlier of unacceptable toxicity, symptomatic deterioration attributed to disease progression, or any of the other reasons for treatment discontinuation listed above.  
There will be no dose reduction for atezolizumab in this study. **Patients may temporarily**
suspend study treatment for up to 84 days beyond the scheduled date of delayed infusion if study drug-related toxicity requiring dose suspension is experienced. If atezolizumab is held because of AEs for > 84 days beyond the scheduled date of infusion, the patient will be discontinued from atezolizumab and will be followed for safety and efficacy as specified in the protocol. If a patient must be tapered off steroids used to treat AEs, atezolizumab may be held for additional time beyond 84 days from the scheduled dose until steroids are discontinued or reduced to a prednisone dose (or dose equivalent) of ≤ 10 mg/day. The acceptable length of interruption will be at the discretion of the investigator. Dose interruptions for reasons other than toxicity, such as surgical procedures, may be allowed. The acceptable length of interruption will be at the discretion of the Protocol Chair. Patients should be assessed clinically (including review of laboratory values) for toxicity prior to, during, and after each infusion. If unmanageable toxicity due to atezolizumab occurs at any time during the study, treatment with atezolizumab should be discontinued. Management of hepatitis/transaminitis, colitis, rash, and hypothyroidism are presented in this  
 section as they have been observed in this study and are potentially immune related.  
9.2.1 Gastrointestinal Toxicity Immune-mediated colitis has been associated with the administration of atezolizumab. Patients should be advised to inform the investigator if any diarrhea occurs, even if it is mild. If the event is of significant duration or magnitude, or is associated with signs of systemic inflammation or acute phase reactants (e.g., increased CRP or platelet count or bandemia), it is recommended that sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy with three to five specimens for standard paraffin block be performed. If possible, one or two biopsy specimens should be snap frozen and stored. Treatment may be restarted following the resolution of colitis. In addition, if the patient is being managed with corticosteroids, treatment should not be restarted until the steroids have been tapered down to a prednisone dose ≤ 10 mg/day. Patients who resume treatment should be monitored closely for signs of renewed diarrhea.  
| Event            | Management                                                                                                                                       |                                                               |
|------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|
| Diarrhea or      | -                                                                                                                                                | Continue atezolizumab.                                        |
| colitis, Grade 1 | -                                                                                                                                                | Initiate symptomatic treatment.                               |
| -                | Endoscopy is recommended if symptoms persist for > 7 days.                                                                                       |                                                               |
| -                | Monitor closely.                                                                                                                                 |                                                               |
| Diarrhea or      | -                                                                                                                                                | Withhold atezolizumab for up to 12 weeks after event onset. a |
| colitis, Grade 2 | -                                                                                                                                                | Initiate symptomatic treatment.                               |
| -                | Patient referral to GI specialist is recommended.                                                                                                |                                                               |
| -                | For recurrent events or events that persist > 5 days, initiate  treatment with corticosteroids equivalent to 1-2 mg/kg/day oral prednisone.      |                                                               |
| -                | If event resolves to Grade 1 or better, resume atezolizumab. b                                                                                   |                                                               |
| -                | If event does not resolve to Grade 1 or better while  withholding atezolizumab, permanently discontinue  atezolizumab and contact Study Chair. c |                                                               |  
| Diarrhea or                                                                                                   | -                                                                                                                                                | Withhold atezolizumab for up to 12 weeks after event onset. a          |      |                 |            |    |     |
|---------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|------|-----------------|------------|----|-----|
| colitis, Grade 3                                                                                              | -                                                                                                                                                | Refer patient to GI specialist for evaluation and confirmatory biopsy. |      |                 |            |    |     |
| -                                                                                                             | Initiate                                                                                                                                         | treatment                                                              | with | corticosteroids | equivalent | to | 1-2 |
| mg/kg/day IV methylprednisolone and convert to 1-2 mg/kg/day  oral prednisone or equivalent upon improvement. |                                                                                                                                                  |                                                                        |      |                 |            |    |     |
| -                                                                                                             | If event resolves to Grade 1 or better, resume atezolizumab. b                                                                                   |                                                                        |      |                 |            |    |     |
| -                                                                                                             | If event does not resolve to Grade 1 or better while  withholding atezolizumab, permanently discontinue  atezolizumab and contact Study Chair. c |                                                                        |      |                 |            |    |     |
| GI = gastrointestinal.                                                                                        |                                                                                                                                                  |                                                                        |      |                 |            |    |     |  
  
