Clinical trial NCT03566485
Conditions: Stage III Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer Stage IV Breast Cancer Estrogen Receptor-positive HER2/Neu Negative
Sponsor: Vanderbilt-Ingram Cancer Center
Start date: 2018-07-10; Completion date: 2020-12-10
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase I/II trial studies the side effects and best dose of idasanutlin when given together with atezolizumab, and to see how well atezolizumab and cobimetinib or idasanutlin work in treating participants with stage IV estrogen-receptor positive (ER+) breast cancer, or ER+ breast cancer that has come back (recurrent) and cannot be removed by surgery (unresectable). Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Cobimetinib and idasanutlin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab with cobimetinib or atezolizumab with idasanutlin may work better in treating participants with estrogen-receptor positive breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of atezolizumab and idasanutlin in patients with estrogen receptor positive (ER+) metastatic breast cancer (mBC) (Phase I).

II. To determine the anti-tumor effect of atezolizumab and cobimetinib or idasanutlin in patients with ER+ mBC (Phase II).

SECONDARY OBJECTIVES:

I. To determine the anti-tumor duration of effect of atezolizumab and cobimetinib or idasanutlin in patients with ER+ mBC (Phase II).

II. To determine the safety and tolerability of atezolizumab and cobimetinib or idasanutlin in patients with ER+ mBC (Phase II).

EXPLORATORY OBJECTIVES:

I. To evaluate if CD8+ T cells are enhanced in the tumor with either MEK or MDM2 inhibition (Phase II).

II. To evaluate if MHC-I/II and/or PD-L1 expression is enhanced with MEK inhibition (Phase II).

III. To evaluate if T cell chemotractants (CCL5, CXCL9,10,11,13) are upregulated upon MDM2 antagonism (Phase II).

IV. To determine if baseline or changes in PDL1 expression, MHC expression, presence of tumor infiltrating lymphocytes, neoantigen expression/ mutation burden (using ribonucleic acid \[RNA\]-and whole exome sequencing), CCL5, CXCL9, CXCL10, CXCL11, and CXCL13 correlate with clinical outcome (Phase II).

V. To determine if immunological activity of MEK inhibition can be tracked noninvasively using Zr\^89-atezolizumab (Phase II).

OUTLINE: This is a phase 1, dose-escalation study of idasanutlin followed by a phase II study. Participants are assigned to 1 of 2 arms.

ARM I: Participants with TP53 gene mutation receive atezolizumab intravenously (IV) over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib orally (PO) daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Participants without TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and idasanutlin PO daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed for 28 days.

Arms: arm 1: Participants with TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: None
Interventions: intervention 1: Atezolizumab intervention 2: Cobimetinib intervention 3: Idasanutlin
Intervention descriptions: intervention 1: Given by IV intervention 2: Given by mouth intervention 3: Given by mouth

Protocol documents:
Prot_SAP_000.pdf: 
BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
Protocol Chair:  Ingrid Mayer 
Protocol Version 3/14/2019 
CONFIDENTIAL 
This document is confidential 
Do not disclose or use except as authorized 
Page 1 of 113 
 
 
 
 
 
PROTOCOL TITLE: 
 
BRE 17107: A Phase Ib/II Trial of Atezolizumab (an anti-PD-L1 monoclonal antibody) with 
Cobimetinib (a MEK1/2 inhibitor) or Idasanutlin (an MDM2 antagonist) in Metastatic ER+ 
Breast Cancer 
 
Protocol Number 
Protocol Chairs 
 
 
 
 
 
 
 
 
 
 
 
 
Co-Investigators 
Pathology 
 
Statistician 
 
 
Funding Mechanism 
Supporter 
Coordinating Center 
VICC BRE 17107  (NCT03566485) 
 
PI Name: Ingrid A. Mayer, MD, MSCI 
Institution: Vanderbilt-Ingram Cancer Center (VICC) 
Address: 2200 Pierce Ave. 777 PRB, Nashville, TN 37232 
Phone: 615-322-4967 
Fax: 615-343-7602 
Email: Ingrid.mayer@vumc.org 
 
Correlative PI Name: Justin Balko, PharmD, PhD 
Institution Name: Vanderbilt-Ingram Cancer Center (VICC) 
Address: 2200 Pierce Ave. 658 PRB, Nashville, TN 37232 
Phone: 615-875-8666 
Fax: 615-343-7602 
Email: Justin.balko@vumc.org 
 
 
Rita Nanda, MD – University of Chicago 
Hope Rugo, MD - University of California San Francisco 
 
Melinda Sanders, MD 
Melinda.sanders@vumc.org 
Vanderbilt-Ingram Cancer Center (VICC) 
 
Tatsuki Koyama, PhD 
Tatsuki.koyama@vumc.org 
Vanderbilt-Ingram Cancer Center (VICC) 
AACR-SU2C Catalyst Grant 
Roche Genentech 
 
Vanderbilt-Ingram Cancer Center (VICC) 
Multi-Institutional Coordinating Office 
Phone: (615) 936-5770 
Fax: (615) 875-0040 
Email: Coordinating.center@vumc.org 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
Protocol Chair:  Ingrid Mayer 
Protocol Version 3/14/2019 
CONFIDENTIAL 
This document is confidential 
Do not disclose or use except as authorized 
Page 2 of 113 
 
 
 
 
- Protocol Revision Record - 
 
 
Original Protocol: 
12/15/2017 
 
 
Amendment #1: 
[3/29/2018] 
Sections changed: [Immuno-PET removed; information on 
Idasanutlin updated] 
 
 
Amendment #2: 
6/6/2018 
Updated CTCAE  version from  4.03 to 5.0 
 
 
Amendment #3: 
7/16/2018 
Corrected inconsistencies  within protocol 
 
 
Amendment #4: 
3/14/2019 
Updated (1) Atezolizumab safety language per IB version 14 
(October 2018), (2) Idasanutlin safety language per IB version 11 
(November 2018), (3) Vanderbilt and other sites contacts, and (4) 
primary endpoint and statistical considerations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table of Contents 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
Protocol Chair:  Ingrid Mayer 
Protocol Version 3/14/2019 
CONFIDENTIAL 
This document is confidential 
Do not disclose or use except as authorized 
Page 3 of 113 
 
 
 
PROTOCOL SYNOPSIS ............................................................................................................................................5 
SCHEMA.................................................................................................................................................................... 11 
1. 
STUDY DESIGN/ SUMMARY ................................................................................................................... 11 
2. 
OBJECTIVES ............................................................................................................................................... 13 
3. 
BACKGROUND ........................................................................................................................................... 14 
3.1 
BREAST CANCER ......................................................................................................................................... 14 
3.2 
IMMUNE CHECKPOINT INHIBITION IN CANCER THERAPY .............................................................................. 14 
3.3 
THE RAS/RAF/MEK PATHWAY IN BREAST CANCER.................................................................................... 16 
3.4 
SENESCENCE IN CANCER THERAPY .............................................................................................................. 18 
3.5 
CLINICAL TRIAL RATIONALE ...................................................................................................................... 19 
3.6 
CORRELATIVE SCIENCE BACKGROUND ....................................................................................................... 20 
3.7 
INVESTIGATIONAL AGENTS ......................................................................................................................... 22 
4. 
PARTICIPANT SELECTION .................................................................................................................... 28 
4.1 
INCLUSION CRITERIA .................................................................................................................................. 28 
4.2 
EXCLUSION CRITERIA ................................................................................................................................. 30 
4.3 
INCLUSION OF UNDERREPRESENTED POPULATIONS .................................................................................... 32 
5. 
REGISTRATION PROCEDURES ............................................................................................................. 32 
5.1 
GUIDELINES FOR VICC AND PARTICIPATING INSTITUTIONS ........................................................................ 32 
6. 
STUDY CALENDAR ................................................................................................................................... 35 
7. 
TREATMENT PLAN ................................................................................................................................... 38 
7.1 
OVERVIEW .................................................................................................................................................. 38 
7.2 
SCREENING PHASE ...................................................................................................................................... 38 
7.3 
ALLOCATION PROCEDURES ......................................................................................................................... 38 
7.4 
AGENT ADMINISTRATION............................................................................................................................ 39 
7.5 
DEFINITION OF DOSE-LIMITING TOXICITY (DLT) – FOR PATIENTS ON IDASANUTLIN ARM ONLY ................. 41 
7.6 
DEFINITION OF MAXIMUM TOLERATED DOSE (MTD) – FOR PATIENTS ON IDASANUTLIN ARM ONLY .......... 44 
7.7 
CONCOMITANT TREATMENT AND SUPPORTIVE CARE GUIDELINES.............................................................. 45 
7.8 
DURATION OF THERAPY .............................................................................................................................. 46 
7.9 
DURATION OF FOLLOW-UP ......................................................................................................................... 46 
7.10 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................................................... 46 
7.11 
DISCONTINUATION OF TREATMENT............................................................................................................. 46 
7.12 
REPLACEMENT OF PATIENTS WHO DISCONTINUE EARLY ............................................................................ 47 
7.13 
WITHDRAWAL FROM STUDY ....................................................................................................................... 47 
8. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ................................ 47 
8.1 
COBIMETINIB .............................................................................................................................................. 47 
8.2 
IDASANUTLIN .............................................................................................................................................. 51 
8.3 
ATEZOLIZUMAB .......................................................................................................................................... 52 
8.4 
DOSE MODIFICATIONS/ DELAYS AND TOXICITY MANAGEMENT ................................................................. 59 
8.5 
SPECIAL CONSIDERATIONS.......................................................................................................................... 69 
9. 
DRUG FORMULATION/STORAGE/SUPPLY ........................................................................................ 70 
9.1 
COBIMETINIB .............................................................................................................................................. 70 
9.2 
IDASANUTLIN .............................................................................................................................................. 70 
9.3 
ATEZOLIZUMAB .......................................................................................................................................... 70 
9.4 
DRUG ACCOUNTABILITY ............................................................................................................................. 71 
10. 
CORRELATIVE/SPECIAL STUDIES ...................................................................................................... 71 
10.1 
OVERVIEW .................................................................................................................................................. 71 
10.2 
BLOOD SAMPLES ......................................................................................................................................... 72 
10.3 
TISSUES SAMPLES ....................................................................................................................................... 73 
10.4 
QUALITY CONTROL ..................................................................................................................................... 74 
10.5 
GENETIC TESTING ....................................................................................................................................... 74 
11. 
SPECIMEN BANKING ............................................................................................................................... 75 
12. 
MEASUREMENT OF EFFECT ................................................................................................................. 75 
12.1 
DEFINITIONS ............................................................................................................................................... 75 
12.2 
DISEASE PARAMETERS ................................................................................................................................ 75 
12.3 
RESPONSE CRITERIA ................................................................................................................................... 77 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
Protocol Chair:  Ingrid Mayer 
Protocol Version 3/14/2019 
CONFIDENTIAL 
This document is confidential 
Do not disclose or use except as authorized 
Page 4 of 113 
 
 
12.4 
IMMUNE-RELATED RESPONSE CRITERIA (IRRC) ......................................................................................... 79 
12.5 
DURATION OF RESPONSE............................................................................................................................. 80 
13. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................ 81 
13.1 
GENERAL .................................................................................................................................................... 81 
13.2 
DEFINITIONS ............................................................................................................................................... 81 
13.3 
ADVERSE EVENTS OF SPECIAL INTEREST (AESI - IMMEDIATELY REPORTABLE) ......................................... 83 
13.4 
REPORTING PROCEDURES............................................................................................................................ 85 
14. 
DATA AND SAFETY MONITORING ...................................................................................................... 93 
14.1 
DATA MANAGEMENT AND REPORTING ....................................................................................................... 93 
14.2 
DATA HANDLING AND RECORD KEEPING .................................................................................................... 93 
14.3 
MEETINGS ................................................................................................................................................... 94 
14.4 
MONITORING AND QUALITY ASSURANCE ................................................................................................... 95 
15. 
REGULATORY CONSIDERATIONS ...................................................................................................... 96 
15.1 
PRE-STUDY DOCUMENTATION .................................................................................................................... 96 
15.2 
PROTOCOL REVIEW AND AMENDMENTS ...................................................................................................... 96 
15.3 
INFORMED CONSENT ................................................................................................................................... 97 
15.4 
CONFIDENTIALITY AND DISCLOSURE .......................................................................................................... 97 
15.5 
RECORDS RETENTION ................................................................................................................................. 98 
15.6 
STUDY TERMINATION ................................................................................................................................. 98 
15.7 
ETHICS AND GCP ........................................................................................................................................ 99 
15.8 
COMPLIANCE WITH TRIAL REGISTRATION AND RESULTS POSTING REQUIREMENTS .................................... 99 
16. 
MULTI-CENTER GUIDELINES ............................................................................................................... 99 
16.1 
STUDY DOCUMENTATION............................................................................................................................ 99 
16.2 
RECORDS RETENTION ................................................................................................................................. 99 
16.3 
PUBLICATION ............................................................................................................................................ 100 
17. 
STATISTICAL CONSIDERATIONS ...................................................................................................... 100 
17.1 
PHASE IB TRIAL OF IDASANUTLIN AND ATEZOLIZUMAB............................................................................ 100 
17.2 
PHASE II TRIAL OF ATEZOLIZUMAB WITH COBIMETINIB OR IDASANUTLIN STUDY DESIGN ....................... 101 
17.3 
SAMPLE SIZE/ ACCRUAL RATE .................................................................................................................. 102 
17.4 
REPORTING AND EXCLUSIONS ................................................................................................................... 103 
18. 
REFERENCES ........................................................................................................................................... 104 
19. 
APPENDIX A:  ECOG PERFORMANCE STATUS SCALE ................................................................ 109 
20. 
APPENDIX B: CONTRACEPTIVE GUIDELINES ............................................................................... 110 
21. 
APPENDIX C: PROHIBITED AND CAUTIONARY CONCOMITANT MEDICATIONS .............. 111 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
Protocol Chair:  Ingrid Mayer 
Protocol Version 3/14/2019 
CONFIDENTIAL 
This document is confidential 
Do not disclose or use except as authorized 
Page 5 of 113 
 
 
1.1. PROTOCOL SYNOPSIS 
 
Sponsor 
Vanderbilt-Ingram Cancer Center 
Protocol Title 
BRE 17107: A Phase Ib/II Trial of Atezolizumab (an anti-PD-L1 monoclonal 
antibody) with Cobimetinib (a MEK1/2 inhibitor) or Idasanutlin (an MDM2 
antagonist) in Metastatic ER+ Breast Cancer 
Protocol 
Number 
BRE 17107 
Phase of 
Development 
Phase Ib/II 
Investigational 
Product and 
Mechanism 
• 
Cobimetinib - MEK inhibitor 
• 
Idasanutlin  - MDM2 antagonist 
• 
Atezolizumab - PD-L1 inhibitor 
Treatment 
Schedule 
Dose/Route 
• 
Cobimetinib 60 mg PO Days 1 – 21, every 28 days 
• 
Idasanutlin (final dose to be determined by the phase Ib portion of the 
study) PO Days 1 – 5, every 28 days 
• 
Atezolizumab 840 mg IV on Days 1 and 15, every 28 days 
Objectives 
• 
Phase Ib portion: determine the safety and tolerability of ATEZO and 
IDASA in patients with ER+ mBC 
• 
Phase II portion: determine the anti-tumor effect and adverse effects 
profile of ATEZ with COBI or IDASA in patients with ER+ mBC 
Endpoints 
Primary Endpoint: 
• 
Phase Ib: Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) 
and Recommended Phase II Dose (RP2D) determination for the ATEZO 
and IDASA combination 
• 
Phase II: Progression Free Survival (PFS) for each treatment arm 
Secondary Endpoints: 
• 
Clinical Benefit Rate (CBR; percentage of patients without disease 
progression at 6 months) for each treatment arm 
• 
Immune-related Response Criteria (irRC), 
• 
Duration of Response (DOR) 
• 
Overall Response Rate (ORR; by RECIST 1.1 – for patients with 
measurable disease), 
• 
Percentage of patients alive at 12 months (% OS) 
• 
Adverse Event profile for each treatment arm 
Other: Exploratory Endpoints 
Trial Design 
This is an open-label, multicenter, two-arm phase Ib/II clinical trial that will 
evaluate the anti-tumor effect of atezolizumab (ATEZ; an anti- PD-L1 mAb) 
in combination with cobimetinib (COBI; a MEK inhibitor) in patients with 
TP53-mutated ER+ mBC, or idasanutlin (IDASA; an MDM2 antagonist) in 
patients with TP53-wt ER+ mBC. 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
Protocol Chair:  Ingrid Mayer 
Protocol Version 3/14/2019 
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This document is confidential 
Do not disclose or use except as authorized 
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Number of 
Patients 
• 
Phase Ib: minimum of 9, maximum of 18 patients 
• 
Phase II: minimum of 33, maximum of 66 patients 
Duration of 
Therapy 
In the absence of treatment delays due to adverse events, treatment will 
continue until: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patients decides to withdraw from the study 
• 
Significant patient non-compliance with protocol 
Duration of 
Follow-up 
• 
Patients will be followed until 28 days (+/- 7 days) following study 
treatment discontinuation due to disease progression 
• 
Patients removed from study treatment for unacceptable treatment 
related adverse event(s) will be followed until resolution or stabilization 
of all treatment related adverse events to Grade 1 or lower 
• 
Patients who have discontinued atezolizumab, cobimetinib or idasanutlin 
for any reason other than disease progression will be followed until 
disease progression 
Patient 
Selection 
Inclusion Criteria 
1. Signed and dated written informed consent. 
2. Subjects ≥ 18 years of age. 
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 
1. 
4. Clinical stage IV invasive mammary carcinoma or unresectable 
locoregional recurrence of invasive mammary carcinoma that is: 
• 
ER/PR-positive (> 1% cells) by IHC and HER2 negative (by IHC or 
FISH) 
• 
Previously exposed to an aromatase inhibitor (AI) or a selective 
estrogen-receptor modulator/ downregulator (SERM; SERD) + a 
CDK4/6 inhibitor 
• 
Appropriate candidates for chemotherapy 
• 
Amenable to biopsy at the time of study entry 
5. Adequate organ function including: 
• 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
• 
Platelets ≥ 100 × 109/L 
• 
Hemoglobin ≥ 9/g/dL (may have been transfused) 
• 
Total serum bilirubin ≤ 1.5 times upper limit of normal (ULN) 
• 
Aspartate 
aminotransferase 
(AST/SGOT) 
and 
alanine 
aminotransferase (ALT/SGPT) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver 
metastases are present) 
• 
Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 50 
mL/min as calculated using the Cockcroft-Gault (CG) equation 
• 
Thyroid Stimulating Hormone (TSH) ≤ 1 x ULN 
• 
Amylase ≤ 1 x ULN 
• 
Lipase ≤ 1 x ULN 
• 
CPK ≤ 1.5 x ULN 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
Protocol Chair:  Ingrid Mayer 
Protocol Version 3/14/2019 
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Do not disclose or use except as authorized 
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• 
LVEF (echo) ≥ LLN (Cobi arm only) 
6. Female patients of childbearing potential must agree to use at least two 
methods of acceptable contraception from 15 days prior to first trial 
treatment administration until at least 5 months after study participant’s 
final dose of study drugs. See appendix C for details. 
Note: Females of childbearing potential are defined as those who are not 
surgically sterile or post-menopausal (i.e. patient has not had a bilateral 
tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or 
has not been amenorrheic for 12 months without an alternative medical 
cause). Post-menopausal status in females under 55 years of age 
should be confirmed with a serum follicle-stimulating hormone (FSH) 
level within laboratory reference range for postmenopausal women. 
7. Patients unable to read/write in English are eligible to participate in the 
overall study but will not participate in the Patient-Reported Outcome 
questionnaires throughout the trial 
8. Re-enrollment of a subject that has discontinued the study as a pre- 
treatment screen failure (i.e. a consented patient who did not receive 
study drugs) is permitted. If re-enrolled, the subject must be re- 
consented. Only the screening procedures performed outside of 
protocol-specified timing must be repeated. 
Exclusion Criteria 
1. Prior therapy with anti-PD-L1 and anti-PD1 antibodies, MEK inhibitors or 
MDM2 antagonists. 
2. No more than 3 lines of chemotherapy in the metastatic setting 
3. No concurrent anticancer therapy. Required washout from prior therapy: 
• 
Endocrine therapy: no required wash-out 
• 
Chemotherapy: 14 days 
• 
Major surgery: 14 days (provided wound healing is adequate) 
• 
Radiation: 7 days 
• 
Investigational/Biologic Therapy (half –life ≤ 40 hours): 14 days 
• 
Investigational/Biologic Therapy (half –life > 40 hours): 28 days 
• 
Use of corticosteroids or immunosuppressive medication is 
exclusionary, except the following in the absence of active 
autoimmune disease: 
o Subjects are permitted the use of corticosteroids with minimal 
systemic 
absorption 
(e.g. 
topical, 
ocular, 
intra-articular, 
intranasal, and inhaled); 
o Systemic corticosteroids at physiologic doses ≤10 mg/day of 
prednisone or equivalent are permitted; 
o Adrenal replacement steroid doses including doses > 10 mg daily 
prednisone are permitted; 
o A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (e.g. CT scan premedication against contrast dye 
allergy) or for treatment of non-autoimmune conditions (e.g. 
delayed-type hypersensitivity reaction caused by a contact 
allergen) is permitted. 
4. Previous malignant disease other than breast cancer within the last 5 
years, with the exception of basal or squamous cell carcinoma of the skin, 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
Protocol Chair:  Ingrid Mayer 
Protocol Version 3/14/2019 
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Do not disclose or use except as authorized 
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cervical carcinoma in situ, or low-risk cancers considered curatively 
treated (i.e. complete remission achieved at least 2 years prior to first 
dose of study drugs AND additional therapy not required while receiving 
study treatment). 
5. All subjects with brain metastases, except those meeting the following 
criteria: 
• 
Brain metastases that have been treated locally and are clinically 
stable for at least 2 weeks prior to enrollment 
• 
No history of intracranial or spinal cord hemorrhage 
• 
No evidence of interim CNS disease progression 
• 
Metastasis to the midbrain, pons, and medulla 
• 
No ongoing neurological symptoms that are related to the brain 
localization of the disease (sequelae that are a consequence of the 
treatment of the brain metastases are acceptable. 
• 
Subjects must be either off steroids or on a stable or decreasing dose 
of ≤ 10 mg daily prednisone (or equivalent) 
6. Receipt of any organ transplantation including allogeneic stem-cell 
transplantation. 
7. Significant acute or chronic infections including, among others: 
• 
Known history of testing positive for human immunodeficiency virus 
(HIV), or acquired immunodeficiency syndrome (AIDS). 
• 
Active tuberculosis 
• 
Positive test for hepatitis B virus (HBV) surface antigen (and/or core 
antibody) and/or confirmatory hepatitis C virus (HCV) RNA (if anti- 
HCV antibody tested positive). 
8. Interstitial lung disease that is symptomatic or which may interfere with 
the detection or management of suspected drug-related pulmonary 
toxicity. 
9. Active autoimmune disease with reasonable possibility of clinically 
significant deterioration when receiving an immunostimulatory agent: 
• 
Subjects with Type 1 diabetes mellitus, vitiligo, psoriasis, hypo- or 
hyperthyroid disease not requiring immunossupressive treatment are 
eligible 
• 
Subjects requiring hormone replacement with corticosteroids are 
eligible if the steroids are administered only for the purpose of 
hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent 
prednisone per day 
• 
Administration of steroids through a route known to result in a minimal 
systemic exposure (topical, intranasal, intra-ocular, or inhalation) are 
acceptable. 
10. Uncontrolled asthma [defined as having 3 or more of the following 
features of partially controlled asthma within 28 days prior to starting 
study treatment: Daytime symptoms more than twice per week, any 
limitation of activities, any nocturnal symptoms/awaking, need for 
reliever/rescue inhaler more than twice per week, or known lung function 
(PEF or FEV1) without administration of a bronchodilator that is < 80% 
predicted or personal best (if known)]. 
11. Current   symptomatic   congestive   heart   failure    (New   York Heart 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
Protocol Chair:  Ingrid Mayer 
Protocol Version 3/14/2019 
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Do not disclose or use except as authorized 
Page 9 of 113 
 
