A Phase II Multi-Center Trial of Abemaciclib With or Without Atezolizumab in Metastatic Castration Resistant Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer, Metastatic Castration-resistant Prostate Cancer
Sponsor: Dana-Farber Cancer Institute

1
DF/HCC Protocol #: 20-701
TITLE:  A Phase II Multi-Center Trial of Abemaciclib with or without Atezolizumab in 
Metastatic Castration Resistant Prostate Cancer
Sponsor-Investigator:           Atish Choudhury, MD PhD
Dana-Farber Cancer Institute
450 Brookline Ave, Dana 930
Boston, MA 02215
Phone: (617) 632-6328
Fax: (617) 632-2165
Email: achoudhury@partners.org
Co-Investigators:
Zachery Reichert, MD
University of Michigan
Email: zreiche@med.umich.edu
 Aihua Yen, MD 
Baylor College of Medicine
E-mail:  ay044661@bcm.edu 
Melissa Reimers, MD
Washington University
E-mail: mreimers@wustl.edu
David Einstein, MD
Beth Israel Deaconess Medical Center
E-mail: deinstei@bidmc.harvard.edu
Statistician:
    Lucia Kwak, MS
    Dana-Farber Cancer Institute
    Email: lkwak@ds.dfci.harvard.edu
Supplied Agents:  Abemaciclib, Eli Lilly; Atezolizumab, Genentech
IND Exempt
IND Sponsor:  Atish Choudhury, MD PhD 
Protocol Type / Version # / Version Date: Version 8: 08/15/2023

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ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase
ALC
Absolute Lymphocyte Count
AST
Aspartate Aminotransferase
BID
Twice (two times) a Day
BUN
Blood Urea Nitrogen
CBCD
Complete Blood Count with Differential
CLIA
Clinical Laboratory Improvement Amendments
CMP
Comprehensive Metabolic Panel
CPI
Checkpoint Inhibitor Immunotherapy
CPK
Creatinine Phosphokinase
CR
Complete Response
CRS
Cytokine Release Syndrome
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTSU
Clinical Trials Support Unit
DLCO
Diffusing capacity of the Lungs for Carbon Monoxide
DLT
Dose Limiting Toxicity
DSMC
Data and Safety Monitoring Committee
ECMO
Extracorporeal Membrane Oxygenation
FEV1
Forced Expiratory Volume in 1 second
FVC
Forced Vital Capacity
GGT
Gamma-glutamyl Transferase
HLH
Hemophagocytic lymphohistiocytosis
H&P
History & Physical Exam
HRPP
Human Research Protections Program
HRR
Homologous Recombination Repair
Ig
Immunoglobulin
IND
Investigational New Drug
INR
International Normalized Ratio
irAE
Immune-related Adverse Event
IRB
Institutional Review Board
irPD
Immune-related Progressive Disease
IRR
Infusion-Related Reaction
IV (or iv)
Intravenously
LFTs
Liver Function Tests
LLN
Lower Limit of Normal
MAS
Macrophage activation syndrome
MTD
Maximum Tolerated Dose

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mCRPC
Metastatic castration resistant prostate cancer
NCI
National Cancer Institute
ORR
Objective Response Rate
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
PFS
Progression Free Survival
PFT
Pulmonary Function Test
PI
Principal Investigator
P.O.
per os/by mouth/orally
PR
Partial Response
PRC
Protocol Review Committee
pts
Patients
RBC
Red Blood Cell count
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
STIAMP
Suspected transmission of an infectious agent
UaP
Unanticipated Problem
ULN
Upper Limit of Normal
VAD
Ventricular Assist Device
WBC
White Blood Cells
ULN
Upper Limit of Normal

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SUMMARY OF CHANGES
Protocol changes
Section
Change
Title Page
Updated version number and date. Changed Baylor College of Medicine PI 
from Arpit Rao to Aihua Yen
Abbreviations
Added “pts” = Patients
Schema, 
Synopsis, 1.1, 
5 
Updated study design to account for closure of Arm B and combination cohort 
of Arm C to further enrollment.  Updated study design for Arm C such that 
after the exploratory cohort of 5 patients treated with atezolizumab are 
enrolled, the subsequent 16 patients will be treated with abemaciclib 
monotherapy rather than abemaciclib with atezolizumab. 
Synopsis, 1.4, 
13.1.3, 13.5
Updated primary biomarker objective and statistical plan to note that “the 
FoxP3+/CD8+ T-cell ratio in all biopsy specimens and the change between 
pre-treatment and on-treatment specimens will be reported descriptively for 
each treatment arm separately” rather than comparing monotherapy to 
combination therapy.
Synopsis, 
13.2
Updated sample size for Arms A and B from 27 in each arm to 27 in Arm A 
and 8 in Arm B (i.e. from 54 to 35 total across Arms A and B) and for the 
total trial from 75 to 56 patients 
Synopsis, 1.1, 
5
Removed Arm B and combination cohort for Arm C from Treatment Plan and 
added abemaciclib monotherapy for 16 patients in Arm C.
Synopsis, 
3.3.27
Added exclusion criterion for treatment with systemic immunosuppressive 
medication
Synopsis, 
13.2
Updated efficacy analysis as follows:

Removed efficacy analysis and sample size justification for Arm B, 
and instead noted “The efficacy endpoints of 6m-PFS and ORR in 
patients treated with combination of abemaciclib and atezolizumab in 
arm B will be listed individually due to small number.”

Updated efficacy analysis for Arm C to reflect 16 patients treated with 
abemaciclib monotherapy rather than abemaciclib with atezolizumab
Synopsis, 1.1, 
13.3
Updated the safety analysis to note: “Due to two grade 5 sepsis events 
observed in the 8 patients treated on Arm B with unclear relationship to the 
study medications, the Sponsor-Investigator and co-investigators elected to 
halt enrollment to combination treatment rather than following the Bayesian 
toxicity monitoring plan” and modified the analysis plan accordingly
Synopsis, 1.1, 
13.3, Table 
28, Table 29
Clarified the Bayesian toxicity monitoring plan such that de-escalation and 
stopping rules are based on the number of patients experiencing DLT rather 
than the total number of DLTs.
1.3
Added arm names for clarification

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2.2
Updated FDA approvals for atezolizumab
6.1
Added general recommendations for management of any other adverse events 
related to atezolizumab that may occur and are not specifically listed
Added to Pulmonary Event, Grade 3 or 4: “Oral or IV broad-spectrum 
antibiotics should be administered in parallel to the immunosuppressive 
treatment.”
Added to Diarrhea or colitis, Grade 2 or 3: “If the event does not improve 
within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.”
Updated language and management guidelines for endocrine events, cardiac 
events, neurologic disorders, per most current atezolizumab template.
Added to Hemophagocytic lymphohistiocytosis and macrophage activation 
syndrome: "Clinical and laboratory features of severe CRS overlap with HLH, 
and HLH should be considered when CRS presentation is atypical or 
prolonged."
7.1.2
Added facial paresis and myelitis as expected toxicities of atezolizumab, 
changed “pericarditis” to “pericardial disorders.”
7.2.2
Added “i.e., the AE results in substantial disruption of the subject’s ability to 
conduct normal life functions” that was missing in error
7.2.8
Added facial paresis and myelitis as adverse events of special interest with 
atezolizumab
7.4
Adverse event reporting requirements clarified 
7.6
Added MedWatch 3500A Reporting Guidelines to Reporting Procedures to 
Genentech
7.6.1
In Case Transmission Verification of Single Case Reports, added information 
regarding Reporting to Regulatory Authorities, Ethics Committees and 
Investigators
8.1.4
Added “In the event a subject cannot be seen for a cycle visit due to COVID-
19 infection or suspicion for COVID-19 infection, abemaciclib may be 
shipped upon approval of PI.”
9.1.2
Added “The window for the on-treatment biopsy can be extended per PI 
discretion if the patient required dose interruption(s) prior to the biopsy.”
11.1.4
Replaced “Cohorts B and C” with “Patients receiving Atezolizumab”
13.1.1, 13.3
Corrected erroneous reference to DLT definition from section 7.4 to section 
7.3.

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13.3, Table 
28
Clarified that patients must have received at least 28 days of trial therapy (or 
have experienced a DLT) to be considered DLT-evaluable.
Appendix E
Added autoimmune myelitis to the list of Autoimmune Diseases and Immune 
Deficiencies
 
Informed Consent Form changes
Section
Change
2
Edited to include note that the combination of atezolizumab and 
abemaciclib is no longer being studied
4
Removed reference to combination. Updated new total enrollment 
number from 75 to 56.
A. Why is this 
Research 
Study Being 
done
Edited to include note that the combination of atezolizumab and 
abemaciclib is no longer being studied, and added rationale for 
atezolizumab monotherapy and abemaciclib monotherapy in patients 
with CDK12 mutations as follows: 

“Atezolizumab is ineffective on its own in most patients with 
prostate cancer, but may be effective in certain subsets of 
patients and is being tested in combination with other drugs for 
prostate cancer in other clinical trials.”

“There are other studies that have demonstrated that cancers with 
mutations in the CDK12 gene often have other genetic changes 
that may lead them to be sensitive to cyclin dependent kinase 
inhibitors, so we are also testing whether abemaciclib is effective 
in these patients.”
B. What is 
involved in this 
Research 
Study?
Removed information about randomization. Removed information about 
arm B and the combination treatment information for arm C due to 
cohort closures.
C. What are the 
risks or 
discomforts of 
the research 
study?
Added the following to risks associated with abemaciclib:
“Rare (Less than a 1% chance that this will happen)
• Fever with decreased number of white blood cells in the blood 
(neutropenia) has been reported in less than 1% of patients 
exposed to abemaciclib across trials. This can lead to severe 
generalized infection (sepsis) with side effects involving several 
organs in your body (for example, liver, kidney, lungs, and bone 
marrow), causing a serious condition, which could lead to 
hospitalization, life-threatening circumstances, or even death.  
Two deaths due to neutropenic sepsis were observed in a study of 
abemaciclib called MONARCH 2.”
C. What are 
the risks or 
discomforts 
of the 
research 
Added the following to risks associated with atezolizumab:
“Abemaciclib may be an immune-modulating drug that when 
combined with atezolizumab could increase the risk of sepsis 
resulting in death, so the combination of atezolizumab with 
abemaciclib is no longer being studied.”

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study?
 

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SCHEMA
SYNOPSIS
Title
A Phase II Trial of Abemaciclib with or without Atezolizumab in 
Metastatic Castration Resistant Prostate Cancer
Phase
Phase II
Methodology
Open-label
Study Duration
36 months
Study Center(s)
Multi-Center: up to 5 sites including lead site: Dana-Farber Cancer 
Institute
Objectives
Primary Objectives:
1. To determine the efficacy of abemaciclib monotherapy in biomarker-
unselected patients with metastatic CRPC (Arm A).
2. To determine the efficacy of abemaciclib in combination with 
atezolizumab in biomarker-unselected patients with metastatic CRPC 
(Arm B). 
3. To determine the safety of abemaciclib in combination with 
atezolizumab in mCRPC (Arm B).

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Secondary Objectives:
1. To evaluate secondary measures of clinical efficacy of abemaciclib 
monotherapy (Arm A) and abemaciclib in combination with 
atezolizumab (Arm B)in biomarker-unselected cohort.
2. To identify the clinical variables associated with response and 
resistance to therapy including type of prior antiandrogen therapy 
(CYP17 inhibitor or AR antagonist), duration since prior 
antiandrogen therapy, receipt of prior chemotherapy, and visceral- 
versus bone- predominant disease (Arms A and B).
3. To determine the safety and adverse event profiles of abemaciclib 
monotherapy and abemaciclib in combination with atezolizumab in 
mCRPC (all Arms).
Exploratory/Translational Objectives:
1. To assess the efficacy of atezolizumab alone and abemaciclib 
monotherapy in the CDK12 loss cohort (Arm C).
2. Primary translational objective: To assess FoxP3+/CD8+ ratio in all 
biopsy specimens and the change between pre-treatment and on-
treatment specimens will be reported descriptively for each treatment 
arm separately).
3. To perform detailed profiling of tumor immune infiltrate from paired 
baseline (where available) and on-treatment tumor biopsies in 
biomarker-unselected and CDK12 mutant cohorts (all Arms).
4. Evaluate changes in androgen-receptor signaling pathway with 
exposure to abemaciclib monotherapy and abemaciclib in 
combination with atezolizumab (all Arms).
5. Identify the biomarkers of response and resistance to abemaciclib 
monotherapy and in combination with atezolizumab in biomarker-
unselected patients (Arm A and B).
Number of Subjects
Arms A and B: 35 total (27 in Arm A and 8 in Arm B)
Arm C: 21 total
Total trial: 56 patients
Inclusion Criteria
(All patients)
1
Diagnosis of metastatic castration resistant prostate cancer 
(mCRPC), with histologic confirmation of adenocarcinoma of the 
prostate, without evidence of small cell carcinoma. 
2
Adult males 18 years of age or older. 
3
ECOG performance status of 0 or 1. 
4
Presence of a lesion (bone or soft tissue) amenable to image-guided 
percutaneous biopsy, and patient evaluable for response based on: 
baseline PSA ≥ 2 ng/mL OR 
measurable disease per RECIST 1.1 criteria.
5
Past progression or intolerance to at least one novel antiandrogen 
therapy (abiraterone, enzalutamide, galeterone, apalutamide, 
darolutamide, orteronel, seviteronel or equivalent) in either the 
hormone-sensitive or castration-resistant disease setting. 
6
Not a candidate for docetaxel or cabazitaxel chemotherapy due to: 

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progression within 12 months of completion or intolerance to prior 
taxane OR 
refusal of taxane OR 
contraindication to, or lack of fitness for taxane OR 
Investigator assessment that taxane is not clinically indicated or 
preferred. 
7
Maintenance of castration status, defined as serum testosterone level 
of less than 50 ng/dL. Patients must be surgically castrate or 
maintained on LHRH agonist or antagonist therapy for the duration 
of the study period. 
8
Must have recovered from any treatment-related toxicities to ≤ 
CTCAE grade 1. 
Patients with ≤ CTCAE grade 2 anorexia, alopecia, neuropathy, 
and/or fatigue however, are also permitted to enroll.
9
Patients must have normal organ and marrow function as defined 
below:
-leukocytes ≥3,000/mcL
-absolute neutrophil count ≥1,500/mcL
-lymphocyte count ≥500/mcL
-hemoglobin ≥9 g/dL (without transfusion or growth factor in prior 
28 days, except for patients assigned to atezolizumab 
monotherapy in Arm C for whom transfusion to meet this 
eligibility criterion is permitted)
-platelets ≥100,000/mcL (without transfusion or growth factor in 
prior 28 days)
-serum albumin ≥ 25 g/L (2.5 g/dL)
-total bilirubin ≤1.5 × institutional upper limit of normal, unless the 
subject has known or suspected Gilbert’s syndrome in which case 
total bilirubin must be ≤ 2 × ULN
-AST(SGOT)/ALT(SGPT) ≤1.5 × institutional upper limit of normal, 
except for patients assigned to atezolizumab monotherapy in Arm 
C for whom ≤2.5 × upper limit of normal is permitted
-INR and aPTT ≤1.5 × institutional upper limit of normal, unless the 
subject is receiving therapeutic anticoagulation, in which case 
they must be on a stable anticoagulant regimen
-creatinine clearance ≥30 mL/min/1.73 m2
10 Life expectancy of at least 6 months, as determined by a study 
Investigator. 
11 Ability to swallow oral medications.
12 Ability to understand and willingness to sign an IRB-approved 
informed consent. 
(Arm C patients, additional criterion)
1
Must have documentation (via CLIA approved, CAP certified next 
generation sequencing [NGS] assay report) of genomic aberration 
resulting in CDK12 loss of function in metastatic tumor tissue.
Exclusion Criteria 
(All patients)
1
History of leptomeningeal disease, or clinical evidence of, or known 
and untreated metastatic CNS disease. 

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2
Concurrent active malignancy with the exception of malignancies 
with a negligible risk of metastasis or death (e.g., 5-year OS rate > 
90%). 
Patients with adequately treated non-melanomatous skin cancer, 
cancer not needing active therapy for at least 2 years, cancer for 
which the treating investigator deems the subject to be in remission, 
or any prior malignancy that was treated with curative intent (no 
evidence of disease for at least 3 years) are also permitted to enroll. 
3 
Treatment with chemotherapy or radiotherapy within 4 weeks prior 
to planned cycle 1 day 1 of study treatment. 
4 
Treatment with investigational therapy within 28 days prior to 
initiation of study treatment.
5 
Treatment with oral anti-neoplastic intervention such as an oral 
hormonal agent, PARP inhibitor, or AR targeted therapy within 14 
days prior to planned cycle 1 day 1 of study treatment.
6
Treatment with systemic immunostimulatory agents (including, but 
not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 
5 half-lives of the drug (whichever is longer) prior to initiation of 
study treatment.
7
Major surgical procedure, other than for diagnosis, within 4 weeks 
prior to initiation of study treatment, or anticipation of need for a 
major surgical procedure during the study.
8
Prior treatment with an inhibitor of CDK4 and/or 6.
9
Prior treatment with CD137 agonists or immune checkpoint 
blockade therapies, including anti– CTLA-4, anti–PD-1, PD-L1, or 
PD-L2 therapeutic antibodies. 
10 History of severe allergic anaphylactic reactions to chimeric or 
humanized antibodies or fusion proteins.
11 Known hypersensitivity to Chinese hamster ovary cell products or to 
any component of the atezolizumab formulation.
12 Known allergy or hypersensitivity to any component of the 
abemaciclib formulation.
13 Patients on concurrent therapy with a moderate or strong CYP3A4 
inducer or inhibitor, which cannot be safely stopped at least five 
half-lives prior to initiation of therapy with abemaciclib.
14 Active or history of autoimmune disease or immune deficiency, 
including, but not limited to, myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid 
arthritis, inflammatory bowel disease, antiphospholipid antibody 
syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-
Barré syndrome, or multiple sclerosis (see Appendix E for a more 
comprehensive list of autoimmune diseases and immune 
deficiencies), with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who 
are on thyroid-replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an 
insulin regimen are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo 
with dermatologic manifestations only (e.g., patients with 

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psoriatic arthritis are excluded) are eligible for the study 
provided all of following conditions are met:
-Rash must cover < 10% of body surface area
-Disease is well controlled at baseline and requires only low-
potency topical corticosteroids
-There has been no occurrence of acute exacerbations of the underlying 
condition requiring psoralen plus ultraviolet A radiation, 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, 
or high-potency or oral corticosteroids within the previous 12 
months
15 Prior allogeneic stem cell or solid organ transplantation
16 Treatment with a live attenuated vaccine within 4 weeks prior to 
initiation of study treatment, or anticipation of need for such a 
vaccine during atezolizumab treatment or within 5 months after the 
final dose of atezolizumab
17 Active smoking (of tobacco, marijuana, or any other substance) or 
vaping at time of enrollment, or a history of smoking equivalent to 
greater than 20 pack-years of cigarettes.
18   Prior history of radiation therapy to thorax (including to 
lungs/pleura, esophagus, intrathoracic lymph nodes, C7-L2 
vertebrae, or ribs) for any reason and any duration/dose. This 
exclusion criterion does not apply to patients assigned to 
atezolizumab monotherapy in Arm C, who may have received prior 
radiation to thorax. 
19   History of idiopathic pulmonary fibrosis, organizing pneumonia 
(e.g., bronchiolitis obliterans), drug-induced pneumonitis, or 
idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest computed tomography (CT) scan.
20   Active tuberculosis
21   Uncontrolled pleural effusion, pericardial effusion, or ascites 
requiring recurrent drainage procedures (once monthly or more 
frequently)
Patients with indwelling catheters (e.g., PleurX®) are allowed.
22   Any history of lung cancer, regardless of stage or treatment
23   Any of the following abnormalities on pre-treatment pulmonary 
function testing:
a.
FEV1/FVC ratio < lower limit of normal (LLN) and FEV1 < 
75% predicted OR
b.
FVC < 70% of predicted, regardless of FEV1/FVC ratio OR
c.
DLCO (corrected for hemoglobin) < 70% of predicted
24 Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at 
study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing 
nerve impingement) amenable to palliative radiotherapy should 
be treated prior to enrollment.  Patients should be recovered 
from the effects of radiation.  There is no required minimum 
recovery period.
Asymptomatic metastatic lesions that would likely cause functional 

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deficits or intractable pain with further growth (e.g., epidural 
metastasis that is not currently associated with spinal cord 
compression) should be considered for loco-regional therapy if 
appropriate prior to enrollment.
25 Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 
mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
26 Severe infection, or active known detectable viral infection (e.g., 
Human Immunodeficiency Virus [HIV] or viral hepatitis) within 4 
weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteremia, 
or severe pneumonia, or any active infection that could impact 
patient safety.
27 Treatment with systemic immunosuppressive medication (including, 
but not limited to, corticosteroids, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks 
prior to initiation of study treatment, or anticipation of need for 
systemic immunosuppressive medication during study treatment, 
with the following exceptions:
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) 
are eligible for the study.
Patients who received mineralocorticoids (e.g., fludrocortisone), 
corticosteroids for chronic obstructive pulmonary disease (COPD) 
or asthma, or low-dose corticosteroids for orthostatic hypotension 
or adrenal insufficiency are eligible for the study. 
28 Treatment with therapeutic oral or IV antibiotics within 2 weeks 
prior to initiation of study treatment.
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary 
tract infection or chronic obstructive pulmonary disease 
exacerbation) are eligible for the study.
29 Current treatment with anti-viral therapy for HBV.
30 Arterial or venous thromboembolic event within the last 3 months.
31 Significant cardiovascular disease (such as New York Heart 
Association Class II or greater cardiac disease, myocardial 
infarction, cerebrovascular accident, unstable arrhythmia, or unstable 
angina) within 3 months prior to initiation of study treatment.
32 Any other disease, metabolic dysfunction, physical examination 
finding, or clinical laboratory finding that contraindicates the use of 
an investigational drug, may affect the interpretation of the results, 
or may render the patient at high risk from treatment complications.
33 Significant infection, medical condition, or social situation which, in 
the opinion of the investigator, would preclude participation or limit 
the patient’s ability to comply with study requirements.
Study Product(s), Dose, 
Route, Regimen
Arm A:
Abemaciclib 200 mg orally BID Days 1-21 
Arm C: 

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Atezolizumab 1200 mg IV on Day 1
  OR
Abemaciclib 200 mg orally BID Days 1-21
All cycles are 21 days in length. Starting doses are subject to safety 
analyses. 
Duration of 
Administration
Patients may be treated until disease progression or unacceptable toxicity 
or other reasons subject to Investigator/patient discretion. 
Statistical Methodology
Efficacy Analysis
27 total evaluable patients in Arm A will provide 86% power for 6 
month progression-free survival (with null 6m-PFS 12% and alternative 
of 34%) and 85% power for objective response rate (with null ORR 10% 
and alternative of 30%) and with a one-sided type 1 error of 8%.  When 
12 patients in Arm A have been enrolled and followed for maximum 6 
months, Arm A will close if there is no patient with response or with 6m-
PFS. Otherwise, the 2nd stage will open, and 15 more patients will be 
enrolled in that arm for 8 months for a total of 27 patients.  The 6m-PFS 
Kaplan-Meier estimate for Arm A will be reported with a 90% 
confidence interval. If 6 patients experience 6m-PFS or 5 patients have 
an objective response by the end of stage 2, this study would suggest 
meaningful clinical activity.
For Arm C (CDK12 loss CRPC), similar assumptions will be made with 
expected efficacy with a null 6m-PFS rate of 12% and an alternative 
response of 34% or greater with abemaciclib therapy. Due to accrual 
limitations in this arm, we will use a single stage design. Five patients 
with CDK12 loss will be accrued to an atezolizumab monotherapy as 
exploratory group. Then, 16 additional subjects with CDK12 loss will be 
accrued to therapy with abemaciclib for 18 months, the same accrual 
time as arm A. A one-sided, one-sample log-rank test calculated from a 
sample of 16 subjects achieves 80-85% power at a 0.05 significance 
level to detect 22% of difference in 6m-PFS. Follow-up continues for 12 
months after the last subject is added. The 6m-PFS Kaplan-Meier 
estimate will be reported with a 90% confidence interval.
Safety analysis  
Safety and tolerability for abemaciclib monotherapy and for the 
combination of abemaciclib and atezolizumab will be summarized by rate 
of dose-limiting toxicities (DLTs) as defined in section 8.3.8 using 
percentage and 90% confidence interval, and by incidence and grade of 
adverse events (AEs) by CTCAE version 5.0.
Bayesian toxicity monitoring was planned to be used for all patients 
enrolled to Arm B and to the combination treatment cohort of Arm C (up 
to a maximum of 43 patients).  If the rate of patients experiencing dose 
limiting toxicities (DLTs) at the starting dose exceeded the pre-specified 
threshold for excessive toxicity, then subsequent patients randomized to 