- If event does not resolve to Grade 1 or better while  
withholding atezolizumab, permanently discontinue  
atezolizumab and contact Study Chair. c  
GI = gastrointestinal.  
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset)  
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  
≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time must be agreed upon by the investigator and the Study Chair.  
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the  
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed.  
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have  
fully recovered from the immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an  
appropriate delegate) and the Study Chair.
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9.2.2 hepatotoxicity

Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
While in this study, patients presenting with right upper-quadrant abdominal pain felt by the investigator to be possibly related to study treatment and/or unexplained nausea or vomiting should have LFTs performed immediately, and LFTs (AST/ALT) should be reviewed before administration of the next dose of study drug. In the presence of LFT abnormalities, neoplastic, concurrent medications, viral hepatitis, and toxic etiologies should be considered and addressed, as appropriate. Imaging of the liver, gall bladder, and biliary tree should be performed to rule out neoplastic or other causes of increased LFTs. Anti-nuclear antibody, perinuclear anti-neutrophil cytoplasmic antibody, anti-liver kidney microsomal, and anti-smooth muscle antibody tests should be performed if an autoimmune etiology is suspected. Patients with LFT abnormalities should be managed according to the guidelines in table below.  
| Event                                       | Management                                                                                                   |                |
|---------------------------------------------|--------------------------------------------------------------------------------------------------------------|----------------|
| Hepatic  event, Grade  1                    | CTCAE v4.0 guidelines - Continue atezolizumab.  - Monitor LFTs until values resolve to within normal limits. |                |
| Protocol Version 11/13/2020                 | CONFIDENTIAL                                                                                                 | Page 38 of 103 |
| This document is confidential               |                                                                                                              |                |
| Do not disclose or use except as authorized |                                                                                                              |                |
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dose modification guidelines for hepatic

| CTCAE v5.0 guidelines - Continue atezolizumab. - Monitor LFTs until values resolve to within normal limits  or to baseline values.                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                  |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------|
| Hepatic  event, Grade  2                                                                                                                                                                                                                                                | All events: - Monitor LFTs more frequently until return to baseline values. Events of > 5 days' duration:  - Withhold atezolizumab for up to 12 weeks after event onset.  aa - Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral prednisone.  - If event resolves to Grade 1 or better, resume atezolizumab.b - If event does not resolve to Grade 1 or better while  withholding atezolizumab, permanently discontinue  atezolizumab and contact Study Chair. c |                                                                  |
| Event                                                                                                                                                                                                                                                                   | Management                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                  |
| Hepatic  event, Grade  3 or 4                                                                                                                                                                                                                                           | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Permanently discontinue atezolizumab and contact Study  Chair. c |
| -                                                                                                                                                                                                                                                                       | Consider patient referral to gastrointestinal specialist  for evaluation and liver biopsy to establish etiology of  hepatic injury.                                                                                                                                                                                                                                                                                                                                                     |                                                                  |
| -                                                                                                                                                                                                                                                                       | Initiate treatment with corticosteroids equivalent  to 1-2 mg/kg/day oral prednisone.                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                  |
| -                                                                                                                                                                                                                                                                       | If event does not improve within 48 hours after initiating  corticosteroids, consider adding an immunosuppressive  agent.                                                                                                                                                                                                                                                                                                                                                               |                                                                  |
| -                                                                                                                                                                                                                                                                       | If event resolves to Grade 1 or better, taper corticosteroids over  ≥ 1 month.                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                  |
| LFT = liver function tests. CTCAE =Common Terminology Criteria for Adverse Events a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event  onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                  |  
  
- Consider patient referral to gastrointestinal specialist  
for evaluation and liver biopsy to establish etiology of hepatic injury.  
- Initiate treatment with corticosteroids equivalent  
to 1-2 mg/kg/day oral prednisone.  
- If event does not improve within 48 hours after initiating  
corticosteroids, consider adding an immunosuppressive agent.  
- If event resolves to Grade 1 or better, taper corticosteroids  
over ≥ 1 month.  
LFT = liver function tests. CTCAE =Common Terminology Criteria for Adverse Events  
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event  
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time must be agreed upon by the investigator and the Study Chair.  
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the  
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed.  
c Resumption of atezolizumab may be considered in patients who are deriving benefit  
and have fully recovered from the immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator  
(or an appropriate delegate) and the Study Chair.
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9.2.3 dermatologic toxicity