 
 
 
Association > class II), unstable cardiac arrhythmia requiring therapy 
(e.g. medication or pacemaker), unstable angina (e.g. new, worsening or 
persistent chest discomfort), or uncontrolled hypertension (systolic > 160 
mmHg or diastolic > 100mmHg). Or any of the following occurring within 
6 months (180 days) prior to first dose of study drugs: Myocardial 
infarction, coronary/peripheral artery bypass graft, cerebrovascular 
accident or transient ischemic attack. (Use of antihypertensive 
medication to control blood pressure is allowed.) 
12. Concurrent treatment with a non-permitted drug as well as foods or 
supplements that are strong or moderate CYP3A4 enzyme inducers or 
inhibitors. Any of the above has to be discontinued at least 7 days prior 
to Cycle 1/ Day 1 of study treatment. See supplemental packet for 
guidance. 
13. Requirement of anticoagulant therapy with oral vitamin K antagonists 
such as Coumadin (warfarin). Low-dose anticoagulants for the 
maintenance of patency in a central venous access device or the 
prevention of deep vein thrombosis or pulmonary embolism is allowed. 
Therapeutic use of low molecular weight heparin is allowed provided 
patients are safely able to interrupt it prior to biopsy procedures. 
14. Persisting non-hematological toxicity related to prior therapy that has not 
reduced to Grade 1 [National Cancer Institute Common Toxicity Criteria 
for Adverse Events (NCI CTCAE) version 5.0]; however, alopecia and 
sensory neuropathy Grade ≤ 2 are acceptable and Grade ≤ 2 non- 
hematological toxicities well controlled with medical management are 
allowed (for example: hypomagnesemia well controlled on magnesium 
replacement). 
15. Known severe (Grade ≥ 3 NCI-CTCAE) hypersensitivity reactions to 
monoclonal antibodies, or history of anaphylaxis. 
16. Vaccination within 28 days of the first dose of study drugs and while on 
trial is prohibited, except for administration of inactivated vaccines (for 
example, inactivated influenza vaccine). 
17. Pregnant or breastfeeding females. 
18. Known current alcohol or drug abuse 
19. Prisoners or subjects who are involuntarily incarcerated. 
20. Known psychiatric condition, social circumstance, or other medical 
condition reasonably judged by the patient’s study physician to 
unacceptably increase the risk of study participation; or to prohibit the 
understanding or rendering of informed consent or anticipated 
compliance with scheduled visits, treatment schedule, laboratory tests 
and other study requirements. 
21. Known risk factors for ocular toxicity (cobi arm only), consisting of any of 
the following: 
• 
presence of serous retinopathy within 6 months of protocol enrollment 
• 
presence of retinal vein occlusion (RVO) within 6 months of protocol 
enrollment 
Study 
Assessments 
Safety Assessment: 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
Protocol Chair:  Ingrid Mayer 
Do not disclose or use except as authorized 
 
 
 
 
• 
History, physical exam, and routine blood work such as blood counts and 
comprehensive metabolic panel will be performed on day 1 of each 
treatment cycle. Echocardiograms and ophthalmologic examinations will 
be performed periodically for those on the cobi arm. 
• 
Analyses will be performed for all patients having received at least one 
dose of study drugs. The study will use the NCI CTCAE v5.0. 
Anti-tumor Assessments: 
• 
CT scans of the chest, abdomen, and pelvis and bone scan (when 
applicable) are to be performed approximately every 8 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Version 3/14/2019 
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Do not disclose or use except as authorized 
 
BRE 17107: Atezolizumab, ldasanutlin and Cobimetinib in metastatic ER+ breast cancer 
Protocol Chair:  lngrid Mayer 
 
 
 
 
SCHEMA 
 
 
 
 
1. STUDY DESIGN/ SUMMARY 
The experience with immune checkpoint inihibitors (ICI) in other cancer types demonstrate 
responses tend to be more durable and more likely to lead to improved overall survival than other 
therapies, highlighting their importance. Therefore, strategically combining molecularly-targeted 
agents that may support an ICI response will be especially advantageous to clinical outcomes. 
Improving response rates to ICI in ER+ metastatic breast cancer (ER+ mBC) may be a challenge 
because these tumors typically demonstrate a 'cold' immune microenvironment - that is to say 
they often have few T cells in the tumor microenvironment - which is indicative of an overall failure 
of the immune system to recognize the tumor, rather than a reliance on peripheral tolerance (i.e. 
engagement of PD-1-PD-L1). One strategy to engage the immune system, thereby promoting 
response to immunotherapies, is to administer therapies that increase recognition of tumor cells 
through enhanced antigen presentation and/or increase T cell homing. This clinical trial will 
incorporate each of these different strategies in a genotype-specific (mutually exclusive and 
exhaustive across all ER+ breast cancers) manner that is supported by scientific preclinical data. 
The approaches have been shown to either 1) enhance Major Histocompatibility Complex (MHC)- 
mediated antigen presentation and PD-L1 expression or 2) increasing T cell homing to the tumor 
through upregulation of T cell homing chemokines, setting the stage for clinical response to 
checkpoint inhibitors. 
The clinical trial associated with this proposal is a multicenter, open-label, 2-arm phase Ib/II trial 
that will evaluate the anti-tumor effect of Atezolizumab (an anti- PD-L1 mAb) in combination with 
Cobimetinib (a MEK inhibitor) in patients with TP53-mutated ER+ mBC, or Idasanutlin (an MDM2 
antagonist) in patients with TP53-wt ER+ mBC. All participants will have targeted Next Generation 
Sequencing (NGS) performed prior to treatment arm allocation for TP53 mutation status 
determination and assess tumor mutation burden. We would expect about - 40% of all patients 
with ER+ mBC to have a TP53 mutation (TP53-mut) in their tumor3. Briefly, patient's eligibility 
criteria will include: ER+ mBC refractory to endocrine therapies with biopsy-accessible tumor, no 
prior use of MEK, MDM2, PD-1 or PD-L1 inhibitors/ antagonists, no more than 3 lines of 
chemotherapy in the metastatic setting, ECOG performance status ::1, normal baseline blood 
counts and chemistry laboratory profile, no concurrent use of immunosuppressive  medications, 
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and no concurrent uncontrolled illness, including autoimmune diseases with reasonable 
possibility of clinically significant complications. In the phase Ib portion of the trial we will 
determine the safety and tolerability [Dose Limiting Toxicity (DLT), Maximum Tolerated Dose 
(MTD) and Recommended Phase II Dose (RP2D) determination] of Atezolizumab and Idasanutlin 
in patients with ER+ mBC. With three possible dosing cohorts, a minimum of 9 and a maximum 
of 18 subjects may be recruited for the dose escalation portion of the study. In the phase II portion 
of the trial we will determine the anti-tumor effect and adverse event profile of Atezolizumab with 
Cobimetinib or Idasanutlin in patients with ER+ mBC [Progression Free Survival (PFS) and/or 
Clinical Benefit Rate (CBR; percentage of patients without disease progression at 6 months); 
immune-related Response Criteria (irRC), Overall Response Rate (ORR; by RECIST 1.1 – for 
patients with measurable disease), Percentage of patients alive at 12 months (% OS), and 
Adverse Event profile]. A minimum of 33 and a maximum of 66 patients (total in both arms) will 
be allocated to receive: 
• 
Arm 1 (TP53-mut) – Atezolizumab 840 mg IV, on Days 1 and 15, and Cobimetinib 60 mg 
PO daily, on Days 1 - 21, every 28 days (on Cycle 1 only Atezolizumab will start on Day 
15); or 
• 
Arm 2 (TP53-wt) – Atezolizumab 840 mg IV, on Days 1 and 15, and Idasanutlin (final dose 
to be determined by the phase Ib portion of the trial) PO daily, on Days 1 - 5, every 28 
days (on Cycle 1 only Atezolizumab will start on Day 15), 
until disease progression, unacceptable adverse event(s), concurrent illness that prevents further 
administration of treatment, patient withdrawal from study, or significant non-compliance with 
protocol. To assess the anti-tumor effect of therapy, we will estimate the overall tumor burden at 
baseline to which subsequent measurements (performed every 8 weeks using the Solid Tumor 
Response Criteria [RECIST] v1.1) will be compared. 
Tumor biopsies (fixed for IHC analysis and snap-frozen for RNA extraction) and peripheral blood 
will be collected prior to initiating Cobimetinib (COBI)/Idasanutlin (IDASA) (PRE-Bx), after 15 days 
of COBI/IDASA and prior to adding Atezolizumab (ATEZ) (POST-Bx). The following parameters 
will be assessed from these samples: 
 
Parameter 
Arm 
Sample 
type 
Comparison 
Expectatio 
n 
Endpoint 
CD8+ T cells, IHC/multiplexed IF 
BOTH 
FFPE 
PRE:POST 
Increase 
Primary 
tumor 
Other cell markers: CD4, PD-L1, Foxp3, 
IHC/multiplexed IF 
BOTH 
FFPE 
tumor 
PRE:POST 
Increase 
Secondary 
TILs, H&E 
BOTH 
FFPE 
PRE:POST 
Increase 
Secondary 
tumor 
HLA-DR, HLA-A/B/C IHC/IF 
COBI 
FFPE 
PRE:POST 
Increase 
Secondary 
tumor 
CCL5, CXCL9, CXCL10, CXCL1 mRNA, 
RNAseq 
IDASA 
Frozen 
tumor 
PRE:POST 
Increase 
Secondary 
Immune signatures, RNAseq 
BOTH 
Frozen 
PRE:POST 
Increase/de 
Exploratory 
tumor 
crease 
CyTOF/T cell compartments 
BOTH 
PBMCs 
PRE:POST 
Increase/de 
Exploratory 
crease 


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2. OBJECTIVES 
 
Objective 
Endpoint 
Phase I 
Primary 
To determine the safety and tolerability of 
Atezolizumab and Idasanutlin in patients 
with ER+ mBC 
• 
Dose Limiting Toxicity (DLT) 
• 
Maximum Tolerated Dose (MTD) 
• 
Recommended Phase II Dose (RP2D) 
Phase II 
Primary 
To determine the anti-tumor effect of 
Atezolizumab and Cobimetinib or 
Idasanutlin in patients with ER+ mBC 
• 
Progression Free Survival (PFS) 
Secondary 
To determine the anti-tumor duration of 
effect of Atezolizumab and Cobimetinib or 
Idasanutlin in patients with ER+ mBC 
• 
Clinical Benefit Rate (CBR; percentage of 
patients without disease progression at 6 
months) – for all patients 
• 
Immune related response criteria (irRC) 
• 
Duration of Response (DOR) 
• 
Overall Response Rate (ORR; by RECIST 
1.1 – for patients with measurable 
disease) 
• 
Percentage of patients alive at 12 months 
(% OS) 
To determine the safety and tolerability of 
Atezolizumab and Cobimetinib or 
Idasanutlin in patients with ER+ mBC 
Adverse event profile 
Exploratory 
To evaluate if CD8+ T cells are enhanced 
in the tumor with either MEK or MDM2 
inhibition. 
• 
Multiplexed IHC for CD8 (also CD4, 
FoxP3, PD-L1, MHC-I, MHC-II) 
To evaluate if MHC-I/II and/or PD-L1 
expression is enhanced with MEK 
inhibition 
• 
PD-L1 expression in the tumor and on 
TILs 
• 
Expression of MHC I and II in the tumor 
To evaluate if T cell chemotractants 
(CCL5, CXCL9,10,11,13) are upregulated 
upon MDM2 antagonism 
• 
RNAseq gene expression data 
To determine if baseline or changes in PD- 
L1 expression, MHC expression, presence 
of tumor infiltrating lymphocytes, 
neoantigen expression/ mutation burden 
(using RNA-and whole exome 
sequencing), CCL5, CXCL9, CXCL10, 
CXCL11, and CXCL13 correlate with 
clinical outcome. 
• 
Multiplexed IHC 
• 
Presence of tumor infiltrate lymphocytes 
(TIL) 
• 
Tumor RNA-sequencing (RNA-Seq) 
Tumor whole exome sequencing 


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3. BACKGROUND 
 
3.1. Breast Cancer 
Despite advances in early detection and therapeutic options, unresectable or metastatic breast 
cancer remains incurable and is one of the leading causes of cancer-related mortality4. Breast 
cancer is a molecularly heterogeneous disease with three distinct molecular subtypes5. The first 
group is characterized by estrogen receptor (ER) expression positivity and/or progesterone 
receptor (PgR) positivity with the absence of over-expression or amplification of HER2 (ER+ BC). 
The second group is characterized by over-expression or amplification of HER2 (HER2+ BC), 
with more than half of these tumors being positive (+) for expression of ER/PgR. The third group 
lacks detectable ER and PgR, and overexpression of HER2, and is thus referred to as triple- 
negative breast cancer (TNBC). Approximately 65% of newly diagnosed breast cancers are 
ER/PgR+ and HER2-negative (also referred to as luminal tumors), while an additional 20% of 
newly diagnosed cases are HER2+. 
 
3.1.1 Estrogen receptor-positive (ER+) Breast Cancer 
ER-targeted drugs, specifically drugs that antagonize estrogen binding to the ER (tamoxifen), 
drugs that block estrogen biosynthesis (non-steroidal and steroidal aromatase inhibitors [AI] - only 
effective in postmenopausal patients), and drugs that antagonize and downregulate the ER 
(fulvestrant), have been the mainstay of systemic treatment for patients with both localized and 
metastatic ER/PgR+ breast cancers6. However, acquired resistance (and occasionally primary 
resistance) to anti-estrogen therapy universally develops in patients with ER+ MBC7. 
Although ER+ disease is generally less aggressive and can be treated with endocrine agents, 
there is still a high mortality rate for ER+ MBC. Multiple targeted agents (i.e. endocrine agents, 
cyclin-dependent kinase 4/6 [CDK4/6] inhibitors, and mammalian target of rapamycin [mTOR] 
inhibitors) and chemotherapy are usually effective in ER+ MBC, but complete clinical cures are 
rare, and acquired resistance is commonplace. Due to the high prevalence of mBC patients with 
ER+ disease, new strategies with curative potential are sought. Contrary to TNBC, in ER+BC, the 
tumor’s total mutation burden (TMB) is generally low, but in a subset of tumors following extensive 
prior endocrine therapy, TMB increases8, suggesting that in these cancers immunotherapeutic 
strategies could be further explored. 
 
3.2. Immune checkpoint inhibition in cancer therapy 
PD-L1 is a 40kD type I transmembrane protein that functions as a ligand for its primary receptor, 
PD-1. PD-L1 is broadly expressed on professional antigen-presenting cells (APC) among other 
hematopoietic and non-hematopoietic cells, while PD-1 is expressed on activated lymphocytes 
and myeloid cells9. PD-L1 can also be potently up-regulated on many cell types, including 
epithelial cells upon interferon-gamma (IFNγ) stimulation. Upon ligation of PD-L1 to PD-1, an 
activated lymphocyte (most notably T-cells) is modulated toward regulatory (suppressive; Treg) 
phenotype, or induced to anergy/apoptosis (Fig. 1)9,10. 