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Arm B or enrolled to the combination cohort of Arm C were planned to  
receive abemaciclib at one dose level reduction (100 mg BID) with 
atezolizumab 1200 mg every 21 days.  If the rate of patients experiencing 
DLTs at the reduced dose exceeded the pre-specified threshold for 
excessive toxicity, then enrollment to Arm B and the combination cohort 
of Arm C was planned to be halted. Due to two grade 5 sepsis events 
observed in the 8 patients treated on Arm B with unclear relationship to 
the study medications, the Sponsor-Investigator and co-investigators 
elected to halt enrollment to combination treatment rather than following 
the Bayesian toxicity monitoring plan. Unselected patients will continue 
to enroll on Arm A in a non-randomized fashion (up to 27 patients in 
total in Arm A) and patients with CDK12 loss subsequently enrolled on 
Arm C after the 5 patients treated with atezolizumab monotherapy will 
receive abemaciclib 200 mg BID as monotherapy (total enrollment on 
Arm C up to 21 patients in total).
TABLE OF CONTENTS
ABBREVIATIONS
2
SUMMARY OF CHANGES...........................................................................................................4
SCHEMA
8
SYNOPSIS
8
TABLE OF CONTENTS...............................................................................................................15
1.
OBJECTIVES19
1.1
Study Design..........................................................................................................19
1.2
Primary Objectives.................................................................................................20
1.3
Secondary Objectives.............................................................................................20
1.4
Exploratory/Translational Objectives....................................................................20
2.
BACKGROUND ...............................................................................................................20
2.1
Study Disease(s).....................................................................................................20
2.2
IND Agent(s) .........................................................................................................22
2.3
Rationale ................................................................................................................22
2.4
Correlative Studies Background ............................................................................27
3.
PARTICIPANT SELECTION...........................................................................................29
3.1
Eligibility Criteria..................................................................................................29
3.2
Additional Inclusion Criteria (Arm C patients) .....................................................31
3.3
Exclusion Criteria ..................................................................................................31
3.4
Inclusion of Women and Minorities ......................................................................35
4
REGISTRATION And Randomization PROCEDURES..................................................35
4.1
General Guidelines for DF/HCC Institutions ........................................................35

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4.2
Registration Process for DF/HCC Institutions.......................................................36
4.3
General Guidelines for Other Investigative Sites ..................................................36
4.4
Registration Process for Other Investigative Sites.................................................36
5.
TREATMENT PLAN........................................................................................................37
5.1.
Treatment Regimen................................................................................................37
5.2.
Pre-Treatment Criteria ...........................................................................................38
5.3.
General Concomitant Medication and Supportive Care Guidelines......................39
5.4
Criteria for Taking a Participant Off Protocol Therapy.........................................40
5.5
Duration of Follow Up...........................................................................................41
5.6
Criteria for Taking a Participant Off Study ...........................................................41
5.7
Patient Replacement...............................................................................................42
5.8
Treatment Beyond Progression..............................................................................42
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................42
6.1
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab ....................................................44
6.2
Abemaciclib Toxicity Management.......................................................................66
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................72
7.1
Expected Toxicities................................................................................................72
7.2
Adverse Event Characteristics and Definitions .....................................................72
7.3
Dose-Limiting Toxicities (DLT)............................................................................79
7.4
Adverse Event Reporting.......................................................................................81
7.5
Reporting procedures to Eli Lilly ..........................................................................82
7.6
Reporting Procedures to Genentech.......................................................................83
MedWatch 3500A Reporting Guidelines...........................................................................83
7.7
Reporting to Hospital Risk Management...............................................................85
7.8
Routine Adverse Event Reporting .........................................................................85
7.9
Study Close-Out.....................................................................................................85
7.10
Queries...................................................................................................................86
7.11
Signal Management and Risk Management ..........................................................86
7.12
Compliance with Pharmacovigilance Agreement / Audit .....................................86
8.
PHARMACEUTICAL INFORMATION..........................................................................87
8.1
Abemaciclib...........................................................................................................87
8.2
Atezolizumab.........................................................................................................89
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................91
9.1
Tissue Collection ...................................................................................................91
9.2
Blood Collection....................................................................................................92
9.3
Specimen Banking .................................................................................................93
9.4
Analysis Plan for Correlative Studies....................................................................93
10.
STUDY CALENDAR .......................................................................................................94

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11.
MEASUREMENT OF EFFECT .......................................................................................97
11.1
Antitumor Effect....................................................................................................97
11.2
Radiographic Disease Criteria .............................................................................104
12.
DATA REPORTING / REGULATORY REQUIREMENTS.........................................105
12.1
Data Reporting.....................................................................................................105
12.2
Data Safety Monitoring........................................................................................105
12.3
Multi-Center Guidelines ......................................................................................106
13.
STATISTICAL CONSIDERATIONS.............................................................................106
13.1
Study Design/Endpoints ......................................................................................106
13.2
Primary Efficacy Endpoint Statistical Plan and Sample Size..............................107
13.3
Primary Safety Endpoint Statistical Plan.............................................................108
13.4
Secondary Endpoint Analysis Plan......................................................................109
13.5
Statistical Plan for Primary Exploratory Endpoint Requiring Biopsies...............110
14.
PUBLICATION PLAN ...................................................................................................110
REFERENCES
111
APPENDIX A
PERFORMANCE STATUS CRITERIA ................................................118
APPENDIX B
MULTI-CENTER GUIDELINES ...........................................................119
B-1.
INTRODUCTION ...........................................................................................................119
B-1.1 Purpose...................................................................................................................119
B-2. GENERAL ROLES AND RESPONSIBILITIES ...............................................................119
B-2.1 Coordinating Center...............................................................................................119
B-2.2 External Site...........................................................................................................120
B-3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ...............................121
B-3.1 Protocol Revisions and Closures ...........................................................................121
B-3.2 Informed Consent Requirements ...........................................................................121
B-3.3 IRB Re-Approval...................................................................................................122
B-3.4 DF/HCC Multi-Center Protocol Confidentiality ...................................................122
B-3.5 Participant Registration and Randomization .........................................................122
B-3.6 Initiation of Therapy ..............................................................................................123
B-3.7 Eligibility Exceptions.............................................................................................123
B-3.8 Data Management..................................................................................................123
B-3.9 Protocol Reporting Requirements..........................................................................123
B-4. MONITORING: QUALITY CONTROL............................................................................124
B-4.1 Ongoing Monitoring of Protocol Compliance.......................................................124
B-4.2 Monitoring Reports................................................................................................125
B-4.3 Accrual Monitoring................................................................................................125

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B-5. AUDITING: QUALITY ASSURANCE .............................................................................125
B-5.1 DF/HCC Internal Audits........................................................................................125
B-5.2 Audit Notifications.................................................................................................126
B-5.3 Audit Reports.........................................................................................................126
B-5.4 External Site Performance .....................................................................................126
Appendix C
127
Appendix D
128
Appendix E
129
Appendix F
130

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1. OBJECTIVES
1.1 Study Design
This is a multi-center, open label Phase II study of patients with metastatic castration resistant 
prostate cancer (mCRPC) treated with abemaciclib monotherapy, atezolizumab monotherapy or 
with combination therapy of abemaciclib and atezolizumab. 
An unselected mCRPC cohort was initially randomized in a 1:1 fashion, to either abemaciclib 
monotherapy (Arm A) dosed at 200 mg orally BID each day during the 21-day cycle, or 
combination therapy (Arm B) of atezolizumab 1,200 mg IV once every 21 days and abemaciclib 
dosed at 150 mg orally BID each day during the 21-day cycle. Enrollment to Arm B was halted, 
so subsequent unselected patients are enrolled to Arm A in a non-randomized fashion. 
Enrollment to the unselected mCRPC cohort will be halted for efficacy analysis after 12 patients 
have been enrolled on Arm A of the study. After the efficacy interim analysis, if the efficacy 
threshold is achieved, then non-randomized, single-arm accrual will continue. 
An exploratory cohort of mCRPC patients with CDK12 loss (Arm C) will be enrolled as follows: 
the first 5 patients will receive atezolizumab monotherapy 1,200 mg IV every 21 days.  
Subsequently an additional 16 patients were planned to receive a combination of atezolizumab 
1,200 mg IV once every 21 days and abemaciclib dosed at 150 mg orally BID each day during 
the 21-day cycle; however enrollment to combination treatment was halted and the subsequent 
16 patients will instead receive abemaciclib dosed at 200 mg orally BID each day during the 21-
day cycle. 
Bayesian toxicity monitoring was planned to be used for all patients enrolled to Arm B and to the 
combination treatment cohort of Arm C (up to a maximum of 43 patients) as detailed in 
Statistical Considerations.  If the rate of patients experiencing dose limiting toxicities (DLTs) at 
the starting dose exceeded the pre-specified threshold for excessive toxicity, then subsequent 
patients randomized to Arm B or enrolled to the combination cohort of Arm C were planned to 
receive abemaciclib at one dose level reduction (100 mg BID) with atezolizumab 1200 mg every 
21 days.  If the rate of patients experiencing DLT at the reduced dose exceeded the pre-specified 
threshold for excessive toxicity, then enrollment to Arm B and the combination cohort of Arm C 
was planned to be halted. Due to two grade 5 sepsis events observed in the 8 patients treated on 
Arm B with unclear relationship to the study medications, the Sponsor-Investigator and co-
investigators elected to halt enrollment to combination treatment rather than following the 
Bayesian toxicity monitoring plan. Unselected patients will continue to enroll on Arm A in a 
non-randomized fashion (up to 27 patients in total in Arm A) and patients with CDK12 loss 
subsequently enrolled on Arm C after the 5 patients treated with atezolizumab monotherapy will 
receive abemaciclib 200 mg BID as monotherapy (total enrollment on Arm C up to 21 patients in 
total).
All patients will undergo an on-treatment biopsy after six weeks of therapy. Treatment will be 
continued until disease progression and/or Section 5.4 criterion is met.

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1.2 Primary Objectives

To determine the efficacy of abemaciclib monotherapy in biomarker-unselected patients 
with metastatic CRPC (Arm A).

To determine the efficacy of abemaciclib in combination with atezolizumab in 
biomarker-unselected patients with metastatic CRPC (Arm B). 

To determine the safety of abemaciclib in combination with atezolizumab in mCRPC 
(Arm B).
1.3 Secondary Objectives

To evaluate secondary measures of clinical efficacy of abemaciclib monotherapy and 
abemaciclib (Arm A) in combination with atezolizumab (Arm B) in biomarker-
unselected cohort.

To identify the clinical variables associated with response and resistance to therapy 
including type of prior antiandrogen therapy (CYP17 inhibitor or AR antagonist), 
duration since prior antiandrogen therapy, receipt of prior chemotherapy, and visceral- 
versus bone- predominant disease (Arms A and B).

To determine the safety and adverse event profiles of abemaciclib monotherapy and 
abemaciclib in combination with atezolizumab in mCRPC (all Arms).
1.4 Exploratory/Translational Objectives

To assess the efficacy of atezolizumab alone and abemaciclib monotherapy in the CDK12 
loss cohort (Arm C).

Primary translational objective: To assess FoxP3+/CD8+ ratio in all biopsy specimens 
and the change between pre-treatment and on-treatment specimens will be reported 
descriptively for each treatment arm separately (all Arms).

To perform detailed profiling of tumor immune infiltrate from paired baseline (where 
available) and on-treatment tumor biopsies in biomarker-unselected and CDK12 mutant 
cohorts (all Arms).

Evaluate changes in androgen-receptor signaling pathway with exposure to abemaciclib 
monotherapy and abemaciclib in combination with atezolizumab (all Arms).

Identify the biomarkers of response and resistance to abemaciclib monotherapy and in 
combination with atezolizumab in biomarker-unselected patients (Arms A and B).
2. BACKGROUND
2.1 Study Disease(s)
Prostate cancer is the most common non-cutaneous malignancy and second most common cause 
of cancer death in men in the United States (1).  The backbone of systemic treatment for 
metastatic prostate cancer is androgen deprivation therapy (ADT), most commonly accomplished 
through agonists or antagonists of luteinizing hormone releasing hormone (LHRH).  However, 

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depth and duration of response to ADT is highly variable, and eventual resistance to ADT, i.e. 
progression to metastatic castration-resistant prostate cancer (mCRPC) is nearly universal.  
Castration-resistant prostate cancers most commonly remain dependent on signaling through the 
androgen receptor (AR), and secondary AR pathway-targeted therapies abiraterone (2, 3) and 
enzalutamide (4, 5) have demonstrated overall survival benefit in mCRPC. Other agents that 
have demonstrated overall survival benefit in Phase III studies in mCRPC include the 
chemotherapeutics docetaxel (6) and cabazitaxel (7), the immunotherapeutic Sipuleucel-T (8), 
the radiopharmaceuticals Radium-223 (9) and 177Lu-PSMA-617 (10), and the PARP inhibitor 
olaparib (in patients with pathogenic BRCA1/2 and ATM alterations) (11).  However, patients 
eventually progress through these therapies and succumb to their disease, and thus novel 
therapeutic approaches to treating mCRPC is a major clinical need.
The genetic landscapes of both primary prostate cancer (12) and mCRPC (13) have been 
characterized, and have nominated oncogenic drivers of prostate cancer, as well as mechanisms 
of resistance to ADT and potential therapeutic targets in mCRPC.  For example, genetic 
alterations in the AR gene locus (including amplifications, point mutations, or structural variants 
(14)) and the presence of ligand-independent splice variants (such as AR-v7 (15)) seen in 
mCRPC have been implicated in resistance to ADT.  In addition, other genetic alterations 
involving the AR, PTEN/PI3K (Phosphatase and Tensin Homolog/Phosphatidylinositol 3-
kinase), Wnt/β-catenin, and cell cycle pathways, as well as genes involved in DNA damage 
repair and epigenetic modulation are commonly seen in metastatic castration-resistant prostate 
cancer (13)  and are enriched in mCRPC compared to primary treatment-naïve prostate cancer 
(16, 17).
Despite this extensive genetic characterization, clinical benefit to molecularly targeted agents 
other than those targeting the androgen receptor has so far been limited primarily to genetically-
defined subsets of patients with mCRPC with defects in DNA repair pathways.  The immune 
checkpoint inhibitor immunotherapy (CPI) pembrolizumab is approved for use in unresectable or 
metastatic microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) solid 
tumors progressing following prior treatment and who have no satisfactory alternative treatment 
options (18), and can thus be prescribed for the subset of patients with mCRPC with this 
phenotype. In addition, patients with deleterious alterations in genes involved in homologous 
recombination repair (HRR) can respond to inhibitors of Poly (ADP-ribose) polymerase (PARP) 
(19, 20) – the FDA has approved olaparib for patients with HRR gene mutations and rucaparib 
for patients with deleterious mutations involving BRCA1 or BRCA2.  However, only ~3% of 
patients with mCRPC are phenotypically MSI-H/dMMR (21), and only ~18-20% have mutations 
in BRCA1, BRCA2 or ATM (16, 17) – even in these subpopulations responses to pembrolizumab 
(21, 22) and PARP inhibitors (19, 20) are not universal.  As such, alternative paradigms for 
molecularly targeted therapy in mCRPC warrant exploration.  
Genetic alterations involving cell cycle signaling are common in mCRPC (13) and may 
contribute to resistance to AR-targeted therapies (23).  Inhibitors of cyclin-dependent kinases 4 
and 6 have demonstrated anti-tumor activity in multiple pre-clinical models of castration-
resistant prostate cancer (24, 25), and have demonstrated synergistic activity with CPIs directed 
against PD-1 (Programmed Death 1) or PD-L1 (Programmed Death Ligand 1) in pre-clinical 
models of many cancer types (26-29).  Herein, we propose a phase II study of the CDK4/6 
inhibitor abemaciclib with or without the anti-PD-L1 antibody atezolizumab in mCRPC resistant 

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to secondary AR-targeted therapy.   
2.2 IND Agent(s)
2.2.1
Abemaciclib
Abemaciclib is an oral inhibitor of cyclin-dependent kinases (CDK4 and CDK6). Binding to 
Cyclin D activates CDK4 and CDK6, which in turn promote retinoblastoma protein (Rb) 
phosphorylation, leading to cell cycle progression and cell proliferation via an E2F mediated 
mechanism. Through inhibition of CDK4 and CDK6, abemaciclib prevents Rb phosphorylation 
and subsequently results in cellular apoptosis. 
Abemaciclib is FDA-approved for the treatment of women with hormone-receptor positive, 
HER2-negative breast cancer, in combination with endocrine therapy for adjuvant treatment of 
node-positive early breast cancer at high risk of recurrence and a Ki-67 score ≥20%, in 
combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of 
postmenopausal women or in combination with fulvestrant after disease progression on 
endocrine therapy for metastatic breast cancer, and as monotherapy in the same patient 
population after progression on endocrine therapy but prior to systemic chemotherapy 
administration. 
The most common adverse events associated with abemaciclib observed in ≥ 20% of the study 
population are diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, 
leukopenia, decreased appetite, vomiting, headache, and thrombocytopenia.
2.2.2
Atezolizumab
Atezolizumab is a PD-L1 monoclonal antibody. Inhibiting the immune suppressive interaction of 
PD-L1 on tumor cells or tumor infiltrating immune cells and PD-1 on T cells has been shown in 
multiple cancer types to result in an increased anti-tumor immune response.  
Atezolizumab has been FDA-approved in metastatic non-small cell lung cancer with disease 
progression during or after receiving platinum-containing chemotherapy, and more recently for 
first-line treatment of non-small cell lung cancer, small-cell lung cancer. 
The most common adverse effects associated with atezolizumab observed in ≥ 20% of the 
urothelial carcinoma study population were fatigue, decreased appetite, nausea, constipation, 
urinary tract infection, diarrhea, and pyrexia, and in the metastatic non-small cell lung cancer 
population were fatigue, decreased appetite, dyspnea and cough.
2.3 Rationale
2.3.1
Rationale for CDK4/6 inhibition in mCRPC
Cell cycle signaling mediated through cyclin dependent kinases 4 and 6 (CDK4/6) is a critical 
pathway conferring oncogenic phenotypes in multiple cancer types. Small molecule inhibitors of 

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CDK4/6, including abemaciclib, palbociclib and ribociclib have already been FDA approved for 
the treatment of metastatic hormone receptor-positive HER2-negative breast cancer (30). In pre-
clinical models of castration-resistant prostate cancer (CRPC), inhibitors of CDK4/6 have 
demonstrated single-agent activity in enzalutamide-resistant cells in vitro (24) and in CRPC in 
vivo model systems (25). Activity was seen even in the context of alterations in AR commonly 
seen as resistance mechanisms in mCRPC, including AR-V7 splice variant expression, the AR 
F876L mutation, and loss of AR expression.  A genome-wide open reading frame (ORF) screen 
identified CDK4 and CDK6 as mediators of resistance to enzalutamide in LNCaP cells, and 
whole exome sequencing of paired pre-treatment and post-treatment biopsies obtained from 
patients treated with enzalutamide suggest the CDK4/6 pathway as a mediator of both intrinsic 
and acquired resistance to androgen-receptor targeted therapy (23). 
Multiple clinical trials of CDK4/6 inhibitors in prostate cancer are ongoing including 1) 
palbociclib monotherapy in mCRPC (NCT02905318), 2) palbociclib with ADT for metastatic 
RB1 (retinoblastoma)-proficient castration-sensitive prostate cancer (NCT02059213), 3) 
ribociclib with docetaxel in mCRPC (NCT02494921), 4) enzalutamide with or without ribociclib 
in mCRPC (NCT02555189), 5) abiraterone with or without abemaciclib in 1st line mCRPC 
(NCT03706365) and 6) abemaciclib in men with heavily treated mCRPC (NCT04408924).  
Abemaciclib has some mechanistic differences compared with palbociclib and ribociclib 
including a higher potency in inhibiting CDK4 and CDK6 and greater specificity for CDK4 in 
vitro, and demonstrates some inhibitory activity against CDK9 as well (31, 32). Clinically, 
abemaciclib has lower rates of bone marrow suppression, which allows for an uninterrupted 
delivery of therapy, compared with palbociclib and ribociclib, which require a 1 week break after 
3 weeks of therapy for recovery of the bone marrow function (33).  In metastatic hormone 
receptor-positive, HER2-negative breast cancer, palbociclib (34), ribociclib (35) and abemaciclib 
(36) are all FDA-approved in combination with aromatase inhibition for 1st line treatment; 
however, only abemaciclib is approved as monotherapy in treatment-resistant patients (37).  
Given this experience in breast cancer, along with evidence that CDK4/6 signaling is associated 
with resistance to secondary AR-targeted therapy in mCRPC (23) and that CDK4/6 inhibitors 
demonstrate single agent activity in pre-clinical models (24, 25), abemaciclib warrants study 
both as a single agent and in combination with other agents in therapy-resistant mCRPC.
2.3.2
Rationale for anti-PD1/PD-L1 checkpoint immunotherapy in mCRPC
While anti-PD1/PD-L1 checkpoint inhibitor immunotherapies (CPIs) have demonstrated 
remarkable anti-tumor activity in multiple cancer types, the activity of these agents as 
monotherapy in prostate cancer is modest. In an early report of 296 patients with metastatic solid 
tumors treated with the anti-PD-1 antibody BMS-936558 (nivolumab), no objective responses 
were seen in patients with castration-resistant prostate cancer (38). However, in the KEYNOTE-
028 study of the anti-PD-1 antibody pembrolizumab in treatment-resistant mCRPC patients with 
measurable disease and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells (39), 4 
of 23 patients experienced radiographic response (overall response rate = 17.4%) while 8 of 23 
patients (34.8%) had stable disease. 
The KEYNOTE-199 study of pembrolizumab monotherapy in metastatic CRPC (Cohort 1 - PD-
L1 positive measurable disease; cohort 2 - PD-L1 negative measurable disease; and Cohort 3 - 

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bone-only disease) (40) also reported modest clinical activity in this population. The response 
rate per central radiology review across Cohorts 1 and 2 was 5% (although 10% of patients with 
measurable disease achieved a >30% reduction in sum of target lesions from baseline), and the 
rate of PSA reduction by >50% across cohorts 1-3 was about 10%. No obvious biomarkers were 
identified that correlated with response to pembrolizumab, though alterations in genes involved 
in DNA damage response were identified in some of the responders.  Of the 6 patients with 
available genetic sequencing data among the 9 responders in KEYNOTE-199, only 1 showed 
evidence for an alteration in a gene involved in mismatch repair (MLH3 T930Qfs*35 deletion in 
patient 1).  As such, pembrolizumab can have clinical activity even in patients without an MSI-
high/dMMR phenotype.
Some hypotheses for why prostate cancer is less responsive to anti-PD-1/PD-L1 CPI than other 
tumor types include relatively low tumor mutational burden (41), low/variable expression of PD-
L1 (42), and low T cell cytolytic activity in prostate tumors (43). Thus, strategies to promote a 
cytolytic immune infiltrate in prostate cancer (i.e. rendering immunologically “cold” tumors 
“hot”) to increase likelihood of response to CPI are of great interest. One strategy to increase 
immunogenicity of prostate cancer tumors is combining anti-PD-1/PD-L1 CPI with enzalutamide 
based on pre-clinical findings that resistance to enzalutamide was associated with increased 
levels of tumor-intrinsic PD-L1, and that patients progressing on enzalutamide had significantly 
increased PD-L1/2+ dendritic cells (DC) in blood compared to those naïve or responding to 
treatment (44).  In an early study of pembrolizumab administered in combination with 
enzalutamide (45), 5 of the first 28 patients experienced a response; of the 3 patients with 
available genetic sequencing data among the 5 responders, only one was found to be MSI-high.  
The combination of pembrolizumab and enzalutamide has been further explored in Cohorts 4 
and 5 of KEYNOTE-199 (NCT02787005) (46) and cohort C of KEYNOTE-365 
(NCT02861573) (47), with preliminary evidence for activity such that Phase 3 trials of 
pembrolizumab vs. placebo in combination with enzalutamide are currently in progress for 
patients with patients with metastatic hormone-sensitive prostate cancer (NCT04191096) and 
mCRPC (NCT03834493).
The IMbassador250 study of enzalutamide with or without atezolizumab in abiraterone-resistant 
mCRPC (NCT03016312) (48) did not demonstrate an overall survival benefit to atezolizumab 
compared to placebo in this unselected patient population. A variety of other strategies to 
increase the activity of atezolizumab in mCRPC are currently being explored including 
combination with the autologous dendritic cell vaccine Sipuleucel-T (NCT03024216), the alpha 
particle-emitting radiopharmaceutical Radium-223 (NCT02814669) (49), the AKT inhibitor 
ipatasertib (NCT03673787), and the multi-kinase inhibitor cabozantinib (NCT03170960).  In 
particular, the combination of atezolizumab with cabozantinib in the COSMIC-021 study (50) 
has demonstrated promising clinical activity with an overall response rate per RECIST 1.1 
among the 44 pts of 32% (2 CRs [4.5%] and 12 PRs [27%]); 21 (48%) pts had SD resulting in a 
disease control rate of 80% in all patients. 
However, the relative merits of these various approaches are not currently known, and 
biomarkers identifying patients likely to benefit from particular strategies have yet to be 
identified.  Thus, other combination strategies warrant investigation, along with companion 
translational studies to explore the biology of novel combinations and establish predictive 
biomarkers.