Treatment-emergent rash has been associated with atezolizumab. The majority of cases of rash were mild in severity and self-limited, with or without pruritus. A dermatologist should evaluate persistent and/or severe rash or pruritus. A biopsy should be performed unless contraindicated. Low-grade rash and pruritus irAEs have been treated with symptomatic therapy (e.g., antihistamines). Topical or parenteral corticosteroids may be required for more severe symptoms. Dermatologic toxicity and rash should be managed according to the guidelines in table below.  
| Dose Modification Guidelines for Dermatologic Events                                                                                  |                                                                                                                                                                  |                                                              |
|---------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|
| Event                                                                                                                                 | Management                                                                                                                                                       |                                                              |
| -                                                                                                                                     | Continue atezolizumab.                                                                                                                                           |                                                              |
| Dermatologic event,                                                                                                                   | -                                                                                                                                                                | Consider treatment with topical corticosteroids and/or other |
| Grade 1                                                                                                                               | symptomatic therapy (e.g. antihistamines).                                                                                                                       |                                                              |
| Dermatologic event,                                                                                                                   | -                                                                                                                                                                | Continue atezolizumab.                                       |
| Grade 2                                                                                                                               | -                                                                                                                                                                | Consider patient referral to dermatologist.                  |
| -                                                                                                                                     | Initiate treatment with topical corticosteroids.                                                                                                                 |                                                              |
| -                                                                                                                                     | Consider treatment with higher-potency topical corticosteroids if event does not improve.                                                                        |                                                              |
| -                                                                                                                                     | Initiate treatment with higher-potency topical corticosteroids if  event does not improve.                                                                       |                                                              |
| -                                                                                                                                     | Withhold atezolizumab for up to 12 weeks after event onset. a                                                                                                    |                                                              |
| Dermatologic event,  Grade 3                                                                                                          | -                                                                                                                                                                | Refer patient to dermatologist.                              |
| -                                                                                                                                     | Initiate treatment with corticosteroids equivalent to 10mg/day  oral prednisone, increasing dose to 1-2 mg/kg/day if event does  not improve within 48-72 hours. |                                                              |
| -                                                                                                                                     | If event resolves to Grade 1 or better, resume atezolizumab.b                                                                                                    |                                                              |
| -                                                                                                                                     | If event does not resolved to Grade 1 or better while withholding  atezolizumab, permanently discontinue ateazolizumab and  c contact Study Chair.               |                                                              |
| -                                                                                                                                     | Permanently discontinue atezolizumab and contact Study Chair. c                                                                                                  |                                                              |
| Dermatologic event,  Grade 4 a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow |                                                                                                                                                                  |                                                              |
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9.2.4 endocrine toxicity

Hypothyroidism has been associated with the administration of atezolizumab. Patients with unexplained symptoms such as fatigue, myalgias, impotence, mental status changes, or constipation should be investigated for the presence of thyroid, pituitary, or adrenal endocrinopathies, as well as for hyponatremia or hyperkalemia. An endocrinologist should be consulted if an endocrinopathy is suspected. Thyroid-stimulating hormone (TSH) and free T4 levels should be obtained to determine whether thyroid abnormalities are present. TSH, prolactin, and a morning cortisol level will help to differentiate primary adrenal insufficiency from primary pituitary insufficiency. Hypothyroidism should be managed according to the guidelines in the table below.  
| Event                                                                                          | Management                                                                                                           |                                                                                          |
|------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------|
| Asymptomatic                                                                                   | -                                                                                                                    | Continue atezolizumab.                                                                   |
| hypothyroidism                                                                                 | -                                                                                                                    | Initiate treatment with thyroid replacement hormone.                                     |
| -                                                                                              | Monitor TSH weekly.                                                                                                  |                                                                                          |
| Symptomatic                                                                                    | -                                                                                                                    | Withhold atezolizumab.                                                                   |
| hypothyroidism                                                                                 | -                                                                                                                    | Initiate treatment with thyroid replacement hormone.                                     |
| -                                                                                              | Monitor TSH weekly.                                                                                                  |                                                                                          |
| -                                                                                              | Consider patient referral to endocrinologist.                                                                        |                                                                                          |
| -                                                                                              | Resume atezolizumab when symptoms are controlled and thyroid function is improving.                                  |                                                                                          |
| Asymptomatic                                                                                   | TSH ≥ 0.1 mU/L and < 0.5 mU/L:                                                                                       |                                                                                          |
| hyperthyroidism                                                                                | -                                                                                                                    | Continue atezolizumab.                                                                   |
| -                                                                                              | Monitor TSH every 4 weeks.                                                                                           |                                                                                          |
| TSH < 0.1 mU/L:  - Follow guidelines for symptomatic hyperthyroidism. - Withhold atezolizumab. |                                                                                                                      |                                                                                          |
| Symptomatic  hyperthyroidism                                                                   | -                                                                                                                    | Initiate treatment with anti-thyroid drug such as  methimazole or carbimazole as needed. |
| -                                                                                              | Consider patient referral to endocrinologist.                                                                        |                                                                                          |
| -                                                                                              | Resume atezolizumab when symptoms are controlled and thyroid function is improving.                                  |                                                                                          |
| -                                                                                              | Permanently discontinue atezolizumab and contact Study  Chair for life-threatening immune-related  hyperthyroidism.c |                                                                                          |
| MRI=magnetic resonance imaging; TSH = thyroid-stimulating hormone.                             |                                                                                                                      |                                                                                          |
|                                                                                                | Note: Management guidelines are presented by adverse event severity based on                                         |                                                                                          |
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management guidelines for endocrine events