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These molecules exist as a putative mechanism 
to protect against immune self-recognition, and 
this pathway is thought to be hijacked by cancer 
cells in a variety of malignancies10-15. In some 
tumors, interruption of this ligation with blocking 
antibodies for PD-1 or PD-L1 can induce 
profound 
and 
durable 
anti-tumor 
immune 
responses9-11,17,18. However, only a subset of 
patients benefit from these targeted agents thus 
emphasizing the need for surrogate biomarkers 
of response. 
Immune checkpoint 
inhibitors 
(ICIs) 
have 
transformed the treatment of many cancers 
including melanoma, NSCLC, RCC, head and 
neck SCC, and urothelial cancer16. Single agent 
monoclonal antibody (mAb)-mediated blocking 
of 
immune 
checkpoint 
ligand/receptor 
interactions (e.g. CTLA-4, PD-1, and PD-L1) has 
resulted in unprecedented anti-tumor responses 
in lung and renal cancer, as well as melanoma 
and Hodgkins disease13,15. In particular, targeting 
the PD-1/PD-L1 axis has produced substantial 
responses  with  significantly  more manageable 
toxicity profiles compared to CTLA-4 mAb (ipilimumab). Phase I and II results for PD-1/PD-L1 
mAbs in other solid tumors are also promising14. In light of these single agent results, synergistic 
combinations of PD-1/PD-L1 targeted agents with other active therapeutics are being 
investigated17. 
Despite some success of PD-1/PD-L1 targeted therapy in triple-negative breast cancers 
(response rates of ~20%)18,19, data in ER+ breast cancer are more limited and results thus far 
have not been encouraging (response rates of ~12%, median progression free survival of 2 
months)18,20,21,22. The experience with ICI in other cancer types demonstrate responses tend to 
be more durable and more likely to lead to improved overall survival than other therapies, 
highlighting their importance. Therefore, strategically combining molecularly-targeted agents that 
may support an ICI response will be especially advantageous to clinical outcomes. Improving 
response rates to ICI in ER+ mBC may be a challenge because these tumors typically 
demonstrate a ‘cold’ immune microenvironment - that is to say they often have few T cells in the 
tumor microenvironment - which is indicative of an overall failure of the immune system to 
recognize the tumor, rather than a reliance on peripheral tolerance (i.e. engagement of PD-1-PD- 
L1). One strategy to engage the immune system, thereby promoting response to IT, is to 
administer therapies that increase recognition of tumor cells through enhanced antigen 
presentation and/or increase T cell homing. This proposal will incorporate each of these different 
strategies in a genotype-specific (mutually exclusive and exhaustive across all ER+ breast 
cancers) manner that is supported by scientific preclinical data. The approaches have been 
shown to either 1) enhance Major Histocompatibility Complex (MHC)-mediated antigen 
presentation and PD-L1 expression or 2) increasing T cell homing to the tumor through 
upregulation of T cell homing chemokines, setting the stage for clinical response to checkpoint 
inhibitors. 
Figure 1: Immune checkpoint receptor/ligand 
signaling axis in cancer. Image reproduced from 
ref 2. 


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3.3. The RAS/Raf/MEK pathway in breast cancer 
The Ras/Raf/MEK pathway conveys growth factor receptor signals from cell surface receptors to 
the nucleus to activate transcriptional programs of proliferation and survival. The commonly 
activated oncogenes K-Ras and B-Raf are mutated in a variety of malignancies, but are rarely 
observed in breast cancer23-26. Nonetheless, this pathway appears to be highly transcriptionally 
activated in TNBC as opposed to ER+ and HER2+ primary breast cancers, which frequently 
redirect growth factor signals to the PI3K pathway27-30. We have previously shown that at least 
one mechanism of Ras/Raf/MEK pathway activation in TNBC and some ER+ breast cancers can 
result from frequent genomic or epigenetic loss of DUSP4, a negative regulator of ERK31-33. Of 
those ER+ breast cancers that demonstrate DUSP4 loss, the majority lie in the Luminal B 
subtype31,33, which are often resistant to endocrine therapy and are more likely to metastasize, 
both of which lead to increased patient mortality34. The Ras/Raf/MEK pathway has frequently 
been implicated in the acquisition of endocrine resistance in ER+ breast cancers and ovarian 
cancer35-38. 
Molecularly, ER+ breast cancer can be divided into “luminal A” and “luminal B” phenotypes34,39. 
While being more intrinsically resistant to endocrine therapy, luminal B tumors may be more 
reliant of growth factor pathways, such as RAS/MEK. Indeed, genetic activation of the Ras/MEK 
pathway in preclinical ER+ mouse models generates metastatic phenotypes which replicate 
luminal B disease40. One marker of luminal A/B status is the presence of highly clonal TP53 
mutations, which exist in only 5-15% of the luminal A subtype, and ~30-40% of luminal B 
tumors41,42. TP53 mutations also mark ER+ tumors that may be more likely to be of the Her2- 
enriched (despite lack of HER2 amplification) or basal-like subgroups, both of which have a high 
degree of intrinsic MEK activity31. TP53-mutated ER+ tumors are more likely to demonstrate 
luminal B like behavior, which is partially characterized by loss of Ras/MAPK negative 
regulators33,43. In these tumors, inability to present antigen, rather than T cell recruitment, appears 
to be the limiting factor. MEK activation suppresses antigen presentation, while MEK inhibition 
(i.e. Cobimetinib) can derepress it, leading to enhanced responses to PD-L1 targeted therapy1. 
This principle was recently demonstrated in patient samples by Genentech44. Thus, MEK inhibition 
may have the greatest value in TP53-mutant ER+ breast tumors. 
We have published multiple preclinical models and mechanistic data demonstrating that MEK 
inhibition is synergistic with PD-1/PD-L1 inhibition45. In this work, we found that treatment with a 
MEK inhibitor upregulates antigen-presenting MHC-I and II molecules, both innate, and in 
response to interferon γ (IFNγ). Enhanced antigen presentation is likely to improve anti-tumor 
immunity through increase in T-cell recognition. Likewise, MEK inhibition sensitizes tumors to 
PD-L1 inhibition by unmasking the tumor from the immune system, leaving the PD-1/PD-L1 
interaction as the ‘gatekeeper’ of a full anti-tumor response (Fig. 2). 
 
Figure 2: Proposed mechanism of MEK 
inhibition in sensitizing TNBC to PD-L1 
inhibition. 
IFNγ 
secreted 
from 
activated 
immune cells in the tumor microenvironment 
stimulates expression of MHC-I and MHC-II via 
activation of STAT1, which increases antigen 
presentation 
thereby 
perpetuating 
immune 
activation. However, PD-L1 expression is also 
stimulated by the same pathway, promoting 
immune tolerance. The Ras/Raf/MEK pathway 
suppresses both of these signals, while MEK 
inhibition upregulates them. Co-treatment with a 
PD-L1 
inhibitor 
counteracts 
the 
immune 
evasion arm of this response. 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
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Additional 
beneficial 
immune- 
mediate mechanisms of action of 
MEK 
 inhibitors 
include 
downregulation of COX2 (PTGS2), 
which is an immediate early gene that 
is 
robustly 
modulated 
by 
the 
Ras/MAPK pathway. In the TCGA 
breast 
cancer 
data, 
COX2 
expression 
is 
tightly 
linked 
to 
Ras/MAPK transcriptional activity. 
Furthermore, inhibition of MEK in 
MDA-231 TNBC cell lines potently 
downregulates 
PTGS2 
gene 
expression 
while 
loss 
of 
the 
Ras/MAPK 
suppressor 
DUSP4 
upregulated PTGS2 (Fig 3). This 
finding is important because a recent 
study 
demonstrated 
 
that 
prostaglandin synthesis by COX-2 
from tumor cells can induce immune- 
evasion,       and       inhibition        of 
prostaglandin   synthesis  augmented  response  to   PD-1/PD-L1  therapy46. 
Thus,  although 
exploratory, these data suggest a possible 
additional immune-mechanistic effect of MEK 
inhibition in breast cancer. This effect can be 
explored in the context of molecular biomarker 
studies in the proposed trial herein. 
Collectively, these data suggest that MEK 
inhibition may upregulate the expression of 
antigen presenting molecules, aiding in CTL 
recognition of tumor cells. Additional beneficial 
effects on anti-tumor immunity likely include 
suppression of prostaglandin synthesis, and 
immune-independent effects of suppression of 
tumor cell proliferation. 
We already know from recently presented data 
that PD-1/PD-L1 axis inhibition is effective in a 
fraction of TNBC18,19 and ER+ tumors21. Although 
not confined to TNBC, PD-L1 expression is higher 
in basal-like and claudin-low breast cancers, which 
are often clinically triple-negative47-52, making this 
subtype an attractive target. In metastatic luminal- 
like ER+ disease, the potential for a breakthrough 
in therapy lies in our preclinical data demonstrating 
activity of the combination of MEK and PD-L1 
inhibition in two independent luminal-like breast 
cancer models (Fig. 4) with separate MEK 
inhibitors 
(trametinib 
and 
selumetinib) 
and 
separate   mAbs   targeting   PD-1   and    PD-L1, 
Figure 4: Preclinical activity. A) MEKi and PD-1 
therapy do NOT synergize in a T-cell deficient host 
(RAG 
-/-), 
but 
DO 
synergize 
in 
an 
immunocompetent host. C) In the luminal MMTV- 
neu model, MEK inhibition synergizes with PD-L1 
targeted therapy, and is required for anti-PD-L1 
activity in the presence of genetic MEK activation 
(MEKDD). Details of these studies can be found in 
ref1. 
Figure 
3: 
Role 
of 
MAPK 
pathway 
on 
COX2/PTGS2 
expression. Prostaglandin synthesis is rate-limited by PTGS2 
expression which is tightly controlled in breast cancer by MEK 
activation (A). In B, we show that loss of DUSP4, a frequent 
event in TNBC and some ER+ tumors which activates MEK, 
upregulates PTGS2 gene expression, while MEK inhibition 
reduces it. C) Mass-spec analysis demonstrates loss of DUSP4 
enhances, 
while 
MEK 
(or 
COX2) 
inhibition 
decreases 
prostaglandin E2 secretion into conditioned 
media. 


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respectively. Thus, this activity is a class-effect since different agents were used with similar 
results1. These data have been independently reproduced in a variety of other solid tumor 
models53. Furthermore, preliminary clinical data presented at ASCO 2016 showed that patients 
with microsatellite-stable colorectal cancer achieved a 20% response rate44 with dual MEK and 
PD-L1 inhibition, compared to a near 0% response rate in previous studies with single agents 
targeting the PD-1/PD-L1 interaction15,54. The significance of the activity of this combination has 
prompted Genentech to proceed directly to a Phase III (NCT02788279) trial, without a Phase II, 
in patients with metastatic colorectal cancer. Thus, the breadth of existing preclinical data and the 
timing are highly supportive for this trial. 
 
3.4. Senescence in cancer therapy 
CD8+ T-cell marker expression correlates with expression of CXCL9 and CCL5 chemokines, and 
high CXCL9 and CCL5 expression correlates with enhanced survival based on TCGA analysis of 
1105 invasive breast cancers41,42. Therapies that induce senescence would activate NF-κB and 
recruit CD45+ immune cells, which is accompanied by enhanced production of T-cell recruiting 
chemokines CCL5, CXCL9, and CXCL11 (Fig. 5). 
 
TP53 is the most highly mutated gene in breast cancer as a whole. Functionally, TP53 mutations 
uncouple p53 protein from its natural negative regulator MDM2, but also inhibit or alter its ability 
to induce apoptosis or senescence55. MDM2 antagonists (such as nutlin or Idasanutlin) de- 
repress wild-type (wt)-p53, but not mutant p53, and prevent the ubiquitination and proteosomal 
degradation of wt-p53. This effect allows wt-p53-mediated senescence programs (Fig. 6). While 
senescence is not a preferred therapeutic outcome, as it does not eliminate cancer cells, the 
innate senescence program (termed Senescence-Associated Secretory Program [SASP]) 
recruits immune cells through secretion of T cell homing chemokines (i.e. CCL5, CXCL-9,11, and 
13 et al)56. Thus, we hypothesize that the TME of wt-p53 tumors can be enhanced by MDM2 
antagonists. 
 
 
 
 
 
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Figure 5: Senescence and T cell recruitment. (Left) Senescence-associated 
T cell recruiting cytokines CXCL9 and CCL5 are strongly correlated with the 
expression of CD8A in the tumor microenvironment across >1000 breast 
cancers (TCGA,
41,42). (Right) Patients with high expression of these cytokines 
have improved outcomes. 


Do not disclose or use except as authorized 
 
p53-wildtype 
p53- mutant 
igure  6: p53  mediated  senescence programs. Left) I 
p53 wt tumors, Idasanutlin treatment   will 
disengage and activate p5 mediated senescence transcriptional programs leading to upregulation of 
ell chemokines, and the recruitment of T cells to the tumor microenvironment.   (Right)    In p53 mutant
umors, MDM2 antagonism will be largely ineffective, as mutated p53 will not engage MDM2.  However, 
p53 mutated ER+ tumors are more likely to demonstrate luminal B like behavior, which is partiall 
haracterized by loss of Ras/MAPK negative regulator 
33,43
In these tumors, inability to present antigen, 
ather than T cell recruitment, appears to be the limiting factor. MEK activation suppresses antige 
presentation, while MEK inhibition (i.e. Cobimetinib) can d 
epress it, leading to enhanced responses to
PD L1 target 
therapy
This principle was recently demonstrated in patient samples by Genentec 
44
BRE 17107: Atezolizumab, ldasanutlin and Cobimetinib in metastatic ER+ breast cancer 
Protocol Chair:  lngrid Mayer 
 
 
 
3.5. Clinical Trial Rationale 
Immune checkpoint inhibitors therapy in ER+ breast cancer has not been encouraging thus    
far. However, strategically combining molecularly-targeted agents that may increase immune 
recognition of tumor cells through enhanced antigen presentation and/or increase T cell homing 
may increase ICI response. This clinical trial will examine these different strategies in a genotype- 
specific (mutually exclusive and across all ER+ breast cancers) manner: 
 MEK inhibition (MEKi) in TP53-mutant ER+ breast cancer: ER+ tumors with MAPK pathway 
activation exhibit metastatic phenotypes of luminal B (more often TP53-mutated) disease. In 
luminal-like breast cancer models, a combination of MEKi and PD-1/PD-L1 ICI induces 
profound anti-tumor effects, in part by blocking na"ve CD8+ T cell priming, increasing 
neoantigen-specific CD8+ T effector cells in the tumor microenvironment (TME), and by 
protecting CD8+TIL cytotoxicity through inhibition of apoptosis driven by chronic TCR 
stimulation. 
 MDM2 antagonism in TP53-wt ER+ breast cancer: MDM2 antagonists both de-repress wt- 
p53, not mutant p53 and prevent proteosomal degradation of TP53-wt allowing wt-p53 to 
activate its transcriptional program of senescence (termed Senescence-Associated Secretory 
Program [SASP]) The SASP recruits immune cells through secretion of T cell homing 
chemokines. 
We hypothesize that approaches which enhance antigen presentation (MHC-I/II) or PD-L1 
through MEK inhibition, or enhance expression of T-cell recruiting chemokines via MDM2 
inhibition, will increase activated tumor-specific CD8+ T cells in the TME and augment the efficacy 
of the anti-PD-L1 mAb Atezolizumab in ER+ mBC. 
 
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5 wildtype 
5 
Figure 6: p53 mediated senescence programs. (Left) In p53-wt tumors, Idasanutlin treatment will 
disengage and activate p53-mediated senescence transcriptional programs leading to upregulation of T- 
cell chemokines, and the recruitment of T cells to the tumor microenvironment. (Right) In p53-mutant 
tumors, MDM2 antagonism will be largely ineffective, as mutated p53 will not engage MDM2. However, 
p53-mutated ER+ tumors are more likely to demonstrate luminal B like behavior, which is partially 
characterized by loss of Ras/MAPK negative regulators
33,43. In these tumors, inability to present antigen, 
rather than T cell recruitment, appears to be the limiting factor. MEK activation suppresses antigen 
presentation, while MEK inhibition (i.e. Cobimetinib) can de-repress it, leading to enhanced responses to 
PD-L1 targeted therapy
1. This principle was recently demonstrated in patient samples by Genentech
44. 


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Correlative studies using tumor tissue and blood will determine whether the respective 
molecularly-targeted agent enhances CD8+ T cells in the tumor microenvironment, enhances 
antigen presentation, and/or increases T cell homing chemokines. These molecular endpoints 
will be tested for their association with patient-specific clinical outcome. If these strategies indeed 
modify the tumor microenvironment as predicted, we may turn immune-unresponsive tumors like 
ER+BC into immune-responsive to anti-PD-L1 therapies. This would have major implications on 
the use of anti-PD-L1 in other “cold” solid tumors as well, by defining one or more approaches to 
turn “non-inflamed into inflamed tumors”. Thus, the breadth of existing preclinical data and the 
timing are highly supportive for this trial. 
 
3.6. Correlative Science Background 
A number of correlatives for response to immunotherapies have been proposed using 
retrospective data analyses, but almost none of them have been conclusively shown to associate 
with PD-1/PD-L1 targeted therapy response in well-controlled clinical trials to date, including PD- 
L1. Other proposed biomarkers have been tumor infiltrating lymphocytes (TILs)57,58, CD8+ T 
cells59, mutation burden60, neoantigen burden61-63. It will be important to collect these data to 
determine their utility in breast cancer patients, and how combinations of molecularly-targeted 
therapies affect these correlatives. 
MEK signaling pathway. Our previous preclinical studies have clearly demonstrated a connection 
between enhanced MHC-I/MHC-II and PD-L1 expression following MEK inhibition and improved 
response to anti-PD-L1 immunotherapy1. Furthermore, in melanoma, we have demonstrated an 
association between MHC-II expression and clinical outcome including objective response, 
progression-free survival, and overall survival64. This finding has now been confirmed in over 100 
clinical specimens. MEK inhibition sensitizes tumors to PD-L1 inhibition by upregulating MHC-I 
and MHC-II antigen presentation while leaving the PD-1/PD-L1 interaction as the ‘gatekeeper’ of 
a full anti-tumor response. Upregulation of CD8, MHC-I, and PD-L1 was observed with 
cobimetinib in Phase I-treated colorectal cancer patients44. Thus, we have reason to hypothesize 
that MEK inhibition will alter the expression of MHC-I and II, and that this will be correlated to 
clinical response in patients. 
Senescence-associated transcriptional programs. The work of our colleagues65-67 have 
demonstrated that senescence-associated cytokines can recruit T cells to the tumor 
microenvironment and facilitate T cell responses. This program can in part be activated by 
senesence-inducing therapies that stabilize p53. Nutlin, or idasanutlin (MDM2 antagonsts) are 
an effective way to activate senescence-associated transcriptional programs. Thus, our 
correlatives in the Idasanutlin arm will be aimed at ascertaining whether Idasanutlin activates 
these transcriptional programs in p53-wildtype tumors, whether this associates with increased T 
cell homing, and finally, whether these effects correlate with patient response. 
 
3.6.1.   Proposed Correlative Studies 
Tissue and blood 
The comprehensive correlative studies proposed within this trial were designed to provide further 
understanding of both tumor and immune factors that predict response or resistance. Our main 
goals are to determine the therapeutic predictive role of the biomarkers proposed on clinical 
outcome, and to determine if the cfDNA results will discriminate pseudoprogression from true 
progression. Results will be compared before and after single agent therapy, and immune cell 
phenotyping in blood will be evaluated during therapy. The following correlative studies will be 
included: 
1. TIL analysis from H&E 


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2. CD8, CD4, Foxp3, PD-L1, MHC-I and II expression via multiplexed IHC 
3. DNA exomes: to identify neoantigens, neoantigen load and mutations/copy number 
changes. 
4. HLA haplotyping for neoantigen prediction 
5. RNA-seq: to identify gene expression patterns for the following purposes: 
a. Molecular subtype (PAM50) 
b. MEK activation signatures68 
c. Immune cell composition by CIBERSORT69 
d. SASP gene expression profile (CCL5, CXCL9,10,11,13) 
e. Expression level of potential neoantigens 
6. CyTOF for T cell subsets in peripheral blood 
7. Collection of plasma for future cfDNA based analyses. 
 
