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9.2.9 infusion-related reactions and cytokine-release

No premedication is indicated for the administration of Cycle 1 of atezolizumab. However, patients who experience an infusion-related reaction (IRR) or cytokine-release syndrome (CRS) with atezolizumab may receive premedication with antihistamines, antipyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions. Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its potential for causing agranulocytosis. IRRs are known to occur with the administration of monoclonal antibodies and have been reported with atezolizumab. These reactions, which are thought to be due to release of cytokines and/or other chemical mediators, occur within 24 hours of atezolizumab administration and are generally mild to  
 moderate in severity. CRS is defined as a supraphysiologic response following administration of any immune therapy that results in activation or engagement of endogenous or infused T cells and/or other immune effector cells. Symptoms can be progressive, always include fever at the onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction (Lee et al. 2019). CRS has been well documented with chimeric antigen receptor T-cell therapies and bispecific T-cell engager antibody therapies but has also been reported with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and Feldman 2019), including atezolizumab. There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of the challenges in clinically distinguishing between the two, consolidated guidelines for medical management of IRRs and CRS are provided in the table below.  
| Event                                                                                                                                     | Management                                                                                                                                                                                                                     |                                 |
|-------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------|
| Grade 1 a Fever b with or without  constitutional  symptoms                                                                               | -                                                                                                                                                                                                                              | Immediately interrupt infusion. |
| -                                                                                                                                         | Upon symptom resolution, wait for 30 minutes and then restart  infusion at half the rate being given at the time of event onset.                                                                                               |                                 |
| -                                                                                                                                         | If the infusion is tolerated at the reduced rate for 30 minutes, the infusion rate may be increased to the original rate.                                                                                                      |                                 |
| -                                                                                                                                         | If symptoms recur, discontinue infusion of this dose. Administer  symptomatic treatment, c including maintenance of IV fluids for  hydration.                                                                                  |                                 |
| -                                                                                                                                         | In case of rapid decline or prolonged CRS (> 2 days) or in  patients with significant symptoms and/or comorbidities, onsider  managing as per Grade 2.                                                                         |                                 |
| -                                                                                                                                         | For subsequent infusions, consider administration of oral  premedication with antihistamines, anti-pyretics, and/or  analgesics, and monitor closely for IRRs and/or CRS.                                                      |                                 |
| Grade 2 a Fever b with hypotension not  requiring  vasopressors and/or Hypoxia requiring  low-flow oxygen d  by nasal cannula or  blow-by | -                                                                                                                                                                                                                              | Immediately interrupt infusion. |
| -                                                                                                                                         | Upon symptom resolution, wait for 30 minutes and then restart  infusion at half the rate being given at the time of event onset.                                                                                               |                                 |
| -                                                                                                                                         | If symptoms recur, discontinue infusion of this dose.                                                                                                                                                                          |                                 |
| -                                                                                                                                         | Administer symptomatic treatment. c                                                                                                                                                                                            |                                 |
| -                                                                                                                                         | For hypotension, administer IV fluid bolus as needed.                                                                                                                                                                          |                                 |
| -                                                                                                                                         | Monitor cardiopulmonary and other organ function closely (in  the ICU, if appropriate). Administer IV fluids as clinically  indicated, and manage constitutional symptoms and organ  toxicities as per institutional practice. |                                 |
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management guidelines for infusion-related reactions

| -   | Rule out other inflammatory conditions that can mimic CRS                                                                                                                                                                                                                                      |
|-----|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| -   | (e.g., sepsis). If no improvement within 24 hours, initiate  workup and assess for signs and symptoms of HLH or MAS.                                                                                                                                                                           |
| -   | Consider IV corticosteroids (e.g., methylprednisolone 2  mg/kg/day or dexamethasone 10 mg every 6 hours).                                                                                                                                                                                      |
| -   | Consider anti-cytokine therapy. e                                                                                                                                                                                                                                                              |
| -   | Consider hospitalization until complete resolution of symptoms. If no improvement within 24 hours, manage as per Grade 3, that  is, hospitalize patient (monitoring in the ICU is recommended),  permanently discontinue atezolizumab, and contact Study Chair.                                |
| -   | If symptoms resolve to Grade 1 or better for 3 consecutive days,  the next dose of atezolizumab may be administered. For  subsequent infusions, consider administration of oral  premedication with antihistamines, anti-pyretics, and/or  analgesics and monitor closely for IRRs and/or CRS. |
| -   | If symptoms do not resolve to Grade 1 or better for 3  consecutive days, contact Study Chair.                                                                                                                                                                                                  |
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table. management guidelines for infusion-related

| Event                                                                                                             | Management                                                                                                                                                                                               |                                                                  |
|-------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------|
| Grade 3 a Fever b with hypotension requiring a vasopressor (with or without vasopressin) and/or Hypoxia requiring | -                                                                                                                                                                                                        | Permanently discontinue atezolizumab and contact  Study Chair. f |
| -                                                                                                                 | Administer symptomatic treatment. c                                                                                                                                                                      |                                                                  |
| -                                                                                                                 | For hypotension, administer IV fluid bolus and  vasopressor as needed.                                                                                                                                   |                                                                  |
| -                                                                                                                 | Monitor cardiopulmonary and other organ function  closely; monitoring in the ICU is recommended.  Administer IV fluids as clinically indicated, and  manage constitutional symptoms and organ toxicities |                                                                  |
| Protocol Version 11/13/2020                                                                                       | CONFIDENTIAL                                                                                                                                                                                             | Page 52 of 103                                                   |
| This document is confidential                                                                                     |                                                                                                                                                                                                          |                                                                  |
| Do not disclose or use except as authorized                                                                       |                                                                                                                                                                                                          |                                                                  |  

TBCRC 043  
| TBCRC 043 high-flow oxygen d by nasal cannula, face mask, non-rebreather mask, or venturi mask                                                                                                             | as per institutional practice.                                                                                                                                                                                             |                                                                  |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------|
| -                                                                                                                                                                                                          | Rule out other inflammatory conditions that can  mimic CRS (e.g., sepsis). If no improvement within  24 hours, initiate workup and assess for signs and  symptoms of HLH or MAS.                                           |                                                                  |
| -                                                                                                                                                                                                          | Administer IV corticosteroids (e.g.,  methylprednisolone 2 mg/kg/day or dexamethasone  10 mg every 6 hours).                                                                                                               |                                                                  |
| -                                                                                                                                                                                                          | Consider anti-cytokine therapy. e                                                                                                                                                                                          |                                                                  |
| -                                                                                                                                                                                                          | Hospitalize patient until complete resolution of  symptoms. If no improvement within 24 hours,  manage as per Grade 4, that is, admit patient to ICU  and initiate hemodynamic monitoring, mechanical  ventilation, and/or IV fluids and vasopressors as  needed; for patients who are refractory to anticytokine therapy, experimental treatments may be  considered at the discretion of  the investigator and in consultation with the Study  Chair.                                                                                                                                                                                                                            |                                                                  |
| Grade 4 a Fever b with hypotension requiring multiple vasopressors (excluding vasopressin) and/or Hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation) | -                                                                                                                                                                                                                          | Permanently discontinue atezolizumab and contact  Study Chair. f |
| -                                                                                                                                                                                                          | Administer symptomatic treatment. c                                                                                                                                                                                        |                                                                  |
| -                                                                                                                                                                                                          | Admit patient to ICU and initiate hemodynamic  monitoring, mechanical ventilation, and/or IV fluids  and vasopressors as                                                                                                   |                                                                  |
| -                                                                                                                                                                                                          | needed. Monitor other organ function closely.  Manage                                                                                                                                                                      |                                                                  |
| -                                                                                                                                                                                                          | constitutional symptoms and organ toxicities as per  institutional practice.                                                                                                                                               |                                                                  |
| -                                                                                                                                                                                                          | Rule out other inflammatory conditions that can  mimic CRS                                                                                                                                                                 |                                                                  |
| -                                                                                                                                                                                                          | (e.g., sepsis). If no improvement within 24 hours,  initiate workup and assess for signs and symptoms of  HLH or MAS.                                                                                                      |                                                                  |
| -                                                                                                                                                                                                          | Administer IV corticosteroids (e.g.,  methylprednisolone 2 mg/kg/day or dexamethasone  10 mg every 6 hours).                                                                                                               |                                                                  |
| -                                                                                                                                                                                                          | Consider anti-cytokine therapy. e For patients who  are refractory to anti-cytokine therapy, experimental  treatments g may be considered at the discretion of  the investigator and in consultation with the Study  Chair |                                                                  |
| -                                                                                                                                                                                                          | Hospitalize patient until complete resolution of  symptoms                                                                                                                                                                 |                                                                  |
| Protocol Version 11/13/2020                                                                                                                                                                                | CONFIDENTIAL                                                                                                                                                                                                               | Page 53 of 103                                                   |
| This document is confidential                                                                                                                                                                              |                                                                                                                                                                                                                            |                                                                  |
| Do not disclose or use except as authorized                                                                                                                                                                |                                                                                                                                                                                                                            |                                                                  |  
TBCRC 043 ASTCT =American Society for Transplantation and Cellular Therapy; BiPAP =bi-level  
  
positive airway pressure; CAR =chimeric antigen receptor; CPAP =continuous positive airway pressure; CRS =cytokine-release syndrome; CTCAE =Common Terminology Criteria for Adverse Events; eCRF =electronic Case Report Form; HLH =hemophagocytic lymphohistiocytosis; ICU =intensive care unit; IRR =infusion-related reaction; MAS =macrophage activation syndrome; NCCN =National Cancer Comprehensive Network; NCI =National Cancer Institute. Note: The management guidelines have been adapted from NCCN guidelines for management of CAR T-cell-related toxicities (Version 2.2019).  
a Grading system for management guidelines is based on ASTCT consensus grading for CRS. NCI CTCAE (version as specified in the protocol) should be used when reporting severity of IRRs, CRS, or organ toxicities associated with CRS on the Adverse Event eCRF. Organ toxicities associated with CRS should not influence overall CRS grading.  
b Fever is defined as temperature ≥ 38°C not attributable to any other cause. In patients who develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no longer required when subsequently determining event severity (grade). In this case, the grade is driven by the presence of hypotension and/or hypoxia.  
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, bronchodilators, and/or oxygen. For bronchospasm, urticaria, or dyspnea, additional treatment may be administered as per institutional practice.  
d Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as oxygen delivered at > 6 L/min.  
e There are case reports where anti-cytokine therapy has been used for treatment of CRS with immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019),
but data are limited, and the role of such treatment in the setting of antibody-associated CRS has not been established.  
f Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 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. For subsequent infusions, administer oral premedication with antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS. Premedication with corticosteroids and extending the infusion time may also be considered after consulting the Study Chair and considering the benefit-risk ratio.  
g Refer to Riegler et al. (2019) for information on experimental treatments for CRS.
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9.2.10 neurologic disorders

Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent atezolizumab. Patients may present with signs and symptoms of sensory and/or motor neuropathy. Diagnostic workup is essential for an accurate characterization to differentiate between alternative etiologies. Management guidelines for neurologic disorders are provided below.  
  
| Management Guidelines for Neurologic Disorders Event                                                                           | Management                                                                                                                                                                                                                                                                                            |
|--------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Immune-mediated neuropathy,                                                                                                    | Continue atezolizumab.                                                                                                                                                                                                                                                                                |
| Grade 1                                                                                                                        | Investigate etiology.                                                                                                                                                                                                                                                                                 |
| Immune-mediated neuropathy,                                                                                                    | Withhold atezolizumab for up to 12 weeks after                                                                                                                                                                                                                                                        |
| Grade 2                                                                                                                        | event onset.a Investigate etiology. Initiate treatment as per institutional guidelines. If event resolves to Grade 1 or better, resume  atezolizumab.b If event does not resolve to Grade 1 or better while  withholding atezolizumab, permanently  discontinue atezolizumab and contact Study Chair. |
| Immune-mediated neuropathy,                                                                                                    | Permanently discontinue atezolizumab and contact                                                                                                                                                                                                                                                      |
| Grade 3 or 4                                                                                                                   | Study Chair.c Initiate treatment as per institutional guidelines.                                                                                                                                                                                                                                     |
| Myasthenia gravis and Guillain-Barré                                                                                           | Permanently discontinue atezolizumab and contact  Study Chair.c                                                                                                                                                                                                                                       |
| syndrome (any grade)                                                                                                           | Refer patient to neurologist.  Initiate treatment as per institutional guidelines. Consider initiation of corticosteroids equivalent to  1-2 mg/kg/day oral or IV prednisone.                                                                                                                         |
| a Atezolizumab may be withheld for longer period of time (i.e., >12 weeks after event onset) to allow for corticosteroids  (if |                                                                                                                                                                                                                                                                                                       |
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9.2.11 immune-mediated meningoencephalitis

Immune-related meningoencephalitis is an identified risk associated with the administration of atezolizumab. Immune-mediated meningoencephalitis should be suspected in any patient presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or depressed level of consciousness. Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from potential  
 meningoencephalitis resulting from infection (bacterial, viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process. All patients being considered for meningoencephalitis should be urgently evaluated with a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If deemed safe by the treating physician, a lumbar puncture should be performed and a neurologist should be consulted. Patients with signs and symptoms of meningoencephalitis, in the absence of an identified alternate etiology, should be treated according to the guidelines below.  
| Management Guidelines for Immune-Mediated Meningoencephalitis Event Management                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
|----------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Immune-mediated meningoencephalitis,  all grades                                                   | Permanently discontinue atezolizumab and contact  Study Chair.  Refer patient to neurologist. 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. |
| a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
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9.2.12 immune-mediated myositis