investigator and the Study Chair.  
  
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral prednisone before atezolizumab can be resumed.  
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Study Chair.  
| Management Guidelines for Endocrine Events (cont.)  Event Management   |                                                                                                                                                                                                  |                                                                                                                                                                       |
|------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Symptomatic  adrenal  insufficiency,  Grade 2-4                        | -                                                                                                                                                                                                | Withhold atezolizumab for up to 12 weeks after event onset.  a                                                                                                        |
| -                                                                      | Refer patient to endocrinologist.                                                                                                                                                                |                                                                                                                                                                       |
| -                                                                      | Perform appropriate imaging.                                                                                                                                                                     |                                                                                                                                                                       |
| -                                                                      | Initiate treatment with corticosteroids equivalent to  1-2 mg/kg/day IV methylprednisolone and convert  to 1-2 mg/kg/day oral prednisone or equivalent  upon improvement.                        |                                                                                                                                                                       |
| -                                                                      | If event resolves to Grade 1 or better and patient is stable on replacement therapy, resume atezolizumab. b                                                                                      |                                                                                                                                                                       |
| -                                                                      | If event does not resolve to Grade 1 or better or patient is  not stable on replacement therapy while withholding  atezolizumab, permanently discontinue atezolizumab and  contact Study Chair.C |                                                                                                                                                                       |
| Hyperglycemia,                                                         | -                                                                                                                                                                                                | Continue atezolizumab.                                                                                                                                                |
| Grade 1 or 2                                                           | -                                                                                                                                                                                                | Investigate for diabetes. If patient has Type 1 diabetes,  treat as a Grade 3 event. If patient does not have Type 1 diabetes, treat as per institutional guidelines. |
| -                                                                      | Monitor for glucose control.                                                                                                                                                                     |                                                                                                                                                                       |
| Hyperglycemia,                                                         | -                                                                                                                                                                                                | Withhold atezolizumab.                                                                                                                                                |
| Grade 3 or 4                                                           | -                                                                                                                                                                                                | Initiate treatment with insulin.                                                                                                                                      |
| -                                                                      | Monitor for glucose control.                                                                                                                                                                     |                                                                                                                                                                       |
| -                                                                      | Resume atezolizumab when symptoms resolve and  glucose levels are stable.                                                                                                                        |                                                                                                                                                                       |
| Hypophysitis  (panhypopituitarism),  Grade 2 or 3                                                                        | -                                                                                                                                                                                                | Withhold atezolizumab for up to 12 weeks after event onset.  a                                                                                                        |
| -                                                                      | Refer patient to endocrinologist.                                                                                                                                                                |                                                                                                                                                                       |
| -                                                                      | Perform brain MRI (pituitary protocol).                                                                                                                                                          |                                                                                                                                                                       |
| -                                                                      | Initiate treatment with corticosteroids equivalent to  1-2 mg/kg/day IV methylprednisolone and convert  to 1-2 mg/kg/day oral prednisone or equivalent  upon improvement.                        |                                                                                                                                                                       |
| -                                                                      | Initiate hormone replacement if clinically indicated.                                                                                                                                            |                                                                                                                                                                       |
| -                                                                      | If event resolves to Grade 1 or better, resume atezolizumab.b                                                                                                                                    |                                                                                                                                                                       |
| Protocol Version 11/13/2020                                            | CONFIDENTIAL                                                                                                                                                                                     | Page 42 of 103                                                                                                                                                        |
| This document is confidential                                          |                                                                                                                                                                                                  |                                                                                                                                                                       |
| Do not disclose or use except as authorized                            |                                                                                                                                                                                                  |                                                                                                                                                                       |  
| -   | If event does not resolve to Grade 1 or better while  withholding atezolizumab, permanently discontinue  atezolizumab and contact Study Chair. c   |
|-----|----------------------------------------------------------------------------------------------------------------------------------------------------|
| -   | For recurrent hypophysitis, treat as a Grade 4 event.                                                                                              |  
  