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2.3.3
Rationale for CDK4/6 inhibitor in combination with anti-PD-L1 checkpoint 
inhibition
The combination of abemaciclib with atezolizumab is a potentially promising therapeutic 
strategy in mCRPC, as multiple preclinical studies have demonstrated synergy between CDK4/6 
inhibition and anti-PD-1/PD-L1 targeted immunotherapy. In a breast cancer model, abemaciclib 
led to enhanced tumor antigen presentation and suppressed the proliferation of regulatory T cells, 
triggering anti-tumor immunity – abemaciclib showed synergistic activity with anti-PD-L1 
targeted therapy in this model (26). A second report suggested that CDK4/6 inhibition increased 
PD-L1 protein levels by impeding its degradation; synergistic activity of CDK4/6 inhibition with 
anti-PD-1 immunotherapy was seen in this study as well (27). In a third report, single-cell RNA 
sequencing (scRNA-seq) from 33 melanoma tumors identified a resistance program expressed by 
malignant cells that is associated with T cell exclusion and immune evasion. Abemaciclib was 
shown to repress this immune resistance program, and the combination of abemaciclib with anti-
PD-1 and anti-CTLA4 monoclonal antibodies demonstrated synergistic activity in a xenograft 
model (28). A fourth report demonstrated in an immunocompetent syngeneic mouse model that 
abemaciclib increased a T cell inflammatory signature in tumors.  The combination of 
abemaciclib with anti-PD-L1 therapy led to complete tumor regressions and immunological 
memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and 
enhanced cell cycle control (29).
Clinically, preliminary safety and efficacy of the combination of abemaciclib with the anti-PD-1 
CPI pembrolizumab (I3Y-MC-JPCE; NCT02779751) has been reported for KRAS mutated PD-
L1 positive non-small cell lung cancer (NSCLC) (Arm A) and squamous NSCLC (Arm B)(51), 
as well as for hormone receptor positive, HER2 negative (HR+ HER2-) metastatic breast cancer 
as a two-drug combination (Arm C) (52) and as a three-drug combination with anastrozole (Arm 
D) (53). Clinical activity was seen in all four cohorts, with the activity of abemaciclib plus 
pembrolizumab in HR+ HER2- breast cancer (Arm C) appearing particularly promising with 
29% overall response rate, 82% disease control rate (complete response [CR]+partial response 
[PR]+stable disease [SD]), and 46% clinical benefit rate (CR+PR+SD persisting for ≥6 months).
Adverse effects of the combination in I3Y-MC-JPCE were similar to what would be expected for 
the single agents, except for a higher than expected rate of grade 3 or higher elevations in liver 
function tests (LFTs), which were reversible upon discontinuation, and interstitial lung disease 
(ILD)/pneumonitis events.  Grade 3 or higher increase of alanine aminotransferase (ALT) was 
seen in 24% of patients in Arm A, 0% in Arm B, 11% in Arm C, and 31% in Arm D; grade 3 or 
higher ILD/pneumonitis was seen in 3 patients in Arm A, 1 patient in Arm B, not reported for 
Arm C, and 2 patients in Arm D who subsequently died as a result of pneumonitis.
There are key differences in patient population and choice of CPI between I3Y-MC-JPCE and 
the current trial.  A recent meta-analysis reported the incidence of grade >= 3 adverse events to 
be greater for anti-PD-1 agents compared to anti-PD-L1 agents (OR 1.58; 95% CI 1.00-2.54) 
(54).  In similar patient populations (understanding the limitations of cross-trial comparisons), 
incidence of grade >=3 pneumonitis appeared to be numerically higher with anti-PD-1 agents in 
trials of monotherapy in urothelial carcinoma (2.3% for pembrolizumab in KEYNOTE-045 (55), 
none reported for atezolizumab in IMvigor211 (56)) and in PD-L1+ NSCLC (2.6% for 
pembrolizumab in KEYNOTE-010 (57), 1% for avelumab in JAVELIN Lung 200 (58)), and in 

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combination trials with chemotherapy in non-squamous NSCLC (3% for pembrolizumab in 
KEYNOTE-189 (59), 2% for atezolizumab in IMpower132 (60)) and in squamous NSCLC 
(2.5% for pembrolizumab in KEYNOTE-407 (61), 1% for atezolizumab in IMpower131 (62)).  
Safety data of the combination of abemaciclib with an anti-PD-L1 CPI (such as atezolizumab, 
avelumab or durvalumab) has yet to be reported.
The risk of anti-PD-1 related pneumonitis has been reported to be higher in patients with lung 
cancer than patients with other metastatic malignancies (63, 64). In addition, a recent analysis of 
pooled data from 66 prospective trials of CPIs submitted to the FDA suggested an increased risk 
of pneumonitis in patients who received radiation therapy (65).  As such, excluding patients with 
history of lung cancer or radiation to the thorax, as well as current smokers/patients with 
extensive smoking history (> 20 pack years), prior ILD/pneumonitis and those with evidence for 
baseline restrictive pattern on pulmonary function testing is likely to prevent those patients most 
likely to experience treatment-related pneumonitis from enrolling on the study.
Promising clinical activity of cabozantinib with atezolizumab in mCRPC seen in the COSMIC-
021 study (50) is a proof-of-concept that atezolizumab combinations may be effective in this 
disease setting.  As the proposed mechanism of immune modulation is distinct for CDK4/6 
inhibitors vs. cabozantinib, these inhibitors may benefit different patient populations.  Findings 
from the pre-clinical studies summarized above as well as from Arm C of I3Y-MC-JPCE in HR+ 
HER2- breast cancer (given biological similarities with prostate cancer as a hormonally-driven 
epithelial cancer with limited efficacy of pembrolizumab as monotherapy) would suggest that the 
combination of CDK4/6 inhibition with anti-PD-1/PD-L1 checkpoint immunotherapy warrants 
study in mCRPC.
2.3.4
Rationale for investigation in CDK12 mutant mCRPC
Whole exome and transcriptome sequencing have extensively characterized the mCRPC 
genomic landscape (13, 66). A novel subset of prostate cancer typified by biallelic inactivation of 
CDK12 has been identified at a frequency of 6.7% in mCRPC (67, 68) and is associated with 
aggressive clinical behavior (69). CDK12 biallelic loss is characterized by focal tandem 
duplications and a large number of gene fusions, which has been shown to be associated with 
gains in cell cycle and DNA replication genes, including CCND1. In addition, mCRPC with 
biallelic loss has a higher neoantigen burden than other subtypes of advanced prostate cancer, 
suggesting a potentially increased sensitivity to checkpoint inhibitor therapy (68, 70, 71). 
CDK12 and CDK13 are associated with cyclin K and play a role in regulating transcription 
elongation and RNA splicing. In an evaluation of CDK12 gene modification prevalence across 
various tumor types, there was a 1.08% mutation rate across 1203 prostate cancer samples, 
compared with 2.3% in 915 ovarian cancer samples (72). Impairing CDK12 function in ovarian 
cancer cells has been shown to decrease BRCA1 levels and disrupt homologous recombination 
repair, leading to reported increased sensitivity to cisplatin and PARP inhibition (73). In a series 
of 556 ovarian carcinomas, 17 tumors were found to have markedly increased genomic copy 
number, with 15 of these 17 cases also harbored CDK12 mutations, the majority of which were 
deleterious (74). 
D-type cyclins, in particular cyclin D1 (CCND1), function to regulate CDK4/6 activity (30). 
While amplification of CCND1 has been inconsistently predictive of response to CDK4/6 

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inhibition in the literature, CCND1 upregulation in mCRPC with biallelic CDK12 loss 
nonetheless suggests response to CDK4/6 inhibitors, as CCND1 amplification is indicative of 
increased CDK4/6 activity.
2.3.5
Hypotheses:
1. Abemaciclib monotherapy will demonstrate clinical efficacy in patients with biomarker-
unselected metastatic CRPC.  
2. Exploratory: Atezolizumab alone will demonstrate clinical efficacy in patients with 
CDK12-mutant metastatic CRPC.
2.4 Correlative Studies Background
2.4.1
ImmunoProfile
Based on pre-clinical studies suggesting that abemaciclib can alter the immune 
microenvironment in tumors (26, 29), we plan to characterize immune infiltrate in biopsy 
specimens obtained 6 weeks after starting on trial therapy using the ImmunoProfile assay at 
Dana-Farber Cancer Institute (DFCI).  This assay is already being used to develop an in-depth 
database of immunoprofiles for all patients seen at DFCI, Brigham and Women’s Hospital, and 
Boston Children’s Hospital to better predict response to immunotherapies.  This is an optimized 
multiplex immunofluorescence assay performed in a Clinical Laboratory Improvement 
Amendments (CLIA) environment with standardized reporting across all samples for research or 
standard clinical care.  The report includes levels of a particular biomarker in both tumor and 
tumor-stroma interface compartments; PD-L1 expression is reported for both malignant cells and 
inflammatory cells.   As a research test in the same environment, we plan to assay for FoxP3, 
CD8, PD-L1, and Granzyme B expression, with DAPI as a counterstain.  FoxP3 is a marker of 
regulatory T cells, whereas CD8 is a marker of cytotoxic T-cells; Goel et al. (26) reported a 
significant decrease in FoxP3+/CD8+ ratio in a tumor model with abemaciclib treatment 
compared to vehicle control, which was proposed to be one mechanism by which CDK4/6 
inhibition may synergize with anti-PD1/PD-L1 checkpoint inhibitor immunotherapy. 
The primary biomarker endpoint of this study is the change in FoxP3+/CD8+ ratio in on-
treatment biopsy specimens compared to matched archival metastatic biopsy specimens from the 
same patient (when available) in patients treated with abemaciclib and atezolizumab (arm B) or 
with abemaciclib alone (arm A). We will also explore correlation of immune infiltrate with 
genetic features as described below.
2.4.2
Targeted exome sequencing from tumor biopsy
Whole exome sequencing in mCRPC has characterized the genetic landscape of this disease state 
and has identified potential biomarkers for prediction of therapeutic vulnerabilities (13, 16, 75).  
University of Minnesota team is validating a CRPC-biology panel that consists of androgen-
receptor gene and its targets, and genes that are known or are considered highly likely to be 
important in disease progression, treatment response or resistance (AR, PTEN, TP53, RB, E2F, 
ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, MRE11A, MSH2, MSH6, 
NBN, PALB2, PMS2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, RBBP8, SLX4, and 

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XRCC2). We will correlate genetic features from biopsy specimens with response and resistance 
to therapy.  Specifically, we would predict that a combination of aberrant AR signaling and 
alterations in the CDK4/6 pathway (i.e. amplifications of CCND1, CCND3, CDK4, CDK6; 
deletions of CDKN2A) would correlate with response to abemaciclib in this study (33). Loss of 
RB1 or amplification of CCNE1 would be predicted to correlate with resistance to abemaciclib 
monotherapy (76), but may not necessarily lead to resistance to abemaciclib + anti-PD-L1 given 
that the mechanism of immune activation by CDK4/6 inhibition may be independent of these 
alterations.
In addition, we would predict that alterations in genes involved in DNA damage repair, 
particularly those that would lead to an increase in neoantigen burden, would correlate with 
response to checkpoint inhibitor immunotherapy (77).  These are included in the CRPC-biology 
panel and we will correlate loss-of-function alterations in these genes with response and 
resistance to therapy, as well as with composition and changes in immune infiltrate.  
2.4.3
Whole transcription sequencing from tumor biopsy
Whole transcriptome sequencing from tumor specimens can be used both to identify variant 
transcripts not easily assessed by DNA sequencing alone (such as splice variants or 
transcriptional products of genetic structural alterations/rearrangements). This will help identify 
the locations of canonical and aberrant AR splicing events (14) and allow determination of 
expression profiles a broad array of genes involved in AR signaling and cell cycle regulation.  
We would hypothesize that cancers that express a T cell-inflamed gene expression signature 
upon treatment with abemaciclib with or without atezolizumab would be more likely to respond 
to checkpoint immunotherapy.
2.4.4
Whole transcriptome sequencing from exosomes
Serial assessment of tumor biology in prostate cancer is challenging due to bone-predominant 
metastatic disease in a majority of patients. This results in a lower biopsy yield, loss of RNA and 
phosphorylated proteins due to specimen processing. “Liquid biopsy” approaches have gained 
traction in the field as these allow sequential characterization with low burden to the patient. 
More commonly used approaches have certain limitations including low CTC yield in patients 
with lower burden of disease and lack of RNA and proteins for analysis with cfDNA approaches. 
Tumor-derived circulating blood exosomes have thus emerged as an area of interest. Whole 
transcriptome sequencing from exosomes derived from blood is feasible and can detect tumor-
specific transcripts (78). Advantages of a blood-based biomarker include the ability to sample 
from a patient’s entire tumor burden rather than a single metastatic site, and greater ease in 
monitoring changes over time (i.e. pre-treatment, on-treatment and at progression).
2.4.5
Tumor Profiling from circulating free DNA (cfDNA)
Analysis of circulation cell-free DNA (cfDNA) is a promising approach to genetic 
characterization of a patient’s tumor burden over time.  Sparse whole genome sequencing at 0.1x 
coverage, termed ultra-low pass whole genome sequencing (ULP-WGS), can be used to identify 
copy number alterations (CNA) in the tumor, as well as the tumor fraction (i.e. percentage of 

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cfDNA derived from tumor rather than non-cancerous tissues), using an algorithm called 
ichorCNA (79). 
In addition, comprehensive genomic characterization can be performed through whole exome 
sequencing (79) and targeted sequencing panels (80).  We have designed a custom bait set 
specifically for prostate cancer including allowing for identification of SSNVs in all genes 
known to be recurrently mutated in metastatic prostate cancer (16), genes involved in DNA 
damage repair, as well as sequencing of intronic and intergenic regions of genes known to be 
translocated or have complex structural alterations in prostate cancer (AR (14), ERG, TMPRSS2, 
ETV1, ETV4, SLC45A3, RAF1).  We plan to perform targeted next generation sequencing from 
circulating free DNA at baseline, at 6 weeks, and at progression.  This analysis will allow us to 
identify alterations at baseline not detected from the tumor biopsy (i.e. if DNA from tumor 
biopsy is insufficient or if alterations are derived from other non-sampled metastatic sites), and 
will allow us to detect new alterations at the time of progression to nominate mediators of 
resistance.
3.
PARTICIPANT SELECTION
3.1 Eligibility Criteria 
3.1.1
Diagnosis of metastatic castration resistant prostate cancer (mCRPC), with histologic 
confirmation of adenocarcinoma of the prostate (without evidence of small cell 
carcinoma), with progressive disease at the time of study entry by either

Sequence of at least 2 rising PSA values at a minimum of 1-week intervals 

Radiographic progression per RECIST1.1 for soft tissue and/or per PCWG3 (81) for 
bone, with or without PSA progression
3.1.2
Adult males 18 years of age or older.
3.1.3
ECOG performance status of 0 or 1
3.1.4
Patients must have metastatic disease by bone scintigraphy or other nodal or visceral 
lesions on CT or MRI with a bone or soft tissue lesion amenable to image-guided 
percutaneous biopsy at acceptable risk for research biopsy per institutional standards, 
and the patient must be evaluable for disease response by either
•
Baseline PSA ≥ 2.0 ng/mL OR
•
Measurable disease per RECIST 1.1

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3.1.5
Past progression or intolerance to at least one novel antiandrogen therapy 
(abiraterone, enzalutamide, galeterone, apalutamide, darolutamide, orteronel, 
seviteronel or equivalent) in either the hormone-sensitive or castration-resistant 
disease setting. 
3.1.6
Not a candidate for docetaxel or cabazitaxel chemotherapy due to: 

progression within 12 months of completion or intolerance to prior taxane OR

refusal of taxane OR 

contraindication to, or lack of fitness for taxane OR 

Investigator assessment that taxane is not clinically indicated or preferred.
3.1.7
Maintenance of castration status, defined as serum testosterone level of less than 50 
ng/dL. Patients must be surgically castrate or maintained on LHRH agonist or 
antagonist therapy for the duration of the study period. 
3.1.8
Must have recovered from any treatment-related toxicities to ≤ CTCAE grade 1. 

Patients with ≤ CTCAE grade 2 anorexia, alopecia, neuropathy, and/or fatigue 
however, are also permitted to enroll.
3.1.9
Participants must have adequate organ and marrow function as defined below:

leukocytes           
≥3,000/mcL

absolute neutrophil count 
≥1,500/mcL

lymphocyte count 
≥500/mcL

hemoglobin
≥9 g/dL (without transfusion or growth factor in 
prior 28 days, except for patients assigned to atezolizumab monotherapy in Arm 
C for whom transfusion to meet this eligibility criterion is permitted)

platelets
≥100,000/mcL (without transfusion or growth factor 
in prior 28 days)

Serum albumin
≥ 25 g/L (2.5 g/dL)

total bilirubin
≤1.5 × institutional upper limit of normal, unless the 
subject has known or suspected Gilbert’s syndrome in which case total bilirubin 
must be ≤ 2 × ULN

AST(SGOT)/ALT(SGPT)
≤1.5 × institutional upper limit of normal, except for 
patients assigned to atezolizumab monotherapy in Arm C for whom ≤2.5 × upper 
limit of normal is permitted

INR and aPTT
≤1.5 × institutional upper limit of normal, unless the 
subject is receiving therapeutic anticoagulation, in which case they must be on a 
stable anticoagulant regimen

creatinine clearance
≥30 mL/min/1.73 m2 (by Cockcroft-Gault formula 
or 24-hour urine collection)

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3.1.10 Life expectancy of at least 6 months, as determined by a study Investigator. 
3.1.11 Ability to swallow oral medications.
3.1.12 Ability to understand and willingness to sign an IRB-approved informed consent. 
3.2 Additional Inclusion Criteria (Arm C patients)
3.2.1
Must have documentation (via CLIA approved, CAP certified next generation 
sequencing [NGS] assay report) of genomic aberration resulting in CDK12 loss of 
function in metastatic tumor tissue.  

Patients whose tumors have not previously undergone NGS are not eligible 
for Arm C but are eligible for the randomized unselected cohorts.
3.3 Exclusion Criteria
3.3.1
History of leptomeningeal disease, or clinical evidence of, or known and untreated 
metastatic CNS disease.
3.3.2
Concurrent active malignancy with the exception of malignancies with a negligible 
risk of metastasis or death (e.g., 5-year OS rate > 90%). 

Patients with adequately treated non-melanomatous skin cancer, cancer not 
needing active therapy for at least 2 years, cancer for which the treating 
investigator deems the subject to be in remission, or any prior malignancy that 
was treated with curative intent (no evidence of disease for at least 3 years) are 
also permitted to enroll.
3.3.3
Treatment with chemotherapy or radiotherapy within 4 weeks prior to planned cycle 1 
day 1 of study treatment.
3.3.4
Treatment with investigational therapy within 28 days prior to initiation of study 
treatment.
3.3.5
Treatment with oral anti-neoplastic intervention such as an oral hormonal agent, 
PARP inhibitor, or AR targeted therapy within 14 days prior to planned cycle 1 day 1 
of study treatment.
3.3.6
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug 
(whichever is longer) prior to initiation of study treatment.

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3.3.7
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation 
of study treatment, or anticipation of need for a major surgical procedure during the 
study.
3.3.8
Prior treatment with an inhibitor of CDK4 and/or 6.
3.3.9
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including anti– CTLA-4, anti–PD-1, PD-L1, or PD-L2-therapeutic antibodies
3.3.10 History of severe allergic anaphylactic reactions to chimeric or humanized antibodies 
or fusion proteins.
3.3.11 Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab formulation.
3.3.12 Known allergy or hypersensitivity to any component of the abemaciclib formulation.
3.3.13 Patients on concurrent therapy with a moderate or strong CYP3A4 inducer or 
inhibitor which cannot be safely stopped at least five half-lives prior to initiation of 
therapy with abemaciclib.
3.3.14 Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see Appendix E for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on thyroid-
replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are 
met:
-Rash must cover < 10% of body surface area
-Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
-There has been no occurrence of acute exacerbations of the underlying 
condition requiring psoralen plus ultraviolet A radiation, methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral 
corticosteroids within the previous 12 months

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3.3.15 Prior allogeneic stem cell or solid organ transplantation
3.3.16 Treatment with a live attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of atezolizumab
3.3.17 Active smoking (of tobacco, marijuana, or any other substance) or vaping at time of 
enrollment, or a history of smoking equivalent to greater than 20 pack-years of 
cigarettes (i.e. # packs of cigarettes [or equivalent per the below] smoked per day × # 
of years patient has smoked > 20).
Equivalents (per https://www.smokingpackyears.com/): 
1 pack/day equivalent
(20 cigarettes/pack)
20 pack-year 
equivalent
Marijuana joints
10 / day
200 joint-years
Cigars
5 / day
100 cigar-years
Pipes
8 / day
160 pipe-years
Water pipe (20 minute session)
5 / day
100 water pipe-years
3.3.18 Prior history of radiation therapy to thorax (including to lungs/pleura, esophagus, 
intrathoracic lymph nodes, C7-L2 vertebrae, or ribs) for any reason and any 
duration/dose.  This exclusion criterion does not apply to patients assigned to 
atezolizumab monotherapy in Arm C, who may have received prior radiation to 
thorax.
3.3.19 History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan
3.3.20 Active tuberculosis
3.3.21 Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX®) are allowed.
3.3.22 Any history of lung cancer, regardless of stage or treatment
3.3.23 Any of the following abnormalities on pre-treatment pulmonary function testing:
a.
FEV1/FVC ratio < lower limit of normal (LLN) and FEV1 < 75% predicted OR
b. FVC < 70% of predicted, regardless of FEV1/FVC ratio OR
c.
DLCO (corrected for hemoglobin) < 70% of predicted
The LLN of the FEV1/FVC ratio, which recognizes the change with age of this 
measurement, is determined by subtracting 10% or 0.10 from the age-specific FEV1/FVC 

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predicted for any individual (82).
3.3.24 Uncontrolled tumor-related pain
-Patients requiring pain medication must be on a stable regimen at study entry.
-Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is no 
required minimum recovery period.
-Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment.
3.3.25 Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium 
> 12 mg/dL or corrected serum calcium > ULN)
3.3.26 Severe infection, or active known detectable viral infection (e.g., Human 
Immunodeficiency Virus [HIV] or viral hepatitis) within 4 weeks prior to initiation of 
study treatment, including, but not limited to, hospitalization for complications of 
infection, bacteremia, or severe pneumonia, or any active infection that could impact 
patient safety
3.3.27 Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during study 
treatment, with the following exceptions:
-Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study.
-Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the 
study.
3.3.28 Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of 
study treatment.
-Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study.
3.3.29 Current treatment with anti-viral therapy for HBV.

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3.3.30 Arterial or venous thromboembolic event within the last 3 months.
3.3.31 Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, cerebrovascular accident, unstable 
arrhythmia, or unstable angina) within 3 months prior to initiation of study treatment.
 
3.3.32 Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high risk from treatment 
complications.
3.3.33 Significant infection, medical condition, or social situation which, in the opinion of 
the investigator, would preclude participation or limit the patient’s ability to comply 
with study requirements. 
3.4 Inclusion of Women and Minorities
Every effort will be made to include men from minority populations. The enrollment of 
minority men will reflect the proportion of minority subjects at the sites participating in 
the trial. Women are not affected by prostate cancer and therefore are not eligible.
4
REGISTRATION AND RANDOMIZATION PROCEDURES 
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
The eligibility checklist(s) and all pages of the consent form(s) will be faxed to the ODQ at 617-
632-2295. The ODQ will (a) review the eligibility checklist, (b) register the participant on the 
protocol, and (c) randomize the participant.
Randomization can only occur during ODQ business hours (8:30am - 5pm Eastern Time, 
Monday through Friday excluding holidays).
An email confirmation of the registration and/or randomization will be sent to the study 
coordinator(s) from the registering site, treating investigator and registering person immediately 
following the registration and/or randomization.
Following registration, participants may begin protocol-specific therapy and/or intervention. 