We expect Cobimetinib treatment to result in the following changes in paired tumor biopsies: 
 DECREASE in MEK activation signature (transcriptionally defined68), demonstrating on-target 
pharmacodynamics activity of Cobimetinib. This will be performed as we have previously 
published1,32,70. A paired T-test (or non-parametric equivalent) will be used to test the 
hypothesis. 
 INCREASE in TILs, CD8,CD4, PD-L1, MHC-I and MHC-II IHC expression, which we expect 
will also be associated with a higher likelihood of response. A paired T-test (or non-parametric 
equivalent) in patients WITH clinical benefit versus patients WITHOUT clinical benefit will be 
used. 
• 
INCREASE in IFNγ-response transcriptional signatures71, which is a marker of both the 
activity of the local immune environment, and a marker of the robustness of the tumor 
response to IFNγ. 
 DECREASE in PTGS2 mRNA expression and transcriptional signatures46 
 EXPANSION of effector T cell compartments in the peripheral blood (CyTOF) which we expect 
will also be associated with a higher likelihood of response. 
 
We expect Idasanutlin treatment to result in the following changes in paired tumor biopsies: 
 INCREASE in mRNA expression of CCL5, CXCL9, CXCL10, CXCL11, CXCL13. A paired T- 
test (or non-parametric equivalent) in patients WITH clinical benefit versus patients WITHOUT 
clinical benefit will be used. We will correct for multiple comparisons with a Bonferroni 
adjustment. 
 INCREASE in mRNA expression of SASP/SIRS and senescence-associated markers 
 INCREASE in TILs, CD8, and CD4 IHC expression, which we expect will also be associated 
with a higher likelihood of response. A paired T-test (or non-parametric equivalent) in patients 
WITH clinical benefit versus patients WITHOUT clinical benefit will be used. 
 
At PRE-Bx or POST-Bx, we expect the following associations in both arms (Cobimetinib and 
Idasanutlin): 
 HIGHER expression of mutations AND/OR predicted neoantigens to be associated with 
higher likelihood of response, as analyzed by a 2-sample one-tailed T-test in patients WITH 
clinical benefit versus patients WITHOUT clinical benefit. 


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3.7. Investigational Agents 
 
3.7.1 Cobimetinib 
Cobimetinib (GDC-0973) is a potent and highly selective inhibitor of MEK1/2, which is a MAPK 
kinase that activates ERK1/2. Inhibition of the RAS/RAF/MEK/ERK pathway affects tumor-cell 
proliferation and survival. Cobimetinib is a next-generation inhibitor of MEK1/2 with the previous 
generation represented by the comparator compound PD0325901 (PD901; Pfizer). Observations 
from the clinical experience with PD032590172 indicate a significant occurrence of AEs in the 
central nervous system (CNS) that may be mechanistically related to the RAS/RAF/MEK/ERK 
signaling pathway in the brain. Therefore, Cobimetinib was selected for possessing anti-tumor 
activity while sparing significant brain exposure. 
Cobimetinib is currently approved, in combination with vemurafenib as a treatment for adult 
patients with unresectable or metastatic BRAFV600 mutation−positive melanoma who have been 
diagnosed with the cobas 4800 BRAF V600 Mutation Test in a number of countries worldwide, 
including the United States, Canada, members of the European Union, and several other 
countries worldwide. 
 
3.7.1.1 Clinical experience with Cobimetinib 
Please refer to Cobimetinib Investigator’s Brochure for full safety profile of cobimetinib. Study 
MEK4592g is a multicenter, Phase I, non-randomized, open-label, dose-escalation study. The 
study consisted of five treatment stages: 
 Stage I: Dose-escalation cohorts; patients were treated on a 21 days on, 7 days off (21/7) 
schedule to determine the maximal tolerated dose (MTD). The MTD for the 21/7 schedule 
was found to be 60 mg. 
 Stage IA: Dose-escalation cohorts; patients were treated on a 14 days on, 14 days off (14/14) 
schedule to determine the MTD on an alternate dosing regimen. The MTD for the 14/14 
schedule was found to be 100 mg. 
• 
Stage II: Expansion cohort with the MTD determined in Stage I (60 mg qd 21/7) in 
approximately 20 patients using fluorodeoxyglucose Positron Emission Tomography (FDG- 
PET) scans of avid tumors that harbored a BRAF, NRAS, or KRAS mutation and with FDG- 
PET−avid disease. 
• 
Stage IIA: Expansion cohort with the MTD determined in Stage IA (100 mg qd 14/14) in 
approximately 20 patients with FDG-PET−avid tumors that harbored a BRAF, NRAS, or KRAS 
mutation. 
 Stage III: A dedicated DDI study at the MTD determined in Stage I (60 mg qd 21/7) in 
approximately 20 patients with solid tumors. 
The primary objectives of Stages I, IA, II, and IIA of this study were to evaluate the safety and 
tolerability of Cobimetinib administered orally as repeated doses in patients with solid tumors and 
to determine the MTD of daily oral administration of Cobimetinib in patients with solid tumors. The 
primary objective of Stage III of this study was to evaluate the possible effect of Cobimetinib on 
the pharmacokinetics of dextromethorphan and midazolam. Study MEK4592g has been 
completed; a total of 115 subjects were treated. 
 
3.7.1.2 Dose-Limiting Toxicities 
Four DLTs were observed in Stage I (21/7 dosing schedule) of Study MEK4592g. At the 40-mg 
dose level, a DLT of Grade 4 hepatic encephalopathy was reported, which resolved following 
lactulose therapy, routine supportive care, and discontinuation of Cobimetinib. At the 60-mg dose 


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level, a DLT of Grade 3 rash was reported that improved with skin toxicity management and drug 
holiday. At the 80-mg dose level, two DLTs were reported: Grade 3 diarrhea despite treatment 
with anti-diarrheal medications and Grade 3 rash. Two DLTs were observed in Stage IA (14/14 
dosing schedule) of Study MEK4592g. At the 125-mg dose level, 1 patient had Grade 3 rash and 
another had Grade 3 blurred vision associated with neurosensory detachment of the retina. 
 
3.7.1.3 Adverse Events 
All patients in Study MEK4592g experienced an adverse event. The most frequent adverse events 
were diarrhea (67.0%), fatigue (50.4%), rash (49.6%), nausea and vomiting (33.9% each), and 
edema peripheral (28.7%). Other events that occurred in≥10% of patients included anemia, 
abdominal pain, constipation, hypokalemia, decreased appetite, headache, dizziness, back pain, 
increased AST, dermatitis acneiform, pruritus, and dry skin. Among the patients who received 
Cobimetinib 60 mg qd 21/7, the most frequent treatment-emergent adverse events were diarrhea 
(64.4%),  rash  (53.3%),  fatigue  (48.9%),  nausea  and  edema  peripheral  (31.1%  each), and 
vomiting (28.9%). 
Among all Cobimetinib-treated patients, 5 patients (4.3%) experienced a Grade 4 adverse event, 
and 53 patients (46.1%) experienced a Grade 3 adverse event. The most frequent Grade 3 and 
Grade 4 adverse events were hyponatremia (9.6%), fatigue (8.7%), anemia (7.8%), diarrhea, and 
hypokalemia (6.1% each). Grade 5 adverse events, which in Study MEK4592g included disease 
progression reported as an adverse event, are discussed separately below. 
 
3.7.1.4 Serious Adverse Events 
A total of 49 patients (42.6%) experienced a serious adverse event. The most common types of 
serious adverse events were gastrointestinal disorders (n = 17), but there were no trends in 
specific preferred terms. The gastrointestinal serious adverse events, such as intestinal 
obstructions and gastrointestinal hemorrhages, occurred in patients with gastrointestinal 
malignancies. Serious adverse events reported for ≥ 2 patients among all patients in the study 
were anemia, bile duct obstruction, dehydration, syncope, and respiratory arrest (3 patients each 
[2.6%]). 
 
3.7.1.5 Deaths 
Study MEK4592g accrued a patient population with metastatic or unresectable solid tumors for 
which standard curative or palliative measures did not exist or were no longer effective. In 
addition, in Study MEK4592g disease progression was reported as an adverse event (Grade 5) 
instead of an outcome measure. 
As of the clinical data cutoff date (20 September 2013), a total of 29 patients (25.2%) had died, 
including 11 patients in the Cobimetinib 60 mg qd 21/7 group. 
A total of 14 deaths were reported for patients treated in Stage I of the study. With the exception 
of 1 patient who died of cardiopulmonary arrest secondary to progressive disease, all deaths in 
Stage I occurred because of progressive disease, and no death was considered by the 
investigator to be related to the study drug. 
During Stages IA, II, and IIA of the study, 12 deaths were reported, all of which occurred ≥30 days 
after the last dose of study drug. Of these, 2 deaths were considered by the investigator to be 
possibly related to study drug. In both cases, the investigator considered the metastatic cancer to 
be a contributing etiologic factor to the patient’s death. 


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Three deaths were reported in Stage III of this study. None of the deaths were assessed by the 
investigator as treatment related. Other etiologic factors that contributed to the deaths included 
the patients’ underlying diseases and malignant tumor progression. 
 
3.7.1.6 Clinical Efficacy 
Assessment of responses was an exploratory endpoint in Study MEK4592g. Best overall 
response was assessed for 74 of 97 patients in Stages I, IA, II and IIA of the study who had 
measurable lesions and at least 1 post-baseline tumor assessment. Overall, 6 patients (all of 
whom had melanoma; 6.2%) had a confirmed partial response, 28 patients (28.9%) had stable 
disease, and 40 patients (41.2%) had progressive disease. Twenty-three patients had non- 
measurable lesions or measurable lesions with no post-baseline tumor assessments. 
In Stage III of Study MEK4592g, 18 patients were accrued. Best overall response was assessed 
for 14 of 18 patients in Stage III with measurable lesions and at least 1 post-baseline tumor 
assessment. Overall, 4 patients (22.2%) had stable disease as their best overall response, 8 
patients (44.4%) had disease progression, and 2 patients (11.1%) had unconfirmed tumor 
response. 
 
3.7.1.7 Rationale for Cobimetinib and Atezolizumab Dosing 
A recent phase Ib dose escalation trial combining Cobimetinib and Atezolizumab in patients with 
advanced solid tumors was conducted (NCT01988896)44. No dose-limiting toxicities were 
observed, and expansion occurred at Atezolizumab 800 mg q2w and Cobimetinib 60 mg. The 
most common treatment-related adverse events included diarrhea (69.6%), fatigue (52.2%), 
dermatitis acneiform (43.5%), rash (34.8%), maculopapular rash (26.1%), pruritus (26.1%) and 
nausea (26.1%). Incidence of treatment-related G3-4 adverse events was 34.8%. The only 
treatment-related G3-4 adverse event in ≥ 2 pts was diarrhea (8.7%). No G5 adverse events were 
reported. Results from the serial biopsy cohort showed enhanced PD-L1 upregulation, CD8 T-cell 
infiltration and MHC I expression while on treatment, providing mechanistic rationale for the 
combination. Responses were not associated with baseline PD-L1 expression. 
Currently, a phase III, multicenter, open-label, three-arm, randomized study of regorafenib versus 
Cobimetinib plus Atezolizumab versus Atezolizumab monotherapy has been initiated in 
participants with unresectable locally advanced or metastatic colorectal cancer who have received 
at least two prior regimens of cytotoxic chemotherapy for metastatic disease (NCT02788279). 
Because Atezolizumab is formulated at a concentration of 60 mg/mL, 800 mg corresponds to a 
volume of 13.33 mL. In the interest of simplifying administration, the exact dose being used on all 
studies moving forward will be 840 mg, corresponding to a volume of 14 mL, which can be 
accurately administered with a single seringe. The 840 mg dose is not expected to result in 
meaningful different exposures compared to the 800 mg dose. 
 
3.7.2 Idasanutlin 
The tumor suppressor protein 53 (p53) is a powerful growth suppressive and pro-apoptotic protein 
that plays a central role in protection from tumor development and is frequently inactivated in 
human cancer. Some tumors overproduce the negative p53 regulator, murine double minute 2 
(MDM2), to disable its function. Idasanutlin (RO5503781) is a selective inhibitor of the p53-MDM2 
binding that frees p53 from negative control and activates the p53 pathway in cancer cells, which 
leads to cell cycle arrest and apoptosis in vitro and in vivo. In view of the existing unmet medical 
need in advanced cancers and the frequency of p53/MDM2 pathway abnormalities in cancer, 
idasanutlin represents a first-in-class MDM2 antagonist anticancer therapy with a unique 
mechanism of action and is believed to be a promising agent that may offer a new therapeutic 


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option. 
 
3.7.2.1 Clinical Experience with Idasanutlin 
Two Phase I studies in patients with solid tumors (Studies NP27872 and NP28902) and a Phase 
I/Ib study of idasanutlin monotherapy or combination therapy with cytarabine in AML patients 
(Study NP28679) are complete. A Phase Ib/II study in combination with venetoclax in AML 
patients (Study GH29914), and a Phase III study in patients with AML (Study WO29519) are 
ongoing. In addition, a Phase Ib/II study (Study BH29812) in combination with obinutuzumab in 
patients with relapsed or refractory follicular lymphoma (FL) and in combination with 
obinutuzumab or rituximab in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and 
a Phase Ib/II study (BH39147) evaluating the safety and efficacy of obinutuzumab in combination 
with idasanutlin and venetoclax in patients with relapsed or refractory FL and obinutuzumab or 
rituximab in combination with idasanutlin and venetoclax in patients with relapsed or refractory 
DLBCL are ongoing. Another Phase I Study NP29910 investigating the excretion balance, PK, 
metabolism and absolute oral bioavailability of a single oral dose of [14C]- labeled idasanutlin and 
an intravenous tracer dose of [13C]-labeled idasanutlin in a single cohort of patients with solid 
tumors has completed enrollment and is undergoing clinical study report preparation. 
 
3.7.2.2 Clinical Safety in Solid Tumors 
A total of 168 patients with advanced malignancies (excluding leukemia) received idasanutlin in 
Study NP27872 (99 patients), Study NP28902 (61 patients) and Study NP29910 (8 patients). All 
patients in Study NP27872 experienced at least one adverse event (AE), with diarrhoea, nausea, 
vomiting, decreased appetite, and thrombocytopenia being the most frequent. Grade 3−5 AEs 
were reported in 63.6% of patients treated with idasanutlin in Study NP27872, most commonly 
within the system organ classes (SOCs) of blood and lymphatic system disorders, gastrointestinal 
disorders, and metabolism and nutrition disorders. In Study NP28902, the five most frequent AEs 
reported were diarrhoea, nausea, vomiting, fatigue, and constipation. In this study, 
gastrointestinal events were the most common related AEs across all these treatment groups. In 
study NP29910, the most frequent AEs of any grade of gastrointestinal disorders were vomiting, 
diarrhoea, nausea, and constipation; and general disorders and administration site conditions 
were pain and pyrexia. Grade 3-5 AEs were supraventricular tachycardia, jaundice, sepsis, and 
hypertonia. Serious adverse events (SAEs) were reported in 32.3% of patients in Study NP27872, 
most commonly thrombocytopenia, febrile neutropenia, neutropenia, anaemia, and leukopenia. 
SAEs were reported in 21.3% of patients in Study NP28902, most commonly pyrexia and cellulitis. 
One SAE (Sepsis) was reported in 1 of 8 patients (12.5%) in Study NP29910. Seven patients died 
in Study NP27872, 3 patients died in 
Study NP28902, and 2 patients died in Study NP29910. Of the 7 deaths reported in Study 
NP27872, 5 were attributed to disease progression, one was due to intra-abdominal haemorrhage 
with pulmonary embolism (considered unrelated), and one was due to pulmonary embolism 
(remotely related). In Study NP28902, the cause of death for 2 patients was disease progression. 
The cause of death for the other patient in Study NP28902 was pneumonia aspiration, considered 
unrelated to study drug. In Study NP29910, the cause of death for both patients was disease 
progression. 
 
3.7.2.3 Dose-Limiting Toxicities 
In Study NP27872, 31 dose-limiting toxicity (DLT) AEs were reported and 21 of 99 patients 
(21.2%) experienced at least one DLT AE. The SOCs affected by DLT AEs were blood and 
lymphatic system disorders (19 patients, 19.2%), gastrointestinal disorders (3 patients, 3%), and 
investigations (1 patient, 1%).  The most frequently reported DLT AE was thrombocytopenia   or 


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platelet count decreased (17 patients, 17.2%). Additionally, neutropenia (5 patients, 5.1%), 
febrile neutropenia (3 patients, 3.0%), and nausea (2 patients, 2%) were reported. Three of thirty- 
six patients (8.3%) on the weekly schedule experienced DLT AEs, whereas 6 of 15 patients (40%) 
and 11 of 34 patients (32%) on the daily schedules for 3 days and 5 days, respectively, 
experienced DLT AEs. DLTs from the blood and lymphatic system disorder were more frequently 
reported with the daily dosing schedules than with the weekly dosing schedule. DLTs were not 
assessed in Study NP28902 and Study NP29910. 
 
3.7.2.4 Adverse Events 
In Study NP27872, 1432 AEs were reported by 99 patients enrolled in the study. The five most 
frequent AEs of any grade were diarrhoea, nausea, vomiting, decreased appetite, and 
thrombocytopenia. Overall, 976 of 1432 AEs were considered by the investigator to be related 
to idasanutlin, and all patients (100%) experienced at least one AE. Grade 3-5 AEs were reported 
in 63 of 99 patients (63.6%), and the most frequent SOCs affected were blood and lymphatic 
system disorders, gastrointestinal disorders, and metabolism and nutrition disorders. Overall, 
137 of 193 AEs with Grade ≥ 3 were considered by the investigator to be related to idasanutlin. 
Among the AEs of Grade ≥ 3, platelet count decrease was reported in 4 patients (4%), 
thrombocytopenia was reported in 29 patients (29.3%), neutrophil count decrease was reported 
in 5 patients (5.1%), and neutropenia was reported in 16 patients (16.2%). Two Grade 5 events 
were reported in a patient in the dose-escalation cohort who received QW dosing for 3 weeks 
(intra- abdominal haemorrhage with pulmonary embolism) and a patient in the biomarker cohort 
who received daily dosing for 5 days (pulmonary embolism). 
In Study NP28902, 374 AEs were reported by 61 patients enrolled in the study. The five most 
frequent AEs of any grades reported by the patients were diarrhoea, nausea, vomiting, fatigue, 
and constipation. Overall, 194 of 374 AEs were considered by the investigators to be related to 
study drug. Grade 3-5 AEs were reported in 21 of 61 patients (34.4%), and the most frequent 
SOCs affected were infections and infestations, metabolism and nutrition disorders, blood and 
lymphatic system disorders, and gastrointestinal disorders. Among the AEs of Grade ≥ 3, platelet 
count decrease or thrombocytopenia were reported in 5 of 61 patients (8.2%) and neutrophil 
count decrease or neutropenia were reported in 3 of 61 patients (4.9%). One Grade 5 AE of 
aspiration pneumonia was reported in optional treatment extension part of this study. 
In Study NP29910, 40 AEs were reported by the 8 patients enrolled in the study as of 1 August 
2017. The most frequent AEs (≥2 patients) of any grade of SOC gastrointestinal disorders were 
vomiting, diarrhoea, nausea, and constipation; and SOC general disorders and administration 
site conditions were pain and pyrexia. Overall, 18 of 40 AEs were considered by the investigators 
to be related to study drug. Grade 3-5 AEs were reported in 4 of 8 patients (50%) as 
supraventricular tachycardia, jaundice, sepsis, and hypertonia. 
 