Immune-mediated myositis has been associated with the administration of atezolizumab. Myositis or inflammatory myopathies are a group of disorders sharing the common feature of inflammatory muscle injury; dermatomyositis and polymyositis are amongst the most common disorders. Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in dermatomyositis), biochemical (serum creatine-kinase increase), and imaging (electromyography/MRI) features, and is confirmed with a muscle-biopsy. Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, should be treated according to the guidelines below.
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management guidelines for immune-mediated myositis

| Event                              | Management                                                                                                                                                                                                                                                                                                                      |                                                             |
|------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|
| Immune-mediated myositis,  Grade 1 | -                                                                                                                                                                                                                                                                                                                               | Continue atezolizumab                                       |
| -                                  | Refer patient to rheumatologist or neurologist.                                                                                                                                                                                                                                                                                 |                                                             |
| -                                  | Initiate treatment as per institutional guidelines                                                                                                                                                                                                                                                                              |                                                             |
| Immune-mediated                    | -                                                                                                                                                                                                                                                                                                                               | Withhold atezolizumab for up to 12 weeks after event onseta |
| myositis, Grade 2                  | and contact Study Chair.                                                                                                                                                                                                                                                                                                        |                                                             |
| -                                  | Refer patient to rheumatologist or neurologist.                                                                                                                                                                                                                                                                                 |                                                             |
| -                                  | Initiate treatment as per institutional guidelines .                                                                                                                                                                                                                                                                            |                                                             |
| -                                  | Consider treatment with corticosteroid equivalent to 1-2  mg/kg/day IV methylprednisolone and convert to 1-2  mg/kg/day oral prednisone or equivalent upon improvement.                                                                                                                                                         |                                                             |
| -                                  | If corticosteroids are initiated and event does not improve  within 48 hours after initiating corticosteroids, consider adding  an immunosuppressive agent.                                                                                                                                                                     |                                                             |
| -                                  | If event resolves to Grade 1 or better, resume atezolizumab.b                                                                                                                                                                                                                                                                   |                                                             |
| -                                  | If event does not resolve to Grade 1 or better while  withholding atezolizumab, permanently discontinue  atezolizumab and contact Study Chair.                                                                                                                                                                                  |                                                             |
| Immune-mediated                    | -                                                                                                                                                                                                                                                                                                                               | Withhold atezolizumab for up to 12 weeks after event onseta |
| myositis, Grade 3                  | and contact Study Chair.                                                                                                                                                                                                                                                                                                        |                                                             |
| -                                  | Refer patient to rheumatologist or neurologist.                                                                                                                                                                                                                                                                                 |                                                             |
| -                                  | Initiate treatment as per institutional guidelines .                                                                                                                                                                                                                                                                            |                                                             |
| -                                  | Respiratory support may be required in more severe cases .                                                                                                                                                                                                                                                                      |                                                             |
| -                                  | Initiate treatment with corticosteroids equivalent to 1-2  mg/kg/day IV methylprednisolone or higher-dose bolus if  patient is severely compromised (e.g. cardiac or respiratory  symptoms, dysphagia, or weakness that severely limits  mobility); convert to 1-2 mg/kg/day oral prednisolone or  equivalent upon improvement. |                                                             |
| -                                  | If event does not improve within 48 hours after initiating  corticosteroids, consider adding an immunosuppressive agent.                                                                                                                                                                                                        |                                                             |
| -                                  | If event resolves to Grade 1 or better, resume atezolizumab.b                                                                                                                                                                                                                                                                   |                                                             |
| -                                  | If event does not resolve to Grade 1 or better while  withholding atezolizumab, permanently discontinue  atezolizumab and contact Study Chair.c                                                                                                                                                                                 |                                                             |
| -                                  | For recurrent events, treat as a Grade 4 event.                                                                                                                                                                                                                                                                                 |                                                             |  
Event Management  
  
Immune-mediated myositis, Grade 4  
- Permanently discontinue atezolizumab and contact Study  
Chair.c  
- Refer patient to rheumatologist or neurologist. - Initiate treatment as per institutional guidelines. Respiratory  
support may be required in more severe cases.  
- Initiate treatment with corticosteroids equivalent to 1-2  
mg/kg/day IV methylprednisolone or higher-dose bolus if patient is severely compromised (e.g. cardiac or respiratory symptoms, dysphagia, or weakness that severely limiting mobility); convert to 1-2 mg/kg/day oral prednisone or  
equivalent upon improvement.  
- If event does not improve within 48 hours after initiating  
corticosteroids, consider adding an immunosuppressive agent.  
- If event resolves to Grade 1 or better, taper corticosteroids over  
≥ 1 month. 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.
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9.2.13 severe cutaneous adverse reactions

Severe Cutaneous Adverse Reactions (SCARs) are rare but potentially fatal skin toxicities frequently associated with drug use including immune checkpoint inhibitor as a class. A comprehensive analysis of the data available across the TECENTRIQ® (atezolizumab) program has identified cases of SCARs following atezolizumab use. SCARs were previously a potential risk of atezolizumab, and have been monitored continuously. Based upon the totality of evidence in a recent analysis, SCARs are now considered to be an identified risk for atezolizumab. SCARs are a heterogeneous group of immunologically mediated skin eruptions.  
Although **rare, these events are potentially fatal**, and mainly constituted by **erythema**
multiforme, acute generalised exanthematous pustulosis, Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and drug rash with eosinophilia and systemic symptoms (DRESS). As per epidemiology data, the incidence of SJS and TEN ranges from 0.8 to 5.3 and 1.2 to 6 per million person-years respectively (19, 20) A cumulative analysis of the company safety database across the TECENTRIQ  
 (atezolizumab) program identified at total of 99 cases of SCARs, of which 36 were confirmed by histopathology or specialist diagnosis, in patients who have received TECENTRIQ (atezolizumab). Approximately 23,654 clinical trial patients and 106,316 patients in post-marketing settings have been exposed to TECENTRIQ (atezolizumab) as of 17 May 2020. The incidence rates of SCAR, regardless of severity, from pooled atezolizumab monotherapy (N=3178) and combination therapy (N=4371) companysponsored clinical studies were 0.7% and 0.6% respectively. One fatal case of TEN was reported in a 77 year old female patient who received atezolizumab monotherapy.
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management guidelines for scars

- For suspected SCARs the patients should be referred to a dermatologist for further diagnosis and management - Atezolizumab should be withheld for patients with suspected SJS or TEN - Atezolizumab should be permanently withdrawn for any grade confirmed SJS or TEN - Caution should be used when considering the use of atezolizumab in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents
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9.2.14 overdose

In clinical trials with atezolizumab, doses of up to 20 mg/kg have been administered. The standard fixed dose of 1200 mg is equivalent to 15 mg/kg in a typical patient. No dose-limiting toxicities were observed at the 20 mg/kg dose level and the incidence and intensity of AEs reported have not been shown to be dependent on dose. A maximum tolerated dose has not been established. Atezolizumab is supplied in vials containing the fixed 1200 mg dose of drug substance, which minimizes the chance of overdose. Because the dose per patient is not based on weight or body surface area, and no dose calculation is required, the risk of overdose due to medication errors is minimal. The data available to date suggest that the potential for harm from overdose is very low.
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anticipated toxicities of carboplatin and

Carboplatin is known to cause bone marrow suppression including myelosuppression, anemia, and thrombocytopenia. Carboplatin-based chemotherapy is considered to be moderately emetogenic. Patients will be monitored for carboplatin-related adverse events.
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9.3.1 hematologic toxicity

At the start of each cycle if the patient is receiving carboplatin, the ANC must be ≥1000/mm3 and the platelet count must be **≥ 80,000/mm3**. Platelets must be > 100,000 for study entry.  
Growth factors may be used in accordance with American Society of Clinical Oncology (ASCO)
and National Comprehensive Cancer Network (NCCN) guidelines (Smith et al. 2006; NCCN 2012).  
Upon recovery, dose adjustments at the start of a subsequent cycle will be made on the basis of the lowest platelet and neutrophil values from the previous cycle (see Table below).  
9.3.1.1 Carboplatin Dose Modification for Hematologic Toxicities  
| Toxicity                                                          | Carboplatin Dose   |
|-------------------------------------------------------------------|--------------------|
| ANC <500/mm3 and platelets ≥ 50,000/mm3                           | Decrease AUC by 1  |
| Platelets < 50,000/mm3 , regardless of ANC                        | Decrease AUC by 1  |
| Platelets < 50,000/mm3 with Grade ≥ 2                             | Decrease AUC by 2  |
| bleeding, regardless of ANC ANC < 1000/mm3 plus fever of ≥ 38.5°C | Decrease AUC by 1  |  
All dose reductions for the first episode of neutropenic fever or thrombocytopenia (platelet count < 25,000 or < 50,000 with bleeding or that requires transfusion) are permanent. If a second episode of neutropenic fever or thrombocytopenia requiring dose reduction occurs, the dose of carboplatin will be reduced according to physician judgment and local standard practice. Colony-stimulating factors, such as granulocyte colony-stimulating factor, may be used instead of dose reduction for neutropenic fever or Grade 4 neutropenia, according to the local standard practice and ASCO guideline. Patients who require a third dose reduction will immediately discontinue chemotherapy. In the event that dose adjustments are needed for both ANC and platelets, patients are to receive the lower dose.  
For Grade 3 ANC toxicity ( ANC <1000-500/ml), carboplatin should be withheld until the patient recovers completely or to Grade 1 toxicity. The treatment should then be resumed at 50% dose (permanent dose reduction). If recovery to Grade 1 toxicity does not occur within 3 weeks, the patient's chemotherapy will be discontinued.  
Treatment with carboplatin can be delayed for up to 3 weeks until the Day 1 ANC is ≥1000/mm3 and the platelet count is ≥ 80,000/mm3. However, if the counts have not recovered in 3 weeks, the patient's chemotherapy will be dose-reduced, held until adequate neutrophil recovery, or discontinued, according to physician judgment and local standard practice. If chemotherapy is held  
 longer than 42 days, all study treatment should be discontinued. Investigators should be vigilant and alert to early and overt signs of myelosuppression, infection, or febrile neutropenia so that these complications can be promptly and appropriately managed. Patients should be made aware of these signs and encouraged to seek medical attention at the earliest opportunity. If chemotherapy must be withheld because of hematologic toxicity, full blood counts (including differential WBC) should be obtained weekly until the counts reach the lower limits for treatment as outlined. The treatment schedule will then proceed in the usual sequence. No dose reductions will be made for anemia. Patients should be supported per the treating physician's institution's guidelines.
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9.3.2 non-hematologic toxicity

For Grade 3 or 4 non-hematologic toxicities, treatment should be delayed until resolution to less than or equal to the patient's baseline value. Dose reductions at the start of the subsequent cycle will be made on the basis of non-hematologic toxicities from the dose administered in the preceding cycle. The table below provides the relevant dose adjustments for non-hematologic toxicities.  
9.3.2.1 Carboplatin Dose Modification on the Basis of Non-Hematologic
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toxicities in the preceding cycle

| Toxicity                                 | Adjusted Carboplatin Dosea                            |                   |
|------------------------------------------|-------------------------------------------------------|-------------------|
| Diarrhea                                 | Grade 3 or 4b : 100% of dose                          |                   |
| Oral mucositis                           | Grade 3 or 4:                                         | Decrease AUC by 1 |
| Nausea/Vomiting                          | Grade 3 or 4:                                         | Decrease AUC by 1 |
| Neurotoxicity (motor or sensory)         | Grade 2: 100% of dose Grade 3 or 4: Decrease AUC by 1 |                   |
| Transaminase Elevation                   | Grade 3:                                              | Decrease AUC by 1 |
| Grade 4:                                 | discontinue                                           |                   |
| Other                                    | Grade 3 or 4: Decrease AUC by 1                       |                   |
| AUCarea under the concentration curve. |                                                       |                   |  
a If deemed appropriate by the treating physician, adjust carboplatin dose to the specified percentage of the previous AUC. b Or any grade of diarrhea requiring hospitalization.  
Nausea and/or vomiting should be controlled with adequate anti-emetics. If Grade 3 or 4 nausea/vomiting occurs in spite of anti-emetics, the dose should be reduced by 25% for the next course. If tolerated, the dose should be increased back to 100% as soon as possible. If, on Day 1 of any treatment cycle, the patient has grade 2 oral mucositis, the treatment can be  
 withheld until the oral mucositis is cleared. If the oral mucositis has not cleared in 3 weeks, the patient's chemotherapy will be discontinued. If acute Grade 3 oral mucositis occurs at any time, the dose should be given at a 75% dose when the oral mucositis is completely cleared. This is a permanent dose reduction.
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9.3.3 special considerations

- For toxicities which are considered by the treating investigator unlikely to develop into serious or life–threatening events (e.g. alopecia, altered taste etc.), treatment may be continued at the same dose without reduction or interruption.  
- The treating investigator may reduce a subject's dose for a toxicity of any grade/duration where s/he believes it to be in the best interests of the subject.  
- Any consideration to modification of the above dose modification guidelines should be discussed with the Principal Investigator for approval or disapproval in advance.
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drug formulation/storage/supply

Atezolizumab (Mpdl3280A)  
Atezolizumab is an investigational agent and will be supplied free-of-charge from Genentech.
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10.1.1 formulation