MRI=magnetic resonance imaging; TSH = thyroid-stimulating hormone.  
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset)
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time must be agreed upon by the investigator and the Study Chair.  
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed.  
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Study Chair.  
| Event                                                                | Management                                                                                                                                                                |                                                                  |
|----------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------|
| Hypophysitis  (panhypopituitarism),  Grade 4                                                                      | -                                                                                                                                                                         | Permanently discontinue atezolizumab and contact Study  Chair. c |
| -                                                                    | Refer patient to endocrinologist.                                                                                                                                         |                                                                  |
| -                                                                    | Perform brain MRI (pituitary protocol).                                                                                                                                   |                                                                  |
| -                                                                    | Initiate treatment with corticosteroids equivalent to  1-2 mg/kg/day IV methylprednisolone and convert  to 1-2 mg/kg/day oral prednisone or equivalent  upon improvement. |                                                                  |
| -                                                                    | Initiate hormone replacement if clinically indicated.                                                                                                                     |                                                                  |
| MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. |                                                                                                                                                                           |                                                                  |  
- Initiate treatment with corticosteroids equivalent to  
1-2 mg/kg/day IV methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement.  
- Initiate hormone replacement if clinically indicated.  
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone.  
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset)  
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone. The acceptable length of the extended period of time must be agreed upon by the investigator and the Study Chair.  
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the  
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed.  
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have  
fully recovered from the immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an  
appropriate delegate) and the Study Chair.
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management guidelines for endocrine events

Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated with the administration of atezolizumab and have primarily been observed in patients with underlying NSCLC.  
Protocol Version 11/13/2020 CONFIDENTIAL Page 43 *of 103* This document is confidential Do not disclose or use except as authorized Mild-to-moderate events of pneumonitis have been reported with atezolizumab. All  
 pulmonary events should be thoroughly evaluated for other commonly reported etiologies such as pneumonia/infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, chronic obstructive pulmonary disease (COPD), or pulmonary hypertension and the following should be performed:  
- Measurement of oxygen saturation (i.e., arterial blood gas) - High-resolution CT scan of the chest - Bronchoscopy with bronchoalveolar lavage and biopsy
- Pulmonary function tests (with diffusion capacity of the lung for carbon monoxide
[DLCO])
Patients will be assessed for pulmonary signs and symptoms throughout the study. Patients will also have CT scans of the chest at every tumor assessment. Pulmonary toxicity should be managed according to the guidelines in the table below.  
| Management Guidelines for Pulmonary Events, Including Pneumonitis  Event Management Pulmonary  - Continue atezolizumab and monitor closely. event, Grade 1  - Re-evaluate on serial imaging.  - Consider patient referral to pulmonary specialist. Pulmonary  - Withhold atezolizumab for up to 12 weeks after event onset. a event, Grade 2  - Refer patient to pulmonary and infectious disease  specialists and consider bronchoscopy or BAL. - Initiate treatment with corticosteroids equivalent to 1-2  mg/kg/day oral prednisone.  - If event resolves to Grade 1 or better, resume atezolizumab. b - If event does not resolve to Grade 1 or better while  withholding atezolizumab, permanently discontinue  atezolizumab and contact Study Chair. c - For recurrent events, treat as a Grade 3 or 4 event. Pulmonary  event, Grade 3  or 4  - Permanently discontinue atezolizumab and contact Study Chair.  c - Bronchoscopy or BAL is recommended. - Initiate treatment with corticosteroids equivalent to 1-2  mg/kg/day oral prednisone.  - If event does not improve within 48 hours after initiating  corticosteroids, consider adding an immunosuppressive  agent.  - If event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. BAL = bronchoscopic alveolar lavage. a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset)   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Protocol Version 11/13/2020 CONFIDENTIAL Page 44 *of 103* This document is confidential Do not disclose or use except as authorized  
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral  
 prednisone. The acceptable length of the extended period of time must be agreed upon by the investigator and the Study Chair.  
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed.  
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Study Chair
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9.2.6 potential pancreatic toxicity management