3.7.2.5 Serious Adverse Events and Deaths 
Seven patients died in Study NP27872, 3 patients died in Study NP28902 and 2 patients died in 
Study NP29910. In Study NP27872, the cause of death was disease progression for 5 patients; 
intra-abdominal haemorrhage with concurrent pulmonary embolism, considered unrelated to 
study drug for 1 patient; and pulmonary embolism, considered remotely related to study drug for 
1 patient. In Study NP28902, the cause of death was disease progression for 2 patients and 
pneumonia aspiration, considered unrelated to study drug for 1 patient. 
In Study NP27872, 53 SAEs were reported in total and 32 of 99 patients (32.3%) reported at least 
one SAE. The 5 most frequent SAEs were thrombocytopenia or platelet count decrease (14 
patients each, 14.1%), febrile neutropenia (5 patients, 5.1%), neutropenia or neutrophil count 
decrease (5 patients, 3%), leukopenia (2 patients, 2%), and anaemia (3 patients, 3%). Thirty-six 
SAEs (67.9%) were assessed as either remotely, possibly, or probably related to study treatment 
by the Investigator. Related SAEs were reported in a higher percentage of patients on Schedule 


BRE 17107: Atezolizumab, Idasanutlinand Cobimetinib inmetastatic ER+breast cancer 
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VAN   D E 1tn  1 LT  V 
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MliOICAI.. G ENT ER 
 
 
B who receivedtreatmendt aliy (7 of 15 patients, 46.7%, fordaliy dosni g for 3 days; 13 of 34 
patients, 38.2%, for daily dosing for 5 days, excluding the apoptosis-imaging cohort) than patients 
on Schedule A who received weekly treatment (4 of 36 patients, 11.1%, excluding the food-effect 
cohort). 
In Study NP28902, 15 SAEs were reported in total and 13 of 61 patients (21.3%) reported at least 
one SAE. The SAEs reported in D 1 patient were pyrexia (3 of 61 patients, 4.9%) and cellulitis (2 
of 61 patients, 3.3%). Three of the 15 SAEs (20.0%) were assessed as relatedto study treatment 
by the Investigator. These were thrombocytopenia, nausea, and dehydration. 
In Study NP29910, 1 SAE was reported in 1 of 8 patients (12.5%).The SAE was reported as 
sepsis and was assessed as unrelated to study treatment by the Investigator. 
 
3.7.2.6 Clinical Efficacy in Solid Tumors 
No patients with solid tumors achieved an objective responseaccording to Response Evaluation 
Criteria in Solid Tumors (RECIST) in Study NP27872 and Study NP28902. The best overall 
response was stable disease in both studies. In Study NP27872 30.6% of patients had stable 
disease as the best tumor response. The median overall duration of stable disease was 72.5 days 
with a wide range lasting from 8- 696 days. In Study NP28902, the combined rate of stable 
diseaseacross Part 1 to Part 3 was 41.1%. 
 
3.7.2.7 Dose rationale for this study 
Based on the new SDP formulation, all ongoing and future studies of idasanutlin will utilize the 
SDP formulation, which correspondsto 50% of the older MBP formulation. Therefore, the MTD 
for solid tumors on the 5 day schedule was 500 mg daily on the original formulation, and 250 mg 
of the current SDPformulation. Therefore, the doses tested in this study will range from 50 - 200 
mg from D1 - 5 of each 28-day cycle. 
 
3.7.3 
Atezolizumab 
Atezolizumab is a human immunoglobulin ( Jg) G 1 mo n o cl onal antibody consisting of two heavy 
chains (448 amino acids) and two light chains (214 amino acids) and is produced in Chinese 
hamster ovary cells. Atezolizumab was engineered to eliminate Fe-effector function via a single 
amino acid substitution  (asparagine to  alanine) at position 298 on the heavy chain,  which  results 
in a non-glycosylated antibody that has minimal binding to Fe receptors and preventsFe-effector 
function at expected concentrations in humans. Atezolizumab targets human programmed death­ 
ligand 1 (PD-L1) and inhibits its interaction with its receptor, programmed death-1 (PD-1). 
Atezolizumab also blocks the binding of PD-L1 to 87.1, an interaction that is reported to provide 
additional inhibitory signals to T cells. Atezolizumab is being investigated as a potential therapy 
against solid tumors and  hematologic malignancies  in humans. 
3.7.3.1 Clinical Experience with Atezolizumab 
Onging Clinical Studies 
Currentstudies of Atezolizumab include one ongoing Phase la monotherapy study, three ongoing 
combination studies, five Phase JI  stud  i es,   a n d  one  Phase Ill study.  Details of all ongoing studies 
can  be  found  in  the  Atezolizumab  Investigator's  Brochure. 
 
3.7.3.2 Clinical Safety 
For  further  details,  see  the  Atezolizumab  Investigator's  Brochure.   As  of  10  May    2016, 
 
 
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Atezolizumab has been administered to approximately 6053 patients with solid and hematologic 
malignancies. Safety findings of single-agent atezolizumab across multiple tumor types in the 
clinical development program are consistent with the known mechanism of action of atezolizumab 
and the underlying disease. Overall, treatment with atezolizumab is well tolerated, with a 
manageable adverse event profile. Currently, no maximum tolerated dose, no dose limiting 
toxicities, and no clear dose-related trends in the incidence of adverse events have been 
determined. Across all studies and tumor types, the most commonly reported adverse events with 
single-agent atezolizumab include fatigue, nausea, decreased appetite, diarrhea, constipation, 
and cough. 
 
3.7.3.3 Immune-Related Adverse Events 
Given the mechanism of action of Atezolizumab, events associated with inflammation and/or 
immune-mediated AEs have been closely monitored during the Atezolizumab clinical program. 
These include potential dermatologic, hepatic, endocrine, and respiratory events as well as events 
of hepatitis/elevated liver function tests (LFTs) and influenza-like illness. 
Immune-related adverse events are consistent with the role of the PD-L1/PD-1 pathway in 
regulating peripheral tolerance. Given the mechanism of action of atezolizumab, events 
associated with inflammation and/or immune-related adverse events are closely monitored during 
the atezolizumab clinical program. As of this IB update, immune-related adverse events 
associated with atezolizumab include hepatitis, pneumonitis, colitis, pancreatitis, diabetes 
mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré syndrome, 
myasthenic syndrome/myasthenia gravis, and meningoencephalitis. 
 
3.7.3.4 Clinical Activity in Patients with TNBC 
As of 2 September 2014, clinical activity analyses have been performed on 21 patients with PD- 
L1−selected (IC2/3) TNBC in Study PCD4989g who received Atezolizumab treatment by 21 July 
2014. Unconfirmed responses were recorded for 5 patients. Two of these patients experienced a 
complete response and 3 patients experienced a partial response. As of 2 September 2014, 4 of 
these 5 patients were still responding and 1 patient experienced disease progression. The median 
duration of response has not been reached. The Kaplan-Meier estimated overall 24-week PFS 
rate was 33% (95% CI: 12%, 53%). 
 
 
4. PARTICIPANT SELECTION 
 
4.1. Inclusion Criteria 
 
1. Signed and dated written informed consent. 
 
2. Subjects ≥ 18 years of age. 
 
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
 
4. Clinical stage IV invasive mammary carcinoma or unresectable locoregional recurrence 
of invasive mammary carcinoma that is: 
• 
ER/PR-positive (> 1% cells) by IHC and HER2 negative per ASCO guidelines (by IHC 
or FISH) 


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• 
Previously exposed to an aromatase inhibitor (AI) or a selective estrogen-receptor 
modulator/ downregulator (SERM; SERD) + a CDK4/6 inhibitor 
• 
Appropriate candidates for chemotherapy 
• 
Amenable to biopsy at the time of study entry 
 
5. Adequate organ function including: 
• 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
• 
Platelets ≥ 100 × 109/L 
• 
Hemoglobin ≥ 9/g/dL (may have been transfused) 
• 
Total serum bilirubin ≤ 1.5 times upper limit of normal (ULN) 
• 
Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) 
≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases are present) 
• 
Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 50 mL/min as 
calculated using the Cockcroft-Gault (CG) equation 
• 
Thyroid Stimulating Hormone (TSH) ≤ 1 x ULN 
• 
Amylase ≤ 1 x ULN 
• 
Lipase ≤ 1 x ULN 
• 
CPK ≤ 1.5 x ULN 
• 
LVEF (echo) ≥ LLN (Cobi arm only) 
 
6. Female patients of childbearing potential must agree to use at least two methods of 
acceptable contraception with a failure rate of < 1% per year from 15 days prior to first trial 
treatment administration until at least 5 months after study participant’s final dose of study 
drugs. See appendix C for details. 
Note: Females of childbearing potential are defined as those who are not surgically sterile 
or post-menopausal (i.e. patient has not had a bilateral tubal ligation, a bilateral 
oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 12 months 
without an alternative medical cause). Post-menopausal status in females under 55 years 
of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within 
laboratory reference range for postmenopausal women. 
 
7. Patients unable to read/write in English are eligible to participate in the overall study but 
will not participate in the Patient-Reported Outcome questionnaires throughout the trial 
 
8. Re-enrollment of a subject that has discontinued the study as a pre-treatment screen 
failure (i.e. a consented patient who did not receive study drugs) is permitted. If re- 
enrolled, the subject must be re-consented. Only the screening procedures performed 
outside of protocol-specified timing must be repeated. 


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4.2. Exclusion Criteria 
 
1. Prior therapy with anti-PD-L1 and anti-PD1 antibodies, MEK inhibitors or MDM2 
antagonists. 
 
2. No more than 3 lines of chemotherapy in the metastatic setting 
 
3. No concurrent anticancer therapy. Required washout from prior therapy: 
• 
Endocrine therapy: no required wash-out 
• 
Chemotherapy: 14 days 
• 
Major surgery: 14 days (provided wound healing is adequate) 
• 
Radiation: 7 days 
• 
Investigational/Biologic Therapy (half –life ≤ 40 hours): 14 days 
• 
Investigational/Biologic Therapy (half –life > 40 hours): 28 days 
• 
Use of corticosteroids or immunosuppressive medication is exclusionary, except the 
following in the absence of active autoimmune disease: 
o Subjects are permitted the use of corticosteroids with minimal systemic absorption 
(e.g. topical, ocular, intra-articular, intranasal, and inhaled); 
o Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or 
equivalent are permitted; 
o Adrenal replacement steroid doses including doses > 10 mg daily prednisone are 
permitted; 
o A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g. CT scan 
premedication against contrast dye allergy) or for treatment of non-autoimmune 
conditions (e.g. delayed-type hypersensitivity reaction caused by a contact 
allergen) is permitted. 
 
4. Previous malignant disease other than breast cancer within the last 5 years, with the 
exception of basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, or 
low-risk cancers considered curatively treated (i.e. complete remission achieved at least 
2 years prior to first dose of study drugs AND additional therapy not required while 
receiving study treatment). 
 
5. All subjects with brain metastases, except those meeting the following criteria: 
• 
Brain metastases that have been treated locally and are clinically stable for at least 2 
weeks prior to enrollment 
• 
No history of intracranial or spinal cord hemorrhage 
• 
No evidence of interim CNS disease progression 
• 
Metastasis to the midbrain, pons, and medulla 
• 
No ongoing neurological symptoms that are related to the brain localization of the 
disease (sequelae that are a consequence of the treatment of the brain metastases 
are acceptable. 
• 
Subjects must be either off steroids or on a stable or decreasing dose of ≤ 10 mg daily 
prednisone (or equivalent) 


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6. Receipt of any organ transplantation including allogeneic stem-cell transplantation. 
 
7. Significant acute or chronic infections including, among others: 
• 
Known history of testing positive for human immunodeficiency virus (HIV), or acquired 
immunodeficiency syndrome (AIDS). 
• 
Active tuberculosis 
• 
Positive test for hepatitis B virus (HBV) surface antigen (and/or core antibody) and/or 
confirmatory hepatitis C virus (HCV) RNA (if anti-HCV antibody tested positive). 
 
8. Active autoimmune disease with reasonable possibility of clinically significant 
deterioration when receiving an immunostimulatory agent: 
• 
Subjects with Type 1 diabetes mellitus, vitiligo, psoriasis, hypo- or hyperthyroid 
disease not requiring immunosuppressive treatment are eligible. 
• 
Subjects requiring hormone replacement with corticosteroids are eligible if the steroids 
are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg 
or 10 mg equivalent prednisone per day. 
• 
Administration of steroids through a route known to result in a minimal systemic 
exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable. 
 
9. Interstitial lung disease that is symptomatic or which may interfere with the detection or 
management of suspected drug-related pulmonary toxicity. 
 
10. Uncontrolled asthma [defined as having 3 or more of the following features of partially 
controlled asthma within 28 days prior to starting study treatment: Daytime symptoms 
more than twice per week, any limitation of activities, any nocturnal symptoms/awaking, 
need for reliever/rescue inhaler more than twice per week, or known lung function (PEF 
or FEV1) without administration of a bronchodilator that is < 80% predicted or personal 
best (if known)]. 
 
11. Current symptomatic congestive heart failure (New York Heart Association > class II), 
unstable cardiac arrhythmia requiring therapy (e.g. medication or pacemaker), unstable 
angina (e.g. new, worsening or persistent chest discomfort), or uncontrolled hypertension 
(systolic > 160 mmHg or diastolic > 100mmHg).  Or any of the following occurring  within 
6 months (180 days) prior to first dose of study drugs: Myocardial infarction, 
coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic 
attack.  (Use of antihypertensive medication to control blood pressure is allowed.) 
 
12. Concurrent treatment with a non-permitted drug (refer to prohibited medication list) as 
well as foods or supplements that are strong or moderate CYP3A4 enzyme inducers or 
inhibitors. Any of the above has to be discontinued at least 7 days prior to Cycle 1/ Day 1 
of study treatment. 
 
13. Requirement of anticoagulant therapy with oral vitamin K antagonists such as Coumadin 
(warfarin). Low-dose anticoagulants for the maintenance of patency in a central venous 
access device or the prevention of deep vein thrombosis or pulmonary embolism is 


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allowed. Therapeutic use of low molecular weight heparin is allowed provided patients 
are safely able to interrupt it prior to biopsy procedures. 
 
14. Persisting toxicity related to prior therapy that has not reduced to Grade 1 [National Cancer 
Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5.0]; 
however, alopecia and sensory neuropathy Grade ≤ 2 are acceptable and Grade ≤ 2 non- 
hematological toxicities well controlled with medical management are allowed (for 
example: hypomagnesemia well controlled on magnesium replacement). 
 
15. Known severe (Grade ≥ 3 NCI-CTCAE) hypersensitivity reactions to monoclonal 
antibodies, or history of anaphylaxis. 
 
16. Vaccination within 28 days of the first dose of study drugs and while on trial is prohibited, 
except for administration of inactivated vaccines (for example, inactivated influenza 
vaccine). 
 
17. Pregnant or breastfeeding females. 
 
18. Known current alcohol or drug abuse 
 
19. Prisoners or subjects who are involuntarily incarcerated. 
 
20. Known psychiatric condition, social circumstance, or other medical condition reasonably 
judged by the patient’s study physician to unacceptably increase the risk of study 
participation; or to prohibit the understanding or rendering of informed consent or 
anticipated compliance with scheduled visits, treatment schedule, laboratory tests and 
other study requirements. 
 
21. Known risk factors for ocular toxicity, consisting of any of the following (Cobi arm only): 
• 
presence of serous retinopathy within 6 months of protocol enrollment 
• 
presence of retinal vein occlusion (RVO) within 6 months of protocol enrollment 
 
4.3. Inclusion of Underrepresented Populations 
Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards 
age or race in the clinical trial outlined. 
 
 
5. REGISTRATION PROCEDURES 
 
5.1. Guidelines for VICC and Participating Institutions 
Prior to registration, a copy of the IRB approval at the site will be requested and kept on file at the 
Vanderbilt-Ingram Cancer Center (VICC) Coordinating Center. Eligible participants will be 
entered on study centrally at the VICC Coordinating Center. All sites should email the 
Coordinating Center at coordinating.center@vumc.org to verify treatment availability prior 
to enrollment. 
All patients MUST be registered with the VICC prior to the start of protocol treatment. 
Registration can only be conducted during the business hours of 8AM – 5PM Monday 
through Friday. 


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1) All sites should email the VICC CTSR Coordinating Center at 
coordinating.center@vumc.org to notify of upcoming registration and slot 
availability. 
2) If a subject ID number is required prior to patient enrollment (i.e. screening tissue to be 
collected), the site must submit the following documents with their email notification to the 
Coordinating Center: 
• 
Copy of the patient’s signed and dated Informed Consent including 
documentation of the consent process. 
• 
HIPAA authorization form (if separate from the main consent form) 
• 
VICC Patient Enrollment Form 
The Coordinating Center will then provide a subject ID number via email. 
3) After following your site’s eligibility verification procedures, email the following documents to 
the VICC Coordinating Center for sponsor eligibility review and patient enrollment 
(coordinating.center@vumc.org): 
• 
Copy of the patient’s signed and dated Informed Consent, including 
documentation of the consent process. 
• 
HIPAA authorization form (if separate from the main consent form) 
• 
VICC Patient Enrollment Form 
• 
Copies of laboratory, imaging and pathology reports 
• 
Tissue Block Registration Form (see the Lab  Manual) 
• 
Completed Eligibility Checklist, including all supporting source documents. To be 
eligible for registration to the study, the participant must meet each 
inclusion and exclusion criterion listed in the eligibility checklist. 
 
 
Note: VICC Coordinating Center requests 24-48 hours to review all documents and confirm 
eligibility. Same day treatment registrations will only be accepted with prior notice and 
discussion with the Coordinating Center. Please email the Coordinating Center if enrollment 
is needed sooner. 
Once registration/enrollment confirmation from Coordinating Center is received, proceed with 
protocol procedures. 
Please contact the assigned Project Manager or Regulatory Coordinator with any questions 
regarding this process. You can also reach out to your assigned CRA once the study is activated. 
The VICC Coordinating Center will assign sequence numbers to all patients in screening. Only 
patients deemed eligible will be registered to investigational treatment. Sequence numbers will 
not be re-used if a patient screen fails unless the same patient re-screens at a later point. 
Following registration, eligible participants should begin study treatment consistent with the 
protocol no later than 3 weeks after registration/enrollment by the VICC Coordinating Center. If a 
participant does not receive protocol therapy following registration within the allowed time period 
(2 weeks), the participant’s registration on the study may be canceled. The assigned CRA should 
be notified of cancellations as soon as possible. 


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Issues that would cause treatment delays should be discussed with the Protocol Chair. If a 
participant does not receive protocol therapy following enrollment within allowed time period (2 
weeks), the participant will become ineligible and will be removed from the study. Such patients 
will have to undergo re-screening in order to participate in the study. 
As is generally accepted, standard of care procedures performed prior to consent, but within the 
protocol defined screening window for each assessment, can be used for study purposes. All 
research-only procedures must be performed after the consent date. 