The atezolizumab drug product is typically provided in a single-use 15 mL or 20 mL USP/Ph. Eur. Type 1 glass vial as a colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution intended for IV administration. Other excipients of the atezolizumab drug product include histidine acetate, sucrose and polysorbate 20.  
Atezolizumab must be refrigerated at 2°C − 8°C (36°F − 46°F) upon receipt until use.  
Atezolizumab vials should not be used beyond the expiration date provided by the manufacturer. No preservative is used in the atezolizumab drug product or the diluent; therefore, each vial is intended for single use only. Discard any unused portion of drug left in a vial. Vial contents should not be frozen or shaken and should be protected from direct sunlight. Once prepared, atezolizumab can be stored for up to 8 hours at room temperature. For further details, see the atezolizumab Investigator's Brochure.
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10.1.2 dosage administration and storage

The dose level of atezolizumab to be tested in this study is 1200 mg (equivalent to an average body weight−based dose of 15 mg/kg) administered by IV infusion every 3 weeks (21 [± 2] days).  
Atezolizumab will be delivered in infusion bags with IV infusion lines that have product contacting surfaces of polyvinyl chloride (PVC) or polyolefin and 0.2 µm in-line filters (filter membrane of polyethersulfone [PES]). No incompatibilities have been observed between atezolizumab and PVC or polyolefin infusion materials (bags or infusion lines). Administration of atezolizumab will be performed in a setting with emergency medical facilities and staff who are trained to monitor for and respond to medical emergencies.  
The initial dose of atezolizumab will be delivered over 60 (± 15) minutes. If the first infusion is tolerated without infusion-associated AEs, the second infusion may be delivered over 30 (± 10)
minutes. If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered over 30 (± 10) minutes. For the first infusion, the patient's vital signs (heart rate, respiratory rate, blood pressure, and temperature) should be determined within 60 minutes before, during (every 15 [± 5] minutes), and 30 (± 10) minutes after the infusion. For subsequent infusions, vital signs will be collected within 60 minutes before and within 30 minutes after the infusion. Vital signs should be collected during the infusion only if clinically indicated. Patients will be informed about the possibility of delayed post-infusion symptoms and instructed to contact their study physician if they develop such symptoms. Atezolizumab should be administered prior to carboplatin.  
No premedication will be allowed for the first dose of atezolizumab. Premedication may be  
  
administered for Cycles ≥ 2 at the discretion of the treating physician. The management of infusion-related reactions (IRRs) will be according to severity as follows:
- In the event that a patient experiences a mild (NCI CTCAE Grade 1) IRR, the infusion rate should be reduced to half the rate being given at the time of event onset. Once the event has resolved, the investigator should wait for 30 minutes while delivering the infusion at the reduced rate. If tolerated, the infusion rate may then be increased to the original rate.  
- In the event that a patient experiences a moderate IRR (NCI CTCAE Grade 2) or flushing, fever, or throat pain, the infusion should be immediately interrupted and the patient should receive aggressive symptomatic treatment. The infusion should be restarted only after the symptoms have adequately resolved to baseline grade. The infusion rate at restart should be half of the infusion rate that was in progress at the time of the onset of the IRR.  
- For severe or life-threatening IRRs (NCI CTCAE Grade 3 or 4), the infusion should be stopped immediately, and aggressive resuscitation and supportive measures should be initiated. Patients experiencing severe or life-threatening IRRs will not receive further infusion and will be further managed as clinically indicated until the event resolves.  
For anaphylaxis precautions, see the appendices. Guidelines for dosage modification, treatment interruption, or discontinuation and the management of specific adverse events are provided in the protocol.
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carboplatin

Carboplatin is commercially available. Carboplatin should be administered intravenously according to local practice. **Carboplatin should be administered after atezolizumab if the patient is**
receving atezolizumab.  
The carboplatin dose will be calculated using the Cockcroft and Gault formula. For the purposes of this protocol, the GFR is considered to be equivalent to the creatinine clearance (CrCl). The CrCl is calculated by institutional guidelines or by the method of Cockcroft and Gault (1976) using the following formula:
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(140-age) (wt) (x 0.85 if

Where: CrCl = creatinine clearance in mL/min age = patient's age in years wt = patient's weight in kg Scr = serum creatinine in mg/dL If a patient's GFR is estimated on the basis of serum creatinine measurements by the isotope dilution mass spectroscopy method, the U.S. Food and Drug Administration (FDA) recommends that physicians consider capping the dose of carboplatin for desired Protocol Version 11/13/2020 CONFIDENTIAL Page 64 *of 103* This document is confidential Do not disclose or use except as authorized TBCRC 043 exposure (AUC) to avoid potential toxicity caused by overdosing.  
 The maximum dose is based on a GFR estimate that is capped at 125 mL/min for patients with normal renal function. No higher estimated GFR values should be used. For a target AUC = 6, the maximum dose is 6 × 150 = 900 mg. For a target AUC = 5, the maximum dose is 5 × 150 = 750 mg. For a target AUC = 4, the maximum dose is 4 × 150 = 600 mg.  
See the FDA's communication regarding carboplatin dosing for more details at http://www fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm228974 htm
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drug accountability

Accountability for the drug at all study sites is the responsibility of the site Principal Investigator and designated Pharmacy representative. The investigator will ensure that the investigational drug is used only in accordance with this protocol. Drug accountability records indicating the drug's delivery date to the site, inventory at the site, use by each patient, and destruction locally will be maintained by the clinical site. Atezolizumab should be destroyed locally as per local policy. Accountability records will include dates, quantities, lot numbers, expiration dates, and patient numbers. These records should be sent to Genentech for filing.  
TBCRC 043 exposure (AUC) to avoid potential toxicity caused by overdosing.  
 The maximum dose is based on a GFR estimate that is capped at 125 mL/min for patients with normal renal function. No higher estimated GFR values should be used. For a target AUC = 6, the maximum dose is 6 × 150 = 900 mg. For a target AUC = 5, the maximum dose is 5 × 150 = 750 mg. For a target AUC = 4, the maximum dose is 4 × 150 = 600 mg.  
See the FDA's communication regarding carboplatin dosing for more details at http://www fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm228974 htm  
Accountability for the drug at all study sites is the responsibility of the site Principal Investigator and designated Pharmacy representative. The investigator will ensure that the investigational drug is used only in accordance with this protocol. Drug accountability records indicating the drug's delivery date to the site, inventory at the site, use by each patient, and destruction locally will be maintained by the clinical site. Atezolizumab should be destroyed locally as per local policy. Accountability records will include dates, quantities, lot numbers, expiration dates, and patient numbers. These records should be sent to Genentech for filing.
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correlative/special studies

Archived Tissue **Samples**  
Metastatic tissue is the preferred sample; however, if the remaining tissue is insufficient to fit the requirements below, tissue from the patient's primary tumor is acceptable. Formalin-fixed paraffin embedded tissue blocks from the patient's metastatic lesion collected for diagnostic and therapeutic purposes is requested for all patients enrolled in the study at the time of registration. They will be returned within 8 weeks (or earlier if requested); tissue taken from these blocks will not be returned. In case the participating institutions are not allowed to release clinical paraffin embedded blocks from prior surgeries/biopsies, ideally we will need the following cut in this order:
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a. if sending prior metastatic

1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, levels 2-5 to Genentech for PDL-1 IHC)
2. Six (6) 10 µm unstained sections on non-charged slides (Vanderbilt DNA/RNA isolation) 3. Twelve (12) 4 µm unstained slides on charged slides (level 1 and 12 to be H&E stained upon receipt)
If remaining tissue is insufficient for the complete request, please send:
1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, levels 2-5 to Genentech for PDL-1 IHC)
2. Two 5 x 10 μm peels in a DNAse-free/RNAse-free tube If remaining tissue is very limited, please send:
Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, levels 2,3,4,5 to Genentech for PDL-1 IHC)
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b. if sending primary tumor

1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, levels 2-5 to Genentech for PDL-1 IHC)
2. Six (6) 10 µm unstained sections on non-charged slides (Vanderbilt DNA/RNA isolation) 3. Two (2) 4 µm unstained slides on charged slides (last will be H&E stained upon receipt) If remaining tissue is insufficient for the complete request, please send:
1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, levels 2-5 to Genentech for PDL-1 IHC)
If remaining tissue is very limited, please send:
Protocol Version 11/13/2020 CONFIDENTIAL Page 66 *of 103* This document is confidential Do not disclose or use except as authorized Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment,  
 levels 2,3,4,5 to Genentech for PDL-1 IHC)
After removing all stray tissue from the area, the microtome blade and surrounding area should be wiped with 70% ETOH before starting to section the block and between patients to prevent contamination with extraneous tissue. All formalin-fixed paraffin embedded tissue and/or slides should be sent with a cold pack to avoid melting that could damage tissue analysis.  
Once a patient meets all other eligibility, and registers for the study, **collection of tissue from a**
metastatic site, if reasonably safe, is also a requirement for entry to **this study. Pre-trial and**
post-progression **biopsies should be collected.** Research tissue blocks prepared from these metastatic biopsies will not be returned. All patients must have a biopsy of a metastatic site (if reasonably safe) at the end of treatment if the patient is removed for disease progression, or if on the carboplatin only arm and crossing over to atezolizumab.
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11.1.1 guidelines for tissue acquisition

Tissue specimens, when feasible, will be collected from recurrent or metastatic lesions using standard institutional procedures. The amount of tissue collected will follow the guidelines listed below. If a patient has more than one site of disease, only one site needs to be biopsied, and the site is left to the discretion of the patient and the treating physician. If a patient is undergoing resection of a lesion for clinical reasons (i.e. wedge resection of a new lung lesion for confirmation of diagnosis or re-testing of hormone receptor or HER2 status; or, resection of a chest wall lesion; or, resection of a lymph node), then the patient may opt to have a portion of that tissue (roughly equivalent to the goal amount of tissue listed in the guidelines above, i.e. the equivalent of two 5mm punch biopsies of the skin, or 3-6 18-gauge core biopsies) stored for research at the time of the procedure. Listed below are the goal amounts of tissue for patients who undergo core biopsy or punch biopsy, or who have either ascites fluid or pleural fluid accessible for collection. Please note that the below are guidelines for the amount of tissue to be obtained at the baseline biopsy, and are not meant to replace clinical judgment at the time the procedure is performed. Less than the goal quantity of tissue is accepted for each type of biopsy, and will be left to the clinical judgment of the physician performing the procedure.  
- Breast: A goal of 3-6 core biopsy specimens will be obtained using standard institutional guidelines for a diagnostic core biopsy of a breast mass
- Skin/chest wall: A goal of one to two 5-mm punch biops(ies) - Lymph node: A goal of 3-6 core biopsy specimens will be obtained using an 18-gauge needle
- Liver: A goal of 3-6 core biopsy specimens will be obtained using an 18-gauge needle - Lung: A goal of 3 core biopsy specimens will be obtained using an 18-gauge needle. Due to the risk of pneumothorax associated with core needle biopsies of lung nodules, peripheral lesions should be carefully selected.  
- Bone: Because the yield of malignant tissue from bone biopsies tends to be relatively low, if  
  
a patient has another accessible site of disease (i.e. skin, lymph node, liver), that site should be biopsied preferentially. If bone is the only biopsy-accessible site, then a goal of 3-6 core biopsy specimens will be obtained using an 18-gauge needle.  
- Pleural Fluid (known or suspected to be due to malignancy): This should only be used if there is no other site noted above that can be biopsied and this should be discussed with the VICC coordinating center. A goal of 500 cc of pleural fluid will be obtained with a standard thoracentesis procedure, with or without image guidance, according to the clinical judgment of the treating physician and clinician performing the procedure. Less than the goal amount is acceptable, and should be based upon the clinical judgment of the Investigator and the clinician performing the procedure. If more than the goal amount of fluid is obtained, then the entire specimen (with the exception of what is needed for clinical purposes, if applicable) will be stored at Vanderbilt.  
- Ascites fluid: This should only be used if there is no other site noted above that can be biopsied and this should be verified by the VICC coordinating center. A goal of 500 cc of ascites fluid will be obtained with a standard paracentesis procedure, with or without image guidance, according to the clinical judgment of the treating physician and clinician performing the procedure. Less than the goal amount is acceptable, and should be based upon the clinical judgment of the Investigator and the clinician performing the procedure.
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11.1.2 instructions on fresh tissue

*Tissue obtained at Vanderbilt will be handled differently as it does not need to be shipped. Please see the Vanderbilt lab manual for handing if obtaining a biopsy at Vanderbilt*
- First core biopsy should be suspended in 10% buffered formalin.  
- Second core biopsy should be suspended in 5-10 volumes "RNAlater" solution* - Third core biopsy should be suspended in 10% buffered formalin.  
- Fourth core biopsy should be suspended in 5-10 volumes "RNAlater" solution*
- Fifth core biopsy should be suspended in 10% buffered formalin
*RNAlater kits will be provided. 1 core should be placed in one 1.5ml specimen tube. All samples should be shipped immediately, according to the lab manual. For patients in whom a core biopsy is not possible and who thus undergo fine needle aspiration (FNA), 3 passes should be collected.  
- First pass should be evacuated and rinsed directly into 10% buffered formalin - Second pass should be evacuated and rinsed directly into 5-10 volumes "RNAlater" solution*
- Last pass should be evacuated and rinsed directly into 10% buffered formalin.
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blood/plasma collection

Streck Cell-Free DNA BCT kits will be provided for circulating tumor DNA. One vial of whole blood should be collected in a Cell-Free DNA BCT tube (Streck tube). Fill the tube completely. Remove the tube from the adapter and immediately mix by gentle inversion 8 to 10 times. Collection times are: cycle 1/day 1, cycle 2/day 1, and end-of-treatment, see study calendar. Tube should be packed and shipped according to the lab manual and sent immediately (within 24 hours) to VICC at the address provided. Do not freeze specimens collected in Streck **tube.**
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tissue specimen and blood/plasma labeling