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Issues that would cause treatment delays should be discussed with the Principal Investigator (PI) 
of the registering site. If the subject does not receive protocol therapy following registration, the 
subject must be taken off study in the CTMS (OnCore) with an appropriate date and reason 
entered.  
4.2
Registration Process for DF/HCC Institutions
Applicable DF/HCC policy (REGIST-101) must be followed.  
4.3
General Guidelines for Other Investigative Sites
Eligible participants will be entered on study centrally at DF/HCC by the Study Coordinator. 
Following registration, participants should begin protocol therapy within 7 days.  Issues that 
would cause treatment delays should be discussed with the Sponsor-Investigator.  If the subject 
does not receive protocol therapy following registration, the subject must be taken off study in 
the CTMS (OnCore) with an appropriate date and reason entered.  
4.4
Registration Process for Other Investigative Sites
To register a participant, the following documents should be completed by the participating site 
and e-mailed to the Coordinating Coordinator:

Current IRB approved informed consent document informed consent document 
signed by participant and investigator. Participant name and MRN must be 
redacted. Please ensure the participant’s initials are written on each page of the 
informed consent document.

HIPAA authorization form (if separate from the informed consent document)

Signed and dated Eligibility Checklist 

The following source documentation is required:
o
Documentation of prior treatments/procedures performed to treat RCC
o
Reports documenting disease status

Chest CT

CT or MRI Abdomen and Pelvis

Tc99m Bone Scan 
o
Pathology Report
o
Concomitant medication list
o
Progress note or equivalent documentation of consenting visit
o
Progress note documenting medical history and oncologic history
o
Screening Labs
o
Screening visit note with vital signs, weight, height, ECOG performance 
status, physical examination
 The participating site will then e-mail the Coordinating Coordinator to verify eligibility.  The 
Study Coordinator will follow DF/HCC policy (REGIST-101) and register the participant on the 
protocol.  The Study Coordinator will fax or e-mail the participant study number, and if 
applicable the dose treatment level, to the participating site.  The Study Coordinator will also 
contact the participating site and verbally confirm registration.

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5.
TREATMENT PLAN
5.1.
Treatment Regimen
Protocol treatment must start within 7 calendar days of enrollment. All study therapy will be 
administered on an outpatient basis. Unless otherwise specified, treatment delay of more than 28 
days from date of last intended therapy will result in treatment discontinuation. For combination 
therapy regimens, a new cycle will not start until atezolizumab and/or abemaciclib are given. No 
minimum time interval is required between abemaciclib and atezolizumab administration. 
Vomited should be skipped, and abemaciclib dosing resumed at the next scheduled dose. If a 
dose is missed, it may be taken when remembered if there are at least 6 hours before the next 
scheduled dose. Held doses of atezolizumab or abemaciclib will be considered omitted for that 
cycle.
Table 1. ARM A Treatment 
ARM A - Regimen Description
Prophylaxis Details 
& Precautions
Starting 
Dose
Route
Schedule
Cycle 
Length
Abemaciclib 
Refer to Table 20 
for diarrhea 
supportive care and 
management 
guidance.
200mg 
BID
Oral
Days 1-
21
21 Days
Table 3. ARM C Treatment
ARM C - Regimen Description
Initial 5 patients
Prophylaxis 
Details & 
Precautions
Starting 
Dose
Route2
Schedule
Cycle 
Length

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Atezolizumab 
Consult with study 
PI regarding use 
of corticosteroids. 
G-CSF/GM-CSF 
is prohibited.
1200mg
IV over 60 (+/-5) 
minutes
If the first infusion 
is tolerated, 
subsequent 
infusions may be 
administered over 
30 (+/-5) minutes.
Day 1
21 Days
Subsequent 16 patients
Abemaciclib
Refer to Table 20 
for diarrhea 
supportive care 
and management 
guidance.
200mg 
BID
Oral
Days 1-
21
21 Days
1Based on results of Bayesian toxicity monitoring, the starting dose of abemaciclib may be subsequently 
modified to a lower dose level.
2Infusion times may be extended as needed for safety (e.g., infusion reaction occurs). These instances 
must be documented in the patient medical records.
Local intervention is discouraged unless medically unavoidable. Radiation therapy to the thorax 
(including to lungs/pleura, esophagus, intrathoracic lymph nodes, C7-L2 vertebrae, or ribs) is not 
permitted while on study and is strongly discouraged for at least 90 days after the last dose of 
abemaciclib and atezolizumab (whichever is later) unless for medical emergency such as 
impending spinal cord compression after approval in each individual case by Sponsor-
Investigator.  Palliative radiation to a symptomatic solitary lesion/area outside the thorax may be 
considered on a case-by-case basis and only after consultation with the Sponsor-Investigator. 
Subjects receiving local intervention (e.g., palliative radiation) are allowed to continue to receive 
study treatment at the treating investigator’s discretion.
5.2.
Pre-Treatment Criteria
Pre-treatment assessments should be performed within 72 hours of planned treatment dose. 
Results from the patient’s complete blood counts and serum chemistry must be reviewed prior to 
drug dosing. Study agents must be dispensed or administered only to subjects enrolled in the 
study and in accordance with the protocol. Standard institutional procedures for administering an 
oral agent via by mouth will be followed. An adequate supply will be provided with instructions 
on home administration.
5.2.1. Cycle 1, Day 1
The patient’s laboratory parameters must meet eligibility criteria (section 3.1.9) to initiate 
cycle 1 day 1 of trial therapy.  Transfusion or growth factors are not permitted between 
screening up to and including cycle 1 day 1 to re-meet eligibility criteria except for 

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patients assigned to atezolizumab monotherapy in Arm C for whom red blood cell 
transfusion to meet eligibility criterion for hemoglobin is permitted.
5.2.2. Subsequent Cycles 
Eligibility to receive subsequent doses is based on dose delay/modification criteria 
detailed in Section 6.  
5.3.
General Concomitant Medication and Supportive Care Guidelines
The treating investigator should discuss any questions regarding concomitant medications or 
treatments with the Sponsor-Investigator. The final decision on any supportive therapy or 
vaccination rests with the treating investigator. However, the decision to continue the subject on 
trial therapy or vaccination schedule requires the mutual agreement of the Sponsor-Investigator, 
treating investigator, and subject.
The following medications and treatments are prohibited while the patient is receiving 
protocol therapy: 

Any non-protocol antineoplastic therapy (radiation, chemo-, immuno- or biologic 
therapy) 

Other investigational agents 

Herbal products known to decrease PSA levels (e.g., Saw Palmetto, PC-SPES)

Neulasta® and other granulocyte colony stimulating factors

Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab, and for 5 
months after the last dose of atezolizumab

CYP3A inducers

Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL 2) are prohibited within 4 weeks or five drug elimination half-lives (whichever 
is longer) prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab.

Grapefruit or grapefruit juice

5 α-reductase inhibitors (e.g., finasteride, dutasteride)
For patients in Arms B and C only:

Systemic glucocorticoids or other immunosuppressive drugs (for any purpose 
other than to modulate symptoms from a drug-related AE of immunologic 
etiology - Refer to Section 6 for applicable adjustment of protocol therapy).  

(If precluded by local regulations) live vaccines should not be given for 120 days 
after the last dose of checkpoint inhibitor immunotherapy is administered. 
NOTE:

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Use of strong CYP3A inhibitors is discouraged unless medically unavoidable. 
Introduction of treatment with a strong inhibitor may be considered on a case-by-case 
basis and only after consultation with the Sponsor-Investigator. (use caution with 
moderate [e.g., ciprofloxacin] or weak [e.g., ranitidine] inhibitors). Refer to Section 
6.2 for dosing modification of abemaciclib.
The following medications and treatments are permitted while the patient is receiving 
protocol therapy:

Ongoing androgen deprivation therapy (e.g., LHRH agonist/antagonist)

Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable dose 
or low-molecular-weight heparin)

Megestrol acetate administered as an appetite stimulant 

Vaccinations (such as. influenza, SARS-CoV-2)

Live, attenuated vaccines are not permitted

Physiologic doses of prednisone ≤10 mg (or equivalent) per day

Prophylactic corticosteroids to avoid allergic or other adverse reactions (e.g., 
known IV contrast allergy or prior to transfusions) 

Physiologic doses of corticosteroids (subject to discussion and approval of 
Sponsor-Investigator)

Intermittent inhaled steroids or local injection of corticosteroids (subject to 
discussion and approval of Sponsor-Investigator)

Bisphosphonates/RANKL inhibitors. Starting bisphosphonates while on study, if 
indicated, is also allowed.
5.4
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
indefinitely or until one of the following criteria applies:

Disease progression by PCWG3 criteria (81), including clinical progression. Patients 
should not be discontinued from study therapy for PSA progression alone. PCWG3 
criteria allow treatment beyond radiographic progression if the treating physician 
feels that the patient is continuing to derive clinical benefit from therapy, and the 
patient will continue until felt to be “no longer clinically benefiting” (NLCB).  
Patients in Arm B and the combination cohort of Arm C can be treated beyond 
progression per criteria in section 5.8. 

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements

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
Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
When a participant is removed from protocol therapy and/or is off of the study, the participant’s 
status must be updated in OnCore in accordance with REGIST-OP-1.
5.5
Duration of Follow Up
After treatment discontinuation, patients will be followed every 3 months for 24 months or 
until death, whichever occurs first. Participants removed from protocol therapy for 
unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse 
event and for PSA and/or radiographic progression until a new treatment is started, the 
patient withdraws from study procedures, or death.
5.6
Criteria for Taking a Participant Off Study
Patients can be taken off study at any time at their own request, or they may be withdrawn at 
the discretion of the investigator for safety, behavioral or administrative reasons. The 
reason(s) for discontinuation from study will be documented and may include:

Development of second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment, which would interfere with this study;

Patient withdraws consent (termination of treatment AND follow-up);

Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment;

Physician discretion (e.g., noncompliance or other circumstance);

Lost to Follow-up;

Termination of the study by Sponsor-Investigator or FDA;

Patient completes protocol treatment and follow-up criteria.

Death
Document in the source the reason for ending protocol therapy and the date the patient was 
removed from treatment. All patients who discontinue treatment should comply with protocol 
specific follow-up procedures as outlined in Section 10. The only exception to this 
requirement is when a subject withdraws consent for all study procedures or loses the ability 

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to consent freely.
The reason for taking a participant off study, and the date the participant was removed, must 
be documented in the case report form (CRF). In addition, the study team will ensure the 
participant’s status is updated in OnCore in accordance with REGIST-OP-1.
5.7
Patient Replacement 
Patients who have been registered and receive no protocol therapy will be replaced. 
Patients who receive local intervention (e.g., palliative radiation) may be considered not 
evaluable These patients may subsequently be assigned a conservative censoring or 
progression date.
5.8
Treatment Beyond Progression
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD.
Subjects treated in C will be permitted to continue study treatment beyond initial RECISTv1.1 
defined PD, assessed by the investigator, as long as they meet the following criteria:

Investigator determined clinical benefit

Tolerance of study drug

Stable performance status

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases)
6.
DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Any patient who receives protocol treatment will be evaluable for toxicity. Each patient will be 
assessed for the development of toxicity according to the Study Calendar (Section 10). Toxicity 
will be assessed according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE), version 5.0. Dose adjustments should be made according to the system showing the 
greatest degree of toxicity. The dose delays and modifications described here are requirements, 
but re-escalation of abemaciclib dose is permitted per discretion of the treating investigator if 
there is improvement in the adverse event for which the dose was initially reduced.  Investigators 
are encouraged to contact the Sponsor-Investigative team with any questions.

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Table 4. Abemaciclib Dosing Modifications
Abemaciclib Dosing Modifications
Dose Level
Monotherapy
Combination therapy
1
200mg BID
150mg BID
-1
150mg BID
100mg BID
-2
100mg BID
50mg BID
-3
50mg BID
Discontinue

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6.1
Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice.  Additional tests, such as autoimmune serology or 
biopsies, should be used to evaluate for a possible immunogenic etiology.  
Although most immune-mediated adverse events observed with atezolizumab have been mild 
and self-limiting, such events should be recognized early and treated promptly to avoid potential 
major complications.  Discontinuation of atezolizumab may not have an immediate therapeutic 
effect, and in severe cases, immune-related toxicities may require acute management with topical 
corticosteroids, systemic corticosteroids, or other immunosuppressive agents.
The following are general recommendations for management of any other adverse events that 
may occur and are not specifically listed in the following subsections. 
•
Patients and family caregivers should receive timely and up-to-date information about 
immunotherapies, their mechanism of action, and the clinical profile of possible immune-related 
adverse events prior to initiating therapy and throughout treatment and survival follow-up.  There 
should be a high level of suspicion that new symptoms are treatment related.
•
In general, atezolizumab therapy should be continued with close monitoring for Grade 1 
toxicities, with the exception of some neurologic toxicities.
•
Consider holding atezolizumab for most Grade 2 toxicities and resume when symptoms 
and/or laboratory values resolve to Grade 1 or better.  Corticosteroids (initial dose of 0.5-1 
mg/kg/day of prednisone or equivalent) may be administered.
•
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a Grade 
3 event.  
•
Hold atezolizumab for Grade 3 toxicities and initiate treatment with high-dose 
corticosteroids (1-2 mg/kg/day prednisone or equivalent).  Corticosteroids should be tapered over 
1 month to 10 mg/day oral prednisone or equivalent, before atezolizumab can be resumed.  If 
symptoms do not improve within 48 to 72 hours of high-dose corticosteroid use, other 
immunosuppressants may be offered for some toxicities.
•
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
treatment, with the exception of endocrinopathies that are controlled by hormone replacement 
therapy.
The investigator should consider the benefitrisk balance for a given patient prior to further 
administration of atezolizumab.  In patients who have met the criteria for permanent 
discontinuation, resumption of atezolizumab may be considered if the patient is deriving benefit 
and has fully recovered from the immune-mediated event.  The decision to re-challenge patients 
with atezolizumab should be based on investigator’s assessment of benefitrisk and documented 
by the investigator.
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab in this study.

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TREATMENT INTERRUPTION
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment of the 
toxicity, they must be tapered over 1 month to the equivalent of  10 mg/day oral prednisone 
before atezolizumab can be resumed.  If atezolizumab is withheld for  12 weeks after event 
onset, the patient will be discontinued from atezolizumab.  However, atezolizumab may be 
withheld for  12 weeks to allow for patients to taper off corticosteroids prior to resuming 
treatment.  Atezolizumab can be resumed after being withheld for  12 weeks if the patient is 
likely to derive clinical benefit.  The decision to rechallenge patients with atezolizumab should 
be based on investigator’s assessment of benefitrisk and documented by the investigator.  
Atezolizumab treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures).  The acceptable length of treatment interruption must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the duration 
of treatment and documented by the investigator.
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab.  Patients will be assessed for pulmonary signs and 
symptoms throughout the study and will have computed tomography (CT) scans of the chest 
performed at every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease, or pulmonary hypertension.  Management 
guidelines for pulmonary events are provided in Table 5.

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Table 5. Management Guidelines for Pulmonary Events, Including Pneumonitis
Event
Management
Pulmonary Event, 
Grade 1

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.

For Grade 1 pneumonitis, consider withholding atezolizumab.
Pulmonary Event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and consider 
bronchoscopy or BAL.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. c

For recurrent events, or events with no improvement after 48–72 hours of 
corticosteroids, treat as a Grade 3 or 4 event.

Pulmonary Event, 
Grade 3 or 4

Permanently discontinue abemaciclib and atezolizumab and contact Sponsor-
Investigator.

Oral or IV broad-spectrum antibiotics should be administered in parallel to the 
immunosuppressive treatment.

Bronchoscopy or BAL is recommended.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over  1 month.
BAL    bronchoscopic alveolar lavage.a
Atezolizumab may be withheld for a longer period of time (i.e.,  12 
weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day 
oral prednisone.  The acceptable length of the extended period of time must be based on an assessment of 
benefitrisk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of  10 mg/day oral 
prednisone before atezolizumab can be resumed.
c    Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-mediated event.  The decision to rechallenge patients with atezolizumab should be based on 
investigator's assessment of benefitrisk and documented by the investigator (or appropriate delegate).
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Error! Reference source not 
found.6.

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All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of systemic 
inflammation or acute-phase reactants (e.g., increased C-reactive protein, platelet count, or 
bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with 
three to five specimens for standard paraffin block to check for inflammation and lymphocytic 
infiltrates to confirm colitis diagnosis. 
Table 6. Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis)
Event
Management
Diarrhea or colitis, 
Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for > 7 days.

Monitor closely.
Diarrhea or colitis, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist > 5 days, initiate treatment with 
corticosteroids equivalent to 1-2 mg/kg/day oral prednisone. If the 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 Sponsor-Investigator. c
Diarrhea or colitis, 
Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with 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 the 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 Sponsor-Investigator. c

Grade 4

Permanently discontinue atezolizumab and contact Sponsor-Investigator. c

Refer patient to GIspecialist for evaluation and confirmation biopsy.

Initiate treatment with 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 of initiating corticosteroids, consider 
adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month.
GI = gastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time 
must be based on an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-
related event. The decision to re-challenge patients with atezolizumab should be based on investigator's assessment of benefit-
risk and documented by both the investigator (or an appropriate delegate) and the Sponsor-Investigator. 

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ENDOCRINE EVENTS
Management guidelines for endocrine events are provided in Table 7.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies.  The patient should be referred to an endocrinologist if an 
endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) and free triiodothyronine and 
thyroxine levels should be measured to determine whether thyroid abnormalities are present.  
Pituitary hormone levels and function tests (e.g., TSH, growth hormone, luteinizing hormone, 
follicle-stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone [ACTH] 
levels, and ACTH stimulation test) and magnetic resonance imaging (MRI) of the brain (with 
detailed pituitary sections) may help to differentiate primary pituitary insufficiency from primary 
adrenal insufficiency.
Table 7. Management Guidelines for Endocrine Events
Event
Management
Grade 1 
Hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH closely.
Grade 2 
Hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH closely.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and thyroid function is 
improving.
Grade 3 and 4 
Hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH closely.

Refer to an endocrinologist.

Admit patient to the hospital for developing myxedema (bradycardia, 
hypothermia, and altered mental status).

Resume atezolizumab when symptoms are controlled, and thyroid function is 
improving.

Permanently discontinue atezolizumab. c
Grade 1 
Hyperthyroidism
TSH ≥ 0.1 mU/L and < 0.5 mU/L:

Continue atezolizumab.

Monitor TSH every 4 weeks.

Consider patient referral to endocrinologist.
TSH < 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.

Consider patient referral to endocrinologist.

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Grade 2
hyperthyroidism

Consider withholding atezolizumab.

Initiate treatment with anti-thyroid drug such as methimazole or carbimazole as 
needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled, and thyroid function is 
improving.
 Grade 3 and 4 
Hyperthyroidism

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as methimazole or carbimazole as 
needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and thyroid function is 
improving.

Permanently discontinue atezolizumab and contact Sponsor-Investigator for 
life-threatening immune-related hyperthyroidism. c
Symptomatic 
Adrenal 
Insufficiency, 
Grades 2-4

Withhold atezolizumab for up to 12 weeks after event onset. a

Consider patient referral to endocrinologist.

Perform appropriate imaging.

Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement.

If event resolves to Grade 1 or better and patient is stable on replacement 
therapy, resume atezolizumab. b

If event does not resolve to Grade 1 or better or patient is not stable on 
replacement therapy while withholding atezolizumab, permanently discontinue 
atezolizumab and contact Sponsor-Investigator. c
Hyperglycemia 
Grade 1 or 2

Continue atezolizumab.

Investigate for diabetes.  If patient has Type 1 diabetes, treat as a Grade 3 event.  
If patient does not have Type 1 diabetes, treat as per institutional guidelines.

Monitor for glucose control.
Hyperglycemia
Grade 3 or 4

Withhold atezolizumab.

Initial treatment with insulin. 

Evaluate for diabetic ketoacidosis and manage as per institutional guidelines. 

Monitor for glucose control

Resume atezolizumab when symptoms resolve and glucose levels are stable. 

For recurrent Grade 3 or higher events, permanently discontinue atezolizumab 
and contact Sponsor-Investigator. c
Hypophysitis (pan-
hypopituitarism), 
Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Consider patient referral to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement. a

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor-Investigator. c

For recurrent hypophysitis, treat as Grade 4 event.
Hypophysitis (pan-
hypopituitarism), 
Grade 4

Permanently discontinue atezolizumab and contact Sponsor-Investigator. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

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
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. a

Initiate hormone replacement if clinically indicated.
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of  ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time 
must be based on an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-
related event. The decision to re-challenge patients with atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by both the investigator (or an appropriate delegate) and the Sponsor-Investigator.
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Error! Reference source not found..
Table 8. Management Guidelines for Ocular Events
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time 
must be based on an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-
related event. The decision to re-challenge patients with atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by both the investigator (or an appropriate delegate) and the Sponsor-Investigator. 
Event
Management
Ocular Event, Grade 
1

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended. 

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 

If symptoms persist, treat as a Grade 2 event.
Ocular Event, Grade 
2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended. 

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor-Investigator. c
Ocular Event, Grade 
3 or 4

Permanently discontinue atezolizumab and contact Sponsor-Investigator. c

Refer patient to ophthalmologist.

Initiate treatment with  corticosteroids equivalent to 1-2 mg/kg/day IV oral 
prednisone.

If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month.

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IMMUNE-MEDIATED CARDIAC EVENTS
IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of atezolizumab.  
Immune-mediated myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-type 
natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, 
decreased exercise tolerance, or syncope.  Myocarditis may also be a clinical manifestation of 
myositis or associated with pericarditis (see section on pericardial disorders below) and should 
be managed accordingly.  Immune-mediated myocarditis needs to be distinguished from 
myocarditis resulting from infection (commonly viral, e.g., in a patient who reports a recent 
history of gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An endomyocardial 
biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if clinically 
indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Error! Reference source not found.9.
IMMUNE-MEDIATED PERICARDIAL DISORDERS
Immune-mediated pericarditis should be suspected in any patient presenting with chest pain and 
may be associated with immune-mediated myocarditis (see section on myocarditis above).
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in any patient 
presenting with chest pain associated with dyspnea or hemodynamic instability. 
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac injury related 
(post myocardial infarction or iatrogenic), and autoimmune disorders, and should be managed 
accordingly.
All patients with suspected pericardial disorders should be urgently evaluated by performing an 
ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as appropriate per 
institutional guidelines.  A cardiologist should be consulted.  Pericardiocentesis should be 
considered for diagnostic or therapeutic purposes, if clinically indicated.
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac tamponade, in 
the absence of an identified alternate etiology, should be treated according to the guidelines in 

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Table 9.  Withhold treatment with atezolizumab for Grade 1 pericarditis and conduct a detailed 
cardiac evaluation to determine the etiology and manage accordingly.
Table 9. Management Guidelines for Immune-Mediated Myocarditis and Pericardial 
Disorders
Event
Management
Immune-mediated 
myocarditis, Grades 
2-4
Immune-mediated 
pericardial disorders, 
Grades 2-4

Permanently discontinue atezolizumab. and contact Sponsor-Investigator. 

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider antiarrhythmic 
drugs, temporary pacemaker, ECMO, or VAD as appropriate. 

Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement. 

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month.
ECMO  extracorporeal membrane oxygenation; VAD  ventricular assist device.
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME
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, anti-pyretics, 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 (83).  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 
(84, 85), 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 Table 10.

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Severe COVID-19 appears to be associated with a CRS involving the inflammatory cytokines 
interleukin (IL)-6, IL-10, IL-2, and IFN- (86).  If a patient develops suspected CRS during the 
study, a differential diagnosis should include COVID-19, which should be confirmed or refuted 
through assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator judgment.  If a diagnosis of COVID-19 is confirmed, the disease 
should be managed as per local or institutional guidelines.
Table 10. Management Guidelines for Infusion-related Reactions and Cytokine Release 
Syndrome
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, consider 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.

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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.

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 as described in this appendix.

Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.

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. e

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 
the Sponsor-Investigator.
Grade 3 a
Fever b with 
hypotension 
requiring a 
vasopressor (with or 
without vasopressin)
and/or
Hypoxia requiring 
high-flow oxygen d 
by nasal cannula, 
face mask, 
non-rebreather mask, 
or Venturi mask

Permanently discontinue atezolizumab and contact Sponsor-Investigator. e

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 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 as described in this appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.