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6. STUDY CALENDAR 
Parameter 
Pre- 
Treatment1 
Week/Cycle 
End of 
Treatment6 
C1 
D1 
C1D8 
C1 
D15 
C1 
D1,8, 
15, 2212 
C2 
D1 
C2 
D15 
C3D1 
D1 
Every 
Cycle 
D15 
Every 
Cycle 
Day 1 of Every 
Odd Cycle 
except Cycle  
1 
Every 12 
weeks from 
C2D1 
onwards 
Demographics 
X 
CLINICAL EVALUATIONS: 
History and Physical 
X 
X 
X12 
X 
X 
Height 
X 
Vital signs and Weight3 
X 
X 
X12 
X 
X 
X 
Performance status 
X 
X 
X12 
X 
X 
Ophthalmologic 
evaluation11 
X 
X 
X 
LABORATORY/RADIOLOGIC EVALUATIONS: 
Hematology (CBC/diff, 
plt) 
X 
X 
X12 
X 
Comprehensive 
Metabolic Panel2 
X 
X 
X 
X12 
X 
Pregnancy Test13 
X 
X 
Phosphorus 
X 
X 
Uric Acid 
X 
X 
CPK 
X 
X 
Amylase/ Lipase 
X 
X 
Echocardiogram14 
X 
X 
X 
Thyroid Stimulating 
Hormone (TSH) 
X 
X 
HCV antibody and HBV 
surface antigen 
X 
TP53 status15 
X 
Tumor Assessments 
through Imaging 
Studies4,7 
X 
X 


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Parameter 
Pre- 
Treatment1 
Week/Cycle 
End of 
Treatment6 
C1 
D1 
C1D8 
C1 
D15 
C1 
D1,8, 
15, 2212 
C2 
D1 
C2 
D15 
C3D1 
D1 
Every 
Cycle 
D15 
Every 
Cycle 
Day 1 of Every 
Odd Cycle 
except Cycle  
1 
Every 12 
weeks from 
C2D1 
onwards 
TREATMENT ADMINISTRATION 
Atezolizumab 
IV once every 2 weeks starting on 
Cycle 1 Day 15 
Cobimetinib 
(TP53-mut arm) 
PO once daily from Day 1 – 21 starting on 
Cycle 1 Day 1 
Idasanutlin 
(TP53-wt arm) 
PO once daily from Day 1 – 5 starting on 
Cycle 1 Day 1 
CORRELATIVE STUDIES: 
Tumor  Biopsy5,8, 10 
X 
X 
Blood collection8,  9 
X 
X 
X 
X 
ADDITIONAL INFORMATION: 
Concomitant 
Medications Review 
X 
X 
X 
X 
Adverse Events 
Assessment 
X (AE will be assessed throughout the  study) 
 
Note: 
 Additional tests may be performed at the discretion of the treating investigator as clinically   indicated. 
• 
The sample collection schedules outlined above are based on an ideal subject. The sample schedule should be followed as 
closely as is realistically possible; however, the schedule may be modified (± 4 business days) due to problems such as 
scheduling delays or conflicts (e.g., clinic closure, poor weather conditions, vacations,   etc.). 
 Items highlighted in grey are performed for research purposes (not standard of   care) 
1. Within 4 weeks prior to starting treatment, unless otherwise  noted. 
2. Serum chemistry includes measurement of sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total 
bilirubin, calcium, total protein, albumin, AST, ALT, and alkaline   phosphatase. 
3. On days of Atezolizumab treatment, Pre-Dose vitals should respectively be recorded ≤ 60 minutes prior to the start of the 
Atezolizumab infusion. Post-Dose vitals should be recorded during and after infusion only if clinically indicated. 
4. Baseline evaluation of disease status by CT or MRI within 28 days prior to first dose of study drugs. Baseline and subsequent 
scans to include imaging of the chest, abdomen and pelvis. The first scheduled re-scan should be performed and evaluated 
7 to 8 weeks after Cycle 1, Day 1 treatment, with subsequent scheduled scans intended every ~ 8 thereafter.  Scanning   on 
  
the same day as dosing is discouraged but allowed, provided scan results receive appropriate evaluation prior to study 


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treatment. Additional disease evaluations or increased scan frequency may be performed according to the medical judgment 
of the patient’s study physician. 
5. Fresh biopsy in consenting patients (including those with pre-existing archival tissue) with primary or metastatic lesion judged 
amenable to medically safe excisional, incisional or core needle biopsy. 
6. A 1-month follow-up clinic visit is intended 28 days (±7 days) after the preceding End-of-Treatment visit. Documented 
attempt(s) should be made for patient return to the study clinic. It will not be considered a protocol deviation if the patient is 
physically unable to return for the follow-up visit; such circumstance should be recorded in the study documents, and as much 
of the follow-up information as possible should be obtained via feasible patient contact and from local and outside facilities. 
7. If a patient discontinues the study for reason other than progressive disease confirmed by CT or MRI (e.g. adverse event), 
then CT or MRI scans of the chest, abdomen and pelvis should be continued every 8-9 weeks until disease progression is 
confirmed by imaging. 
8. For tissue collection, refer to Lab Manual for details of collection, processing and shipping. 
9. For peripheral blood, refer to Lab Manual for details of collection, processing and shipping 
10. Please note on Section 10 and Lab Manual that both FFPE and fresh tissue should be obtained. 
11. Complete ophthalmologic exams will be performed prior to treatment initiation, cycle 2 day 1 (± 1 week), and every 12 weeks 
from then on (± 2 weeks) on patients in the cobimetinib arm only. Complete ophthalmologic examination will be performed 
and interpreted by a qualified ophthalmologist, including visual acuity testing, intraocular pressure measurements by 
tonometry, slit-lamp ophthalmoscopy, indirect ophthalmoscopy, and spectral domain optical coherence tomography. 
Ophthalmologic examination may be performed up to 42 days prior to starting study treatment. 
12. For patients on the phase Ib portion of the study only (idasanutlin arm only) 
13. Only for women of childbearing potential 
14. Evaluation of LVEF by Echocardiogram should be performed prior to treatment initiation, cycle 2 day 1 (± 1 week), and every 
12 weeks from then on (± 2 weeks) on patients in the cobimetinib arm only. The treatment discontinuation visit evaluation of 
LVEF does not need to be performed at the treatment discontinuation visit if an evaluation has been performed within the last 
12 weeks and there are no clinically significant findings and/or changes from baseline. All patients restarting treatment with a 
dose reduction of cobimetinib because of a decrease in LVEF should have LVEF measurements taken after approximately 2 
weeks, 4 weeks, 10 weeks, and 16 weeks, and then resume monitoring of LVEF every three treatment cycles. Any patient 
who develops clinical signs or symptoms suspicious of cardiac failure should undergo an LVEF assessment. 
15. TP53 mutation status may be known based on previously checked NGS or cfDNA commercially available assays. If not known, 
an archival FFPB should be sent to the Sponsor (see Section 10 and Lab Manual) for TP53 mutation status determination. 
 
 
 
 
 
 
 


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7. TREATMENT PLAN 
 
7.1. Overview 
This is a multicenter, open-label, 2-arm phase Ib/II trial that will evaluate the anti-tumor effect of 
Atezolizumab (an anti- PD-L1 mAb) in combination with Cobimetinib (a MEK inhibitor) in patients 
with TP53-mutated ER+ mBC, or Idasanutlin (an MDM2 antagonist) in patients with TP53-wt ER+ 
mBC. In the phase Ib portion of the trial we will determine the safety and tolerability [Dose Limiting 
Toxicity (DLT), Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D)] of 
Atezolizumab and Idasanutlin in patients with ER+ mBC. With three possible dosing cohorts, a 
minimum of 9 and a maximum of 18 subjects may be recruited for the dose escalation portion of 
the study. In the phase II portion of the trial we will determine the anti-tumor effect and adverse 
event profile of Atezolizumab with Cobimetinib or Idasanutlin in patients with ER+ mBC 
[Progression Free-Survival (PFS), Overall Response Rate (ORR; by RECIST 1.1) and/or Clinical 
Benefit Rate (CBR; percentage of patients without disease progression at 6 months); immune- 
related Response Criteria (irRC), Percentage of patients alive at 12 months (% OS), and Adverse 
Event profile]. All participants will have targeted Next Generation Sequencing (NGS) performed 
prior to treatment arm allocation for TP53 mutation status determination and assess tumor 
mutation burden. We would expect about ~ 40% of all patients with ER+ mBC to have a TP53 
mutation (TP53-mut) in their tumor3. For the phase II portion of the trial, a minimum of 33 and a 
maximum of 66 patients (total in both arms) will be receive study drugs (atezolizumab with 
cobimetinib or idasanutlin, based on TP53 mutation status) until disease progression, 
unacceptable adverse event(s), concurrent illness that prevents further administration of 
treatment, patient withdrawal from study, or significant non-compliance with protocol. To assess 
the anti-tumor effect of therapy, we will estimate the overall tumor burden at baseline to which 
subsequent measurements (performed every 8 weeks using the Solid Tumor Response Criteria 
[RECIST] v1.1) will be compared. Tumor biopsies (fixed for IHC analysis and snap-frozen for RNA 
extraction) and peripheral blood will be collected prior to initiating Cobimetinib/Idasanutlin (PRE- 
Bx), and after 15 days of Cobimetinib/Idasanutlin, prior to adding Atezolizumab (POST-Bx). 
 
7.2. Screening Phase 
At screening, the patient will provide a signed informed consent form prior to any study related 
activities. Patients with known TP53 mutation status (by NGS or cfDNA) will not be required to 
wait to initiate study treatment provided all other screening requirements have been met. For 
patients without known TP53 mutation status, archival tissue (FFPB from primary or metastatic 
lestion) should be sent to the Coordinating Center (see Section 10 for details on tissue submission 
requirements and testing procedures), and once tissue is received at the Coordinating Center, 
results for TP53 status will take an average of 2 weeks. Once patients are deemed eligible and 
TP53 mutation status is known, participants should begin study treatment consistent with the 
protocol, as soon as possible, but no later than 2 weeks after authorization to start treatment is 
given by the VICC Coordinating Center. 
 
7.3. Allocation Procedures 
Once eligibility is confirmed and TP53 mutation status is known, patients will then be allocated 
to receive: 
• 
Arm 1 (TP53-mut) –Atezolizumab 840 mg IV, on Days 1 and 15, and Cobimetinib 60 mg 
PO daily, on Days 1 - 21, every 28 days; or 


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• 
Arm 2 (TP53-wt) –Atezolizumab 840 mg IV, on Days 1 and 15, and Idasanutlin (final dose 
to be determined by the phase Ib portion of the trial) PO daily, on Days 1 - 5, every 28 
days, 
Note that on cycle 1 (in both arms) Atezolizumab will start on Cycle 1 Day 15 instead of Day 1. 
 
7.4. Agent Administration 
The investigator will instruct the patient to take the study drugs exactly as specified in the protocol. 
A pill diary will be given to all patients enrolled in the study. A cycle will last 28 days. 
 
1 cycle = 28 days 
N of 
pts. 
Dose 
Level 
Atezolizumab 
(IV q15 days) 
Cobimetinib 
(PO daily x 21 out of 
28 days) 
Idasanutlin 
(PO daily x 5 out of 
28 days) 
Phase Ib 
3-6 
3 
840 mg 
----- 
200 mg 
3-6 
2 
840 mg 
----- 
150 mg 
3-6 
1 
840 mg 
----- 
100 mg 
3-6 
–1 
840 mg 
----- 
50 mg 
Phase II 
40 
---- 
840 mg 
60 mg 
----- 
40 
840 mg 
----- 
TBD 
 
7.4.1 Atezolizumab 
Patients will receive Atezolizumab 840 mg IV, on Days 1 and 15 of a 28-days cycle, and its first 
dose will be started on Cycle 1 Day 15. Administration of Atezolizumab will be performed in a 
setting with emergency medical facilities and staff who are trained to monitor for and respond to 
medical emergencies. Atezolizumab infusions will be administered per the instructions outlined 
below: 
First Infusion: 
• 
No premedication is administered. 
• 
Record patient’s vital signs (heart rate, respiratory rate, blood pressure, and temperature) 
within 60 minutes before starting infusion. 
• 
Infuse 14 mL Atezolizumab (840 mg) in 250 mL NaCl) over 60 (± 15) minutes. 
• 
Record patient’s vital signs (heart rate, respiratory rate, blood pressure, and temperature) 
during and after the infusion if clinically indicated 
• 
Patients will be informed about the possibility of delayed symptoms following infusion and 
instructed to contact their study physician if they develop such symptoms. 


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Subsequent Infusions: 
• 
If patient experienced infusion-related reaction during any previous infusion, 
premedication with antihistamines may be administered for Cycles ≥2 at the discretion of 
the treating physician. 
• 
Record patient’s vital signs (heart rate, respiratory rate, blood pressure, and temperature) 
within 60 minutes before starting infusion. 
• 
If the patient tolerated the first infusion well without infusion-associated adverse events, 
the second infusion may be administered over 30 (± 10) minutes. • If no reaction occurs, 
subsequent infusions may be administered over 30 (± 10) minutes Continue to record vital 
signs within 60 minutes before starting infusion and during and after the infusion if clinically 
indicated. 
• 
If the patient had an infusion-related reaction during the previous infusion, the subsequent 
infusion must be administered over 60 (± 15) minutes. Record patient’s vital signs (heart 
rate, respiratory rate, blood pressure, and temperature) during and after the infusion if 
clinically indicated. 
 
7.4.2 Cobimetinib 
Patients will receive and self-administer Cobimetinib at 60 mg PO daily, on Days 1 – 21 of a 28- 
days cycle. 
Patients will be given a sufficient number of tablets to last until the next visit. In some cases, extra 
tablets may be dispensed if there is a possibility that the patient’s next visit may be delayed (e.g., 
due to holiday, inclement weather, or distance of patient’s home from study center). 
Study drugs should be taken at approximately the same time each day, preferably in the morning, 
and no earlier than 1 hour and no later than 4 hours after the scheduled time. Each dose of 
Cobimetinib should be taken with a glass of water. Cobimetinib may be dosed with or without 
food. Cobimetinib tablets should never be chewed, cut, or crushed. 
If a dose is missed (i.e., not taken within 4 hours after the scheduled dosing time), the patient 
should resume dosing with the next scheduled dose. Missed or vomited doses will not be made 
up. These events should be noted in the medication diary. 
Patients will be asked to record the time and date they take each dose in a medication diary 
(located in the supplemental packet). Patients will also be given instructions for self- 
administration as to the number and strength of the tablets to take. Patients will be instructed to 
bring all unused tablets and their medication diary to each study visit for assessment of 
compliance and medication disposal. 
 
7.4.3 Idasanutlin 
Patients will receive and self-administer Idasanutlin at (TBD) mg PO daily, on Days 1 – 5 of a 28- 
days cycle. 
Patients will be given a sufficient number of tablets to last until the next visit. In some cases, extra 
tablets may be dispensed if there is a possibility that the patient’s next visit may be delayed (e.g., 
due to holiday, inclement weather, or distance of patient’s home from study center). 
Study drugs should be taken at approximately the same time each day, preferably in the morning, 
and no earlier than 1 hour and no later than 4 hours after the scheduled time. Each dose of 
Idasanutlin should be taken with a glass of water. Idasanutlin may be dosed with or without food. 
Idasanutlin tablets should never be chewed, cut, or crushed. 


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If a dose is missed (i.e., not taken within 4 hours after the scheduled dosing time), the patient 
should resume dosing with the next scheduled dose. Missed or vomited doses will not be made 
up. These events should be noted in the medication diary. 
Patients will be asked to record the time and date they take each dose in a medication diary 
(located in the supplemental packet). Patients will also be given instructions for self- 
administration as to the number and strength of the tablets to take. Patients will be instructed to 
bring all unused tablets and their medication diary to each study visit for assessment of 
compliance and medication disposal. 
 
7.5. Definition of Dose-Limiting Toxicity (DLT) – for patients on idasanutlin arm only 
Any of the following events that occur during cycle 1 (first 6 weeks) will be considered a DLT 
when classified as possibly, probably or definitively related to study treatment (according to NCI 
CTEP Adverse Event Reporting Requirements). Apart from the criteria listed below, if a lower 
grade AE leads to a dose interruption of more than 14 consecutive days of study drugs for the 
first 4 weeks of Cycle 1, this AE will be considered a DLT; patients must receive at least 75% of 
study drug during cycle 1 in order to be evaluable for the DLT observation period. Whenever a 
patient experiences toxicity that fulfills the criteria for a DLT, treatment with the study drug 
responsible for the toxicity will be interrupted (patient may continue the remainder study drugs) 
and the toxicity will be followed up. The Protocol Chair must be notified immediately of any DLT: 
 
TOXICITY 
DLT CRITERIA 
Blood and lymphatic 
system disorders 
Anemia CTCAE Grade ≥ 3 > 14 consecutive days 
Febrile neutropenia CTCAE Grade ≥ 3 
ANC CTCAE Grade 3 for > 14 consecutive days 
ANC CTCAE Grade 4 
Platelet count CTCAE Grade 3 for > 7 consecutive days and/or 
with signs of bleeding 
Platelet count CTCAE Grade 4 
Ocular disorders 
CTCAE Grade ≥ 2 for > 14 days 
CTCAE Grade ≥ 3 
General disorders and 
administration site 
conditions 
Fatigue CTCAE Grade 3 for > 14 consecutive days 
Skin and subcutaneous 
tissue disorders 
Skin, mucosal or nail toxicity CTCAE Grade ≥ 3 for > 14 
consecutive days despite treatment 
GI disordersa 
Diarrhea CTCAE Grade ≥ 3 for ≥ 48 hrs, despite the use of anti- 
diarrhea therapy 
Nausea/vomiting CTCAE Grade ≥ 3 for ≥ 48 hrs, despite the use of 
anti-emetic therapy 


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TOXICITY 
DLT CRITERIA 
Constipation CTCAE Grade ≥ 3 for ≥ 48 hrs, despite the use of 
anti-constipation therapy 
Investigationsb 
Blood bilirubinc CTCAE Grade 2 for > 7 consecutive days 
Blood bilirubinc CTCAE Grade ≥ 3 
AST or ALT CTCAE Grade ≥ 3 in conjunction with blood bilirubinc 
CTCAE Grade ≥ 2 of any duration 
AST or ALT CTCAE Grade 3 for > 7 consecutive days 
AST or ALT CTCAE Grade 4 
Alkaline phosphatase CTCAE Grade 4 
Other hematologic and 
non-hematologic 
toxicities 
Any other CTCAE ≥ Grade 3 toxicity except for: 
• Decreased lymphocyte count [lymphopenia] that is not clinically 
significant 
• Grade 3 fatigue for less than 7 days 
• Grade 3 diarrhea, nausea/ vomiting, or constipation for less or 
equal to 48 hours with appropriate supportive medication 
a Patients will not initially receive prophylactic treatment for nausea/vomiting during Cycle 1. 
However, prophylactic treatment may be initiated in all patients at the dose level where these 
toxicities have been observed and in all further patients if at least 1 patient has experienced 
nausea/vomiting CTCAE Grade ≥ 3 or if at least 2 patients experienced nausea/vomiting 
CTCAE Grade ≥ 2. However, anti-emetics may be applied for treatment if the patient has 
experienced nausea/vomiting CTCAE Grade ≥ 1 at the discretion of the treating physician. 
b For any hepatic toxicity CTCAE Grade 4, or CTCAE Grade 3 that does not resolve within 7 
days to CTCAE Grade ≤ 1 (or CTCAE Grade ≤ 2 if liver infiltration with tumor present), an 
abdominal CT scan should be performed to assess if it is related to disease progression. 
c Refers to total bilirubin. 
Apart from the criteria listed above, if a lower grade AE leads to a dose interruption of more 
than 14 consecutive days of Idasanutlin, this AE may be considered as DLT (the determination 
will be based on clinical significance and patient risk; discussion with the Protocol Chair will 
determine if the event should or should not count as a DLT). 
Patients whose treatment is interrupted or permanently discontinued due to an AE or clinically 
significant laboratory value, must be followed as outlined in the table below, at least once a week 
for 4 weeks, and subsequently at 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Patients that require a dose delay of > 28 days due to a cause unrelated 
to study participation will have the opportunity to continue study if deemed eligible to do so by the 
Protocol Chair of the study. 