Label each collection containers with Patient ID sequence number/code letter, site and location of biopsy, date and time.  
If sample comes in contact with contaminate, make note in information section of paperwork. Enter time core biopsy was collected on paperwork. Outside sites should ship specimens along with Tissue Registration Form as directed in the lab manual. The specimens will be logged in as a consented specimen and available for molecular pathology studies.
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peripheral blood mononuclear cell collection

Blood will be collected on Cycle 1/ Day 1, Cycle 2/ Day 1, and at the end-of-treatment (also Cycle 1/Day 1, Cycle 2/Day 1, and end-of-treatment for those crossing over to carboplatin + atezolizumab). BD Vacutainer® CPT™ Mononuclear Cell Preparation Tubes are included to collect blood. One vial of whole blood should be collected in a BD Vacutainer® CPT™ (CPT tube). Whole blood is drawn directly into the CPT™ using standard phlebotomy techniques and in accordance with the lab manual. Samples should be shipped according to the lab manaul.
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genetic testing

Participants will be given information as part of the informed consent process that samples will be used for research tests that will include genetic studies and testing. The intent is not to give participants (or his/her medical providers) the results of any testing done for research purposes; however, incidental germline (heritable) mutations may be identified of which a participant may or may not already be aware. In the case that an incidental genetic finding is identified, the Protocol Chair of this project will be notified. The possible decisions for handling incidental findings may include notification of the participant (and provider); recommendation for genetic counseling, which may or may not include genetic testing (e.g., if the finding was not done in a CLIA certified laboratory); or, neither. In general, a member of the participant's treating team will be given the information to help with notification. In all cases, the current policy of the Vanderbilt and local/participating site IRB, as applicable, will be followed and any additional approvals that may  
 be required prior to participant notification will be secured in advance.
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specimen banking

Any leftover study tissue or blood samples may be stored for future research studies. The subjects will consent to the future use of samples in the consent form for the study, which includes the transfer of specimens to Genentech for product development. The study PI and collaborators have approval by the TBCRC, which has custodial oversight of all biospecimens collected as part of a TBCRC trial, to address the research questions described in the protocol document. All future use as part of residual or repository specimens collected in this trial for purposes not prospectively defined will require review and approval by the TBCRC according to its established policies, whether the specimens are stored in a central site or at a local institution or in a virtual repository. Secondary use of bio-specimens for new endpoints must be submitted to the TBCRC Central Office for possible review by the TBCRC Correlative Science Review Committee.
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biopsy questionnaire

A questionnaire will be given to each participant to complete at cycle 2, day 1. This questionnaire is designed to assess the impact of the biopsy on the patient's quality of life and overall experience with the study.
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imaging correlative study

Evaluation of muscle mass, muscle attenuation, and adipose mass will be determined using baseline abdominal CT scans collected for central review. A transverse cut at the L3 level will be extracted, as muscle and adipose area at this level is linearly related to whole body mass16. SliceOmatic software (version 5, Tomovision) will be used to process images, providing a highly accurate estimation of cross-sectional skeletal muscle area and muscle attenuation with high inter-observer reliability17. The software is semi-automated and will be run by two independent investigators, with a subset of images read by both investigators to determine a coefficient of variation. Muscle mass, muscle attenuation, and adiposity will be evaluated both as continuous and categorical variables (LMM: yes/no, LMA: yes/no, adipose: tertiles). LMM is defined as skeletal muscle index (SMI,
lean muscle area/height, cm2/m2) less than 41 and LMA will be defined as average muscle density less than 25 HU, or less than 33 HU if the patient is overweight/obese by BMI. These cut-points are based on previously determined thresholds associated with reduced survival in patients with metastatic solid tumors18. We will also explore whether there are alternate cut-points predictive of survival in this particular population based on optimal stratification. Total adiposity will be defined as the sum of visceral adipose tissue, subcutaneous adipose tissue, and intramuscular adipose tissue and evaluated by tertiles.
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measurement of effect

For the purposes of this study, patients should be re-evaluated for response after every 3 cycles. Response and progression will be evaluated in this study using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1). Any evaluable or measurable disease must be documented at screening and reassessed at each subsequent tumor evaluation. For PFS analysis, patients will be considered to have disease progression if their tumor assseessment shows PD by RECIST. However, as conventional response criteria may not adequately assess the activity of immunotherapeutic agents because radiographic  
 progressive disease does not necessarily reflect therapeutic failure, for patients on the carboplatin + atezolizumab arm, if a patient is found to have disease progression by RECIST, at the discretion of the treating physician, the patient may remain on study and managed by irRECIST (see section 12.5) provided he/she meets the following criteria:
- Evidence of clinical benefit as assessed by the investigator.  
- Absence of symptoms and signs (including worsening laboratory values [e.g., new or worsening hypercalcemia]) indicating clinically significant progression of disase
- No decline in ECOG performance status that can be attributed to disease progression
- Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) and no other signs/symptoms of unequivocal disease progression. This includes tumor progression that cannot be managed by protocol-allowed medical interventions (ie., pain secondary to disease or unmanageable ascites, etc.), as determined by the investigator after an integrated review of radiographic data and clinical status.  
Scans should be repeated after 6 weeks, and if progression is confirmed by irRECIST, the patient should be removed from study. If scans by irRECIST show the patient to not have disease progression, the patient may remain on study after discussion with the Protocol Chair. Patients on the carboplatin alone arm who show progression by RECIST must either be removed from study or cross over to receive atezolizumab. Conventional response criteria may not adequately assess the activity of immunotherapeutic agents because radiographic progressive disease does not necessarily reflect therapeutic failure. In Phase Ia Study PCD4989g, several patients who progressed per RECIST v1.1 continued on atezolizumab treatment and subsequently demonstrated durable anti-tumor activity. Of the 21 patients with TNBC in the study who were evaluable for response 3 patients with IC2/3 TNBC showed evidence of target lesion shrinkage after an initial increase in tumor burden or following the appearance of new lesions. These patients likely experienced pseudoprogression or delayed response (Emens et al. 2014). Additionally, in some responding patients with NSCLC in Study PCD4989g, the growth of known lesions or the appearance of new radiographic lesions were shown to contain immune cells and no viable cancer cells on biopsy (Gettinger et al. 2013). The expected rate of pseudoprogression or delayed anti-tumor immunity when atezolizumab is administered in combination with carboplatin is not known. On the other hand, radiographic progression when carboplatin is given alone is likely to represent true disease progression requiring a change in therapy. Although the primary endpoint measures of efficacy (PFS) will be performed using RECIST v1.1, noncomparative analyses of these measures will be performed with use of immune-modified RECIST for patients who continue treatment beyond radiographic progression. The immune-modified RECIST allows the incorporation of new lesions into the calculation of total tumor burden after baseline.
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definitions

Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first  
 treatment with atezolizumab and/or carboplatin. Evaluable for objective response. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.)
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disease parameters 12.2.1 measurable

12.2.1.1 Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:  
- 10mm by CT scan (CT scan slice thickness no greater than 5 mm). - 10mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable).  
- 20mm by chest X-ray.
12.2.1.2 Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.
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12.2.2 non-measurable

All other lesions, including small lesions (longest diameter <10mm or pathological lymph nodes with ≥10 to <15mm short axis) as well as truly non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques. 12.2.3 Special considerations regarding lesion measurability Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular comment:
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12.2.3.1 bone lesions

- Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure bone lesions. However, these techniques can be used to confirm the presence or disappearance of bone lesions.  
- Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated by cross-sectional imaging techniques such as CTor MRI can be considered as measurable lesions if the soft tissue component  
 meets the definition of measurability described above.  
- Blastic bone lesions are non-measurable.  
12.2.3.2 Cystic lesions:
- Lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts.  
- 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non cystic lesions are present in the same patient, these are preferred for selection as target lesions.
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lesions with prior local treatment

- Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered measurable unless there has been demonstrated active tumor.  
- Progression in the lesion. Study protocols should detail the conditions under which such lesions would be considered measurable.  
12.2.4 Specifications by methods of measurements
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12.2.4.1 measurement of lesions

All measurements should be recorded in metric notation, using calipers if clinically assessed. All baseline evaluations should be performed as close as possible to the treatment start and never more than 21 days before the beginning of the treatment.
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12.2.4.2 method of assessment

The same method of assessment and the same technique should be used to characterise each identified and reported lesion at baseline and during follow-up. Imaging based evaluation should always be done rather than clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam.  
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and ≥10mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, documentation by colour photography including a ruler to estimate the size of the lesion is suggested. When lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be undertaken since it is more objective and may also be reviewed at the end of the study. Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung. CT, MRI: CT is the best currently available and reproducible method to measure lesions  
 selected for response assessment. Guidelines have defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5mm or less. When CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for bodyscans). Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances.
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pet/ct may not be used

Endoscopy, laparoscopy: The utilisation of these techniques for objective tumor evaluation is not advised. However, they can be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response or surgical resection is an endpoint. Tumor markers: tumor markers alone cannot be used to assess objective tumor response. If markers are initially above the upper normal limit, however, they must normalise for a patient to be considered in complete response. Cytology, histology: These techniques can be used to differentiate between PR and CR in rare cases if required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where known residual benign tumors can remain). When effusions are known to be a potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can be considered if the measurable tumor has met criteria for response or stable disease in order to differentiate between response (or stable disease) and progressive disease.
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response criteria 12.3.1 target lesions

When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as **target lesions** and will be recorded and measured at baseline (this means in instances where patients have only one or two organ sites involved a maximum of two and four lesions respectively will be recorded). 12.3.2 Evaluation of Target Lesions  
  
12.3.2.1 Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.  
12.3.2.2 Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.  
12.3.2.3 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).  
12.3.2.4 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.
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12.3.3 non-target lesions

All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required and these lesions should be followed as 'present', 'absent', or in rare cases 'unequivocal progression'. In addition, it is possible to record multiple nontarget lesions involving the same organ as a single item on the case record form (e.g. 'multiple enlarged pelvic lymph nodes' or 'multiple liver metastases'). 12.3.4 Evaluation of Non-Target Lesions 12.3.4.1 Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10mm short axis).
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12.3.4.2 non-cr/non-pd

Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.  
12.3.4.3 Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note:
the appearance of one or more new lesions is also considered progression).  
12.3.5 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the study treatment until the end of treatment.  
| Table 3: Time point response  Target Non-Target   | New           | Overall        |          |
|---------------------------------------------------|---------------|----------------|----------|
| Lesions                                           | Lesions       | Lesions        | Response |
| CR                                                | CR            | No             | CR       |
| CR                                                | Non CR/Non PD | No             | PR       |
| Protocol Version 11/13/2020                       | CONFIDENTIAL  | Page 75 of 103 |          |
| This document is confidential                     |               |                |          |
| Do not disclose or use except as authorized       |               |                |          |  
| CR           | Not evaluated               | No     | PR   |
|--------------|-----------------------------|--------|------|
| PR           | Non PD or not all evaluated | No     | PR   |
| SD           | Non PD or not all evaluated | No     | SD   |
| Not all      | Non PD                      | No     | NE   |
| evaluated PD | Any                         | Yes or | PD   |
| no           |                             |        |      |
| Any          | PD                          | Yes or | PD   |
| no           |                             |        |      |
| Any          | Any                         | Yes    | PD   |  
  
CR= completeresponse, PR= partial response, PD= progressive disease, SD= stable disease, NE= not evaluable. * In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "*symptomatic* deterioration". Every effort should be made to document the objective progression even after discontinuation of treatment.
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duration of response

12.4.1 Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.  
12.4.2 Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.
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immune-related response criteria 12.5.1 introduction

Increasing clinical experience indicates that traditional response criteria (e.g., Response Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1] and World Health Organization [WHO]) may not be sufficient to characterize fully activity in the new era of target therapies and/or biologics. In studies with cytokines, cancer vaccines, and monoclonal antibodies, complete response, partial response, or stable disease has been shown to occur after an increase in tumor burden as characterized by progressive disease by traditional response criteria. Therefore, conventional response criteria may not adequately assess the activity of immunotherapeutic agents because progressive disease (by initial radiographic evaluation) does not necessarily reflect therapeutic failure. Long-term effect on the target disease must also be captured. The immune-related response criteria (irRC) are criteria that attempt to do that by enhancing characterization of new response patterns that have been observed with immunotherapeutic agents (i.e., ipilimumab). (Note: The irRC only index and measurable new lesions are taken into account.)
12.5.2 Glossary  
| Term         | Definition                                                     |
|--------------|----------------------------------------------------------------|
| SPD          | sum of the products of the two largest perpendicular diameters |
| Tumor burden | SPDindex lesions+SPDnew, measurable lesions                    |
| Nadir        | minimally recorded tumor burden                                |
| irCR         | immune-related complete response                               |
| irPD         | immune-related progressive disease                             |
| irPR         | immune-related partial response                                |
| irSD         | immune-related stable disease                                  |
| irBOR        | immune-related best overall response                           |  
  