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 anti-cytokine therapy, 
experimental treatments may be considered at the discretion of the investigator.
Grade 4 a

Permanently discontinue atezolizumab and contact Sponsor-Investigator. e

Administer symptomatic treatment. c

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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)

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 as described in this appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.  For patients who are refractory to anti-cytokine 
therapy, experimental treatments f may be considered at the discretion of the 
investigator.

Hospitalize patient until complete resolution of symptoms.
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:  These management guidelines have been adapted from NCCN guidelines for management of CAR T-cellrelated 
toxicities (Version 2.2019).
a
Grading system for these management guidelines is based on ASTCT consensus grading for CRS.  NCI CTCAE v5.0 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 Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. The decision to re-challenge patients with atezolizumab should be based on investigator's assessment 
of benefitrisk and documented by both the investigator (or an appropriate delegate) and the Sponsor-Investigator. 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 
assessing the benefitrisk ratio.
f
Refer to Riegler et al. (87).
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab.  The differential 
diagnosis of acute abdominal pain should include pancreatitis.  Appropriate workup should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests.  
Management guidelines for pancreatic events, including pancreatitis, are provided in Table 11.
Table 11. Management Guidelines for Pancreatic Events, Including Pancreatitis

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Amylase and/or 
lipase elevation
Management
Amylase and/or 
lipase elevation, 
Grade 2
Amylase and/or lipase  1.52.0  ULN:

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., > 3 weeks), consider treatment with 
corticosteroids equivalent to 10 mg/day oral prednisone.
Asymptomatic with amylase and/or lipase  2.05.0  ULN:

Treat as a Grade 3 event.
Amylase and/or 
lipase elevation, 
Grade 3 or 4

Withhold atezolizumab for up to 12 weeks after event onset. a

Consider patient referral to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider treatment with corticosteroids equivalent to 1-2 
mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor-Investigator. c

For recurrent events, permanently discontinue atezolizumab and contact 
Sponsor-Investigator. c
Immune-mediated 
pancreatitis, Grade 2 
or 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Consider patient referral to GI specialist.

Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b 

If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor-Investigator. c

For recurrent events, permanently discontinue atezolizumab and contact 
Sponsor-Investigator. c
Immune-mediated 
pancreatitis, Grade 4

Permanently discontinue atezolizumab and contact Sponsor-Investigator. c

Refer patient to specialist.

Initiate treatment with 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. 
GI  gastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time 
must be based on an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-
related event. The decision to re-challenge patients with atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by both the investigator (or an appropriate delegate) and the Sponsor-Investigator. 
DERMATOLOGIC EVENTS

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Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of rash 
were mild in severity and self-limiting, with or without pruritus.  Although uncommon, cases of 
severe cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab.  A dermatologist should evaluate persistent 
and/or severe rash or pruritus.  A biopsy should be considered unless contraindicated.  
Management guidelines for dermatologic events are provided in Table 12.
Table 12. Management Guidelines for Dermatologic Events
Event
Management
Dermatologic event, 
Grade 1

Continue atezolizumab 

Consider treatment with topical corticosteroids and/or other symptomatic 
therapy (e.g., antihistamines).
Dermatologic event, 
Grade 2

Continue atezolizumab.

Consider patient referral to dermatologist for evaluation and, if indicated, 
biopsy.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if event does not 
improve.

If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day.
Dermatologic event, 
Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patients to dermatologist for evaluation and, if indicated, biopsy.

Initiate treatment with corticosteroids equivalent to 10 mg/day oral prednisone, 
increasing dose to 1-2 mg/kg/day if event does not improve within 48-72 hours.

If event resolves to Grade 1 or better, resume atezolizumab,b

If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor-Investigator. c
Dermatologic event, 
Grade 4

Permanently discontinue atezolizumab and contact Sponsor-Investigator. c
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
(any grade)
Additional guidance for Stevens-Johnson syndrome or toxic epidermal necrolysis:

Withhold atezolizumab for suspected Stevens-Johnson syndrome or toxic 
epidermal necrolysis.

Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation and, if indicated, 
biopsy.

Follow the applicable treatment and management guidelines above.

If Stevens-Johnson syndrome or toxic epidermal necrolysis is confirmed, 
permanently discontinue atezolizumab.
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of  ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time 
must be based on an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent before 
atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-
related event. The decision to re-challenge patients with atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by both the investigator (or an appropriate delegate) and the Sponsor-Investigator.
NEUROLOGIC DISORDERS

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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 in 
Table 13.
Table 13. Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated 
neuropathy, Grade 1

Continue atezolizumab. 

Investigate etiology.

Any cranial nerve disorder (including facial paresis) should be managed as per 
Grade 2 management guidelines below.
Immune-mediated 
neuropathy, including 
facial paresis, Grade 
2

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology and consider patient referral to neurologist.

Initiate treatment as per institutional guidelines.

For general immune-mediated neuropathy:
-If event resolves to Grade 1 or better, resume atezolizumab. b
-If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. c

For facial paresis:
-If event resolves fully, resume atezolizumab b
-If event does not resolve fully while withholding atezolizumab, permanently 
discontinue atezolizumab. c

Immune-mediated 
neuropathy, including 
facial paresis, Grade 
3 or 4

Permanently discontinue atezolizumab and contact Sponsor-Investigator. c

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.
Myasthenia gravis or 
Guillain Barre 
syndrome (any grade)

Permanently discontinue atezolizumab and contact Sponsor-Investigator. c

Refer patient to neurologist.

Initiate treatment per institutional guidelines.

Consider initiation of 1-2 mg/kg/day oral or IV prednisone.
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time 
must be based on an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-
related event. The decision to re-challenge patients with atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by both the investigator (or an appropriate delegate) and the Sponsor-Investigator. 

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Table 14. Management Guidelines for Immune-Mediated Myelitis
Event
Management
Immune-mediated myelitis, 
Grade 1

Continue atezolizumab unless symptoms worsen or do not improve.

Investigate etiology and refer patient to a neurologist.
Immune-mediated myelitis, 
Grade 2

Permanently discontinue atezolizumab.

Investigate etiology and refer patient to a neurologist.

Rule out infection.

Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone.
Immune-mediated myelitis, 
Grade 3 or 4

Permanently discontinue atezolizumab.

Refer patient to a neurologist.

Initiate treatment as per institutional guidelines.
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated 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 in Table 15.
Table 15. Management Guidelines for Immune-mediated meningoencephalitis
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-
mediated event. The decision to rechallenge patients with atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by both the investigator (or an appropriate delegate) and the Sponsor-Investigator. 
Event
Management
Immune-mediated 
meningoencephalitis, all 
grades

Permanently discontinue atezolizumab and contact Sponsor-Investigator. c

Refer patient to neurologist.

Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone or equivalent and convert to 1-2 mg/kg/day oral 
prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month.

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RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function.  Renal function, including serum creatinine, 
should be monitored throughout study treatment.  Patients with abnormal renal function should 
be evaluated and treated for other more common etiologies (including prerenal and postrenal 
causes, and concomitant medications such as non steroidal anti-inflammatory drugs).  Refer the 
patient to a renal specialist if clinically indicated.  A renal biopsy may be required to enable a 
definitive diagnosis and appropriate treatment.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 16.
Table 16. Management Guidelines for Renal Events
Event
Management
Renal event, Grade 1

Continue atezolizumab

Monitor kidney function, including creatinine and urine protein, closely until 
values resolve to within normal limits or to baseline values.
Renal event, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Consider patient referral to renal specialist.

Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor-Investigator. c
Renal event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact Sponsor-Investigator. c

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of  ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time 
must be based on an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-
related event. The decision to re-challenge patients with atezolizumab should be based on investigator's assessment of benefit-
risk and documented by both the investigator (or an appropriate delegate) and the Sponsor-Investigator.

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HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases, and liver function will be monitored 
throughout study treatment.  Management guidelines for hepatic events are provided in Error! 
Reference source not found.17.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should 
have liver function tests (LFTs) performed immediately and reviewed before administration of 
the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate.
Table 17. Management Guidelines for Hepatic Events
Event
Management
Hepatic event, Grade 
1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits or to baseline values.
Hepatic event, Grade 
2
All events:

Monitor LFTs more frequently until return to baseline values.
Events of > 5 days’ duration: 

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor-Investigator. c
Hepatic event, Grade 
3 or 4

Permanently discontinue atezolizumab and contact Sponsor-Investigator. c

Consider patient referral to gastrointestinal specialist for evaluation and liver 
biopsy to establish etiology of hepatic injury.

Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month.
LFT    liver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time 
must be based on an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-
related event. The decision to re-challenge patients with atezolizumab should be based on investigator's assessment of 
benefitrisk and documented by both the investigator (or an appropriate delegate) and the sponsor-investigator. 

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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 among 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 possible 
myositis should be referred to a rheumatologist or neurologist.  Patients with possible myositis 
should be monitored for signs of myocarditis.
Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 8.
Table 18
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 
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or equivalent 
upon improvement.

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. c

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Immune-mediated 
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

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 prednisone or equivalent upon 
improvement.

If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. c

For recurrent events, treat as a Grade 4 event.
Immune-mediated 
myositis, Grade 4

Permanently discontinue atezolizumab. 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 limits 
mobility); convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over  1 month.
a
Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on an assessment of benefitrisk by the investigator and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.
b
If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of  10 mg/day oral prednisone 
before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event.  The decision to rechallenge patients with atezolizumab should be based on investigator's 
assessment of benefitrisk and documented by the investigator (or an appropriate delegate).

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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), which are considered 
to be potential risks for atezolizumab.  
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.
Patients with suspected HLH should be diagnosed according to published criteria by McClain 
and Eckstein (88).  A patient should be classified as having HLH if five of the following eight 
criteria are met:

Fever  38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old)
–
Platelet count  100  109/L (100,000/L)
–
ANC  1.0  109/L (1000/L)

Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L (150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin  500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated  2 standard deviations above 
age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al. (89).  A febrile patient should be classified as having 
MAS if the following criteria are met:

Ferritin  684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count  181  109/L (181,000/L)
–
AST  48 U/L
–
Triglycerides  1.761 mmol/L (156 mg/dL)
–
Fibrinogen  3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in Table 9.

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Table 19
Management Guidelines for Suspected Hemophagocytic Lymphohistiocytosis or 
Macrophage Activation Syndrome
Event
Management
Suspected HLH or 
MAS

Permanently discontinue atezolizumab.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if indicated per 
institutional guidelines.

Consider initiation of IV corticosteroids, an immunosuppressive agent, and/or anti-
cytokine therapy.

If event does not respond to treatment within 24 hours, initiate treatment as 
appropriate according to published guidelines (90-92).

If event resolves to Grade 1 or better, taper corticosteroids over  1 month.
HLH  hemophagocytic lymphohistiocytosis; MAS  macrophage activation syndrome.
6.2
Abemaciclib Toxicity Management
Table 20. Diarrhea
Diarrhea
Management
(management 
overview)
Clinical trial data indicates the majority of patients who receive abemaciclib will develop 
diarrhea. Our experience indicates early identification and intervention for the 
management of diarrhea has been helpful to patients.
At time of enrollment, patients should receive instructions on the prompt management of 
diarrhea. In the event of diarrhea, supportive care measures should be initiated as early as 
possible. These include the following:
At the first sign of loose stools, the patient should initiate antidiarrheal therapy 
(e.g., loperamide) and notify the investigator for further instructions and 
appropriate follow-up.
Patients should also be encouraged to drink fluids (e.g., 8 to 10 glasses of clear 
liquids per day).
Site personnel should assess response within 24 hours. 
Grade 1
Dose modification not required.
Grade 2
If toxicity does not resolve within 24 hours to ≤ Grade 1, suspend dose until resolution. 
Dose reduction not required.
Grade 2 that persists 
or recurs after 
resuming the same 
dose despite maximal 
supportive measures
Grade 3 or 4, or 
requiring 
hospitalization
Suspend dose until toxicity resolves to ≤ Grade 1. Resume at next lower dose.

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Table 21. Interstitial lung disease (ILD) or Pneumonitis Events
Interstitial lung 
disease (ILD) 
or 
Pneumonitis Events
Management
(management 
overview)
Interstitial lung disease (ILD) / pneumonitis has been identified as an adverse drug 
reaction for abemaciclib. Adverse events reported included events such as interstitial 
lung disease, pneumonitis, obliterative bronchiolitis, organizing pneumonia, pulmonary 
fibrosis. The majority of events were Grade 1 or Grade 2 with serious cases and fatal 
events reported. 
Patients should be asked to report any new or worsening pulmonary symptoms such as 
dyspnea, cough and fever; these symptoms should be investigated and treated as per local 
clinical practice and/or guidelines (including corticosteroids as appropriate). 
Investigations may include imaging such as high resolution computer tomography 
(HRCT), bronchoalveolar lavage (BAL), and biopsy as clinically indicated.
Grade 1, 
development of 
radiological or PFT 
changes suggestive of 
pneumonitis and have 
few or no symptoms

Perform high-resolution CT scan (defined as slice thickness of 1 to 1.25mm and 
use of high special frequency algorithm). 

If after initial workup, the patient does not meet CTCAE 5.0 criteria for grade 
>=2 pneumonitis/ILD (symptomatic or needing medical intervention), treatment 
may be continued

The patient will be monitored closely with high-resolution CT scans and PFTs 
every 8 weeks until resolution of Grade 1 pneumonitis or until worsening to 
grade >=2 pneumonitis/ILD at which time the treatment must be withheld per 
protocol.

Consider patient referral to pulmonary specialist.
Grade 2, 3 or 4

Permanently discontinue abemaciclib and atezolizumab and contact Sponsor-
Investigator.

Referral to pulmonary specialist is recommended with consideration of 
bronchoscopy or BAL.

Initiate treatment with 1-2 mg/kg/day oral prednisone or equivalent.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 

Patients who develop >= grade 2 pneumonitis/ILD must withdraw from further 
study treatment
Table 22. ALT or AST Increase
ALT or AST 
increase
Management
Grade 1 (ULN - 3.0 
x ULN if baseline 
was normal; 1.5 - 
3.0 x baseline if 
baseline was 
abnormal) or Grade 
2 (>3.0 - 5.0 x ULN 
if baseline was 
Dose modification not required. 

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normal; >3.0 - 5.0 x 
baseline if baseline 
was abnormal)
Transient Grade 2
Liver testing, including ALT, AST, ALP, total bilirubin, direct bilirubin, gamma-
glutamyl transferase, and creatine kinase, should be repeated within 2 to 4 days to 
confirm the abnormality and to determine if it is increasing or decreasing.
Persistent or 
Recurrent Grade 2 
that does not resolve 
with maximal 
supportive measures 
within 7 days to 
baseline or Grade 1, 
or Grade 3
Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose.
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation 
for possible causes of abnormal liver tests, should be initiated by the investigator.  At a 
minimum, this evaluation should include physical examination and a thorough medical 
history, including symptoms, recent illnesses (for example, heart failure, systemic 
infection, hypotension, or seizures), history of concomitant medications (including over-
the-counter, herbal and dietary supplements, history of alcohol drinking and other 
substance abuse).  In addition, the evaluation should include a blood test for prothrombin 
time (PT-INR); serological tests for viral hepatitis A, B, C, E, autoimmune hepatitis; and 
an abdominal imaging study (for example, ultrasound or CT scan).
Based on the patient’s history and initial evaluation results, further testing should be 
considered in consultation with the Sponsor-Investigator, including tests for hepatitis D 
virus (HDV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), acetaminophen levels, 
acetaminophen protein adducts, urine toxicology screen, Wilson’s disease, blood alcohol 
levels, urinary ethyl glucuronide, and serum phosphatidylethanol, as well as additional 
laboratory testing from the list below as indicated based on the patient’s medical history, 
risk factors and exposures. Based on the circumstances and the investigator’s assessment 
of the participant’s clinical condition, the investigator should consider referring the 
participant for a hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography 
(ERCP), cardiac echocardiogram, and/or a liver biopsy:
Hematology
Clinical Chemistry
Hemoglobin
Total bilirubin
Hematocrit
Direct bilirubin
Erythrocytes (RBCs - red blood cells)
Alkaline phosphatase (ALP)
Leukocytes (WBCs - white blood cells)
Alanine aminotransferase (ALT)
Differential:
Aspartate aminotransferase (AST)
    Neutrophils, segmented
Gamma-glutamyl transferase (GGT)
    Lymphocytes
Creatine kinase (CK)
    Monocytes
Other Chemistry
    Basophils
Acetaminophen
    Eosinophils
Acetaminophen protein adducts
Platelets
Alkaline phosphatase isoenzymes
Cell morphology (RBC and WBC)
Ceruloplasmin
Copper
Coagulation
Ethyl alcohol (EtOH)

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Prothrombin time, INR (PT-INR)
Haptoglobin
Serology
Immunoglobulin IgA (quantitative)
 
Hepatitis A virus (HAV) testing:
Immunoglobulin IgG (quantitative)
    HAV total antibody
Immunoglobulin IgM (quantitative)
    HAV IgM antibody
Phosphatidylethanol (PEth)
Hepatis B virus (HBV) testing:
Urine Chemistry
    Hepatitis B surface antigen (HBsAg)
Drug screen
    Hepatitis B surface antibody (anti-
HBs)
Ethyl glucuronide (EtG)
    Hepatitis B core total antibody (anti-
HBc)
Other Serology
    Hepatitis B core IgM antibody
Anti-nuclear antibody (ANA)
    Hepatitis B core IgG antibody
Anti-smooth muscle antibody (ASMA)
    HBV DNA
Anti-actin antibody
Hepatis C virus (HCV) testing:
Epstein-Barr virus (EBV) testing:
    HCV antibody
    EBV antibody
    HCV RNA
    EBV DNA
Hepatitis D virus (HDV) testing:
Cytomegalovirus (CMV) testing:
    HDV antibody
    CMV antibody
Hepatitis E virus (HEV) testing:
    CMV DNA
    HEV IgG antibody
Herpes simplex virus (HSV) testing:
    HEV IgM antibody
    HSV (Type 1 and 2) antibody
    HEV RNA
    HSV (Type 1 and 2) DNA
Microbiology
Liver kidney microsomal type 1 (LKM-1) 
antibody
Culture:
 -
    Blood
 -
    Urine
 -
Grade 2 or 3 (>5.0 - 
20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x 
baseline if baseline 
was abnormal) 
with total bilirubin 
>2 x ULN, in the 
absence of 
Discontinue abemaciclib and contact Sponsor-Investigator.

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cholestasis
OR 
Grade 4 (>20.0 x 
ULN if baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal)

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Table 23. Hematologic Toxicity
Hematologic 
Toxicity
Management
(management 
overview)
Hematologic toxicities including neutropenia, leukopenia, anemia, and 
thrombocytopenia have been observed in patients treated with abemaciclib, and causality 
has been established.  Severe (Grade 3 and 4) neutropenia was observed in patients 
receiving abemaciclib.  Patients should be monitored closely for signs of infection, 
anemia, and bleeding.
Grade 1 or 2
Dose modification not required. 
Grade 3
Suspend dose until toxicity resolves to ≤Grade 2. Dose modification not required.
Grade 3, recurrent or 
Grade 4
Suspend dose until toxicity resolves to ≤Grade 2. Resume at next lower dose.
Requiring 
administration of 
blood cell growth 
factor
Suspend abemaciclib dose for at least 48 hours after the last dose of blood cell growth 
factor and until toxicity resolves to ≤Grade 2. Resume abemaciclib at next lower dose 
unless the dose was already reduced for the toxicity that led to the use of the growth 
factor.
Table 24. Non-Hematologic Toxicity
Non-Hematologic 
Toxicity (excluding 
diarrhea, 
hepatotoxicity, and 
ILD/pneumonitis)
Management
Grade 1 or 2
Dose modification not required.
Persistent or 
recurrent Grade 2 
toxicity that does not 
resolve with maximal 
supportive measures 
within 7 days to 
baseline or Grade 1
Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose.
Grade 3 or 4
Suspend dose until toxicity resolves to baseline or Grade 1.
Resume at next lower dose.
6.2.1 Condition requiring introduction (unavoidable) of treatment with strong CYP3A inhibitor
Introduction of strong CYP3A inhibitor is subject to discussion and approval of Sponsor-
Investigator For all but ketoconazole, reduce abemaciclib to 100 mg BID. In the case of 
ketoconazole, reduce abemaciclib to 50 mg BID. For patients who have had dose reduction to 
100 mg BID due adverse events, dose will be further reduced to 50 mg BID. Subsequently, if the 
CYP3A inhibitor is discontinued, increase abemaciclib dose (after inhibitor 3-5 half-lives) to the 
dose that was given prior to starting the inhibitor.  

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7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting.
7.1
Expected Toxicities
7.1.1
Abemaciclib
Most common adverse reactions (incidence ≥20%) are diarrhea, neutropenia, nausea, abdominal 
pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, 
and thrombocytopenia.
Increases in Serum Creatinine and Renal Insufficiency: 
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
transporters without affecting glomerular function (as measured by iohexol clearance). In clinical 
studies, increases in serum creatinine occurred within the first month of abemaciclib dosing, 
remained elevated but stable through the treatment period, were reversible upon treatment 
discontinuation, and were not accompanied by changes in markers of renal function, such as 
blood urea nitrogen (BUN), cystatin C, or calculated glomerular filtration rate based on cystatin 
C.
7.1.2
Atezolizumab
Most common adverse reactions (≥ 20%) in patients with locally advanced or metastatic 
urothelial carcinoma were fatigue, decreased appetite, nausea, constipation, urinary tract 
infection, diarrhea, and pyrexia. Most common adverse reactions (≥ 20%) in patients with 
metastatic non-small cell lung cancer were fatigue, decreased appetite, dyspnea and cough.
Atezolizumab has been associated with risks such as the following:  IRRs and immune-mediated 
hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, 
adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, facial paresis, myelitis, meningoencephalitis, myocarditis, pericardial 
disorders, nephritis, myositis, and severe cutaneous adverse reactions.  In addition, immune-
mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), which are considered 
to be potential risks for atezolizumab.  Refer to Section 6 of the Atezolizumab Investigator's 
Brochure for a detailed description of anticipated safety risks for atezolizumab.   
7.2
Adverse Event Characteristics and Definitions 
7.2.1 Adverse Events
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 

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symptom, or disease temporally associated with the use of an investigational medicinal product 
(IMP) or other protocol-imposed intervention, regardless of attribution.
This includes the following:

AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
prostate cancer that were not present prior to the AE reporting period.

Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as cardiac catheterizations)

If applicable, AEs that occur prior to assignment of study treatment 
associated with medication washout, no treatment run-in, or other protocol-
mandated intervention.

Preexisting medical conditions (other than the condition being studied) judged 
by the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period.
7.2.2 Serious Adverse Events
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 subject 
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 subject’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 subject or may require medical/surgical 
intervention to prevent one of the outcomes listed above).
7.2.3 Methods and timing for assessing and recording safety variables
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. 
in accordance with CFR 312.32 (IND Safety Reports).
7.2.4 Adverse Event Reporting Period
The study period during which AEs and SAEs, where the patient has been exposed to 
atezolizumab and/or abemaciclib must be reported. Reporting period begins after informed 
consent is obtained and initiation of study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is earlier. After 
this period, investigators should only report SAEs that are attributed to prior study treatment.
7.2.5 Assessment of Severity of Adverse Events 

CTCAE term (AE description) and grade:  The descriptions and grading scales found 

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in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version  5.0.  A copy of the CTCAE version  5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
The below table should be used for assessing severity for adverse events that are not specifically 
listed in the NCI CTCAE.
Table 25. Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a.
Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b.
Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are not 
bedridden.
c.
If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event 
d.
Grade 4 and 5 events must be reported as serious adverse events 

For expedited reporting purposes only:  
-
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions.