| Management Guidelines for Pancreatic Events, Including Pancreatitis Event Management Amylase and/or  lipase elevation,  Grade 2 Amylase and/or lipase > 1.5-2.0 x ULN: - Continue atezolizumab. - Monitor amylase and lipase weekly.  - For prolonged elevation (e.g., >3 weeks), consider  treatment with corticosteroids equivalent to 10 mg/day  oral prednisone.  Asymptomatic with amylase and/or lipase > 2.0-5.0  xULN: - Treat as a Grade 3 event. Amylase and/or  lipase elevation,  Grade 3 or 4  - Withhold atezolizumab for up to 12 weeks after event  onset. a - Refer patient to GI specialist. - Monitor amylase and lipase every other day.  - If no improvement, consider treatment with  corticosteroids equivalent to 1-2 mg/kg/day oral prednisone.  - If event resolves to Grade 1 or better, resume atezolizumab. b - If event does not resolve to Grade 1 or better  while withholding atezolizumab, permanently discontinue atezolizumab and contact Study  Chair. c - For recurrent events, permanently discontinue  atezolizumab and contact Study Chair. c GI = gastrointestinal.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Protocol Version 11/13/2020 CONFIDENTIAL Page 45 *of 103* This document is confidential Do not disclose or use except as authorized  
10 mg/day oral prednisone before atezolizumab can be resumed.  
  
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Study Chair.  
| Management Guidelines for Pancreatic Events, Including Pancreatitis (cont.)  Event Management - Withhold atezolizumab for up to 12 weeks after event  Immune-related  pancreatitis, Grade 2 or 3  onset. a - Refer patient to GI specialist. - Initiate treatment with corticosteroids equivalent  to 1-2 mg/kg/day IV methylprednisolone and  convert to 1-2 mg/kg/day oral prednisone or  equivalent upon improvement.  - If event resolves to Grade 1 or better, resume atezolizumab. b - If event does not resolve to Grade 1 or better  while withholding atezolizumab, permanently discontinue atezolizumab and contact Study  Chair. c - For recurrent events, permanently discontinue  atezolizumab and contact Study Chair. c - Permanently discontinue atezolizumab and contact Immune-related  pancreatitis, Grade 4 Study Chair. c - Refer patient to GI specialist. - Initiate treatment with corticosteroids equivalent  to 1-2 mg/kg/day IV methylprednisolone and  convert to 1-2 mg/kg/day oral prednisone or  equivalent upon improvement.  - If event does not improve within 48 hours after  initiating corticosteroids, consider adding an immunosuppressive agent.  - If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1month. GI =gastrointestinal.   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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management guidelines for pancreatic events

9.2.7 Potential Eye Toxicity  
  
An ophthalmologist should evaluate visual complaints. Uveitis or episcleritis may be treated with topical corticosteroid eye drops. Atezolizumab should be permanently discontinued for immunemediated ocular disease that is unresponsive to local immunosuppressive therapy.  
Potential eye toxicity should be managed according to the guidelines in the table below.  
| Management Guidelines for Ocular Events  Event Management Ocular  event,  Grade 1 - Continue atezolizumab. - Patient referral to ophthalmologist is strongly recommended.  - Initiate treatment with topical corticosteroid eye drops and topical immunosuppressive therapy.  - If symptoms persist, treat as a Grade 2 event. Ocular  event,  Grade 2 - Withhold atezolizumab for up to 12 weeks after event onset. a - Patient referral to ophthalmologist is strongly recommended.  - Initiate treatment with topical corticosteroid eye drops and topical immunosuppressive therapy.  - If event resolves to Grade 1 or better, resume atezolizumab. b - If event does not resolve to Grade 1 or better while  withholding atezolizumab, permanently discontinue  atezolizumab and contact Study Chair. c Ocular  event,  Grade 3 or 4  - Permanently discontinue atezolizumab and contact  Study Chair. c - Refer patient to ophthalmologist.  - Initiate treatment with corticosteroids equivalent to 1-2  mg/kg/day oral prednisone.  - If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to  allow for corticosteroids (if initiated) to be reduced to the equivalent of   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Study Chair. c  
- Refer patient to ophthalmologist. - Initiate treatment with corticosteroids equivalent to 1-2  
mg/kg/day oral prednisone.  
- If event resolves to Grade 1 or better, taper corticosteroids over  
≥ 1 month. a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to  
allow for corticosteroids (if initiated) to be reduced to the equivalent of  
≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time must be agreed  
upon by the investigator and the Study Chair.  
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent  
of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed.  
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully  
recovered from the immune-related event. Patients can be re-challenged with atezolizumab only after  
approval has been documented by both the investigator (or an appropriate delegate) and the Study  
Chair.
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9.2.8 immune-mediated myocarditis