12.5.3 Baseline Assessment Using irRC
Step 1. Identify the index lesions (five lesions per organ, up to ten visceral lesions and five cutaneous lesions). Step 2. Calculate the SPD of all of these index lesions:
∑
i SPD = (Largest diameter of lesion i) × (Second largest diameter of lesion i).  
12.5.4 Post-baseline Assessments Using irRC
Step 1. Calculate the SPD of the index lesions.  
Step 2. Identify new, measurable lesions (≥ 5 × 5 mm; up to five new lesions per organ: five new cutaneous lesions and ten visceral lesions).  
Step 3. Calculate the SPD of the new, measurable lesions. Step 4. Calculate the tumor burden:
Tumor burden = SPDindex lesions + SPDnew, measurable lesions Step 5. Calculate the change in tumor burden relative to baseline and the change in tumor burden relative to nadir. Step 6. Derive the overall response using the table below.  
| Overall Response   | Criterion                                                                                                                                                                      |
|--------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| irCR               | Complete disappearance of all lesions (whether measurable or not, and  no new lesions) confirmed by a repeat, consecutive assessment ≥ 4  weeks from the date first documented |  
Protocol Version 11/13/2020 CONFIDENTIAL Page 77 *of 103* This document is confidential Do not disclose or use except as authorized Protocol Chair:  V. Abramson TBCRC 043  
| Overall Response                                                                    | Criterion                                                          |
|-------------------------------------------------------------------------------------|--------------------------------------------------------------------|
| irPR                                                                                | Decrease in tumor burden ≥ 50% relative to baseline confirmed by a |
| consecutive assessment ≥ 4 weeks from the date first documented                     |                                                                    |
| irSD                                                                                | Criteria for irCR, irPR, and irPD are not met; does not require    |
| cnfirmation                                                                         |                                                                    |
| irPD                                                                                | Increase in tumor burden ≥ 25% relative to nadir confirmed by a    |
| consecutive assessment ≥ 4 weeks from the date first documented                     |                                                                    |
| irCR = immune-related complete response; irPD = immune-related progressive disease; |                                                                    |  
  
irCR = immune-related complete response; irPD = immune-related progressive disease; irPR = immune-related partial response; irSD = immune-related stable disease.  
12.5.5 Determination of Immune-Related Best Overall Response (irBOR)
Once a patient has completed all tumor assessments, his/her irBOR may be determined:  
| Condition                                                                    | irBOR   |
|------------------------------------------------------------------------------|---------|
| At least one irCR                                                            | irCR    |
| At least one irPR and no irCR                                                | irPR    |
| At least one irSD and no irCR and no irPR                                    | irSD    |
| At least one irPD and no irCR, no irPR, and no irSD                          | irPD    |
| irBOR = immune-related best overall response; irCR = immune-related complete |         |  
response; irPD = immune-related progressive disease; irPR = immune-related partial response; irSD = immune-related stable disease.
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12.6 response review and central

At the end of treatment, all scans (baseline and through disease progression, along with crossover scans) should be sent on a CD to the address below for imaging correlatives. These do not need to be overnighted. Please include patient's study ID number the CD/disc.  
Address to send scans at the end of treatment
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assessment of safety adverse event

Safety assessments will consist of monitoring and reporting AEs and SAEs, all events of death, and any study-specific issue of concern.
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general

Adverse event collection and reporting is a routine part of every clinical trial. This study will use the descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v.5.0) that is available at http://ctep.cancer.gov/reporting//ctc.html. Information on all adverse events, whether reported by the participant, directly observed, or detected by physical examination, laboratory test or other means, will be collected, recorded, followed and reported as described in the following sections.  
Adverse events experienced by participants will be collected and reported from initiation of study medication, throughout the study, and within 30 days of the last dose of study medication. Participants who experience an ongoing adverse event related to a study procedure and/or study medication beyond 30 days will continue to be contacted by a member of the study team until the event is resolved, stabilized, or determined to be irreversible by the participating investigator. Participants should be instructed to report any serious post-study event(s) that might reasonably be related to participation in this study. The investigator should notify the IRB and any other applicable regulatory agency of any unanticipated death or adverse event occurring after a participant has discontinued or terminated study participation that may reasonably be related to the study.
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risks associated with atezolizumab

The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may increase the risk of immune-related AEs, specifically the induction or enhancement of autoimmune conditions. AEs with potentially immune-related causes, including rash, hypothyroidism, hepatitis/transaminitis, colitis, myositis, and myasthenia gravis, have been observed in Study PCD4989g. Although most immune-related AEs observed with immunomodulatory agents have been mild and self-limiting, such events should be recognized early and treated promptly to avoid potential major complications (Di Giacomo et al. 2010). A more detailed safety profile of atezolizumab is provided in the atezolizumab Investigator's Brochure.
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safety parameters and definitions

13.3.1 Adverse Event (Ae)  
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. This includes the following:
- AEs not previously observed in the patient that emerge during the protocol-specified AE
reporting period, including signs or symptoms that were not present prior to the AE reporting period
- Complications that occur as a result of protocol-mandated interventions (e.g., invasive procedures such as cardiac catheterizations)
- If applicable, AEs that occur prior to assignment of study treatment associated with medication washout, no treatment run-in, or other protocol-mandated intervention
- Pre-existing medical conditions (other than the condition being studied) judged by the investigator to have worsened in severity or frequency or changed in character during the protocol-specified AE reporting period
- Abnormal laboratory values or diagnostic test results constitute adverse events only if they induce clinical signs or symptoms or require treatment or further diagnostic tests.  
13.3.2 Serious adverse event (SAE)
An AE should be classified as an SAE if any of the following criteria are met:
- It results in death (i.e., the AE actually causes or leads to death)
- It is life threatening (i.e., the AE, in the view of the investigator, places the patient at immediate risk of death. It does not include an AE that, had it occurred in a more severe form, might have caused death.)
- It requires or prolongs inpatient hospitalization - It results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the patient's ability to conduct normal life functions)
- It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP
- It is considered a significant medical event by the investigator based on medical judgment (e.g.,
may jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed above)
- If a patient is hospitalized to undergo a medical or surgical procedure as a result of an AE, the event responsible for the procedure, not the procedure itself, should be reported as the SAE. For example, if a patient is hospitalized to undergo coronary bypass surgery, record the heart condition that necessitated the bypass as the SAE
Events **not** considered to be serious adverse events (and therefore do not require reporting) are  
  
hospitalizations or prolonged hospitalizations for: - routine treatment or monitoring of the studied indication, not associated with any deterioration in condition, or for elective procedures
- diagnostic, elective or pre-planned surgical procedures/treatment for a pre-existing condition that did not worsen
- efficacy measurement for the study - emergency outpatient treatment for an event not fulfilling the serious criteria outlined above and not resulting in inpatient admission
- respite care
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assessment of adverse events

All AEs and SAEs, whether volunteered by the patient, discovered by study personnel during questioning, or detected through physical examination, laboratory test, or other means, will be reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected relationship to the study drug atezolizumab (, and actions taken. To ensure consistency of AE and SAE causality assessments, investigators should apply the following general guideline:
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yes

There is a plausible temporal relationship between the onset of the AE and administration of atezolizumab or carboplatin, and the AE cannot be readily explained by the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response to atezolizumab or carboplatin; and/or the AE abates or resolves upon discontinuation of atezolizumab or carboplatin or dose reduction and, if applicable, reappears upon rechallenge.
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no

Evidence exists that the AE has an etiology other than atezolizumab or carboplatin (e.g., pre-existing medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no plausible temporal relationship to atezolizumab administration (e.g., cancer diagnosed 2 days after first dose of study drug).
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13.4.1 expectedness

- Expected: Expected adverse events are those that have been previously identified as resulting from administration of the agent. For the purposes of this study, an adverse event is considered expected when it appears in the current adverse event list, the Investigator's Brochure, the package insert or is included in the informed consent document as a potential risk.  
- Unexpected: An adverse event is considered unexpected when it varies in nature, intensity or frequency from information provided in the current adverse event list, the Investigator's Brochure, the package insert or when it is not included in the informed consent document as a potential risk
- For patients receiving combination therapy, causality will be assessed individually  
  
for each protocol-mandated therapy.
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13.4.2 attribution

Attribution is the relationship between an adverse event or serious adverse event and the study treatment. Attribution will be assigned as follows: - Definite - The AE is clearly related to the study treatment. - Probable - The AE is likely related to the study treatment. - Possible - The AE may be related to the study treatment. - Unlikely - The AE is doubtfully related to the study treatment. - Unrelated - The AE is clearly NOT related to the study treatment.
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procedures for eliciting recording and

A consistent methodology for eliciting AEs at all subject evaluation time points should be adopted. Examples of non-directive questions include:
· "How have you felt since your last clinical visit?" · "Have you had any new or changed health problems since you were last here?"
13.5.1 Specific Instructions for Recording Adverse Events Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. Avoid colloquialisms and abbreviations. All adverse events will be captured on the appropriate studyspecific case report forms (CRFs).
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13.5.2 diagnosis versus signs and

If known at the time of reporting, a diagnosis should be reported rather than individual signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report the information that is currently available. If a diagnosis is subsequently established, it should be reported as follow-up information.
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13.5.3 deaths

All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, will be reported to the appropriate parties. When recording a death, the event or condition that caused or contributed to the fatal outcome should be reported as the single medical concept. If the cause of death is unknown and cannot be ascertained at the time of reporting, report "Unexplained Death." Deaths that occur during the protocol-specified adverse event reporting period that are attributed by the investigator solely to progression of disease should be recorded only in the study CRF.
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13.5.4 pre-existing medical conditions

A pre-existing medical condition is one that is present at the start of the study. Such conditions should be reported as medical and surgical history. A pre-existing medical condition should be reassessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or character of the condition worsens during the study. When reporting such events, it is important to convey the concept that the pre-existing condition has changed by including applicable descriptors (e.g., "more frequent headaches").
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13.5.5 hospitalizations for medical or

Any AE that results in hospitalization or prolonged hospitalization should be documented and reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a result of an AE, the event responsible for the procedure, not the procedure itself, should be reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass surgery, record the heart condition that necessitated the bypass as the SAE. Hospitalizations for the following reasons do not require reporting:
- Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for preexisting conditions
- Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study or
- Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the study.  
13.5.6 Assessment of Severity of Adverse Events The adverse event severity grading scale for the NCI CTCAE (v5.0 Update current versions) will be used for assessing adverse event severity. Below Table should be used for assessing severity for adverse events that are not specifically listed in the NCI CTCAE. Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE  
Grade Severity  
| 1   | Mild; asymptomatic or mild symptoms; clinical or diagnostic  observations only; or intervention not indicated   |
|-----|-----------------------------------------------------------------------------------------------------------------|  
  
2 Moderate; minimal, local, or non-invasive intervention indicated; or  
  
  
  
  
limiting age‑appropriate instrumental activities of daily living a TBCRC 043 3 Severe or medically significant, but not immediately  
  
life‑threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self‑care activities of daily living b,c 4 Life-threatening consequences or urgent intervention indicated d 5 Death related to adverse event d NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. Note: Based on the most recent version of NCI CTCAE v.5.0 which can be found at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm a. Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. b. Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using the toilet, and taking medications, as performed by patients who are not bedridden. c. If an event is assessed as a "significant medical event," it must be reported as a serious adverse event d. Grade 4 and 5 events must be reported as serious adverse events
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case transmission verification of single

The Sponsor agrees to conduct the Case Transmission verification to ensure that all single case reports have been adequately received by Genentech via the Investigator emailing Genentech a Quarterly line-listing documenting single case reports sent by the Investigator to Genentech in the preceding time period. The periodic line-listing will be exchanged within seven (7) calendar days of the end of the agreed time period. Confirmation of receipt should be received within the time period mutually agreed upon. If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the discrepancies. The responsible individuals for each party shall handle the matter on a case-by-case basis until satisfactory resolution. The sponsor shall receive reconciliation guidance documents  
 within the 'Activation Package'. Following Case Transmission Verification, single case reports which have not been received by Genentech shall be forwarded by the Investigator to Genentech within five (5) calendar days from request by Genentech.  
At the end of the study, a final cumulative Case Transmission Verification report will be sent to Genentech
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13.5.7 pregnancies in female patients

Female patients of childbearing potential will be instructed to immediately inform the investigator if they become pregnant during the study or within 90 days after the last dose of study drug. A Pregnancy Report should be submitted to the VICC Coordinating Center (i.e., no more than 24 hours after learning of the pregnancy). Pregnancy should not be recorded as an adverse event. The investigator should discontinue study drug and counsel the patient, discussing the risks of the pregnancy and the possible effects on the fetus. Monitoring of the patient should continue until conclusion of the pregnancy. Any SAEs associated with the pregnancy (e.g., an event in the fetus, an event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be reported appropriately (see SAE reporting section 13.5.11.2).
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13.5.8 pregnancies in female partners

Male patients will be instructed through the ICF to immediately inform the investigator if their partner becomes pregnant during the study or within 90 days after completing treatment with atezolizumab. Male patients who received study treatment should not attempt to father a child until after this 90 day period. A Pregnancy Report should be completed by the investigator immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted to the VICC Coordinating Center for processing. Attempts should be made to collect and report details of the course and outcome of any pregnancy in the partner of a male patient exposed to study drug. The pregnant partner will need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy. Once the authorization has been signed, the investigator will update the Pregnancy Report with additional information on the course and outcome of the pregnancy. An investigator who is contacted by the male patient or his pregnant partner may provide information on the risks of the pregnancy and the possible effects on the fetus, to support an informed decision in cooperation with the treating physician and/or obstetrician.
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13.5.9 abortions

Any spontaneous abortion should be classified as an SAE (as the Sponsors consider spontaneous abortions to be medically significant events), recorded as such , and reported to the Vanderbilt Coordinating Center (i.e., no more than 24 hours after learning of the event).  
13.5.10Congenital Anomalies/Birth Defects  
  
Any congenital anomaly/birth defect in a child born to a female patient or female partner of a male patient exposed to study drug should be classified as an SAE, recorded as such, and reported to the Vanderbilt Coordinating Center (i.e., no more than 24 hours after learning of the event).
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13.5.11 adverse events of special

AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the product, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor is required. Such an event might require further investigation in order to characterize and understand it. Depending on the nature of the event, rapid communication by the trial Sponsor to other parties (e.g., Regulatory Authorities) may also be warranted. Adverse events of special interest (AESIs) are defined as a potential safety problem, identified as a result of safety monitoring of the IMP. The following AEs are considered of special interest for Atezolizumab and must be reported to the Coordinating Center expeditiously (following the SAE reporting procedure), irrespective of regulatory seriousness criteria:  
- Pneumonitis
- Colitis
- Endocrinopathies: diabetes mellitus, pancreatitis, hyperthyroidism or hypophysitis  
- Hepatitis, including AST or ALT >10x ULN
- Systemic lupus erythematosus
- Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, and meningoencephalitis
- Events suggestive of hypersensitivity, cytokine release syndrome, influenza-like illness, systemic inflammatory response syndrome, or infusion-reaction syndromes  
- Nephritis
- Ocular toxicities (e.g. uveitis, retinitis, optic neuritis)  
- Myositis
- Myopathies, including rhabdomyolysis
- Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)  
- Vasculitis
- Autoimmune hemolytic anemia
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic epidermal necrolysis)
Non Drug Specific AESIs which require immediately reporting:
Cases of potential drug-induced liver injury that include an elevated ALT or AST in  
  
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's law:
Treatment-emergent ALT or AST > 3 x ULN in combination with total bilirubin > 2 x ULN
.  
Treatment-emergent ALT or AST > 3 x ULN in combination with clinical jaundice
.  
Data related to a suspected transmission of an infectious agent by the study drug (STIAMP),
.  
as defined below:
o Any organism, virus, or infectious particle (e.g., prion protein transmitting  
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent.  A transmission of an infectious agent may be suspected from clinical symptoms or laboratory findings that indicate an infection in a patient exposed to a medicinal product.  This term applies only when a contamination of the study drug is suspected.
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13.5.12 exchange of single case

The Sponsor will be responsible for collecting all protocol-defined Adverse Events (AEs)/Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), Special Situation Reports (including pregnancy reports) and Product Complaints (with or without an AE) originating from the Study for the Product.  
Investigators must report all the above mentioned single case reports adequately to Genentech within the timelines described below. The completed MedWatch or CIOMS I form or Genentech approved reporting forms should be faxed/emailed immediately upon completion to Genentech at the following contacts:
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports)
and Product Complaints with an AE should be sent to:
All Product Complaints without an AE should be sent to:
Protocol Version 11/13/2020 CONFIDENTIAL  
  
This document is confidential Do not disclose or use except as authorized
email kaiseraugst.global impcomplaint management@roche.com
13.5.12 exchange of single case

It is understood and agreed that the Sponsor will be responsible for the evaluation of AEs/SAEs, AESIs, Special Situation Reports (including pregnancy reports) and Product Complaints (with or without an AE) originating from the study. These single case reports will be exchanged between the parties as outlined below so that regulatory obligations are met.
email kaiseraugst.global impcomplaint management@roche.com
13.5.13 serious adverse events

All serious adverse events, regardless of causality to study drug, occurring after the patient's first dose of study treatment will be reported to the Principal Investigator and/or the Study Coordinator at each institution, and also to the Coordinating Center. Serious adverse events that occur during screening do not require reporting unless they are due to a screening procedure (eg biopsy). Serious adverse events (SAEs), AEs of Special Interest (AESIs), pregnancy reports (including pregnancy occurring in the partner of a male study subject), other Special Situation Reports and Product Complaints (with or without an AE), where the patient has been exposed to the Genentech Product, will be sent on a MedWatch form or CIOMS I form or on Genentech approved reporting forms to Genentech Drug Safety. Transmission of these reports (initial and follow-up) will be either electronically or by fax and within the timelines specified below: · SADRs Serious AE reports that are related to the Product shall be transmitted to Genentech within fifteen (15) calendar days of the awareness date. · Other SAEs Serious AE reports that are unrelated to the Product shall be transmitted to Genentech within thirty
(30) calendar days of the awareness date. · AESIs AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the awareness date. · Special Situation Reports Pregnancy reports While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as defined herein, any reports of pregnancy (including pregnancy occurring in the partner of a male study subject), where the fetus may have been exposed to the Product, shall be transmitted to Genentech within thirty (30) calendar days of the awareness date. Pregnancies will be followed up until the outcome of the pregnancy is known, whenever possible, based upon due diligence taken to obtain the follow-up information.  
TBCRC 043 Other Special Situation Reports  
  
In addition to all SAEs, pregnancy reports and AESIs, the following other Special Situations Reports should be collected even in the absence of an Adverse Event and transmitted to Genentech within thirty (30) calendar days:
Data related to the Product usage during breastfeeding Data related to overdose, abuse, misuse or medication error (including potentially exposed or intercepted medication errors)
In addition, reasonable attempts should be made to obtain and submit the age or age group of the patient, in order to be able to identify potential safety signals specific to a particular population
email kaiseraugst.global impcomplaint management@roche.com
13.5.13.1 post-study adverse events

The investigator should expeditiously report any SAE occurring after a patient has completed or discontinued study participation if attributed to prior atezolizumab exposure.  If the investigator should become aware of the development of cancer or a congenital anomaly in a subsequently conceived offspring of a female patient who participated in the study, this should be reported as an SAE.
email kaiseraugst.global impcomplaint management@roche.com
13.5.11.2 sae reporting

All serious adverse events must be reported to the Coordinating Center within 1 business day after the treating institution becomes aware of the event. Events should be reported using the Vanderbilt Serious Adverse Event Form, which is part of the packet of supplemental forms. The form must be fully completed and emailed to:
The email subject line should include the study number, patient number, and clearly state SAE
initial or follow up report. Follow-up information must also be reported within 1 business day of receipt of the information by the investigator.  
The Coordinating Center will disseminate information regarding unexpected serious adverse events to the participating sites quarterly after  review of the information by the Protocol Chair (or her designee in the event of extended absence) only in the case that the event(s) is believed to be related (i.e., possibly, probably, or definitely) to the study medication. The Coordinating Center will be responsible for reporting of events to the FDA and supporters, as appropriate (outlined below).
email kaiseraugst.global impcomplaint management@roche.com
13.5.14 product complaints

A product complaint is any written or oral information received from a complainant that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, effectiveness or performance of a product after it has been released and distributed to the commercial market or clinical trial.  All product complaints (with or without an AE) must be reported as an SAE to the Protocol Version 11/13/2020 Page 89 of 103 Coordinating Center within 1 business day after the treating institution becomes aware of the event,  
 according to SAE reporting instructions in protocol Section 13.5.11.2.
email kaiseraugst.global impcomplaint management@roche.com
13.5.15 institutional review board

All adverse events and serious adverse events will be reported to the IRB per current institutional standards. If an adverse event requires modification of the informed consent or the protocol, these modifications will be provided to the IRB, as will the report of the adverse event.
email kaiseraugst.global impcomplaint management@roche.com
coordinating center reporting procedures

Reporting to Regulatory Authorities, Ethics Committees and Investigators Genentech as the Marketing Authorization Holder will be responsible for the reporting of individual case safety reports from the study to the regulatory authority in compliance with applicable regulations. The Investigator as the Sponsor of the Study, will be responsible for the expedited reporting of safety reports originating from the study to the EMA through Eudravigilance Clinical Trial Module (EVCTM), where applicable. The Investigator will be responsible for the expedited reporting of safety reports originating from the Study to the Ethics Committees and Institutional Review Boards (IRB), where applicable. The Investigator will be responsible for the distribution of safety information to its own investigators, where relevant, in accordance with local regulations.
email kaiseraugst.global impcomplaint management@roche.com
13.6.1 food and drug administration

Unexpected serious adverse events believed to be definitely, probably, or possibly related to the medications will be reported to the Food and Drug Administration via MedWatch Form 3500A (http://www.fda.gov/safety/medwatch/howtoreport/downloadforms/default.htm ) by telephone 1800-FDA-1088; or by fax 1-800-FDA-0178.The Coordinating Center will be responsible for correspondence regarding adverse events with the FDA for all participating sites.  
13.6.2 Additional Reporting Requirements for IND
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ind safety reports

Events meeting the following criteria need to be submitted to the FDA as expedited IND Safety Reports according to the following guidance and timelines: 7 Calendar Day Telephone or Fax Report The investigator is required to notify the FDA of any fatal or life-threatening AE that is unexpected and assessed by the investigator to be possibly related to the use of atezolizumab. An unexpected AE is one that is not already described in the atezolizumab Investigator's Brochure. Such reports are to be telephoned or faxed to the FDA and Genentech within 7 calendar days of first learning of the event.  
TBCRC 043 15 Calendar Day Written Report  
 The Investigator is also required to notify the FDA and all participating investigators, in a written IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly related to the use of atezolizumab. An unexpected AE is one that is not already described in the atezolizumab Investigator's Brochure. Written IND Safety reports should include an Analysis of Similar Events in accordance with regulation 21 CFR § 312.32. All safety reports previously filed by the investigator with the IND concerning similar events should be analyzed and the significance of the new report in light of the previous, similar reports commented on. Written IND safety reports with analysis of similar events are to be submitted to the FDA,
Genentech, and all participating investigators within 15 calendar days of first learning of the event.  
The FDA prefers these reports on a MedWatch 3500 form, but alternative formats are acceptable (e.g., summary letter). Contact Information for IND Safety Reports FDA fax number for IND safety reports:
Fax: (800) FDA-0178 All written IND safety reports submitted to the FDA by the investigator must also be faxed to the local site IRB and Genentech at: Fax: (650) 225-4682 or (650) 225-4630 Genentech Drug Safety CTV mailbox: **ctvist_drugsafety@gene.com**
And the Investigator will be responsible for the distribution of safety information to Site IRB.  
For questions related to safety reporting, please contact Genentech Drug Safety:
Tel: (888) 835-2555 Fax: (650) 225-4682 or (650) 225-4630 IND Annual Reports All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to Genentech Copies of such reports should be emailed to Genentech at: Genentech Drug Safety CTV mail box: ctvist_drugsafety@gene.com Other Reports  
 The Sponsor will forward a copy of the Final Study Report to Genentech upon completion of the Study.
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all fda reports

Any study report submitted to the FDA by the Sponsor-investigator should be copied to Genentech.  
This includes all IND annual reports and the Clinical Study Report (final study report).  
Additionally, any literature articles that are a result of the study should be sent to Genentech. Copies of such reports should be mailed to the assigned Clinical Operations contact for the study.
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13.6.3 genentech

The Sponsor-investigator must report all SAEs to Genentech within the timelines described below. The completed MedWatch or comparable SAE form should be faxed or emailed immediately upon completion to Genentech Drug Safety at:
(650) 225-4682 or (650) 225-4360 usds_aereporting-d@gene.com Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it becomes available Additional reporting requirements to Genentech include the following:
- Any reports of pregnancy following the start of administration with the atezolizumab and within the follow-up period (for female patients within one year after the last dose of atezolizumab or the partner of a male patient within three months of completing therapy) This includes reports of abortions and congenital anomalies /birth defects. Pregnancies will be followed up until the outcome of the pregnancy is known, whenever possible, based upon due diligence taken to obtain the follow-up information.  
- All non-serious atezolizumab AEs originating from the study will be forwarded Genentech quarterly.
Note: Investigators should also report events to their IRB as required. In addition to SAEs, pregnancy reports and AESIs, the following safety reports should be collected and transmitted to Genentech/Roche even in the absence of an Adverse Event within thirty (30) calendar days:
- Data related to product usage during pregnancy or breastfeeding Protocol Version 11/13/2020 CONFIDENTIAL Page 92 *of 103* This document is confidential Do not disclose or use except as authorized
- Data related to overdose, abuse, misuse, inadvertent/erroneous administration, medication error  
  
or occupational exposure, with or without association with an AE/SAE unless otherwise specified in the protocol
- Data related to a suspected transmission of an infectious agent via a medicinal product
(STIAMP)
- Lack of therapeutic efficacy In addition, reasonable attempts should made to obtain and submit the age or age group of the patient, in order to be able to identify potential safety signals specific to a particular population .
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safety reconciliation

The Sponsor-investigator agrees to conduct reconciliation for the product. Genentech and the Sponsor-investigator will agree to the reconciliation periodicity and format, but agree at minimum to exchange quarterly line listings of cases received by the other party. If discrepancies are identified, the Sponsor-investigator and Genentech will cooperate in resolving the discrepancies. The responsible individuals for each party shall handle the matter on a case-by-case basis until satisfactory resolution. The sponsor shall receive reconciliation guidance documents within the 'Activation Package.'
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medwatch 3500a reporting guidelines

In addition to completing appropriate patient demographic and suspect medication information, the report should include the following information within the Event Description (item 5) of the MedWatch 3500A form:
- Protocol description (and number, if assigned)
- Description of event, severity, treatment, and outcome if known
- Supportive laboratory results and diagnostics - Investigator's assessment of the relationship of the AE to each investigational product and suspect medication
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follow-up information

Additional information may be added to a previously submitted report by any of the following methods:
- Adding to the original MedWatch 3500A report and submitting it as follow-up
- Adding supplemental summary information and submitting it as follow-up with the original MedWatch 3500A form
- Summarizing new information and faxing it with a cover letter including patient identifiers
(i.e., date of birth, initial, patient number), protocol description and number, if assigned, brief AE description, and notation that additional or follow-up information is being submitted. (The patient identifiers are important so that the new information is added to the correct initial report.)
Occasionally Genentech may contact the reporter for additional information, clarification, or current  
 status of the patient for whom and AE was reported. For questions regarding SAE reporting, you may contact a Genentech Drug Safety representative. Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it becomes available and/or upon request. MedWatch 3500A (Mandatory Reporting) form is available at https://www.fda.gov/media/69876/download
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study close-out