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

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7.2.7 Procedures For Eliciting, Recording, And Reporting Adverse Events
7.2.7.1 Eliciting Adverse Events
A consistent methodology for eliciting AEs at all subject evaluation time points should be adopted. 
Examples of non-directive questions include:
  “How have you felt since your last clinical visit?”
  “Have you had any new or changed health problems since you were last here?”
7.2.7.2 Specific Instructions for Recording Adverse Events
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations.
Infusion-Related Reactions and Cytokine-Release Syndrome
There may be significant overlap in signs and symptoms of IRRs and cytokine-release syndrome 
(CRS).  While IRRs occur during or within 24 hours after treatment administration, time to onset 
of CRS may vary.  Differential diagnosis should be applied, particularly for late-onset CRS 
(occurring more than 24 hours after treatment administration), to rule out other etiologies such as 
delayed hypersensitivity reactions, sepsis or infections, HLH, tumor lysis syndrome, early 
disease progression, or other manifestations of systemic inflammation.
Adverse events that occur during or within 24 hours after study treatment administration and are 
judged to be related to study treatment infusion should be captured on the Adverse Event eCRF 
as a diagnosis (e.g., "infusion-related reaction" or "cytokine release syndrome").  Avoid 
ambiguous terms such as "systemic reaction."  Cases of late-onset CRS should be reported as 
"cytokine-release syndrome" on the Adverse Event eCRF.  Associated signs and symptoms of an 
IRR should be recorded on the dedicated Infusion-Related Reaction eCRF.
If a patient experiences both a local and systemic reaction to a single administration of study 
treatment, each reaction should be recorded separately on the Adverse Event eCRF, with 
associated signs and symptoms of an IRR also recorded separately on the dedicated Infusion-
Related Reaction eCRF.
In recognition of the challenges in clinically distinguishing between IRRs and CRS, consolidated 
guidelines for medical management of IRRs and CRS are provided in Section 6.1 “Infusion-
Related Reactions and Cytokine-Release Syndrome.”
7.2.7.3 Diagnosis vs. Signs and Symptoms
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report 
the information that is currently available. If a diagnosis is subsequently established, it should be 
reported as follow-up information.

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7.2.7.4 Deaths
All deaths that occur during the protocol-specified AE reporting period (see Section 7.2.4), 
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”.
7.2.7.5 Preexisting Medical Conditions
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be re-
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important to 
convey the concept that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).
Lack of Efficacy or Worsening of Underlying Cancer
Deterioration that is judged by the investigator to have unexpectedly worsened in severity or 
frequency or changed in nature (i.e., deterioration beyond the expected pattern of progression of 
the underlying disease) should be recorded as an adverse event.  When recording an unanticipated 
worsening of underlying cancer on the Adverse Event eCRF, it is important to convey the concept 
that the condition has changed by including applicable descriptors (e.g., “accelerated worsening 
of prostate cancer”). Events that are clearly consistent with the expected pattern of progression of 
the underlying disease should not be recorded as adverse events.  These data will be captured as 
efficacy assessment data only.  In most cases, the expected pattern of progression will be based 
on PCWG3 criteria.  In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration.  However, every effort should be made to document progression 
through use of objective criteria.  If there is any uncertainty as to whether an event is due to disease 
progression, it should be reported as an adverse event.
7.2.7.6 Hospitalizations for Medical or Surgical Procedures
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 

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the study
7.2.8 Adverse Event of Special Interest (AESI) for Atezolizumab
AESIs are a subset of adverse events which may be of scientific and medical concern specific to 
the study drug, for which ongoing monitoring and expedited communication 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.
AESIs applicable to all participants in this trial are:

Cases of potential drug-induced liver injury (DILI) 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× ULN in combination with total bilirubin > 
2× ULN

Treatment-emergent ALT or AST > 3× ULN in combination with clinical 
jaundice

Suspected transmission of an infectious agent by the study drug (STIAMP), as 
defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in a 
patient exposed to a medicinal product. This term applies only when a contamination 
of the study drug is suspected.

ILD/Pneumonitis
AESIs associated with participants receiving Atezolizumab:

Systemic lupus erythematosus

Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, macrophage activating syndrome and hemophagocytic 
lymphohistiocytosis syndrome

Nephritis

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)

Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis

Autoimmune hemolytic anemia

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis)

Myelitis

Facial Paresis
7.2.9 Other Special Situations 

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The following other Special Situations Reports should be collected even in the absence of an 
Adverse Event and transmitted to Genentech:
•
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
Pregnancy
Such events include pregnancy (occurring in the partner of the male study subject), where the 
fetus may have been exposed to the study drug (conception while the study subject was receiving 
protocol therapy or within 5 months after the last dose of study drug); data related to the Product 
usage during breastfeeding; study drug interaction; study drug overdose, abuse or 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
NOTE: Abortions, whether accidental, therapeutic, or spontaneous, should always be classified as 
serious, and reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to 
a female subject exposed to the study drug should be reported as an SAE.
7.2.10 Product complaints
A Product Complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial.
7.2.11 Post-Study Adverse Events
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior atezolizumab and/or abemaciclib exposure. 
If the investigator should become aware of the development of cancer or a congenital anomaly 
in a subsequently conceived offspring of a female subject [including pregnancy occurring in the 
partner of a male study subject] who participated in the study, this should be reported as an SAE 
adequately to Genentech drug Safety during follow up period.
7.3
Dose-Limiting Toxicities (DLT)
A DLT will be defined as any of the following treatment-related events at any point 
during drug dosing:
Hematologic Toxicity

Grade 3 thrombocytopenia associated with clinically significant bleeding and 
requiring platelet transfusion

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
Grade 4 thrombocytopenia

Grade ≥3 febrile neutropenia

Grade ≥3 anemia requiring a blood transfusion

Other Grade 4 toxicity lasting >7 days 
Non-Hematologic Toxicity

Grade ≥3 fatigue lasting >7 days

Grade ≥3 nausea, vomiting, and diarrhea lasting >3 days despite optimal medical 
management

Grade ≥3 hypertension despite maximal medical therapy

Grade 2 pneumonitis that does not resolve to Grade ≤1 within 14 days after 
initiation of optimal medical management including corticosteroid therapy

Grade ≥3 colitis or noninfectious pneumonitis

Grade 3 irAE* (excluding colitis or pneumonitis) that:

does not downgrade to Grade 2 within 14 days after onset of the 
event despite optimal medical management 
or

does not downgrade to Grade ≤1 or the patient’s baseline level 
within 30 days of event onset

Grade 4 irAE* 
Other Toxicity

ALT or AST:

>8 × ULN, if the patient does not have HCC or liver metastasis
or

≥2-fold above the patient’s baseline value that lasts >7 days, if 
the patient has HCC or liver metastasis and had ALT or AST 
>3.0 × ULN at baseline
or

>3 × ULN with concomitant bilirubin >2 × ULN, in the 
absence of cholestasis

Grade 3 bilirubin (total) level

Grade 3 or 4 amylase or lipase that does not resolve to Grade ≤2 within 7 days 
of starting IV corticosteroid therapy

Other Grade 3 or 4 laboratory value lasting >14 days or requiring medical 
intervention

Grade 5 toxicity (i.e. event that results in death)

Toxicity otherwise deemed by the treating and/or Sponsor Investigator to be 
dose limiting (e.g., toxicity that is possibly related to study treatment and 
requires treatment discontinuation prior to completion of Cycle 1; persistent 
Grade >2 toxicities causing a delay of >14 days in initiating Cycle 2)

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*irAE=immune-related Adverse Event (i.e. an Adverse Event consistent with an immune-mediated mechanism of 
action with no clear alternate etiology
7.3.1
Events not considered to be a Dose-Limiting Toxicity
Hematologic Toxicity

Grade 3 or 4 neutropenia if:
not associated with fever or systemic infection
and
improves by at least 1 grade within 7 days

Grade 3 or 4 lymphopenia
Other Toxicity

Grade 3 infusion-related reaction during infusion of atezolizumab, if:
the patient did not receive corticosteroid prophylaxis
and
the Grade 3 reaction resolves (with appropriate clinical management) within 6 h

Isolated Grade 3 electrolyte abnormalities if:
not associated with clinical signs or symptoms
and
reversed with appropriate maximal medical intervention within 2   days

Vitiligo or alopecia (any grade)

Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency), if:
the disorder is manageable with or without systemic corticosteroid therapy and/or 
hormone replacement therapy
and
the patient is asymptomatic

Grade 3 inflammatory reaction attributed to a local antitumor response (such as, 
inflammatory reaction in the lymph nodes or at sites of metastatic disease)

Toxicity that is clearly and directly related to the primary disease or to another etiology
7.4
Adverse Event Reporting 
7.4.1
In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the PI.
7.4.2
Investigators must report to the PI any adverse event (AE) that occurs after the initial 
dose of study treatment, during treatment, or within 30 days of the last dose of treatment. 
Serious adverse events should be reported per the guidelines in Table 26 on the 
MedWatch Adverse Event Reporting form. 
7.4.3
Adverse Event Reporting Guidelines
All participating sites will report AEs to the Sponsor-Investigator per DF/HCC 

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requirements, and the IRB of record for each site as applicable per IRB policies. The 
table below indicates which events must be reported to the DF/HCC Sponsor-
Investigator.
Table 26. DF/HCC Reportable Adverse Events(AEs)
DF/HCC Reportable Adverse Events(AEs)
Attribution
Gr. 2 & 3 AE
Expected
Gr. 2 & 3 AE 
Unexpected
Gr. 4 AE Expected
Gr. 4 AE
Unexpected
Gr. 5 AE Expected 
or Unexpected
Unrelated
Unlikely
Not required
Not required
5 calendar days#
5 calendar days
24 hours*
Possible
Probable
Definite
Not required
5 calendar days
5 calendar days#
5 calendar days
24 hours*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last intervention, 
events must be reported within 1 business day of learning of the event.
7.5
Reporting procedures to Eli Lilly
The following are required for IIT Protocols to comply with applicable laws, regulations and 
standards regarding Investigator’s and Institution’s obligations, as the sponsor of the Study, to 
collect and report adverse events to regulatory authorities, IRBs, Ethics Committees or other 
third parties: 
In addition to the obligations set forth below, Investigator and Institution agree to provide Lilly 
with a copy of all information Investigator and/or Institution submit to regulators related to any 
adverse events for the Study Drug that occur during the Study that Investigator and/or Institution 
have not otherwise provided Lilly; to notify Lilly, sub-investigators, and the IRB of any 
problems involving risk to Study patients and report new safety information to IRBs in 
accordance with applicable requirements; to notify Lilly within fifteen (15) business days of 
Investigator and/or Institution receiving notification of any “serious” adverse event experienced 
by a patient participating in the Study and receiving Study Drug. For purposes of this 
requirement, “serious” means: (1) death; (2) in-patient hospitalization or prolonged 
hospitalization; (3) life-threatening; (4) persistent or significant disability or incapacity; (5) 
congenital anomaly or birth defect; or (6) other serious events that may jeopardize the patient 
and may require medical or surgical intervention to prevent one of the other five listed outcomes. 
Serious adverse events should be reported to Lilly using a CIOMS Form or other form 
acceptable to Lilly. Investigator and Institution further agree to make available promptly to Lilly 
such records as may be necessary and pertinent for Lilly to further investigate an adverse event 
in the Study that is possibly associated with the Study Drug.
SAE Reporting Email Address: mailindata_gsmtindy@lilly.com

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7.6
Reporting Procedures to Genentech
Where the patient has been exposed to atezolizumab, serious adverse events (SAEs), AEs of 
Special Interest (AESIs), pregnancy reports, other Special Situation Reports, and Product 
Complaints with or without AE, as defined above (initial and follow-up), will be reported by the 
Coordinating Center to Genentech Drug Safety at usds_aereporting-d@gene.com or via fax 
(650-238-6067) twenty-four (24) hours of awareness, via the MedWatch Adverse Event 
Reporting form. 
All Product Complaints without an AE should call via:
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST)
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 written IND Safety Reports submitted to the FDA by the Investigator must also be faxed 
to Genentech Drug Safety:
Fax: (650) 225-4682 or (650) 225-4630
Email: usds_aereporting-d@gene.com
For questions related to safety reporting, please contact Genentech Drug Safety:
Tel: (888) 835-2555
Fax: (650) 225-4682 or (650) 225-4630
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
The Sponsor-Investigator will be responsible for the expedited reporting of safety reports 
originating from the Study to the Independent Ethics Committees/ Institutional Review Boards 
(IEC/IRB) of the Concerned Member States, where applicable.
The Sponsor-Investigator will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations.
And the Sponsor-Investigator will be responsible for the distribution of safety information to Site 
IRB: (617) 632-3029.
For questions related to safety reporting, please contact Genentech Drug Safety:
Tel:  (888) 835-2555
Fax:  (650) 225-4682 or (650) 225-4630
MedWatch 3500A Reporting Guidelines
In addition to completing appropriate patient demographic (Section A) and suspect medication 
information (Sections C & D), the report should include the following information within the 
Event Description (Section B.5) of the MedWatch 3500A form:

Protocol number and title description

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
Description of event, severity, treatment, and outcome if known

Supportive laboratory results and diagnostics (Section B.6)

Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication
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., D.O.B., initials, patient number), protocol description and number, if assigned, brief 
adverse event 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)
MedWatch 3500A (Mandatory Reporting) form is available at
https://www.fda.gov/media/69876/download
7.6.1 Case Transmission Verification of Single Case Reports
The Sponsor agrees to conduct the Case Transmission verification to ensure that all single case 
reports have been adequately received by Genentech via Investigator-Sponsor emailing 
Genentech a Quarterly line-listing documenting single case reports sent by Investigator-Sponsor 
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 Investigator-Sponsor 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 

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Genentech.
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.
Sponsor-investigator, as the Sponsor of the study, will be responsible for the expedited reporting 
of safety reports originating from the study to the European Medicine Agency (EMA) through 
Eudravigilance Clinical Trial Module (EVCTM), where applicable.
Sponsor-investigator will be responsible for the expedited reporting of safety reports originating 
from the study to the Independent Ethics Committees/ Institutional Review Boards (IEC/IRB) of 
the Concerned Member States, where applicable.
Sponsor-investigator, as the Sponsor of the study, will be responsible for the preparation of six-
monthly Suspected Unexpected Serious Adverse Reaction (SUSAR) reports and their submission 
to Investigators, Regulatory Authorities and the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC), where applicable
Sponsor-investigagtor will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations.
7.6.2 Aggregate Reports
Other Reports 
Sponsor-Investigator will forward a copy of the Final Study Report to Genentech upon 
completion of the study.
7.7
Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports, sentinel events or unanticipated problems that require reporting per institutional 
policy. 
7.8
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the PI on the toxicity 
case report forms.  AEs reported through expedited processes (e.g., reported to the IRB, 
FDA, etc.) must also be reported in routine study data submissions.
7.9
Study Close-Out

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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: anti-pdl-1-mpd3280a-gsur@gene.com 
And to Genentech Drug Safety CTV oversight mailbox at: ctvistsa@gene.com
7.10
Queries
Queries related to the Study will be answered by Sponsor-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 shall have the final say and control over 
safety queries relating to atezolizumab. Sponsor-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.
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.
7.11 Signal Management and Risk Management
Genentech is responsible for safety signal management (signal detection and/or evaluation) for 
their own Product.  However, it is agreed that the Sponsor of the Study, will be primarily 
responsible for assessment of the benefit-risk balance of the Study.
If the Sponsor-Investigator issues a safety communication relevant for Genentech (i.e., a safety 
issue that notably impacts the benefit-risk balance of the Study and / or triggers any changes to 
the Study) this will be sent to Roche within five (5) business days of its internal approval.
As needed, Genentech will reasonably assist the Sponsor-Investigator with signal and risk 
management activities related to the Product within the Study.
Genentech will also provide the Sponsor-Investigator with any new relevant information that 
may modify or supplement known data regarding the Product (e.g., relevant Dear Investigator 
Letter). 
7.12 Compliance with Pharmacovigilance Agreement / Audit
The Parties shall follow their own procedures for adherence to AE reporting timelines.
Each Party shall monitor and, as applicable, request feedback from the other Party regarding AE 
report timeliness in accordance with its own procedures. The Parties agree to provide written 
responses in a timely manner to inquiries from the other Party regarding AE reports received 

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outside the agreed upon Agreement timelines. If there is any detection of trends of increasing or 
persistent non-compliance to transmission timelines stipulated in this Agreement, both Parties 
agree to conduct ad hoc or institute a regular joint meeting to address the issue.
In case of concerns related to non-compliance of processes, other than exchange timelines, with 
this Agreement, the Parties will jointly discuss and collaborate on clarifying and resolving the 
issues causing non-compliance. Every effort will be made by the non-compliant Party to solve 
the non-compliance issues and inform the other Party of the corrective and preventative actions 
taken.
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an audit 
under the provisions of this Agreement can be requested by either Party. The Parties will then 
discuss and agree in good faith upon the audit scope, agenda and execution of the audit. The 
requesting Party will bear the cost of the audit.
8.
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1.
8.1
Abemaciclib
8.1.1
Mechanism of Action
Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). 
These kinases are activated upon binding to D-cyclins. In estrogen receptor-positive 
(ER+) breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the 
retinoblastoma protein (Rb), cell cycle progression, and cell proliferation. In vitro, 
continuous exposure to abemaciclib inhibited Rb phosphorylation and blocked 
progression from G1 into S phase of the cell cycle, resulting in senescence and apoptosis. 
In breast cancer xenograft models, abemaciclib dosed daily without interruption as a 
single agent or in combination with antiestrogens resulted in reduction of tumor size.
8.1.2
Pharmacokinetics
The pharmacokinetics of abemaciclib were characterized in patients with solid tumors, 
including metastatic breast cancer, and in healthy subjects. Following single and repeated 
twice daily dosing of 50 mg (0.3 times the approved recommended 150 mg dosage) to 
200 mg of abemaciclib, the increase in plasma exposure (AUC) and Cmax was 
approximately dose proportional. Steady state was achieved within 5 days following 
repeated twice daily dosing, and the estimated geometric mean accumulation ratio was 
2.3 (50% CV) and 3.2 (59% CV) based on Cmax and AUC, respectively. The absolute 
bioavailability of abemaciclib after a single oral dose of 200 mg is 45% (19% CV). The 
median Tmax of abemaciclib is 8.0 hours (range: 4.1-24.0 hours). A high-fat, high-
calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 

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calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy 
subjects increased the AUC of abemaciclib plus its active metabolites by 9% and 
increased Cmax by 26%. In vitro, abemaciclib was bound to human plasma proteins, 
serum albumin, and alpha-1-acid glycoprotein in a concentration independent manner 
from 152 ng/mL to 5066 ng/mL. In a clinical study, the mean (standard deviation, SD) 
bound fraction was 96.3% (1.1) for abemaciclib, 93.4% (1.3) for M2, 96.8% (0.8) for 
M18, and 97.8% (0.6) for M20. The geometric mean systemic volume of distribution is 
approximately 690.3 L (49% CV). In patients with advanced cancer, including breast 
cancer, concentrations of abemaciclib and its active metabolites M2 and M20 in 
cerebrospinal fluid are comparable to unbound plasma concentrations. The geometric 
mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV), and the 
mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV). 
Hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is 
metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A4, with 
formation of N-desethylabemaciclib (M2) representing the major metabolism pathway. 
Additional metabolites include hydroxyabemaciclib (M20), hydroxy-N-
desethylabemaciclib (M18), and an oxidative metabolite (M1). M2, M18, and M20 are 
equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total 
circulating analytes in plasma, respectively. After a single 150 mg oral dose of 
radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and 
approximately 3% recovered in urine. The majority of the dose eliminated in feces was 
metabolites.
8.1.3
Form
Abemaciclib, manufactured by Eli Lilly and Company, will be provided in the form of 
50mg tablets in a bottle.
8.1.4
Administration
Doses should be taken at approximately the same times every day, spaced 12 hours apart, 
if there are at least 6 hours between doses, and with or without food. Tablets are to be 
swallowed whole and not chewed, crushed, or split. Vomited doses should be skipped, 
and abemaciclib dosing resumed at the next scheduled dose. If a dose is missed, it may be 
taken when remembered if there are at least 6 hours before the next scheduled dose. 
Broken, cracked, or otherwise not intact tablets should not be ingested. In the event a 
subject cannot be seen for a cycle visit due to COVID-19 infection or suspicion for 
COVID-19 infection, abemaciclib may be shipped upon approval of PI.
8.1.5
Storage and Stability
Storage conditions are described in the medication label.
8.1.6
Handling

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Handling and disposal of abemaciclib should be per institutional guidelines for the 
handling and disposal of biologic and cytotoxic agents.
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
8.1.7
Availability
Abemaciclib will be provided for clinical trial use as 50mg tablets by Eli Lilly and 
Company. 
8.1.8
Ordering
Eli Lilly and Company will supply abemaciclib and ordering will take place through Eli 
Lilly and Company. The study team will complete the Drug Request Form, which is kept 
as a separate document.
8.1.9
Accountability
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.)
8.1.10 Destruction and Return
Drug should be destroyed at the site, after the investigator approves the drug destruction policy at 
the site. Drug will not be returned to Eli Lilly and Company. Destruction will be documented in 
the Drug Accountability Record Form.
8.2
Atezolizumab
8.2.1
Mechanism of Action
Atezolizumab is a monoclonal antibody that binds to PD-L1 and blocks its interactions with both 
PD-1 and B7.1 receptors. This releases the PD-L1/PD-1 mediated inhibition of the immune 
response, including activation of the anti-tumor immune response without inducing antibody 
dependent cellular cytotoxicity. In syngeneic mouse tumor models, blocking PD-L1 activity 
resulted in decreased tumor growth.

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8.2.2
Pharmacokinetics 
Patients’ exposure to atezolizumab increased dose proportionally over the dose range of 1 mg/kg 
to 20 mg/kg, including a dose of 1200 mg administered every 21 days. The clearance (CV%) was 
0.20 L/day (29%), the volume of distribution at steady state was 6.9 L, and the terminal half-life 
was 27 days. Steady state is achieved after 6 to 9 weeks (2 to 3 cycles). The systemic 
accumulation ratio for area under the curve (AUC), maximum concentration (Cmax) and trough 
concentration (Cmin) was 1.9, 1.5 and 2.8-fold, respectively. Atezolizumab clearance was found 
to decrease over time, with a mean maximal reduction (CV%) from baseline value of 
approximately 17% (41%); however, the decrease in clearance was not considered clinically 
relevant.
8.2.3
Form
In the form of 1200 mg/20 mL (60 mg/mL) solution for injection in a single-dose vial will be 
provided by Genentech for the trial.
Atezolizumab injection is a sterile, preservative-free, and colorless to slightly yellow solution for 
intravenous infusion. 
Visually inspect drug product for particulate matter and discoloration prior to administration, 
whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or 
visible particles are observed.
8.2.4
Administration
Prepare the solution for infusion as follows: Withdraw 20 mL of atezolizumab from the vial. 
Dilute into a 250 mL polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) infusion 
bag containing 0.9% Sodium Chloride Injection, USP. Dilute with 0.9% Sodium Chloride 
Injection only. Mix diluted solution by gentle inversion. Do not shake. Discard used or empty 
vials of atezolizumab. This product does not contain a preservative. Administer immediately 
once prepared. If diluted atezolizumab infusion solution is not used immediately, store solution 
either: at room temperature for no more than 6 hours from the time of preparation; this includes 
room temperature storage of the infusion in the infusion bag and time for administration of the 
infusion, or under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from 
time of preparation.
Administer through an intravenous line with or without a sterile, non-pyrogenic, low-protein 
binding in-line filter (pore size of 0.2–0.22 micron). Do not co-administer other drugs through 
the same intravenous line. Do not administer as an intravenous push or bolus.
8.2.5
Storage and Stability
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from 
light. Do not freeze.

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8.2.6
Handling
Handling and disposal of abemaciclib should be per institutional guidelines for the handling and 
disposal of biologic and cytotoxic agents.
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.
8.2.7
Availability
Atezolizumab will be provided for clinical trial use by Genentech/Roche.
8.2.8
Ordering
Genentech/Roche will supply atezolizumab and ordering will take place through 
Genentech/Roche. The study team will complete the Drug Request Form, which is kept as  
separate document. All Drug Request Forms should be sent to the following email: anti-
pdl- mpd3280a-gsur@gene.com
8.2.9
Accountability
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.)
8.2.10 Destruction and Return
Drug should be destroyed at the site, after the investigator approves the drug destruction policy at 
the site. Drug will not be returned to Genentech/Roche. Destruction will be documented in the 
Drug Accountability Record Form.
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
The goal of the planned laboratory correlative studies is to correlate genetic and molecular 
features from tissue and blood specimens with therapeutic responses, and assess changes in 
immune microenvironment with abemaciclib with and without atezolizumab. Submission of 
samples for correlative studies is mandatory, unless patient safety is of concern. 
 