BRE 17107: Atezolizumab, Idasanutlinand Cobimetinib inmetastatic ER+breast cancer 
Protocol Chair.  Ingrid Mayer 
 
VA N D  E 1t n  1 LT  V 
u  N 1 V E R S 1 T Y 
MliOICAI.. G ENT ER 
 
 
TOXICITY 
FOLLOW-UP  EVALUATION 
Hematology 
If 2: CTCA E grade 3 neutropenia, anemia or thrombocytopenia 
have been demonstrated, these parametersmust be repeated at 
least once a week until resolution to s CTCAE grade 1 to allow 
for initiation of re-treatment. 
Renal 
If creatinine 2: 2 x ULN has been demonstrated, this parameter 
must be evaluated at least twice a week until resolution to s 
CTCAE grade 1 to allow for initiation of re-treatment, and then at 
least weeklv until either resolution or until stabilization. 
Creatinine 2: 2.0 x ULN and 3+ proteinuria or hematu ria 2: CTCA E 
grade 2 has beendemonstrated, a 24-hour urine collection for 
total protein and total creatinine must be repeated at least weekly 
until either parameter returns to baseline value or until 
stabilization. Whenever a measured CrCI is obtained, a creatinine 
should be obtained within s 72 h of the urine collection. 
Hepatic 
If total bilirubin 2: 2 x ULN or 2: CTCA ED grade 3 AST/ALT has 
beendemonstrated, these parameters mustbe repeated daily until 
resolution to s CTCAE grade 1 (orsgrade 2 for AST or ALT, if liver 
metastasis are present) to allow for initiation of re-treatment, and 
then at least weeklv until either resolution or until stabilization 
Patients with total bilirubin > ULN (any duration) should have 
fractionation 
of 
bilirubin 
into 
total/direct or 
indirect/direct 
components and any additional work-up as clinically indicated by 
these results. Follow-up of hyperbilirubinemia should proceed as 
per the guidelines above, irrespective of the results of 
fractionation. 
Metabolic/Laboratory 
Parameters of metabolic/ laboratory abnormalities 2: CTCA E grade 
3 must be assessed once at 2 to 4 days and once again at 7 days 
(± 1 day) and be repeatedtwice a week until resolution to s CTCAE 
grade 2 to allow for initiation of re-treatment, and then at least 
weekly until either resolution to s CTCAE grade 1 or until 
stabilization. 
A CT scan or other imaging study to assess the pancreas, liver, 
and gallbladder must be performed within 1 week of the first 
occurrence of anv 2: CTCA E arade 3 of amylase or lipase levels. 
In patients with triglycerides 2: 500 mg/dL, urine amylase needs to 
be tested in addition. 
Ocular toxicity 
Patients who experience ocular toxicity should be followed as per 
Dose Modification auidelines (Section 8) 
 
 
 
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TOXICITY 
FOLLOW-UP EVALUATION 
Non-Laboratory 
Patients who experience non-laboratory DLTs must be evaluated 
at least once a week following demonstration of the toxicity until 
resolution of the toxicity to allow for re-treatment, stabilization of 
the toxicity, or study treatment completion. 
 
 
7.6. Definition of Maximum Tolerated Dose (MTD) – for patients on idasanutlin arm 
only 
The MTD will be defined as the highest dose tested in which a DLT is experienced by 0 out of 3 
or 1 out of 6 patients among the dose levels. The first cohort of patients (3 patients) will be started 
at dose level 1, and each patient will be observed for 6 weeks on the specified dose: 
 If no patient in the first cohort of 3 experiences a DLT, accrual will continue to test the next 
dose level 
 If 1 patient experiences a DLT any given cohort/ dose level, an additional cohort of 3 patients 
will be treated at the same dose level 
 If 1 patient has a DLT out of 6 patients treated at this same dose, accrual will continue to test 
the next dose level 
 If 2 or more patients in 3 or 6 patients treated at a given dose experience DLT, the dose will 
be de-escalated to the next lower dose level. If the current dose level is at -1, the regimen will 
be considered too toxic and the corresponding cohort within the study will be discontinued 
 If 0 out of 3 or 1 out of 6 patients has a DLT treated at dose level 3, accrual will continue to 
the phase II portion of the study 
No new cohort of patients will be treated until the previous cohort has been fully evaluated for 
toxicity and a dose escalation decision has been made. Routine updates regarding patient and 
study status will be conducted. 
Once the MTD is reached, the expansion component of the study will be completed to assess 
tolerability and efficacy. Patients in the phase II portion of the study will initiate study treatment at 
the MTD defined in the escalation component of the trial. Note that dose reduction within patients 
(individually) is allowed after the 4 week DLT observation period in the escalation and in the 
expansion components of the study (see Dose Modification guidelines, Section 8). Intrapatient 
dose escalation will not be allowed. Dose reduction will be required for a given patient in case of: 
 Grade 3 or 4 toxicities 
• 
Grade ≥ 2 elevation of creatinine, bilirubin, AST, or ALT lasting more than 14 days despite 
medical treatment, or 
• 
Grade ≥ 2 ocular, skin or nail toxicity for more than 28 days in a row despite optimal medical 
treatment, or 
• 
Grade ≥ 2 GI toxicity lasting more than 14 days despite medical treatment. 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
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7.7. Concomitant Treatment and Supportive Care Guidelines 
There is a potential for interaction of cobimetinib with other concomitantly administered drugs 
through the cytochrome P450 system, and should not be used with strong inhibitors or inducers 
of CYP3A4. The case report form must capture the concurrent use of all other drugs, over-the- 
counter medications, or alternative therapies. Patients taking any of the prohibited medications 
on the Prohibited Medications list are excluded from entering the study. This list can be found in 
the supplemental packet. Patients already enrolled in the study that initiate and persist taking any 
of the medications on the Prohibited Medications list (except for weak inhibitors) will be 
discontinued from the study. No apparent drug interactions have been identified for idasanutlin, 
but strong inhibitors and/or inducers of CYP2C8 and CYP3A4/5 may affect idasanutlin exposure. 
For idasanutlin, CYP2C8 inhibitors should be avoided when CYP3A4 inhibitors are allowed, since 
the risk of simultaneous administration of CYP3A4 and CYP2C8 inihibitors is unknown. 
Patients on chronic medications that can be given concomitantly with Cobimetinib or Idasanutlin 
should be maintained on the same dose and dose schedule throughout the study period, as 
medically feasible. Caution should be used in patients on antiplatelet or anticoagulant therapy 
due to the risk of bleeding with cobimetinib. The investigator should instruct the patient to notify 
the study site about any new medications he/she takes after the start of the study drug. All 
medications (other than study drug) and significant non-drug therapies (including physical therapy 
and blood transfusions) administered after the patient starts treatment with study drug, and any 
changes in dosing should be recorded. 
All supportive measures consistent with optimal patient care can be given throughout the study 
at the discretion of the treating physician, as long as they are not part of the list of prohibited 
medications (located in the supplemental packet). In general, the use of any concomitant 
medication/therapies deemed necessary for the care of the patient is permitted with the following 
considerations: 
 Prophylactic anti-emetics should be started only once the patient experienced nausea or 
vomiting at the discretion of the investigator. 
• 
G-CSF support will be allowed at the treating physician’s discretion. Hematopoietic growth 
factors may be used according to ASCO guidelines (when applicable, we would suggest 
pegfilgrastim 6 mg subcut on Day 6 of the cycle for the idasanutlin arm; and filgrastim 300 – 
480 mcg subcut [based on body weight] on days 22, 23 and 24 of the cycle for the cobimetinib 
arm) 
• 
Bone directed therapy to prevent skeletal related events (SRE’s) or to treat osteoporosis with 
bisphosphonates or denosumab is permitted. While the use of bisphosphonates has been 
found to reduce the incidence of new bone metastases in patients with metastatic breast 
cancer, we do not anticipate this to affect the results of this trial. Thus, treatment initiated prior 
to registration or after registration with these agents is permitted. The time of initiation of bone 
directed therapy should be clearly recorded on the case report forms 
 Local radiotherapy required for life-threatening situations (e.g., superior vena cava syndrome, 
spinal cord compression, central nervous system metastases) will require the patient to 
discontinue protocol treatment due to symptomatic deterioration. However, limited palliative 
radiotherapy (i.e., to bone metastasis) in subjects who are otherwise benefiting from study 
treatment will be allowed during the study but must be discussed with the Protocol Chair. 
Study treatment should be withheld until palliative radiotherapy is terminated. This treatment 
break should not be considered as treatment interruption. Palliative radiation is permitted if 
done solely for bone pain relief. It should not be delivered to a target lesion and it should not 
encompass more than 25% of irradiated bone marrow. If palliative radiotherapy is initiated 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
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after the start of study treatment, the reason for its use must be clearly documented and 
progression as per RECIST 1.1 must be ruled out 
 Other investigational therapies must not be used while the patient is on the study 
 Anticancer systemic therapy other than the study treatments must not be given to patients 
while on the study. If such agents are required for a patient then the patient must be 
discontinued from the study 
• 
Herbal preparations are not allowed throughout the study. These herbal preparations include, 
but are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Patients should stop 
using these herbal preparations 7 days prior to first dose of study drug 
 
7.8. Duration of Therapy 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue 
until one of criteria in Section 7.11  applies. 
 
7.9. Duration of Follow-Up 
• 
Patients will be followed until 28 days (± 7days) following discontinuation of study treatment 
due to disease progression 
 Patients removed from study treatment for unacceptable treatment related adverse event(s) 
will be followed weekly until resolution or stabilization of all treatment related adverse events 
to Grade 1 or lower 
 Patients who have discontinued study treatment for any reason other than disease 
progression will be followed until disease progression 
 
7.10. 
Criteria for Removal from Study 
Participants will be removed from study treatment when any of the criteria listed in Section 7.11 
applies. All patients who initiate protocol treatment will be included in the safety analysis, and all 
patients who initiate protocol treatment and receive at least 8 weeks of treatment will be included 
in overall evaluation of response. All reasons for discontinuation of therapy should be documented 
clearly in the medical record. 
 
7.11. 
Discontinuation of Treatment 
The reasons for discontinuation or protocol treatment include: 
 
 Evidence of disease progression during treatment as deemed by the treating investigator 
 Non-compliance with the study protocol, including, but not limited to not attending the majority 
of scheduled visits. The Protocol Chair will determine when non-compliance should lead to 
removal from study. Note: These patients will still be included in the overall evaluation of safety 
and response 
 Unacceptable major toxicity. Note: These patients will still be included in the overall evaluation 
of safety and response 
 Intercurrent illness or condition that would, in the judgment of the treating investigator, affect 
assessment of clinical status to a significant degree or require discontinuation of study 
treatment 


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• 
At subject’s own request. Note: The reason for discontinuation from the study must be 
documented. These patients will be included in the overall evaluation of safety and response 
if any protocol therapy was administered prior to withdrawal 
• 
Study is closed for any reason (e.g. new information shows that the patient’s welfare would 
be at risk if she continued study treatment) 
 General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator 
 Patients that require a dose delay of > 28 days. If the delay is due to a cause unrelated to 
study participation, the patient will have the opportunity to continue study if beyond the first 8 
weeks of treatment, if clinical benefit is seen, and if deemed eligible to do so by the Protocol 
Chair of the study 
 If the patient requires dose reduction below dose level -1, the patient should be discontinued 
from the study unless deemed to have clinical benefit that would outweigh the risk. A 
discussion with the Protocol Chair should be carried out prior to final decision on 
discontinuation 
 
7.12. 
Replacement of Patients Who Discontinue Early 
In general, the study intends that patients would be treated until disease progression or intolerable 
toxicity. If a patient discontinues study treatment for reasons clearly not related to study treatment, 
after completing fewer than one planned cycle of study, and/or receiving <75% of the total 
intended dose of study drugs over the first cycle of treatment, then that patient will be considered 
not evaluable for efficacy analysis (will still be included in the safety analysis though) and may be 
replaced with a new patient. 
 
7.13. 
Withdrawal from Study 
The reasons for withdrawal from the study include: 
 Subject withdraws consent for follow-up. 
 Subject is lost to follow-up. 
 Study is terminated for any reason. 
 
8. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
 
8.1. Cobimetinib 
 
8.2. Anticipated Toxicities 
Most common adverse events from Cobimetinib include: 
 Rash 
 Diarrhea 
 Nausea and vomiting 
 Anorexia 
 Fatigue 
 Peripheral edema 
 Visual disturbances 
 Hemorrhage 
 Elevation of CPK and rhabdomyolysis 


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8.2.1. Toxicity Considerations 
 
8.2.1.1. 
Dermatologic toxicity 
Skin toxicities of rash have been reported in patients treated with Cobimetinib as a single agent 
or in combination with other therapies. In the Phase III study (GO28141), combined rash events 
of all types and grades were reported more frequently in patients treated with vemurafenib + 
Cobimetinib than vemurafenib + placebo (71.7% vs. 65.7%), although Grade ≥ 3 events 
(approximately 16%) and types of rash reported were similar between study arms. Specific events 
in patients treated with vemurafenib + Cobimetinib included rash (39% all grades, 5.9% Grade ≥ 
3, 1.6% serious events) and rash maculo-papular (14.6% all grades, 6.3% Grade ≥ 3, 1.2% 
serious events). In the Phase I single-agent study (MEK4592g), reported rash events included 
rash (49.6% all grades, 4.3% Grade≥3 events) and rash maculo-papular (1.7% all grades, 0.9% 
Grade≥3 events). 
The appearance of rash and other dermatologic events will be specifically closely monitored. 
Patients and investigators will be instructed to monitor closely for the development of rash. 
Patients will also be instructed to avoid sun exposure and to use sunscreen regularly while 
receiving study treatment. Prophylactic therapy for rash is not allowed prior to a first event of rash 
in this study; exceptions may be granted with the approval of the Medical Monitor. Patients must 
seek further evaluation promptly if rash develops. 
Patients who develop Grade 1-2 skin toxicity may be treated with concomitant medications (e.g., 
topical agents, oral antibiotics, topical moisturizers for dry skin) at the discretion of the 
investigator. Patients who experience clinically significant acneiform rash should be treated with 
standard therapies for EGFR-related toxicity, for example topical tetracycline, topical clindamycin, 
topical silver sulfadiazine, diphenhydramine or a similar antihistamine, and/or oral antibiotics (e.g., 
tetracycline, doxycycline, minocycline). Treatment of rash should be initiated early (i.e., at onset 
of symptoms). 
General recommendations to avoid skin toxicities: 
 Avoid unnecessary exposure to sunlight and excessive use of soap. 
 Avoid bathing in excess; use tepid rather than hot water. 
 Use moisturizers regularly; apply thick, alcohol-free and oil-in-water based emollient cream 
on exposed and dry areas of the body. 
 Avoid perfumed products, bubble bath, perfumed soaps, and take breaks from shaving. 
• 
Use broad-spectrum sunscreen with a skin protection factor (SPF) ≥15. 
 Wear cotton clothes next to skin rather than wool, synthetic fibers, or rough clothing. 
 Use occlusive alcohol-free emollient creams (jar or tub) for treatment of mild/moderate 
xerosis. 
 For scaly areas, use exfoliants (ammonium lactate 12% or lactic acid cream 12%). 
 
8.2.1.2. 
Diarrhea 
Diarrhea has been reported in all Cobimetinib clinical studies in cancer patients. In the Phase I 
single-agent study (MEK4592g), diarrhea of any grade was reported in 67.0% of patients, 6.1% 
of patients experienced Grade 3 diarrhea, and no Grade 4 or 5 events were reported as of the 
data cutoff date. Serious events of diarrhea were reported in 1.7% of patients. In the Phase III 
study (GO28141), diarrhea was the most common adverse event reported. Diarrhea events of all 
grades were reported in 56.7% of patients, and Grade 3 or 4 events were reported in 6.3% of 
patients treated with vemurafenib + Cobimetinib. No Grade 5 events of diarrhea were reported as 
of the data cutoff date. Serious events of diarrhea were reported in 1.2% of patients treated with 


BRE 17107: Atezolizumab, Idasanutlinand Cobimetinib inmetastatic ER+breast cancer 
Protocol Chair.  Ingrid Mayer 
 
VAN   D E 1tn  1 LT V 
u  N 1V E R S 1 T Y 
MliOICAI.. G ENT ER 
 
vemurafenib + Cobimetinib. 
Diarrhea can frequently be managed with anti-diarrheal agents but can also progress to clinically 
significant dehydration and/or electrolyte imbalances with effects on other organs, possibly 
resulting in renal, hepatic, and/or cardiac failure. Patients should be instructed to promptly contact 
the investigators if they develop diarrhea. Investigators should treat diarrhea  and  intervene 
promptly for patients who appear to be at increased risk of developing significant dehydration, 
electrolyte imbalances, and/or multi-organ failure. Patients should receive maximum supportive 
care per institutional guidelines. 
Patients should be instructed to promptly report and seek medical evaluation for severe GI signs 
and symptoms (e.g., sudden onset of severe abdominal pain and fever, hematemesis, 
hematochezia, melena), and investigators will monitor patients closely for severe GI toxicity, 
perform appropriate medical evaluation and treatment, and promptly refer to a specialist, if 
applicable. Patients with known severe ulcer disease should not be administered Cobimetinib. 
 
8.2.1.3. 
Nausea and vomiting 
For nausea and/or vomiting, maximum supportive care, including ondansetron and aprepitant, 
should be administered at the discretion of the investigator or per institutional guidelines. 
 
8.2.1.4. 
Alteration in Liver Functions 
Liver laboratory test abnormalities, including elevationsin AST and/or ALT, have been reported 
as adverse events and serious adverse events in patients treated with vemurafenib+Cobimetinib. 
In the Phase Ill study (G0 28141), liver laboratory test abnormalities reportedas Grade 3 adverse 
events occurred more frequently in patients treated with vemurafenib+Cobimetinib than 
vemurafenib+placebo (20.5% vs. 15.1%). Liver laboratorytest abnormalities reportedas Grade 3 
adverse eventsat frequencies 2% higher in patients treated with vemurafenib+Cobimetinib than 
vemurafenib+placebo includedincreased ALT (11.4% vs. 6.3%), increased AST (8.3% vs. 2.1%), 
and increasedalkaline phosphatase (4.3% vs. 1.7%). 
In Study MEK4592g, there were no reported adverse events or serious adverse events for 
clinically significant Grade 4 elevations in liver laboratory tests, and no patient experienced 
findings suggestive of drug-induced liver injury or liver failure. Generally, elevations in liver 
laboratory tests were managed effectively with dose modification guidelines. In both study arms 
of G028141, the majority of Grade 3 liver laboratory test abnormalities resolved. 
 
8.2.1.5. 
Visual Disturbances 
Serous retinopathy (fluid accumulation within the layers of the retina) has been observed with 
MEKi, including Cobimetinib. The majority of events in Cobimetinib-treated patients were reported 
as chorioretinopathy or retinal detachment. In the Phase I single-agent study (MEK4592g), also 
with ocu lar exam inat ions presc ribed fo r patients report ing visua l disturbance, 2.6% of patients 
(inc luding 1 patient with a Grade 2 event that was not coded at the time of the data cutoff date) 
experienced serous retinopathy events, all of which were Grade 1 or   2. 
In the Phase Ill study (G028141), with pro spe ctive seria l ocula r exami nations, serous retinopathy 
events were reported more frequently in patients treated with vemurafenib+Cobimetinib than 
vemurafenbi Dplacebo (24%  vs.  2.1%),  and  approximately  50%  were  asymptomatic  Grade 1 
events. Few patients treated with vemurafenibOCobimeti nib experienced Gra de 3 ocular events 
(2.8%); the majority of these were managed with dose modification of both Cobimetinib and 
vemurafenib, and all were resolved or resolving as of the data cutoff date. 
Patients  with neurosensory detachment of  the retina typically present  with visual  disturbances 
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such as blurred vision, seeing spots, and photophobia; however, some patients have been 
asymptomatic. These cases have been reversible and most patients are able to continue 
treatment at the same or reduced dose, but some have experienced recurrence upon re-challenge 
and have discontinued study drug. It should be noted that these events of neurosensory 
detachment have occurred only with doses at or above the MTD. 
To address the potential ocular toxicity, patients with a history of RVO or glaucoma, visible retinal 
pathology, intraocular pressure > 21 mmHg, and predisposing factors to RVO (e.g., uncontrolled 
hypertension, diabetes, or hyperlipidemia, coagulopathy) within 6 months of protocol enrollment 
will be excluded. Patients will be asked about any vision changes at each symptom-directed 
physical examination. All new patients will have complete ophthalmologic examinations 
performed and interpreted by a qualified ophthalmologist, including visual acuity testing, 
intraocular pressure measurements by tonometry, slit lamp ophthalmoscopy, indirect 
ophthalmoscopy, and spectral domain optical coherence tomography. These complete 
ophthalmologic examinations will be performed at baseline. 
For any treatment emergent onset of Grade ≥ 2 visual symptoms or ocular toxicity, Cobimetinib 
must be interrupted pending diagnostic evaluation, which will include a complete ophthalmologic 
examination. If RVO is diagnosed, Cobimetinib dosing should be permanently discontinued and 
the RVO treated per institutional guidelines. 
 General considerations: Avoid unnecessary exposure to sunlight, use sunglasses in bright 
light. 
 Prophylactic management: Frequent use of artificial tear substitutes is strongly recommended. 
 