Any study report submitted to the FDA by the Sponsor-Investigator should be copied to Genentech/Roche. This includes all IND annual reports and the Clinical Study Report (final study report). Additionally, any literature articles that are a result of the study should be sent to Genentech/Roche. Copies of such reports should be mailed to the assigned Clinical Operations contact for the study:
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anti-pdl-1-mpd3280a-gsur@gene.com

And to Genentech Drug Safety CTV oversight mail box at: **ctvist_drugsafety@gene.com**
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queries

Queries related to the Study will be answered by the Investigator. However, responses to all safety queries from regulatory authorities or for publications will be discussed and coordinated between the Parties. The Parties agree that Genentech/Roche shall have the final say and control over safety queries relating to the Product. The Investigator agrees that it shall not answer such queries from regulatory authorities and other sources relating to the Product independently but shall redirect such queries to Genentech/Roche. Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent requests for information or review of data are met. The Parties will clearly indicate on the request the reason for urgency and the date by which a response is required.
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safety crisis management

In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), on the conduct of the Study, may lead to labeling changes or regulatory actions that limit or restrict the way in which the Product is used, or where there is media involvement, the Party where the crisis originates will contact the other Party as soon as possible.  The Parties agree that Genentech/Roche shall have the final say and control over safety crisis management issues relating to the Product. The Investigator agrees that it shall not answer such queries from media and other sources relating to the Product but shall redirect such queries to Genentech/Roche.
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data safety and monitoring

Data Management And Reporting  
Participating institutions will be collaborating with Vanderbilt in patient accrual. Data will be collected using a centralized electronic case report form called ON-line Clinical Oncology Research Environment = Oncore is a highly secure, web based, cancer specific, and customizable system that provides fully integrative clinical data management and study administration capabilities developed in an ongoing collaborative effort with NCI designated Comprehensive Cancer Centers. It fully integrates study administration functionality including protocol tracking, patient registration, NCI reporting, review committee tracking, and SAE tracking, with clinical data management functionality including electronic case report forms (eCRF) design, clinical data capture, protocol and regulatory compliance monitoring. Also the system is capable in storing basic protocol information (e.g., IRB approval dates, dates for annual renewals,) and clinical trials research data. Oncore allows the investigator to define specific protocol requirements and generate data collection forms. Creation of the data collection form is done with a single button click after the parameters of an individual protocol have been specified. Oncore permits specification of study protocols, management of patient enrollment, clinical data entry and viewing, and the generation of patient or study-specific reports based on time stamping. OnCore is embedded with a comprehensive domain repository of standard reference codes and forms to promote standardization. The sources for the repository include CDUS, CTC, CDEs from NCI, ICD, MedDRA and various best practices from contributing NCI-designated Comprehensive Cancer Centers. OnCore provides several reporting features specifically addressing NCI Summary 3 and Summary 4 and other reporting requirements. Data may also be exported in a format suitable for import into other database, spreadsheets or analysis systems (such as SPSS). This system will be used to manage all VICCC clinical trials data. OnCore is maintained and supported in the VICC Clinical and Research Informatics Resource. Specified members at each participating site will submit all pertinent regulatory documents to the Coordinating Center, who will store it in a secure location. The Principal Investigator or designee will inform Genentech as defined in the Safety and Data Exchange Agreement (SDEA) of any serious adverse event, and will inform the IRB in accordance with each institution's IRB policy. The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as provided in this protocol. During the study when there is a safety evaluation, the treating investigator or site staff will be responsible for detecting, documenting, and report AEs and SAEs, as detailed in the protocol. If any problem is identified related to the conduct of this research, the VICC Data Safety and Monitoring Committee (DSMC) will be formally asked to review the study and the situation that required DSMC intervention.
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meetings

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1. Lehmann, B.D., et al., *Identification of human triple-negative breast cancer subtypes and* preclinical models for selection of targeted therapies. J Clin Invest, 2011. 121(7): p. 275067.  
2. Masuda, H., et al., *Differential response to neoadjuvant chemotherapy among 7 triplenegative breast cancer molecular subtypes.* Clin Cancer Res, 2013. 19(19): p. 5533-40.  
3. Jezequel, P., et al., *Gene-expression molecular subtyping of triple-negative breast cancer* tumours: importance of immune response. Breast Cancer Res, 2015. 17(1): p. 43.  
4. Burstein, M.D., et al., *Comprehensive genomic analysis identifies novel subtypes and targets* of triple-negative breast cancer. Clin Cancer Res, 2015. 21(7): p. 1688-98.  
5. Adams, S., et al., *Prognostic value of tumor-infiltrating lymphocytes in triple-negative* breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol, 2014. 32(27): p. 2959-66.  
6. Denkert, C., et al., Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2positive and triple-negative primary breast cancers. J Clin Oncol, 2015. 33(9): p. 983-91.  
7. *Pembrolizumab shows potential in breast cancer.* Cancer Discov, 2015. 5(2): p. 100-1.  
8. Chen, X., et al., *TNBCtype: A Subtyping Tool for Triple-Negative Breast Cancer.* Cancer Inform, 2012. 11: p. 147-56.  
9. Rizvi, N.A., et al., *Cancer immunology. Mutational landscape determines sensitivity to PD1 blockade in non-small cell lung cancer.* Science, 2015. 348(6230): p. 124-8.  
10. Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Can Res 2009;15:7412−20.  
11. Wang Z, Aguilar EG, Luna JI, et al: Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med 25:141-151, 2019 12. Mariathasan S, Turley SJ, Nickles D, et al: TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554:544-548, 2018 13. Tsukamoto H, Fujieda K, Miyashita A, et al: Combined Blockade of IL6 and PD-1/PD-L1  
  
Signaling Abrogates Mutual Regulation of Their Immunosuppressive Effects in the Tumor Microenvironment. Cancer Res 78:5011-5022, 2018 14. Shachar SS, Williams GR, Muss HB, et al: Prognostic value of sarcopenia in adults with solid tumours: A meta-analysis and systematic review. Eur J Cancer 57:58-67, 2016 15. Williams GR, Deal AM, Muss HB, et al: Skeletal muscle measures and physical function in older adults with cancer: sarcopenia or myopenia? Oncotarget 8:33658-33665, 2017 16. Mourtzakis M, Prado CM, Lieffers JR, et al: A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metab 33:997-1006, 2008 17. van Vugt JL, Levolger S, Gharbharan A, et al: A comparative study of software programmes for cross-sectional skeletal muscle and adipose tissue measurements on abdominal computed tomography scans of rectal cancer patients. J Cachexia Sarcopenia Muscle 8:285-297, 2017 18. Martin L, Birdsell L, Macdonald N, et al: Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol 31:1539-47, 2013 19. Li LF, Ma C. Epidemiological study of severe cutaneous adverse drug reactions in a city district of China. Clin Exp Dermatol. 2006;31(5):642-647 20. Yang MS, Lee JY, Kim J, et al. Incidence of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Nationwide Population-Based Study Using National Health Insurance Database in Korea. PLoS One. 2016;11(11):e0165933
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correlative/special studies

Archived Tissue **Samples**  
Metastatic tissue is the preferred sample; however, if the remaining tissue is insufficient to fit the requirements below, tissue from the patient's primary tumor is acceptable. Formalin-fixed paraffin embedded tissue blocks from the patient's metastatic lesion collected for diagnostic and therapeutic purposes is requested for all patients enrolled in the study at the time of registration. They will be returned within 8 weeks (or earlier if requested); tissue taken from these blocks will not be returned. In case the participating institutions are not allowed to release clinical paraffin embedded blocks from prior surgeries/biopsies, ideally we will need the following cut in this order:
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a. if sending prior metastatic

1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, levels 2-5 to Genentech for PDL-1 IHC)
2. Six (6) 10 µm unstained sections on non-charged slides (Vanderbilt DNA/RNA isolation) 3. Twelve (12) 4 µm unstained slides on charged slides (level 1 and 12 to be H&E stained upon receipt)
If remaining tissue is insufficient for the complete request, please send:
1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, levels 2-5 to Genentech for PDL-1 IHC)
2. Two 5 x 10 μm peels in a DNAse-free/RNAse-free tube If remaining tissue is very limited, please send:
Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, levels 2,3,4,5 to Genentech for PDL-1 IHC)
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b. if sending primary tumor

1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, levels 2-5 to Genentech for PDL-1 IHC)
2. Six (6) 10 µm unstained sections on non-charged slides (Vanderbilt DNA/RNA isolation) 3. Two (2) 4 µm unstained slides on charged slides (last will be H&E stained upon receipt) If remaining tissue is insufficient for the complete request, please send:
1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, levels 2-5 to Genentech for PDL-1 IHC)
If remaining tissue is very limited, please send:
Protocol Version 11/13/2020 CONFIDENTIAL Page 66 *of 103* This document is confidential Do not disclose or use except as authorized
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blood/plasma collection

Streck Cell-Free DNA BCT kits will be provided for circulating tumor DNA. One vial of whole blood should be collected in a Cell-Free DNA BCT tube (Streck tube). Fill the tube completely. Remove the tube from the adapter and immediately mix by gentle inversion 8 to 10 times. Collection times are: cycle 1/day 1, cycle 2/day 1, and end-of-treatment, see study calendar. Tube should be packed and shipped according to the lab manual and sent immediately (within 24 hours) to VICC at the address provided. Do not freeze specimens collected in Streck **tube.**
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tissue specimen and blood/plasma labeling

Label each collection containers with Patient ID sequence number/code letter, site and location of biopsy, date and time.  
If sample comes in contact with contaminate, make note in information section of paperwork. Enter time core biopsy was collected on paperwork. Outside sites should ship specimens along with Tissue Registration Form as directed in the lab manual. The specimens will be logged in as a consented specimen and available for molecular pathology studies.
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peripheral blood mononuclear cell collection

Blood will be collected on Cycle 1/ Day 1, Cycle 2/ Day 1, and at the end-of-treatment (also Cycle 1/Day 1, Cycle 2/Day 1, and end-of-treatment for those crossing over to carboplatin + atezolizumab). BD Vacutainer® CPT™ Mononuclear Cell Preparation Tubes are included to collect blood. One vial of whole blood should be collected in a BD Vacutainer® CPT™ (CPT tube). Whole blood is drawn directly into the CPT™ using standard phlebotomy techniques and in accordance with the lab manual. Samples should be shipped according to the lab manaul.
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genetic testing

Participants will be given information as part of the informed consent process that samples will be used for research tests that will include genetic studies and testing. The intent is not to give participants (or his/her medical providers) the results of any testing done for research purposes; however, incidental germline (heritable) mutations may be identified of which a participant may or may not already be aware. In the case that an incidental genetic finding is identified, the Protocol Chair of this project will be notified. The possible decisions for handling incidental findings may include notification of the participant (and provider); recommendation for genetic counseling, which may or may not include genetic testing (e.g., if the finding was not done in a CLIA certified laboratory); or, neither. In general, a member of the participant's treating team will be given the information to help with notification. In all cases, the current policy of the Vanderbilt and local/participating site IRB, as applicable, will be followed and any additional approvals that may  
 be required prior to participant notification will be secured in advance.
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specimen banking

Any leftover study tissue or blood samples may be stored for future research studies. The subjects will consent to the future use of samples in the consent form for the study, which includes the transfer of specimens to Genentech for product development. The study PI and collaborators have approval by the TBCRC, which has custodial oversight of all biospecimens collected as part of a TBCRC trial, to address the research questions described in the protocol document. All future use as part of residual or repository specimens collected in this trial for purposes not prospectively defined will require review and approval by the TBCRC according to its established policies, whether the specimens are stored in a central site or at a local institution or in a virtual repository. Secondary use of bio-specimens for new endpoints must be submitted to the TBCRC Central Office for possible review by the TBCRC Correlative Science Review Committee.
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biopsy questionnaire

A questionnaire will be given to each participant to complete at cycle 2, day 1. This questionnaire is designed to assess the impact of the biopsy on the patient's quality of life and overall experience with the study.
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imaging correlative study

Evaluation of muscle mass, muscle attenuation, and adipose mass will be determined using baseline abdominal CT scans collected for central review. A transverse cut at the L3 level will be extracted, as muscle and adipose area at this level is linearly related to whole body mass16. SliceOmatic software (version 5, Tomovision) will be used to process images, providing a highly accurate estimation of cross-sectional skeletal muscle area and muscle attenuation with high inter-observer reliability17. The software is semi-automated and will be run by two independent investigators, with a subset of images read by both investigators to determine a coefficient of variation. Muscle mass, muscle attenuation, and adiposity will be evaluated both as continuous and categorical variables (LMM: yes/no, LMA: yes/no, adipose: tertiles). LMM is defined as skeletal muscle index (SMI,
lean muscle area/height, cm2/m2) less than 41 and LMA will be defined as average muscle density less than 25 HU, or less than 33 HU if the patient is overweight/obese by BMI. These cut-points are based on previously determined thresholds associated with reduced survival in patients with metastatic solid tumors18. We will also explore whether there are alternate cut-points predictive of survival in this particular population based on optimal stratification. Total adiposity will be defined as the sum of visceral adipose tissue, subcutaneous adipose tissue, and intramuscular adipose tissue and evaluated by tertiles.
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measurement of effect

For the purposes of this study, patients should be re-evaluated for response after every 3 cycles. Response and progression will be evaluated in this study using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1). Any evaluable or measurable disease must be documented at screening and reassessed at each subsequent tumor evaluation. For PFS analysis, patients will be considered to have disease progression if their tumor assseessment shows PD by RECIST. However, as conventional response
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definitions

Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first  
 treatment with atezolizumab and/or carboplatin. Evaluable for objective response. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.)
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disease parameters 12.2.1 measurable