9.1
Tissue Collection

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Tissue will be collected at the time points specified in section 10. Please refer to the lab manual 
for additional sample collection and processing details.
9.1.1
Archival (pre-treatment) Specimen Requirements
Tissue from the most recent metastatic biopsy specimen is preferred, though tissue from primary 
prostate specimen is allowed if obtained after a patient developed metastatic disease. (Tissue 
from primary prostate tissue obtained prior to development of metastatic disease is not relevant 
to these studies.)
The ImmunoProfile assay utilizes 5-micron FFPE slides. Submit 5 unstained slides- if 5 slides 
are unavailable, submit at minimum either 3 unstained slides or 2 unstained slides with the 
adjacent H&E slide. ≥50% tumor tissue on each slide is preferred – thus if multiple biopsy 
specimens were obtained from a patient, the specimen to be sent should be prioritized by 1) 
metastatic (as opposed to primary) biopsy site 2) tumor content and 3) time interval prior to trial 
start (more recent specimens preferred).  
9.1.2
On-Treatment Specimen Requirements
At least 4 (large bore) biopsy cores should be obtained as per institutional standards – 2 fresh 
frozen and at least 2 placed in formalin, for ImmunoProfiling and sequencing. The Investigator 
and interventional radiologist should decide on an appropriate biopsy site likely to yield tissue 
amenable to NGS analysis (80). Possible sites of biopsy are those felt to be of acceptable risk for 
research biopsy per institutional standards and may include lymph nodes, lung, bone, liver, and 
soft tissue. The window for the on-treatment biopsy can be extended per PI discretion if the 
patient required dose interruption(s) prior to the biopsy.
Specimen size requirements: 
 Surface area of 25mm2 is optimal. Minimum of 5mm2.
 Volume of 1mm3 optimal. Minimum volume of 0.2mm3.
9.2
Blood Collection
Blood will be collected at the time points specified in section 10. Please refer to the lab manual 
for additional sample collection and processing details.
9.2.1
Archival (pre-treatment) Specimen Requirements
Two 10mL EDTA tubes will be collected to isolate buffy coat for germline DNA analysis. These 
tubes should be processed per the lab manual and stored at the registering institution until the 
patient is registered for the study. If the patient then does not enroll to the trial within 21 days, 
the respective buffy coats should be discarded.  For patients who do enroll, the buffy coats will 
be shipped as per the lab manual.

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9.2.2
On-Treatment Specimen Requirements 
At each specified time point per section 10, Two x 10mL serum tubes, and 1 x 10mL Streck® 
tube will be collected for exome and cfDNA analysis.
9.3
Specimen Banking 
Patient samples collected for this study will be retained at the institution where the assays above 
will be performed. Specimens will be stored indefinitely or until they are used up. If future use is 
denied or withdrawn by the patient, best efforts will be made to stop any additional studies and to 
destroy the specimens.
9.4
Analysis Plan for Correlative Studies
9.4.1
Immune infiltrate from tumor biopsies
An exploratory endpoint for this study is FoxP3+/CD8+ ratio paired differences between pre-
treatment archival tissue and on-treatment biopsies.  These paired differences will be compared 
between the unselected monotherapy group and the combination therapy group. We estimate that 
15 patients will have evaluable pre-treatment and on-treatment biopsies per treatment group. In 
this case, the study will have at least 80% power to detect an effect size of 1.1 using a two-sided 
Mann-Whitney test at a 0.05 significance level. We are confident that both these effect size 
estimates are attainable and are clinically meaningful in this study population.
We will also explore correlation of immune infiltrate with genetic features as described below.
9.4.2
Genomic Biomarker
The prognostic value of genomic markers will be tested using the Cox proportional hazard 
regression model framework. The response variable will be PFS. Explanatory variables will 
include treatment arm and an indicator for presence of any somatic variant. The prognostic effect 
will be evaluated by the main effect test for the somatic variant indicator. To assess predictive 
value, the interaction between treatment arm and somatic variant will be tested. Similar tests will 
be performed for individual variants. Analysis on these correlative data is exploratory; no 
multiple comparison adjustment will be made.
9.4.3
Exosomal and tumoral whole-transcriptome sequencing
Exosomes are a type of extracellular vesicle that are secreted by all human cells (93). Tumor-
derived exosomes are known to recapitulate the cellular RNA content. Because of their 
abundance in the peripheral blood in men with metastatic prostate cancer (94), exosome-based 
transcriptomics may provide an alternative to invasive needle-biopsies of metastatic tumor sites 
in this setting. We will explore the correlation of RNA-based biomarkers including AR splicing 
events (12)and signatures of AR signaling and cell cycle regulation, as well as “T cell inflamed” 
signature with clinical outcomes in each arm individually and in the combined cohort.

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9.4.4
Circulating free DNA whole-genome sequencing
We will explore the correlation of genomic features (e.g., genetic alterations in the CDK4/6 
pathway and in DNA repair pathways) with clinical outcomes in each arm individually and in the 
combined cohort.   We will also correlate decrease in tumor fraction in cfDNA as (calculated 
from ultra-low pass whole genome sequencing using ichorCNA) from baseline to 6 weeks with 
PFS.  In addition, we will identify new alterations at the time of progression to nominate 
mediators of resistance.
9.4.5
Whole exome sequencing from tumor biopsies
We will explore correlation of genetic features from on-treatment biopsy specimens (e.g., genetic 
alterations in the CDK4/6 pathway and in DNA repair pathways) with clinical outcomes in each 
arm individually and in the combined cohort.   We will explore the correlation of loss-of-
function alterations in genes involved with DNA damage repair, along with a variety of 
mutational signatures (mismatch repair deficiency, homologous recombination deficiency, 
tandem duplicator phenotype, mutational load, neoantigen burden) with composition of immune 
infiltrate as detected through ImmunoProfile. When genetic sequencing data from a prior tumor 
biopsy specimen is available, we will identify new genetic alterations to nominate mediators of 
cancer progression and resistance to prior therapies.
10.
STUDY CALENDAR
Baseline evaluations are to be conducted within 21 days prior to registration.  Scans and x-rays 
must be done <4 weeks prior to the start of therapy. Assessments must be performed prior to 
administration of any study agent. Study assessments and agents should be administered within + 
3 days of the protocol-specified date, unless otherwise noted.

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Table 27. Study Calendar
Procedures
Screening1
Cycle 1 
Day 1
Cycle 2 
Day 1
Cycle 3 
Day 1
Cycle 4+ 
Day 1
EOT2
Follow-
Up3
EDC 
Timepoints
Informed Consent
X
       NA
Physical Exam, Vital 
Signs, Weight4
X
X
X
X
X
X
Every cycle. 
Height only at 
screening
ECOG Performance 
Status
X
X
X
X
X
X
Screening, Every 
cycle, EOT
Toxicity Review5
X
X
X
X
X
X
X
Screening, Every 
cycle, EOT and 
Follow Up
Review of Concomitant 
Medications
X
X
X
X
X
X
Screening, Every 
cycle, EOT
CBC w/ Diff
X
X
X
X
X
X
Screening, Every 
cycle, EOT
Comprehensive 
Metabolic Panel
X
X
X
X
X
X
Screening, Every 
cycle, EOT
TSH, Free T46
X
X6
X6
X
X
Cycle 1 day 1, 
Every cycle when 
collected, EOT
PSA
X
X
X
X
X
X
X
Screening, Every 
cycle, EOT and 
Follow up
Testosterone
X
Screening
Imaging & Response 
Assessment
X
X7
X
Screening, Every 3 
cycles starting at 
C4D1, follow up
Tc99m Bone Scan
X
X7
X
Screening, Every 3 
cycles starting at 
C4D1, follow up
PFTs
X8
X8
Screening and 
Cycle 4 Day 1
Research Blood
X9
X9
X9
X9
X10
C1D1, C3D1, 
C6D1, C9D1, 
C12D1, and EOT
Coagulation Blood Tests 
(PT/INR and aPTT)
X
X
Archival Tumor Tissue
X11
Screening
On-treatment Tumor 
Biopsy
X12
Cycle 3 D1
Abemaciclib13 
(Dispensation, Diary 
Review & 
Reconciliation)
X
X
X
X
X
All cycles and 
EOT
Atezolizumab 
Administration13
X
X
X
X
All Cycles
Survival Status
X
Follow up

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1.
Baseline assessments must be completed within 21 days prior to registration. 
2.
Visit must be completed within 30 days of last dose of protocol therapy. 
3.
Survival follow-up every 3 months for 24 months post EOT visit ± 1 week. For subjects who 
discontinue treatment for reasons other than PD, scans should continue to be completed at regular 
intervals (approximately every 9 weeks or as per institutional standard), and PSA should continue 
to be measured at regular intervals (approximately every 3 weeks or as per institutional standard) 
until a new treatment is started, the patient withdraws from study procedures, or death. 
4.
Vital signs include temperature, pulse, respirations, blood pressure. Height will be obtained at 
screening only. Physical exam can be excluded when a virtual visit is required due to COVID-19 
pandemic.
5.
Data on adverse events will be collected from the time of the initial study drug administration 
through 100 days after the last dose of study drug, Data will also be collected regarding any 
serious adverse event that occurs more than 100 days after the last dose of study drug(s) and is 
considered related to study drug.
6.
Only required for patients receiving atezolizumab-containing regimens on cycle 1 day 1 and 
every 3 cycles, otherwise only as clinically indicated. 
7.
MRI or CT of abdomen and pelvis along with chest CT with or without IV contrast. Brain CT or 
MRI with (preferred) or without IV contrast as indicated. To be assessed every 3 cycles (-1 week 
window) beginning with C4D1, i.e. within 1 week of planned C4D1, C7D1, etc. If the initiation 
of cycle 4, cycle 7, etc. is planned to be delayed (for toxicity management, scheduling, or any 
other reason), then imaging should be delayed as well.  However, if imaging studies are 
performed and intercurrent toxicities preclude initiation of C4D1, C7D1, etc. within 1 week, the 
imaging does not need to be repeated prior to eventual initiation of the next treatment cycle.
8.
PFTs include spirometry, lung volumes and DLCO.  If PFTs after 3 months of trial therapy do not 
meet criteria for grade 1 or higher pneumonitis/ILD, then further monitoring PFTs are not 
required.  If a patient develops grade 1 or higher pneumonitis/ILD, PFTs should be obtained 
every 8 weeks until resolution; if a patient develops grade 2 or higher pneumonitis/ILD, they 
must be discontinued from trial therapy.
9.
Research blood at time of screening is whole blood collected in EDTA tube to isolate buffy coat 
for germline DNA, at subsequent time points are 2 × 10mL serum tubes for exosome analysis, 
and 1 × 10mL Streck® tube for cfDNA analysis. Collect C1D1 prior to administration of protocol 
therapy and after completing 2 cycles of protocol therapy ± 14 days. Collection also at C6D1, 
C9D1, and C12D1 ± 3 business days. 
10. May be collected and submitted up to 30 days after progression and prior to any intervening 
treatment. If progression collection is within 14 days of prior correlative blood collection, these 
research samples do not need to be collected.
11. Refer to section 9.1 for specimen requirement details. 
12. Required after completing 2 cycles of protocol therapy ± 7 days, for all patients. Refer to section 
9.1 for specimen requirement details.  
13. Based on regimen randomized and/or enrolled to, as per section 5.
NOTE: All assessments have a window of ± 3 business days unless otherwise mentioned. Additional 
flexibility (within reason) may be permitted in cases such as vacation and inclement weather; this is at the 
discretion of the Sponsor-Investigative team (whenever possible, team should be notified in advance), and 
such situations must be clearly documented. 

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11. MEASUREMENT OF EFFECT
11.1
Antitumor Effect 
For the purposes of this study, participants should be re-evaluated for response every 3 cycles 
(+/- 7 days).  In addition to a baseline scan, confirmatory scans should also be obtained not less 
than 4 weeks following initial documentation of objective response.
Response and progression will be evaluated in this study using Prostate Cancer Working Group 3 
(PCWG3) modifications (81) (section 11.2) to the new international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 
45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the modified 
RECIST criteria.  Response and progression of osseous disease by bone scintigraphy will be per 
PCWG3 criteria (81).
11.1.1 Definitions
Evaluable for Target Disease response.  Only those participants 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 target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions. 
11.1.2 Disease Parameters
Measurable disease. Measurable lesions are defined as those that can 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 (irrespective of scanner type) for studies with a slice thickness 
of <5mm or twice the slice thickness or MRI
●
10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be record as non-measurable)         
●
20mm by chest X-ray (if clearly defined and surrounded by aerated lung)
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 

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lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed.
Note: Tumor lesions that are situated in a previously irradiated area will only be 
considered measurable if they have had subsequent progression by at least 5mm.
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter < <10 mm or pathological lymph nodes with ≥10 to <15 mm short 
axis), are considered non-measurable disease. Bone lesions without measurable soft 
tissue component, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not 
followed by CT or MRI), and cystic lesions are all non-measurable.
Target lesions. All measurable lesions up to a maximum of 5 lesions per organ and 10 
lesions in total should be identified as target lesions and recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organ(s), but in addition should be 
those that lend themselves to reproducible repeated measurements. If a non-nodal lesion 
is either not present or is initially measured with longest diameter <10mm as a non-target 
then grows to >10mm after baseline, this lesion is assessed as a new target lesion as per 
iRECIST criteria (80). Per iRECIST, new lesions are assessed as per RECIST 1.1 but are 
recorded separately on the case report form (but not included in the sum of lesions for 
target lesions identified at baseline).
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor. Pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥15 mm by CT scan. Only the short axis of these nodes will contribute to 
the baseline sum. The short axis of the node is the diameter normally used by radiologists 
to judge if a node is involved by solid tumor. Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT scan this is almost always 
the axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal). The 
smaller of these measures is the short axis. For example, an abdominal node which is 
reported as being 15 mm x 30mm has a short axis of 15 mm and qualifies as a malignant, 
measurable node. In this example, 15 mm should be recorded as the node measurement. 
All other pathological nodes (those with short axis ≥10mm but <15 mm) should be 
considered non-target lesions. Nodes that have a short axis <10mm are considered non-
pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added into 
the sum. The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. If a non-target 

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lymph node grows to >15 mm after baseline, this node is assessed as a new target lesion 
as per iRECIST. Per iRECIST, new lesions are assessed as per RECIST 1.1 but are 
recorded separately on the case report form (but not included in the sum of lesions for 
target lesions identified at baseline).
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’ (more details to follow). In addition, 
it is possible to record multiple non-target 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’).
11.1.3 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by 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 (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 

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measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
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 data 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 
from CT, MRI may be used instead of CT in selected instances. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.
PSA response and progression. 
PSA response is defined per section 11.1.7, and PSA progression is defined per section 
11.1.8.
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease.
11.1.4 Response Criteria
11.1.4.1
Evaluation of Target Lesions
Prior to the first PD assessment, patients will be evaluated according to the following 
RECISTv1.1 response:
Complete Response (CR): Disappearance of all target lesions, determined by two 
separate observations conducted not less than 4 weeks apart. There can be no 
appearance of new* lesions.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. There can be no appearance 

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of new* lesions.
Progressive Disease (PD):  At least a 20% increase in the sum of the LD of target 
lesions (with a minimum absolute increase of 5 mm), taking as reference the smallest 
sum LD recorded since the treatment started, or the appearance of one or more new* 
lesions.
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR (taking as 
reference the baseline sum LD) nor sufficient increase to qualify for PD (taking as 
reference the smallest sum LD since the treatment started).
For patients receiving atezolizumab only: 
After the first PD assessment per RECISTv1.1 (=iUPD per iRECIST), patients will 
be evaluated for iCPD 4-8 weeks later according to the following definition:
Immune Unconfirmed Progressive Disease (iUPD): At least a 20% increase in the 
sum of the LD of target lesions (with a minimum absolute increase of 5 mm), taking 
as reference the smallest sum LD recorded since the treatment started, or appearance 
of new* lesions since the last evaluation.
Immune Confirmed Progressive Disease (iCPD): If iUPD was assigned based on 
increase in size of target or non-target lesions, iCPD is assigned if a further increase 
in size of lesions is observed or if new lesions appear.  If iUPD was assigned based 
only on the development of new lesions, iCPD is only assigned if at next assessment 
additional new lesions appear or an increase in size of new lesions is seen (≥5 mm for 
sum of new lesion target or any increase in new lesion non-target).
*excludes skeletal lesions
11.1.4.2
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes should be non-pathological in size (<10 mm 
short axis). 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.
Although a clear progression on non-target lesions in absence of stable target lesions 
is exceptional, the opinion of the treating physician should prevail in such 
circumstances.

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11.1.4.3
Evaluation of New Lesions
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered.
11.1.4.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.
Evaluation as per RECISTv1.1 and iRECIST
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
per RECIST 
1.1
Overall
Response
per
iRECIST
(Cohort B 
and C)
Best Response for this 
Category Also 
Requires:
CR
CR
No
CR
iCR
>4 wks. confirmation
CR
CR
Non-CR/SD
No
PR
CR
Non-CR/PD
No
PR
iPR
>4 wks. confirmation
SD
CR
Non-CR/PD
No
SD
iSD
documented at least 
once >4 wks. from 
baseline
PD
Any
Any
Any
PD*
Any
Any
Any
Yes
PD
iUPD
4-8 wks. from baseline 
for iUPD per iRECIST
PD
Any
Any
Any
PD*
Any
Any
Any
Yes
NA
      iCPD
No further 
confirmation required
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression.
NA – Not applicable

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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.
11.1.5 Safety/Tolerability
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the CTCAE version 5.0 for reporting of adverse events 
(http://ctep.cancer.gov/reporting/ctc.html).
11.1.6 6-month progression free survival (PFS) rate
PFS is defined as the duration of time from the start of treatment to disease progression (as 
defined by PCWG3 criteria (79) for Arm A and modified by iRECIST criteria (80) for Arms B 
and C), or death, whichever occurs first. In brief, progression by PCWG3 criteria is clinical 
progression, soft tissue progression by RECIST v1.1, or bone scan progression (the development 
of 2 new lesions compared to the 1st post-treatment bone scan as baseline).  These criteria apply 
to patients with both measurable and non-measurable disease at baseline. PSA progression alone 
does not meet criteria for progression according to PCWG3 criteria.
Radiographic disease progression is modified by immune-related criteria for patients in Arms B 
and C.  Patients in Arms B and C for whom first restaging studies demonstrate PD per 
RECISTv1.1 (=iUPD per iRECIST) but who are treated beyond progression per section 5.8 are 
not considered to have disease progression unless the subsequent confirmatory scan 
demonstrates Immune Confirmed Progressive Disease (iCPD) per section 11.1.4.1.  If the 
confirmatory scan demonstrates iCPD, then the date of progression is the date of original PD by 
RECIST 1.1; otherwise the date of progression is date of iCPD.
11.1.7 Objective Response Rate (ORR)
ORR will be defined as the proportion of subjects who experience radiographic response 
(complete response or partial response) by RECIST 1.1 criteria OR PSA response.
Per PCWG3 criteria, PSA response is defined by at least 50% decline in PSA level from baseline 
measured twice at least 3 weeks apart. Based on PCWG3 criteria, a favorable effect on PSA may 
be delayed for ≥ 12 weeks. PSA will be monitored every 3 weeks, but early rises in PSA before 
12 weeks will not be considered when determining PSA response, i.e. PSA response will be 
determined in relation to baseline even if PSA initially rises after starting on trial therapy.
11.1.8 Criteria for PSA Progression
For rising PSA after an initial decline from baseline, the PSA is recorded from the start of 
therapy to first PSA increase that is ≥ 25% and ≥ 2ng/mL above the nadir, which is confirmed by 
a second value 4 or more weeks later, confirming a rising trend. If there is no initial decline from 

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baseline, PSA progression is defined as ≥ 25% increase and ≥ 2 ng/mL increase from baseline 
beyond 12 weeks. 
Patients who have only documented PSA progression in the absence of radiographic or clinical 
progression should continue on study therapy.
11.1.9 Duration of Response
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for PSA or radiographic response until the first date that 
PCWG3 progression is documented, or if there is interval development of recurrent or 
progressive disease based on clinical, soft tissue or bone scan progression by PCWG3 
criteria.
11.2
Radiographic Disease Criteria
All radiographic response criteria are as per PCWG3 criteria summarized below.
11.2.1 Nodal Disease
Up to five (5) lesions are recorded per site of disease. These will be assessed as per RECIST 1.1 
with the following PCWG3 caveats:
1. Changes in size are recorded using a waterfall plot
2. Favorable change is confirmed with a second scan
3. Complete elimination of disease at any site is recorded separately
4. Only changes in lymph nodes that were ≥15 mm in the short axis are reported
5. Changes in pelvic (regional) nodes versus extrapelvic (distant/metastatic) nodes are 
recorded separately
11.2.2 Visceral Disease

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Visceral disease includes lesions in lung, liver, adrenal, and CNS sites. These will be assessed as 
per RECIST 1.1 with the following PCWG3 caveats:
1. Changes in liver, lung, adrenal, and CNS sites are recorded separately
2. Only changes in lesions ≥1.0 cm in the longest dimension are reported
11.2.3 Bone Disease
Bone disease is evaluated as per PCWG3 criteria, with changes recorded as improved or stable 
(no new lesions) or worse (new lesions). Additional PCWG3 caveats include:
1. Changes in intensity of uptake alone do not constitute progression or regression
2. No new lesions: continue therapy in absence of other signs of progression
3. New lesions (progression) is defined by the following per PCWG3:
a. Exclude pseudoprogression in the absence of symptoms or other signs of 
progression
b. At least two new lesions on first post-treatment scan, with at least two 
additional lesions on the next scan (2+2 rule)
c. If at least two additional new lesions are seen on the next (confirmatory) scan, 
the date of progression is the date of the first post-treatment scan, when the first 
two new lesions were documented
d. For scans after the first post-treatment scan, at least two new lesions relative to 
the first post-treatment scan confirmed on a subsequent scan
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
12.1 Data Reporting
12.1.1 Method
The DF/HCC Office of Data Quality (ODQ) will collect, manage, and perform quality 
checks on the data for this study.
12.1.2 Responsibility for Data Submission
Investigative sites are responsible for submitting data and/or data forms to the Office of 
Data Quality (ODQ) in accordance with DF/HCC policies.
12.2 Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study 
progress, toxicity, safety and other data from this study. The Board is chaired by a medical 
oncologist from outside of DF/HCC and its membership composed of internal and external 
institutional representation. Information that raises any questions about participant safety or 

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protocol performance will be addressed by the Sponsor-Investigator, statistician and study team. 
Should any major concerns arise, the DSMB will offer recommendations regarding whether or 
not to suspend the study.
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual; 
treatment regimen information; all adverse events and serious adverse events reported across all 
sites by category; summary of any deaths on study; audit results; and a summary provided by the 
study team. Other information (e.g. scans, laboratory values) will be provided upon request. 
12.3
Multi-Center Guidelines
This protocol will adhere to DF/HCC Policy MULTI-100 and the requirements of the DF/HCC 
Multi-Center Data and Safety Monitoring Plan. The specific responsibilities of the Sponsor-
Investigator, Coordinating Center, and Participating Institutions and the procedures for auditing 
are presented in Appendix B.
13. STATISTICAL CONSIDERATIONS
13.1 Study Design/Endpoints
13.1.1 Primary Endpoints

Co-primary endpoints for efficacy are 6-month progression free survival (PFS) rate and 
objective response rate (ORR). 
o
PFS is defined as the duration of time from the start of treatment to disease 
progression (as defined by PCWG3 criteria), or death, whichever occurs first (for 
detailed definition please see Section 11.1.6).  
o
ORR is the proportion of evaluable patients who had radiographic response 
(complete response or partial response) by RECIST 1.1 criteria OR  50% decline 
in PSA from pretreatment baseline per PCWG3 criteria (for detailed definition 
please see Section 11.1.7).

Primary endpoint for dose safety for abemaciclib cohort Arm C (for detailed definition 
please see Section 7.3).
13.1.2 Secondary Endpoint

Clinical benefit rate (CBR) estimated by proportion of evaluable patients who had 
complete response (CR), partial response (PR) or stable disease (SD) as their best 
response to treatment by PCWG3 criteria in Arm A.

Duration of response (DOR), duration of therapy (DOT), and time to progression (TTP) 
among responders by PCWG3 criteria in Arm A.

Overall survival (OS) in Arms A..

Safety endpoints include the number and severity of adverse events by CTCAE 5.0 in all 

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Arms.
13.1.3 Exploratory/Translational Endpoint

Efficacy (6-month PFS, ORR, CBR, ORR, DOR, DOT, TTP, OS) of atezolizumab alone 
and abemaciclib alone in the CDK12 loss cohort (Arm C).