Immune-mediated myocarditis has been associated with the administration of atezolizumab. Immune-mediated myocarditis should be suspected in any patient presenting with signs or symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., BNP [BNatriuretic Peptide]) or cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope. Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from infection (commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, or progression of malignancy. All patients with possible myocarditis should be urgently evaluated by performing cardiac enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as appropriate per institutional guidelines. A cardiologist should be consulted. An endomyocardial biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if clinically indicated. Patients with signs and symptoms of myocarditis, in the absence of an identified alternate etiology, should be treated according to the guidelines provided below.  
| Management Guidelines for Immune-Mediated Myocarditis Event Management   |                                                                                                                                                                           |                                                                                      |
|--------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|
| Immune-mediated myocarditis, Grade 1 (CTCAE v4.0 guidelines only)        | CTCAE v4.0 guidelines - Refer patient to cardiologist. - Initiate treatment as per institutional guidelines.                                                              |                                                                                      |
| Immune-mediated  myocarditis,  Grade 2                                   | -                                                                                                                                                                         | Withhold atezolizumab for up to 12 weeks after event onseta and contact Study Chair. |
| -                                                                        | Refer patient to cardiologist.                                                                                                                                            |                                                                                      |
| -                                                                        | Initiate treatment as per institutional guidelines and  consider antiarrhythmic drugs, temporary pacemaker,  ECMO, or VAD as appropriate.                                 |                                                                                      |
| -                                                                        | Consider treatment with corticosteroids equivalent to 1-2  mg/kg/day IV methylprednisolone and convert to 1-2  mg/kg/day oral prednisone or equivalent upon  improvement. | b                                                                                    |
| -                                                                        | If event resolves to Grade 1 or better, resume atezolizumab.                                                                                                              |                                                                                      |
| -                                                                        | If event does not resolve to Grade 1 or better while  withholding atezolizumab, permanently discontinue  atezolizumab and contact Study Chair. c                          |                                                                                      |  
  
| Event                                                                        | Management                                                                                                                                                                |                                                        |
|------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------|
| Immune-mediated myocarditis, Grade 1 (CTCAE v4.0 guidelines only)            | CTCAE v4.0 guidelines - Refer patient to cardiologist. - Initiate treatment as per institutional guidelines.                                                              |                                                        |
| Immune-mediated                                                              | -                                                                                                                                                                         | Permanently discontinue atezolizumab and contact Study |
| myocarditis, Grade 3-4                                                       | Chair. c                                                                                                                                                                  |                                                        |
| -                                                                            | Refer patient to cardiologist.                                                                                                                                            |                                                        |
| -                                                                            | Initiate treatment as per institutional guidelines and consider  antiarrhythmic drugs, temporary pacemaker, ECMO, or  VAD as appropriate.                                 |                                                        |
| -                                                                            | Initiate treatment with corticosteroids equivalent to 1-2  mg/kg/day IV methylprednisolone and convert to 1-2  mg/kg/day oral prednisone or equivalent upon  improvement. |                                                        |
| -                                                                            | If event does not improve within 48 hours after initiating corticosteroids, consider adding an immunosuppressive  agent.                                                  |                                                        |
| -                                                                            | If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month.                                                                                             |                                                        |
| ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. |                                                                                                                                                                           |                                                        |  
a Atezolizumab may be withheld for longer period of time (i.e., >12 weeks after event onset) to allow for corticosteroids
(if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time must be agreed upon by the investigator and the Study Chair. b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone before ateolizumab can be resumed.  
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated event. Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Study Chair.