12.2.1.1 Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:  
- 10mm by CT scan (CT scan slice thickness no greater than 5 mm). - 10mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable).  
- 20mm by chest X-ray.
12.2.1.2 Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.
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12.2.2 non-measurable

All other lesions, including small lesions (longest diameter <10mm or pathological lymph nodes with ≥10 to <15mm short axis) as well as truly non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques. 12.2.3 Special considerations regarding lesion measurability Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular comment:
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12.2.3.1 bone lesions

- Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure bone lesions. However, these techniques can be used to confirm the presence or disappearance of bone lesions.  
- Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated by cross-sectional imaging techniques such as CT, MRI: CT is the best currently available and reproducible method to measure lesions  
 selected for response assessment. Guidelines have defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5mm or less. When CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for bodyscans). Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances.
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pet/ct may not be used

Endoscopy, laparoscopy: The utilisation of these techniques for objective tumor evaluation is not advised. However, they can be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response or surgical resection is an endpoint. Tumor markers: tumor markers alone cannot be used to assess objective tumor response. If markers are initially above the upper normal limit, however, they must normalise for a patient to be considered in complete response. Cytology, histology: These techniques can be used to differentiate between PR and CR in rare cases if required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where known residual benign tumors can remain). When effusions are known to be a potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can be considered if the measurable tumor has met criteria for response or stable disease in order to differentiate between response (or stable disease) and progressive disease.
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response criteria 12.3.1 target lesions

When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as **target lesions** and will be recorded and measured at baseline (this means in instances where patients have only one or two organ sites involved a maximum of two and four lesions respectively will be recorded).  
| CR           | Not evaluated               | No     | PR   |
|--------------|-----------------------------|--------|------|
| PR           | Non PD or not all evaluated | No     | PR   |
| SD           | Non PD or not all evaluated | No     | SD   |
| Not all      | Non PD                      | No     | NE   |
| evaluated PD | Any                         | Yes or | PD   |
| no           |                             |        |      |
| Any          | PD                          | Yes or | PD   |
| no           |                             |        |      |
| Any          | Any                         | Yes    | PD   |  
  
CR= completeresponse, PR= partial response, PD= progressive disease, SD= stable disease, NE= not evaluable. * In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "*symptomatic* deterioration". Every effort should be made to document the objective progression even after discontinuation of treatment.
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duration of response

12.4.1 Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.  
12.4.2 Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.
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immune-related response criteria 12.5.1 introduction

Increasing clinical experience indicates that traditional response criteria (e.g., Response Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1] and World Health Organization [WHO]) may not be sufficient to characterize fully activity in the new era of target therapies and/or biologics. In studies with cytokines, cancer vaccines, and monoclonal antibodies, complete response, partial response, or stable disease has been shown to occur after an increase in tumor burden as characterized by progressive disease by traditional response criteria. Therefore, conventional response criteria may not adequately assess the activity of immunotherapeutic agents because progressive disease (by initial radiographic evaluation) does not necessarily reflect therapeutic
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assessment of safety adverse event

Safety assessments will consist of monitoring and reporting AEs and SAEs, all events of death, and any study-specific issue of concern.
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general

Adverse event collection and reporting is a routine part of every clinical trial. This study will use the descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v.5.0) that is available at http://ctep.cancer.gov/reporting//ctc.html. Information on all adverse events, whether reported by the participant, directly observed, or detected by physical examination, laboratory test or other means, will be collected, recorded, followed and reported as described in the following sections.  
Adverse events experienced by participants will be collected and reported from initiation of study medication, throughout the study, and within 30 days of the last dose of study medication. Participants who experience an ongoing adverse event related to a study procedure and/or study medication beyond 30 days will continue to be contacted by a member of the study team until the event is resolved, stabilized, or determined to be irreversible by the participating investigator. Participants should be instructed to report any serious post-study event(s) that might reasonably be related to participation in this study. The investigator should notify the IRB and any other applicable regulatory agency of any unanticipated death or adverse event occurring after a participant has discontinued or terminated study participation that may reasonably be related to the study.
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risks associated with atezolizumab

The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may increase the risk of immune-related AEs, specifically the induction or enhancement of autoimmune conditions. AEs with potentially immune-related causes, including rash, hypothyroidism, hepatitis/transaminitis, colitis, myositis, and myasthenia gravis, have been observed in Study PCD4989g. Although most immune-related AEs observed with immunomodulatory agents have been mild and self-limiting, such events should be recognized early and treated promptly to avoid potential major complications (Di Giacomo et al. 2010). A more detailed safety profile of atezolizumab is provided in the atezolizumab Investigator's Brochure.
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safety parameters and definitions

13.3.1 Adverse Event (Ae)  
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. This includes the following:
- AEs not previously observed in the patient that emerge during the protocol-specified AE
reporting period, including signs or symptoms that were not present prior to the AE reporting period
- Complications that occur as a result of protocol-mandated interventions (e.g., invasive procedures such as cardiac catheterizations)
- If applicable, AEs that occur prior to assignment of study treatment associated with medication washout, no treatment run-in, or other protocol-mandated intervention
- Pre-existing medical conditions (other than the condition being studied) judged by the investigator to have worsened in severity or frequency or changed in character during the protocol-specified AE reporting period
- Abnormal laboratory values or diagnostic test results constitute adverse events only if they induce clinical signs or symptoms or require treatment or further diagnostic tests.  
13.3.2 Serious adverse event (SAE)
An AE should be classified as an SAE if any of the following criteria are met:
- It results in death (i.e., the AE actually causes or leads to death)
- It is life threatening (i.e., the AE, in the view of the investigator, places the patient at immediate risk of death. It does not include an AE that, had it occurred in a more severe form, might have caused death.)
- It requires or prolongs inpatient hospitalization - It results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the patient's ability to conduct normal life functions)
- It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP
- It is considered a significant medical event by the investigator based on medical judgment (e.g.,
may jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed above)
- If a patient is hospitalized to undergo a medical or surgical procedure as a result of an AE, the event responsible for the procedure, not the procedure itself, should be reported as the SAE. For example, if a patient is hospitalized to undergo coronary bypass surgery, record the heart condition that necessitated the bypass as the SAE
Events **not** considered to be serious adverse events (and therefore do not require reporting) are  
  
hospitalizations or prolonged hospitalizations for: - routine treatment or monitoring of the studied indication, not associated with any deterioration in condition, or for elective procedures
- diagnostic, elective or pre-planned surgical procedures/treatment for a pre-existing condition that did not worsen
- efficacy measurement for the study - emergency outpatient treatment for an event not fulfilling the serious criteria outlined above and not resulting in inpatient admission
- respite care
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assessment of adverse events

All AEs and SAEs, whether volunteered by the patient, discovered by study personnel during questioning, or detected through physical examination, laboratory test, or other means, will be reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected relationship to the study drug atezolizumab (, and actions taken. To ensure consistency of AE and SAE causality assessments, investigators should apply the following general guideline:
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yes

There is a plausible temporal relationship between the onset of the AE and administration of atezolizumab or carboplatin, and the AE cannot be readily explained by the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response to atezolizumab or carboplatin; and/or the AE abates or resolves upon discontinuation of atezolizumab or carboplatin or dose reduction and, if applicable, reappears upon rechallenge.
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no

Evidence exists that the AE has an etiology other than atezolizumab or carboplatin (e.g., pre-existing medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no plausible temporal relationship to atezolizumab administration (e.g., cancer diagnosed 2 days after first dose of study drug).
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13.4.1 expectedness

- Expected: Expected adverse events are those that have been previously identified as resulting from administration of the agent. For the purposes of this study, an adverse event is considered expected when it appears in the current adverse event list, the Investigator's Brochure, the package insert or is included in the informed consent document as a potential risk.  
- Unexpected: An adverse event is considered unexpected when it varies in nature, intensity or frequency from information provided in the current adverse event list, the Investigator's Brochure, the package insert or when it is not included in the informed consent document as a potential risk
- For patients receiving combination therapy, causality will be assessed individually  
  
for each protocol-mandated therapy.
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13.4.2 attribution

Attribution is the relationship between an adverse event or serious adverse event and the study treatment. Attribution will be assigned as follows: - Definite - The AE is clearly related to the study treatment. - Probable - The AE is likely related to the study treatment. - Possible - The AE may be related to the study treatment. - Unlikely - The AE is doubtfully related to the study treatment. - Unrelated - The AE is clearly NOT related to the study treatment.
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procedures for eliciting recording and

A consistent methodology for eliciting AEs at all subject evaluation time points should be adopted. Examples of non-directive questions include:
· "How have you felt since your last clinical visit?" · "Have you had any new or changed health problems since you were last here?"
13.5.1 Specific Instructions for Recording Adverse Events Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. Avoid colloquialisms and abbreviations. All adverse events will be captured on the appropriate studyspecific case report forms (CRFs).
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13.5.2 diagnosis versus signs and

If known at the time of reporting, a diagnosis should be reported rather than individual signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report the information that is currently available. If a diagnosis is subsequently established, it should be reported as follow-up information.
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13.5.3 deaths

All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, will be reported to the appropriate parties. When recording a death, the event or condition that caused or contributed to the fatal outcome should be reported as the single medical concept. If the cause of death is unknown and cannot be ascertained at the time of reporting, report "Unexplained Death." Deaths that occur during the protocol-specified adverse event reporting period that are attributed by the investigator solely to progression of disease should be recorded only in the study CRF. Coordinating Center within 1 business day after the treating institution becomes aware of the event,  
 according to SAE reporting instructions in protocol Section 13.5.11.2.
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13.5.15 institutional review board

All adverse events and serious adverse events will be reported to the IRB per current institutional standards. If an adverse event requires modification of the informed consent or the protocol, these modifications will be provided to the IRB, as will the report of the adverse event.
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coordinating center reporting procedures

Reporting to Regulatory Authorities, Ethics Committees and Investigators Genentech as the Marketing Authorization Holder will be responsible for the reporting of individual case safety reports from the study to the regulatory authority in compliance with applicable regulations. The Investigator as the Sponsor of the Study, will be responsible for the expedited reporting of safety reports originating from the study to the EMA through Eudravigilance Clinical Trial Module (EVCTM), where applicable. The Investigator will be responsible for the expedited reporting of safety reports originating from the Study to the Ethics Committees and Institutional Review Boards (IRB), where applicable. The Investigator will be responsible for the distribution of safety information to its own investigators, where relevant, in accordance with local regulations.
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13.6.1 food and drug administration

Unexpected serious adverse events believed to be definitely, probably, or possibly related to the medications will be reported to the Food and Drug Administration via MedWatch Form 3500A (http://www.fda.gov/safety/medwatch/howtoreport/downloadforms/default.htm ) by telephone 1800-FDA-1088; or by fax 1-800-FDA-0178.The Coordinating Center will be responsible for correspondence regarding adverse events with the FDA for all participating sites.  
13.6.2 Additional Reporting Requirements for IND
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ind safety reports

Events meeting the following criteria need to be submitted to the FDA as expedited IND Safety Reports according to the following guidance and timelines: 7 Calendar Day Telephone or Fax Report The investigator is required to notify the FDA of any fatal or life-threatening AE that is unexpected and assessed by the investigator to be possibly related to the use of atezolizumab. An unexpected AE is one that is not already described in the atezolizumab Investigator's Brochure. Such reports are to be telephoned or faxed to the FDA and Genentech within 7 calendar days of first learning of the event.
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data safety and monitoring

Data Management And Reporting  
Participating institutions will be collaborating with Vanderbilt in patient accrual. Data will be collected using a centralized electronic case report form called ON-line Clinical Oncology Research Environment = Oncore is a highly secure, web based, cancer specific, and customizable system that provides fully integrative clinical data management and study administration capabilities developed in an ongoing collaborative effort with NCI designated Comprehensive Cancer Centers. It fully integrates study administration functionality including protocol tracking, patient registration, NCI reporting, review committee tracking, and SAE tracking, with clinical data management functionality including electronic case report forms (eCRF) design, clinical data capture, protocol and regulatory compliance monitoring. Also the system is capable in storing basic protocol information (e.g., IRB approval dates, dates for annual renewals,) and clinical trials research data. Oncore allows the investigator to define specific protocol requirements and generate data collection forms. Creation of the data collection form is done with a single button click after the parameters of an individual protocol have been specified. Oncore permits specification of study protocols, management of patient enrollment, clinical data entry and viewing, and the generation of patient or study-specific reports based on time stamping. OnCore is embedded with a comprehensive domain repository of standard reference codes and forms to promote standardization. The sources for the repository include CDUS, CTC, CDEs from NCI, ICD, MedDRA and various best practices from contributing NCI-designated Comprehensive Cancer Centers. OnCore provides several reporting features specifically addressing NCI Summary 3 and Summary 4 and other reporting requirements. Data may also be exported in a format suitable for import into other database, spreadsheets or analysis systems (such as SPSS). This system will be used to manage all VICCC clinical trials data. OnCore is maintained and supported in the VICC Clinical and Research Informatics Resource. Specified members at each participating site will submit all pertinent regulatory documents to the Coordinating Center, who will store it in a secure location. The Principal Investigator or designee will inform Genentech as defined in the Safety and Data Exchange Agreement (SDEA) of any serious adverse event, and will inform the IRB in accordance with each institution's IRB policy. The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as provided in this protocol. During the study when there is a safety evaluation, the treating investigator or site staff will be responsible for detecting, documenting, and report AEs and SAEs, as detailed in the protocol. If any problem is identified related to the conduct of this research, the VICC Data Safety and Monitoring Committee (DSMC) will be formally asked to review the study and the situation that required DSMC intervention.