From mandatory on-treatment tissue biopsies:
1. Assessment of FoxP3+/CD8+ ratio in each treatment arm by multiplex 
immunofluorescence (primary biomarker endpoint).
2. Assessment of FoxP3+/CD8+ ratio in on-treatment tumor biopsies compared to 
archival tissue specimens by multiplex immunofluorescence in each treatment 
arm.
3. Correlation of AR aberrations (specifically, AR variants and AR amplifications) 
detected by targeted exome-sequencing or whole transcriptome sequencing with 
response and resistance to therapy.
4. Correlation of genomic features (including alterations in CDK4/6 and DNA 
damage repair pathways, mutational load, neoantigen burden) detected by 
targeted exome sequencing with response and resistance to therapy.
5. Assessment of markers of AR pathway activation, pharmacodynamic markers of 
CDK4/6 inhibition as well as DNMT1 and genes involved with antigen 
presentation and interferon signaling through whole transcriptome sequencing.

From plasma collected pre-treatment, on-treatment (6 weeks after starting therapy), and 
at progression (“Liquid-biopsies”):
1. Correlation of AR aberrations (specifically, AR variants and AR amplifications) 
between circulating blood exosomes and tumor tissue. 
2. Correlation of genomic features (including alterations in CDK4/6 and DNA 
damage repair pathways, mutational load, neoantigen burden) between circulating 
blood exosomes and tumor tissue. 
13.2 Primary Efficacy Endpoint Statistical Plan and Sample Size
A two-stage design with dichotomous co-primary endpoints 6-month progression-free survival 
(6m-PFS) and objective response rate (ORR; PSA reduction by greater than 50% or radiographic 
response by RECIST 1.1) will be used to accrue approximately 27 patients  in arm A (95). This 
study achieves 86% power for 6-month progression-free survival (with null 6m-PFS 12% (7) and 
alternative of 34%) and 85% power for response (with null ORR 10% (38) and alternative of 
30%) simultaneously at a one-sided alpha 0.08. The study will accrue 12 patients at the first 
stage of arm A and will be terminated with 37% of probability of early stopping if no patient 
responds and no patient is progression-free at 6 months. The number of patients with 6m-PFS 
and objective response are independent to each other. Stage 2 will accrue 15 additional patients, 
leaving a cumulative accrual of 27 patients in arm A. If 6 patients experience 6m-PFS or 5 
patients have an objective response by the end of stage 2, this study would suggest meaningful 
clinical activity. 
We assume an accrual rate of 4 patients per month (2 per arm) for all sites combined. Accrual 

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duration of stage 1 will be 6 months and the enrollment will be paused maximum 6 months after 
enrolling 12th patient to observe the patient’s response. If arm A opens stage 2 then another 8 
months will be expected for accrual.
For arm C (CDK12 loss CRPC), similar assumptions will be made with expected efficacy with a 
null 6m-PFS rate of 12% and an alternative rate of 34% or greater. Due to accrual limitations in 
this arm, we will use a single stage design. Five patients with CDK12 loss will be accrued to an 
atezolizumab monotherapy as an exploratory group. Then, additional subjects with CDK12 loss 
will be accrued to therapy with abemaciclib. 
A one-sided, one-sample log-rank test calculated from a sample of 16 subjects treated with 
abemaciclib alone achieves 80-85% power at a 0.05 significance level to detect a 6m-PFS 
proportion of 34% in this population with the combined treatments when the 6m-PFS in the 
historic control group is 12%. Accrual duration will be 18 months, the same period of accrual as 
arm A.  Follow-up continues for 12 months after the last subject is accrued. The expected 
number of events during the study is 14-16. It is assumed that the PFS time distributions of both 
groups are approximated reasonably well by the exponential distribution. 
For the patients treated with abemaciclib alone in each arm A and C, the 6m-PFS and 90% 
confidence interval will be estimated using Kaplan-Meier method and ORR with 90% binomial 
confidence interval will be summarized. The efficacy endpoints of 6m-PFS and ORR in patients 
treated with combination of abemaciclib and atezolizumab in arm B will be listed individually 
due to small number. 
13.3 Primary Safety Endpoint Statistical Plan
Safety and tolerability for abemaciclib monotherapy and for the combination of abemaciclib and 
atezolizumab will be summarized by rate of dose-limiting toxicities (DLTs) as defined in section 
7.3 using percentage and 90% confidence interval, and by incidence and grade of adverse events 
(AEs) by CTCAE version 5.0.  Safety analyses will be performed for all patients who have 
received at least one dose of study drug.
Bayesian toxicity monitoring (https://trialdesign.org/one-page-shell.html#BTOX) was planned to 
be used for all patients enrolled to Arm B and to the combination treatment cohort of Arm C (up 
to a maximum of 43 patients) starting after three patients have initiated treatment.  If the rate of 
patients experiencing dose limiting toxicities (DLTs) at the starting dose exceeded the pre-
specified threshold for excessive toxicity, then subsequent patients randomized to Arm B or 
enrolled to the combination cohort of Arm C were planned to de-escalate abemaciclib dose to 
100 mg BID with atezolizumab 1200 mg every 21 days with Bayesian toxicity monitoring 
resuming once three additional patients have initiated treatment at this lower dose level.  If the 
rate of patients experiencing DLT at the de-escalated dose exceeded the pre-specified threshold 
for excessive toxicity, then enrollment to Arm B and the combination cohort of Arm C were 
planned to be halted. Maximum probability of DLT is 0.3 with prior distribution of Β(0.5, 0.5) 
for the DLT rate. Stopping probability threshold for excessive DLT is 0.7. Dose de-escalation or 
early stopping of enrollment for combination cohort will follow the rules displayed in Table 28.
Table 28. Decision rules for dose de-escalation or early stopping 

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# DLT-evaluable1 
patients treated at 
current dose level
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22
Reduce dose or stop 
early if # pts 
experiencing DLT is >
2
2
2
3
3
4
4
4
5
5
5
6
6
6
7
7
7
8
8
8
# DLT-evaluable1 
patients treated at 
current dose level
23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43
Reduce dose or stop 
early if # of pts 
experiencing DLT is >
9
9
9
9
10 10 10 11 11 11 12 12 12 13 13 13 14 14 14 15 15
1Patients must have received at least 28 days of trial therapy (or have experienced a DLT) to be 
considered DLT-evaluable.
Table 29. Operating characteristics under 5 scenarios of true DLT rates 
Scenario
Probabilit
y of true 
DLT
Probability of 
dose de-
escalation or 
early stopping
Probability of 
declaring DLT
Average # 
patients
Average 
# pts w/ 
DLTs
Observed 
DLT rate
1
0.1
0.09
0.09
39.6
4.0
0.13
2
0.2
0.34
0.34
30.6
6.1
0.29
3
0.3
0.71
0.71
18.7
5.6
0.43
4
0.4
0.94
0.95
9.6
3.9
0.52
5
0.5
1.00
1.00
5.6
2.8
0.59
Due to two grade 5 sepsis events observed in the 8 patients treated on Arm B with unclear 
relationship to the study medications, the Sponsor-Investigator and co-investigators elected to 
halt enrollment to combination treatment rather than following the Bayesian toxicity monitoring 
plan. Unselected patients will continue to enroll on Arm A in a non-randomized fashion (up to 
27 patients in total in Arm A) and patients with CDK12 loss subsequently enrolled on Arm C 
after the 5 patients treated with atezolizumab monotherapy will receive abemaciclib 200 mg BID 
as monotherapy (total enrollment on Arm C up to 21 patients in total).
13.4 Secondary Endpoint Analysis Plan
 Clinical benefit rate estimated by proportion of evaluable patients who had complete response 
(CR), partial response (PR) or stable disease (SD) as their best response to treatment will be 
reported by treatment arm with 95% binomial confidence intervals.  Overall survival (OS) 
among all patients, and among responders, duration of response (DOR), duration of therapy 
(DOT), and time to progression (TTP) will each be reported by treatment arm using Kaplan-
Meier methods. Safety endpoints including the number and severity of adverse events will be 
summarized for each treatment arm using counts and proportions.

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13.5 Statistical Plan for Primary Exploratory Endpoint Requiring Biopsies
The primary biomarker study from the mandatory on-treatment biopsy for unselected mCRPC 
will be FoxP3+/CD8+ T-cell ratio.  We expect the ratio of FoxP3+/CD8+ T-cells in archival pre-
treatment tissue to be ~10% (96). We expect this ratio to decrease to ~5% with abemaciclib 
monotherapy.  With 27 patients in arm A, we expect 22 samples in each arm to be evaluable for 
this endpoint.  The FoxP3+/CD8+_T-cell ratio in all biopsy specimens and the change between 
pre-treatment and on-treatment specimens will be reported descriptively in each treatment arm 
separately. The study will have at least 80% power at a 0.05 significance level to detect an effect 
size of 0.90 in change in FoxP3+/CD8+ T-cells ratio means between the combination group and 
the monotherapy group, using a two-sided Mann-Whitney test.
14. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 

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APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

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APPENDIX B
MULTI-CENTER GUIDELINES
B-1.
INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP serves as a reference for any sites external to DF/HCC that 
are participating in a DF/HCC clinical trial. 
B-1.1 Purpose 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Policies and 
Operations.       
B-2. GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the following general responsibilities apply, in 
addition to those outlined in DF/HCC Policies for Sponsor-Investigators: 
B-2.1 Coordinating Center 
The Coordinating Center is the entity that provides administrative support to the DF/HCC Sponsor in order 
that he/she may fulfill the responsibilities outlined in the protocol document and DSMP, and as specified in 
applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines). 
The general responsibilities of the Coordinating Center may include but are not limited to:

Assist in protocol development. 

Maintain FDA correspondence, as applicable.

Review registration materials for eligibility and register participants from 
Participating Institutions in the DF/HCC clinical trial management system 
(CTMS).

Distribute protocol and informed consent document updates to External Sites as 
needed.

Oversee the data collection process from External Sites.

Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by External Sites and provide to the DF/HCC 
Sponsor for timely review and submission to the IRB of record, as necessary. 

Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the reporting requirements for the IRB of record to all External Sites.

Provide External Sites with information regarding DF/HCC requirements that they 
will be expected to comply with.

Carry out plan to monitor External Sites either by on-site or remote monitoring. 

Maintain Regulatory documents of all External Sites which includes but is not 
limited to the following: local IRB approvals/notifications from all External Sites, 

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confirmation of Federalwide Assurances (FWAs) for all sites, all SAE submissions, 
Screening Logs for all sites, IRB approved consents for all sites

Conduct regular communications with all External Sites (conference calls, emails, 
etc) and maintain documentation all relevant communications.
B-2.2 External Site
An External Site is an institution that is outside the DF/HCC and DF/PCC consortium that 
is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC investigator.  
The External Site acknowledges the DF/HCC Sponsor as having the ultimate authority and 
responsibility for the overall conduct of the study. 
Each External Site is expected to comply with all applicable DF/HCC requirements stated 
within this Data and Safety Monitoring Plan and/or the protocol document. 
The general responsibilities for each External Site may include but are not limited to:

Document the delegation of research specific activities to study personnel.

Commit to the accrual of participants to the protocol.

Submit protocol and/or amendments to their IRB of record. For studies under a 
single IRB, the Coordinating Center will facilitate any study-wide submissions.

Maintain regulatory files as per ICH GCP and federal requirements.

Provide the Coordinating Center with regulatory documents or source documents 
as requested.

Participate in protocol training prior to enrolling participants and throughout the 
trial as required.

Update Coordinating Center with research staff changes on a timely basis.

Register participants through the Coordinating Center prior to beginning research 
related activities when required by the sponsor. 

Submit Serious Adverse Event (SAE) reports to sponsor, Coordinating Center, and 
IRB of record as applicable, in accordance with DF/HCC requirements. 

Submit protocol deviations and violations to the Sponsor, Coordinating Center, and 
IRB of record as applicable..

Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements.

Participate in any quality assurance activities and meet with monitors or auditors 
at the conclusion of a visit to review findings.

Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings.

Notify the sponsor immediately of any regulatory authority inspection of this 
protocol at the External Site.

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B-3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
Certain DF/HCC Policy requirements apply to External Sites participating in DF/HCC 
research. The following section will clarify DF/HCC requirements and further detail the 
expectations for participating in a DF/HCC Multi-Center protocol. 
B-3.1 Protocol Revisions and Closures
The External Sites will receive notification of protocol revisions and closures from the 
Coordinating Center.  When under a separate IRB, it is the individual External Site’s 
responsibility to notify its IRB of these revisions.

Protocol revisions: External Sites will receive written notification of protocol 
revisions from the Coordinating Center. All protocol revisions should be IRB 
approved and implemented within a timely manner from receipt of the notification.

Protocol closures and temporary holds: External Sites will receive notification of 
protocol closures and temporary holds from the Coordinating Center. Closures and 
holds will be effective immediately.  In addition, the Coordinating Center, will 
update the External Sites on an ongoing basis about protocol accrual data so that 
they will be aware of imminent protocol closures.
B-3.2 Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for External Sites. The External Site consent form must follow the consent 
template as closely as possible and should adhere to specifications outlined in the DF/HCC 
Guidance Document on Model Consent Language for Investigator-Sponsored Multi-Center 
Trials.  This document will be provided separately to each External Site upon request.
External Sites must send their version of the informed consent document to the Coordinating 
Center for sponsor review and approval. If the HIPAA authorization is a separate document, 
please submit to the sponsor for the study record. Once sponsor approval is obtained, the 
External site may submit to their IRB of record, as applicable. In these cases, the approved 
consent form must also be submitted to the Coordinating Center after approval by the local 
IRB for all consent versions.
The Principal Investigator (PI) at each External Site will identify the appropriate members 
of the study team who will be obtaining consent and signing the consent form for protocols. 
External Sites must follow the DF/HCC requirement that for all interventional drug, 
biologic, or device research, only attending physicians may obtain initial informed consent 
and any re-consent that requires a full revised consent form.  

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B-3.3 IRB Re-Approval
Verification of IRB re-approval for the External Sites is required in order to continue 
research activities.  There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received 
for the External Site on or before the anniversary of the previous approval date.  
B-3.4 DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should 
be de-identified. It is recommended that the assigned protocol case number be used for all 
participant specific documents. Participant initials may be included or retained for cross 
verification of identification. 
B-3.5 Participant Registration and Randomization 
To register a participant, the following documents should be completed by the External 
Site and e-mailed to the Coordinating Center:

Current IRB approved informed consent document informed consent document 
signed by participant and investigator. Participant name and MRN must be 
redacted. Please ensure the participant’s initials are written on each page of the 
informed consent document.

HIPAA authorization form (if separate from the informed consent document)

Signed and dated Eligibility Checklist 

The following source documentation is required:
o
Documentation of prior treatments/procedures performed to treat RCC
o
Reports documenting disease status

Chest CT

CT or MRI Abdomen and Pelvis

Tc99m Bone Scan 
o
Pathology Report
o
Concomitant medication list
o
Progress note or equivalent documentation of consenting visit
o
Progress note documenting medical history and oncologic history
o
Screening Labs
o
Screening visit note with vital signs, weight, height, ECOG performance 
status, physical examination
The Coordinating Center will review the submitted documents in order to verify 
eligibility and consent. To complete the registration process, the Coordinating Center 
will:

Register the participant on the study with the DF/HCC Clinical Trial Management 
System (CTMS).

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
Upon receiving confirmation of registration, the Coordinating Center will inform 
the External Site and provide the study specific participant case number, and, if 
applicable, assigned treatment and/or dose level. 
At the time of registration, the following identifiers are required for all subjects: initials, 
date of birth, gender, race and ethnicity. Once eligibility has been established and the 
participant successfully registered, the participant is assigned a unique protocol case 
number.  External Sites should submit all de-identified subsequent communication and 
documents to the Coordinating Center, using this case number to identify the subject.
B-3.6 Initiation of Therapy
Participants must be registered with the DF/HCC CTMS before the initiation of treatment 
or other protocol-specific interventions. Treatment and other protocol-specific interventions 
may not be initiated until the External Site receives confirmation of the participant’s 
registration from the Coordinating Center. The DF/HCC Sponsor and IRB of record must 
be notified of any violations to this policy.
B-3.7 Eligibility Exceptions
No exceptions to the eligibility requirements for a protocol without IRB approval will be 
permitted. All External Sites are required to fully comply with this requirement. The process 
for requesting an eligibility exception is defined below.
B-3.8 Data Management
DF/HCC develops case report forms (CRF/eCRFs), for use with the protocol.  These forms 
are designed to collect data for each study. DF/HCC provides a web based training for all 
eCRF users.
  
B-3.9 Data Forms Review
Data submissions are monitored for timeliness and completeness of submission. If study 
forms are received with missing or questionable data, the submitting institution will receive 
a written or electronic query from the DF/HCC Office of Data Quality, Coordinating Center, 
or designee. 
Responses to all queries should be completed and submitted within 14 calendar days.  
If study forms are not submitted on schedule, the External Sites will periodically receive a 
Missing Form Report from the Coordinating Center noting the missing forms. 
B-3.9 Protocol Reporting Requirements

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B-3.9.1 Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor and to the IRB of record.
B-3.9.2 Reporting Procedures
Requests to deviate from the protocol require approval from the IRB of record and the 
sponsor. 
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of 
violations. 
B-3.9.3 Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports per DF/HCC requirements, and 
ensure that all IND Safety Reports are distributed to the External Sites as required by 
DF/HCC Policy. External Sites will review/submit to the IRB according to their 
institutional policies and procedures.
B-4. MONITORING: QUALITY CONTROL
The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides 
quality control oversight for the protocol.
B-4.1 Ongoing Monitoring of Protocol Compliance
The External Sites may be required to submit participant source documents to the 
Coordinating Center for monitoring. External Sites may also be subject to on-site 
monitoring conducted by the Coordinating Center. 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
External Sites are complying with regulatory and protocol requirements, data quality, and 
participant safety. Monitoring practices may include but are not limited to source data 
verification, and review and analysis of eligibility requirements, informed consent 
procedures, adverse events and all associated documentation, review of study drug 
administration/treatment, regulatory files, protocol departures reporting, pharmacy records, 
response assessments, and data management. 
Site visits will generally occur once a year for sites that are actively enrolling participants 
and have participants in treatment. Additional monitoring activities may occur if incidences 

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of non-compliance are discovered or at the request of the DF/HCC Sponsor. Virtual 
monitoring (source documents are sent to DFCI for review) may be performed in lieu of a 
site visit if the study staff and PI determine that virtual monitoring is appropriate for the site. 
The decision to perform virtual monitoring in lieu of a site visit will be based upon the site’s 
enrollment, study compliance history, history collaborating with DFCI on other multi-center 
studies, and number of participants in active treatment.
Monitoring will occur before the clinical phase of the protocol begins and will continue 
during protocol performance through study completion.
Teleconferences between DFCI and the participating sites will be conducted on 
approximately a monthly basis. Meeting minutes for teleconferences will be issued to all 
participating sites. Site initiation visits will be conducted via teleconference. Ongoing 
training will also be conducted via teleconference as needed. The Coordinating Center, 
Dana Farber Cancer Institute will be available to all participating sites for resolving 
questions, concerns and facilitating compliance.
B-4.2 Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. 
The DF/HCC Sponsor may increase the monitoring activities at External Sites that are 
unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. 
B-4.3 Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each External Site. Accrual will be monitored for each External 
Site by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual 
expectations may be subject to termination.
 
The following minimum accrual requirements are recommended: 
1) Phase I: 2 per site/annually
2) Phase II-III: 3 per site/annually.  However, given the additional regulatory burden 
and cost of overseeing each site, a consideration of 5 per site/annually should be a 
minimum target for each site..
3) Note: Diseases that are extremely rare may have accrual expectations of 0-1 
accruals/year.]
B-5. AUDITING: QUALITY ASSURANCE
B-5.1 DF/HCC Internal Audits
 

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All External Sites are subject to audit by the DF/HCC Office of Data Quality (ODQ). 
Typically, approximately 3-4 participants would be audited at the site over a 2-day period. 
If violations which impact participant safety or the integrity of the study are found, more 
participant records may be audited. 
B-5.2 Audit Notifications
It is the External Site’s responsibility to notify the Coordinating Center of all external audits 
or inspections (e.g., FDA, EMA, NCI) that involve this protocol. All institutions will 
forward a copy of final audit and/or re-audit reports and corrective action plans (if 
applicable) to the Coordinating Center, within 12 weeks after the audit date. 
B-5.3 Audit Reports 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the IRB as applicable.
B-5.4 External Site Performance
The DF/HCC Sponsor and the IRB of record are charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol.
External Sites that fail to meet the performance goals of accrual, submission of timely and 
accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be put on hold or closed. 

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Appendix C
Safety Reporting Fax Cover Sheet
SAFETY REPORTING FAX COVER SHEET
GENENTECH SUPPORTED RESEARCH
AE / SAE FAX No: (650) 238-6067
Genentech Study Number
Principal Investigator
Site Name
Reporter name
Reporter Telephone #
Reporter Fax #
Initial Report Date
[DD] / [MON] / [YY]
Follow-up Report Date
[DD] / [MON] / [YY]
Subject Initials
(Enter a dash if patient has no 
middle name)
[ ] - [ ] - [ ]
SAE or Safety Reporting questions, contact Genentech Drug Safety: (888) 835-2555
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET

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Appendix D
Content Required in the Line Listing Used for Exchange of Single 
Case Reports
Note to the author: Appendix D is only applicable when Single Case Reports are exchanged via 
monthly Line Listing.
The following fields must be populated in the Line Listing by the Sponsor-Investigator in order 
for Roche to process the Single Case Reports:

Protocol number

Patient number

Date of birth

Patient initials, as applicable

Primary reporter country (and country of occurrence of event if different to that of primary 
reporter)

AE term and/or Medical Dictionary for Regulatory Activities (MedDRA) term

Seriousness of event and seriousness criteria

Medical History and concomitant medications

Onset date and end date (if applicable) of event

Death date and cause (if applicable)

Study drugs received

First and last dose dates, dosage, frequency and indication of the suspected drug

Cause(s) of event - Roche Medicinal Product

Cause(s) of event - other study drugs attribution (to be specified) and other attributions (to 
be specified)

Common Terminology Criteria for Adverse Events (CTCAE) Grade

AE Event description

AE Event outcome

Action taken

Batch Lot number if biological products

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Appendix E
Preexisting Autoimmune Diseases and Immune Deficiencies
Patients should be carefully questioned regarding their history of acquired or congenital immune 
deficiencies or autoimmune disease.  Patients with any history of immune deficiencies or 
autoimmune disease listed in the table below are excluded from participating in the study.  
Possible exceptions to this exclusion could be patients with a medical history of such entities as 
atopic disease or childhood arthralgias where the clinical suspicion of autoimmune disease is 
low.  Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible for this study.  In addition, transient autoimmune 
manifestations of an acute infectious disease that resolved upon treatment of the infectious 
agent are not excluded (e.g., acute Lyme arthritis).  Caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or lifethreatening skin 
adverse reaction while receiving another immunostimulatory anti-cancer agent.
Autoimmune Diseases and Immune Deficiencies
Acute disseminated 
encephalomyelitis
Addison disease
Ankylosing spondylitis
Antiphospholipid antibody 
syndrome
Aplastic anemia
Autoimmune hemolytic 
anemia
Autoimmune hepatitis
Autoimmune 
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myelitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune 
thrombocytopenic purpura
Behçet disease
Bullous pemphigoid
Chronic fatigue syndrome
Chronic inflammatory 
demyelinating 
polyneuropathy
Churg-Strauss syndrome
Crohn disease
Dermatomyositis
Diabetes mellitus type 1
Dysautonomia
Epidermolysis bullosa 
acquisita
Gestational pemphigoid
Giant cell arteritis
Goodpasture syndrome
Graves disease
Guillain-Barré syndrome
Hashimoto disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki disease
Lambert-Eaton myasthenia 
syndrome
Lupus erythematosus
Lyme disease, chronic
Meniere syndrome
Mooren ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus 
syndrome
Optic neuritis
Ord thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodosa
Polyarthritis
Polyglandular autoimmune 
syndrome
Primary biliary cholangitis
Psoriasis
Reiter syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren syndrome
Stiff-Person syndrome
Takayasu arteritis
Ulcerative colitis
Vitiligo
Vogt-Koyanagi-Harada 
disease
Wegener granulomatosis

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Appendix F
Anaphylaxis Precautions
EQUIPMENT NEEDED

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation monitor, and 
thermometer

Oxygen

Epinephrine for intravenous, intramuscular, and endotracheal administration in accordance 
with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, the following 
procedures should be performed:
1. Stop the study treatment infusion.
2. Call for additional medical assistance.
3. Maintain an adequate airway.
4. Ensure that appropriate monitoring is in place, with continuous ECG and pulse oximetry 
monitoring, if possible.
5. Administer antihistamines, epinephrine, or other medications as required by participant status 
and as directed by the physician in charge.
6. Continue to observe the participant and document observations.
7. Draw serum/plasma samples for immunogenicity testing.
8. Ask participant to return for washout immunogenicity sample if appropriate.