8.2.1.6. 
Cardiac Effects 
Left ventricular dysfunction may occur with signs and symptoms of cardiac failure, or reduction in 
left ventricular ejection fraction (LVEF) may be asymptomatic. Without active surveillance for 
reduction in LVEF, there were no events in this risk category reported in the Phase I single agent 
study (MEK4592g). In the Phase III study (GO28141), with active surveillance, reductions in LVEF 
were reported more frequently in patients treated with vemurafenib+Cobimetinib than 
vemurafenib+placebo (6.7% vs. 2.9%). Of the patients treated with vemurafenib+Cobimetinib, two 
patients (0.8%) had symptomatic reduction in LVEF and the remaining patients were 
asymptomatic. One patient in each arm (0.4% each) experienced serious events; these were 
symptomatic. Most events in patients treated with vemurafenib+Cobimetinib (88%) improved or 
resolved with management according to the dose modification guidelines. No Grade 4 or 5 events 
of reduction in LVEF have been reported in Cobimetinib clinical studies as of the data cutoff dates. 
Reduction in LVEF has also been observed in patients treated with MEKi other than Cobimetinib. 
 
8.2.1.7. 
Hemorrhage 
Hemorrhage, including major hemorrhages, defined as symptomatic bleeding in a critical area or 
organ, can occur with cobimetinib. In clinical studies with cobimetinib, events of cerebral 
hemorrhage, GI tract hemorrhage, reproductive tract hemorrhage, and hematuria have been 
reported. Caution should be used in patients with additional risk factors for bleeding, such as brain 
metastases, and in patients that use concomitant medications that increase the risk of bleeding 
(including antiplatelet or anticoagulant therapy). 
 
8.2.1.8. 
CPK elevations and rhabdomyolysis 
CPK elevations have been observed in patients who received cobimetinib monotherapy, as well 
as in patients administered cobimetinib in combination with other agents. The majority of CPK 
elevations reported were asymptomatic, non-serious, and resolved with or without study drug 


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interruption. One event of rhabdomyolysis was reported in the Phase III Study GO28141 
(cobimetinib + vemurafenib), and rhabdomyolysis has been reported in postmarketing 
experience. In Study GO28141, CPK elevations was reported as an AE more frequently in 
patients treated with cobimetinib + vemurafenib (32.4% all grades, 11.3% Grade 3 events) than 
with placebo + vemurafenib (8.1% all grades, 0% Grade 3 events). 
 
8.2.1.9. 
Potential embryofetal toxicities 
The effect of cobimetinib on human fertility is unknown. No dedicated fertility studies in animals 
have been performed with cobimetinib. In repeat-dose toxicology studies, degenerative changes 
were observed in reproductive tissues including increased apoptosis/necrosis of corpora lutea 
and seminal vesicle, epididymal and vaginal epithelial cells in rats, and epididymal epithelial cells 
in dogs. 
There are no data regarding the use of cobimetinib in pregnant women. When administered to 
pregnant rats, cobimetinib caused embryolethality and fetal malformations of the great vessels 
and skull at systemic exposures approximately 0.9 to 1.4 times the human clinical plasma AUC 
exposure. Therefore, teratogenicity and developmental toxicity is a potential risk for cobimetinib, 
and cobimetinib use is not recommended during pregnancy. The use of effective forms of 
contraception (as defined in appendix C) during treatment with cobimetinib and for the duration 
after the last dose as described in the protocol is mandated. 
 
8.3. Idasanutlin 
 
8.3.1. Anticipated Toxicities 
The majority of AEs recorded for idasanbutlin are transient in nature and reversible. 
 Diarrhea 
 Nausea 
 Vomiting 
 Anorexia 
 Fatigue/ asthenia 
 Thrombocytopenia 
 Neutropenia and febrile neutropenia 
 Anemia 
 Pyrexia 
 Sepsis 
 Pneumonia 
 Fungal Infections 
 Electrolyte Disorders (most commonly Hypokalemia) 
 Tumor Lysis Syndrome 
 
8.3.2. Toxicities Considerations 
 
8.3.2.1. 
Gastrointestinal Toxicities 
Gastrointestinal toxicity has early onset and occurs frequently within hours from dosing. 
Prophylactic antidiarrheal has shown efficacy in moderating symptoms. Antidiarrheal 
prophylaxis is recommended, but not mandatory, for patients who will be treated with 
idasanutlin. If necessary, an oral loading dose of 4 mg loperamide 30 minutes before the 
administration of study medication has been successfully used to reduce the frequency and 
severity of diarrhea. If diarrhea occurs, 2 mg loperamide should be administered orally every   4 


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hours or after every unformed stool to a maximum dose of 16 mg per 24 hours. It is recommended 
to monitor concomitant causes of GI toxicity, including Clostridium difficile infection, 
malabsorption/lactose intolerance, fecal impaction, dietary supplements high in fiber, and 
medications (e.g., stool softeners, laxatives, and antacids). Additional dietary measures could 
help to minimize risk. It is advised to discontinue all lactose-containing products, alcohol, and high 
osmolar supplements. Patients should be instructed to eat frequent small meals that include food 
with anti-diarrheal properties such as bananas, rice, apples, and toast. If diarrhea ≥ Grade 2 
occurs, electrolytes need to be monitored at least daily and adequate hydration may be achieved 
if necessary through IV fluids for electrolyte correction. 
Treatment to mitigate emesis may be given prophylactically and is strongly encouraged. 
The risk of nausea/vomiting should be managed symptomatically throughout treatment with 
idasanutlin. From 30 to 60 minutes before administration of study, 5-HT3-receptor antagonist 
administration with or without dexamethasone orally or IV may be sufficient to control symptoms. 
Rescue medication may include blockers of neurokinin 1 receptor (NK-1 RA). It is recommended 
to administer IV fluids and correct electrolytes as clinically required. 
 
8.3.2.2. 
Hematological Toxicities 
Patients treated with idasanutlin are at increased risk for infections for the effect on bone marrow 
progenitors and the related cytopenia. Patients should be closely monitored for infection, and 
prompt therapy and diagnostic procedures need to be performed as necessary. Idasanutlin has 
exposure-dependent suppressive effects on bone marrow progenitors. Prophylactic platelet 
transfusion is recommended when platelet count is < 10 x109/L or local institutional guidelines, 
and therapeutic transfusions are recommended when clinically indicated (any platelet value in the 
presence of hemorrhagic symptoms). The hemoglobin level should be maintained at > 9 g/dL in 
patients with documented cardiac insufficiency (ejection fraction < 50%). Growth factor support 
may be given per local guidelines for hematologic or solid tumor malignancies. 
 
8.4. Atezolizumab 
 
8.4.1. Anticipated Toxicities 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may 
increase the risk of immune-mediated adverse events, specifically the induction or enhancement 
of autoimmune conditions. Adverse events with potentially immune-mediated causes include: 
 Fatigue 
 Arthralgia 
 Asthenia 
 Anorexia 
 Diarrhea 
 Dyspnea 
 Urinary Tract Infection 
 Cough 
 Pruritis 
 Nausea 
 Fever 
 Rash 
 Vomiting 
 Musculoskeletal pain 
 Chills 


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 Dysphagia 
 Hypotension 
 Nasal congestion 
 Hypoxia 
 Flu-like symptoms 
 Thrombocytopenia 
 Abdominal pain 
 Diabetes 
 Nephritis 
 Endocrinopathies including hypothyroidism, hyperthyroidism, hypophysitis, adrenal 
insufficiency 
 Hepatitis/transaminitis 
 Pneumonitis 
 Colitis 
 Neurological disorders such as Myasthenia gravis, Guillian-Barre syndrome, and 
meningoencephalitis 
 Infusion-related reactions 
 Myocarditis 
 Pancreatitis 
 
8.4.2. Toxicity Considerations 
Toxicities associated or possibly associated with Atezolizumab treatment should be managed 
according to standard medical practice. Additional tests, such as autoimmune serology or 
biopsies, may be used to determine a possible immunogenic etiology. Although most immune- 
related adverse events (irAEs) observed with immunomodulatory agents 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, mycophenolate, or TNFα inhibitors. 
The primary approach to Grade 1 to 2 irAEs is supportive and symptomatic care with continued 
treatment with Atezolizumab; for higher-grade irAEs, Atezolizumab should be withheld and oral 
and/or parenteral steroids administered. Recurrent Grade 2 irAEs may also mandate withholding 
Atezolizumab or the use of steroids. Assessment of the benefit-risk balance should be made by 
the investigator, with consideration of the totality of information as it pertains to the nature of the 
toxicity and the degree of clinical benefit a given patient may be experiencing prior to further 
administration of Atezolizumab. Atezolizumab should be permanently discontinued in patients 
with life-threatening irAEs. 
 
8.4.2.1. 
Infusion-related reactions (IRRs) 
The management of infusion-related reactions (IRRs) will be according to severity as follows: 
 
In the event that a patient experiences a mild (NCI CTCAE Grade 1) IRR, the infusion rate 
should be reduced to half the rate being given at the time of event onset. Once the event 
has resolved, the investigator should wait for 30 minutes while delivering the infusion at the 
reduced rate.  If tolerated, the infusion rate may then be increased to the original rate. 
 
In the event that a patient experiences a moderate IRR (NCI CTCAE Grade 2) or flushing, 
fever, or throat pain, the infusion should be immediately interrupted and the patient should 
receive aggressive symptomatic treatment.  The infusion should be restarted only after  the 


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symptoms have adequately resolved to baseline grade. The infusion rate at restart should 
be half of the infusion rate that was in progress at the time of the onset of the IRR. 
 
For severe or life-threatening IRRs (NCI CTCAE Grade 3 or 4), the infusion should be 
stopped immediately, and aggressive resuscitation and supportive measures should be 
initiated. Patients experiencing severe or life-threatening IRRs will not receive further infusion 
and will be further managed as clinically indicated until the event resolves. 
 
8.4.2.2. 
Gastrointestinal Toxicity 
Immune-mediated colitis has been associated with the administration of Atezolizumab. Patients 
should be advised to inform the investigator if any diarrhea occurs, even if it is mild. 
If the event is of significant duration or magnitude, or is associated with signs of systemic 
inflammation or acute phase reactants (e.g., increased CRP or platelet count or bandemia), it is 
recommended that sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy with three 
to five specimens for standard paraffin block be performed. If possible, one or two biopsy 
specimens should be snap frozen and stored. 
Treatment may be restarted following the resolution of colitis. In addition, if the patient is being 
managed with corticosteroids, treatment should not be restarted until the steroids have been 
tapered down to a prednisone dose ≤ 10 mg/day. Patients who resume treatment should be 
monitored closely for signs of renewed diarrhea. 
 
8.4.2.3. 
Hepatotoxicity 
Immune-mediated hepatitis has been associated with the administration of Atezolizumab. While 
in this study, patients presenting with right upper-quadrant abdominal pain felt by the investigator 
to be possibly related to study treatment and/or unexplained nausea or vomiting should have 
LFTs performed immediately, and LFTs (AST/ALT) should be reviewed before administration of 
the next dose of study drug. 
In the presence of LFT abnormalities, neoplastic, concurrent medications, viral hepatitis, and toxic 
etiologies should be considered and addressed, as appropriate. Imaging of the liver, gall bladder, 
and biliary tree should be performed to rule out neoplastic or other causes of increased LFTs. 
Anti-nuclear antibody, perinuclear anti-neutrophil cytoplasmic antibody, anti-liver kidney 
microsomal, and anti-smooth muscle antibody tests should be performed if an autoimmune 
etiology is suspected. 
 
8.4.2.4. 
Dermatologic Toxicity 
Treatment-emergent rash has been associated with Atezolizumab. The majority of cases of rash 
were mild in severity and self-limited, with or without pruritus. 
A dermatologist should evaluate persistent and/or severe rash or pruritus. A biopsy should be 
performed unless contraindicated. Low-grade rash and pruritus irAEs have been treated with 
symptomatic therapy (e.g., antihistamines). Topical or parenteral corticosteroids may be required 
for more severe symptoms. 
 
8.4.2.5. 
Endocrine Toxicity 
Hypothyroidism has been associated with the administration of Atezolizumab. Patients with 
unexplained symptoms such as fatigue, myalgias, impotence, mental status changes, or 
constipation should be investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies, as well as for hyponatremia or hyperkalemia. 


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An endocrinologist should be consulted if an endocrinopathy is suspected. Thyroid-stimulating 
hormone (TSH) and free T4 levels should be obtained to determine whether thyroid abnormalities 
are present. TSH, prolactin, and a morning cortisol level will help to differentiate primary adrenal 
insufficiency from primary pituitary insufficiency. 
 
8.4.2.6. 
Pulmonary Toxicity 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of Atezolizumab and have primarily been observed in patients with 
underlying NSCLC. 
Mild-to-moderate events of pneumonitis have been reported with Atezolizumab. All pulmonary 
events should be thoroughly evaluated for other commonly reported etiologies such as 
pneumonia/infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, chronic 
obstructive pulmonary disease (COPD), or pulmonary hypertension and the following should be 
performed: 
 
Measurement of oxygen saturation (i.e., arterial blood gas) 
 
High-resolution CT scan of the chest 
 
Bronchoscopy with bronchoalveolar lavage and biopsy 
 
Pulmonary function tests (with diffusion capacity of the lung for carbon monoxide [DLCO]) 
Patients will be assessed for pulmonary signs and symptoms throughout the study. Patients will 
also have CT scans of the chest at every tumor assessment. 
 
8.4.2.7. 
Systemic Immune Activation 
Systemic immune activation (SIA) is a rare condition characterized by an excessive immune 
response. Given the mechanism of action of Atezolizumab, SIA is considered a potential risk 
when given in combination with other immunomodulating agents. SIA should be included in the 
differential diagnosis for patients who, in the absence of an alternative etiology, develop a sepsis 
like syndrome after administration of Atezolizumab, and the initial evaluation should include the 
following: 
 CBC with peripheral smear 
 PT, PTT, fibrinogen, and D-dimer 
 Ferritin 
 Triglycerides 
 AST, ALT, and total bilirubin 
 LDH 
 Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
If SIA is still suspected after the initial evaluation, contact the Medical Monitor for additional 
recommendations. 
 
8.4.2.8. 
Pancreatic Toxicity 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with administration of other immunomodulatory agents. The 
differential diagnosis of acute abdominal pain should include pancreatitis. Appropriate workup 
should include an evaluation for obstruction, as well as serum amylase and lipase tests. 


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8.4.2.9. 
Potential Eye Toxicity 
An ophthalmologist should evaluate visual complaints. Uveitis or episcleritis may be treated with 
topical corticosteroid eye drops. Atezolizumab should be permanently discontinued for immune- 
mediated ocular disease that is unresponsive to local immunosuppressive therapy. 
 
8.4.2.10. 
Immune-mediated Nephritis 
Immune-related nephritis has been associated with the administration of atezolizumab. Eligible 
patients must have adequate renal function, and 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 nonsteroidal 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. If no alternative cause of acute kidney injury is 
identified, patients with signs and symptoms of acute kidney injury, in the absence of an identified 
alternate etiology, should be treated according to the management guidelines for immune-related 
renal events in the table below. 
 
Event 
Management 
Grade 1 Renal Event 
• 
Continue atezolizumab. 
• 
Monitor kidney function, including creatinine, closely until values 
resolve to within normal limits or to baseline values. 
Grade 2 Renal Event 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Refer patient to renal specialist. 
• 
Initiate treatment with corticosteroids equivalent to 1- 2 
mg/kg/day oral prednisone. 
• 
If event resolves to Grade 1 or better, resume atezolizumab.b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Study Chair.c 
Grade 3 or 4 Renal 
Event 
• 
Permanently discontinue atezolizumab and contact Study Chair. 
• 
Refer patient to renal specialist and consider renal biopsy. 
• 
Initiate treatment with corticosteroids equivalent to 1- 2 
mg/kg/day oral prednisone. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE and are applicable to both CTCAE 
Version 4.0 and CTCAE Version 5.0. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if initiated) 
to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Study Chair. 
 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone before 
atezolizumab can be resumed. 
 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune- 
related event. Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Study Chair. 


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8.4.2.11. 
Immune-related Myositis 
Myositis or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are amongst the most common 
disorders. Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 
dermatomyositis), 
biochemical 
(serum 
creatinine-kinase 
increase), 
and 
imaging 
(electromyography/MRI) features, and is confirmed with a muscle-biopsy. One etiology of myositis 
is immune-mediated, which is the current concern with atezolizumab. 
 
It is recommended that atezolizumab should be withheld for moderate or severe (Grade 2 or 3) 
immune-related myositis and permanently discontinued for recurrent severe or life-threatening 
myositis (recurrent Grade 3 and Grade 4). Please refer the patient to rheumatologist and/or 
neurologist and consider muscle biopsy and supportive measures as clinically indicated. 
Corticosteroids treatment with 1-2 mg/kg/day IV methylprednisolone or higher-dose bolus if 
severely compromised (weakness severely limiting mobility, cardiac function, respiratory 
function, dysphagia) and/or additional immunosuppressive agents should be administered for ≥ 
Grade 2 events or if the event does not improve after initial corticosteroids. Please refer to the 
table below for detailed management guidelines for immune-mediated myositis. 
 
Management Guidelines for Immune-Related Myositis: 
 
Event 
Management 
Immune-related Myositis 
Grade 1 
• 
Continue atezolizumab 
• 
Refer patient to a rheumatologist or neurologist 
• 
Initiate treatment per institutional guidelines 
Immune-related Myositis 
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset 
and contact the Study Chair 
• 
Refer patient to a rheumatologist or neurologist 
• 
Initiate treatment per institutional guidelines 
• 
Consider treatment with corticosteroid equivalent to 1-2 
mg/kg/day IV methylprednisolone and convert to 1-2 
mg/kg/day oral prednisone or equivalent upon improvement 
• 
If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, resume atezolizumab 
• 
If event does not improve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Study Chair. 


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


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8.5. Dose Modifications/ Delays and Toxicity Management 
 
 
Atezolizumab 
 There will be no dose reduction for Atezolizumab in this study. 
• 
If atezolizumab is withheld and corticosteroids are initiated for an atezolizumab-related toxicity, 
corticosteroids must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent before 
atezolizumab can be resumed. 
• 
Atezolizumab may be withheld for a period of time up to 12 weeks to allow for corticosteroids to be reduced 
to ≤ 10 mg/day oral prednisone or equivalent. If Atezolizumab is held because of AEs for > 12 weeks beyond 
the scheduled date of infusion, the patient will be discontinued from Atezolizumab and will be followed for 
safety and efficacy as specified in the protocol. 
 Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event. Patients can be rechallenged with atezolizumab only after approval has 
been documented by both the investigator (or an appropriate delegate) and the Medical Monitor. 
 Dose interruptions for reasons other than toxicity, such as surgical procedures, may be allowed. The 
acceptable length of interruption will be at the discretion of the Protocol Chair. 
 Patients should be assessed clinically (including review of laboratory values) for toxicity prior to, during, and 
after each infusion. If unmanageable toxicity due to Atezolizumab occurs at any time during the study, 
treatment with Atezolizumab should be discontinued. 
Cobimetinib 
• All dose modifications should be based on the worst preceding toxicity. Once a dose has been reduced it will 
not be increased at a later time even if there is no toxicity. Patients who require dose reductions of 
Cobimetinib past the lowest dose level will be discontinued from study drugs treatment. 
• If a patient requires a dose delay of > 28 consecutive days from the intended day of the next scheduled dose 
of Cobimetinib, due to study related interventions, then the patient must be discontinued from the study 
treatment. 
• Patients that require a dose delay of > 28 days due to a cause unrelated to study participation will have the 
opportunity to continue study if deemed eligible to do so by the Protocol Chair of the study. 
• Patients who discontinue from the study for a study-related adverse event (AE) or an abnormal laboratory 
value must be followed at least once a week for 4 weeks and subsequently at 4-week intervals, until 
resolution or stabilization of the event, whichever comes first, except specifically mentioned. 
Cobimetinib dose level reductions 
Starting 
dose 
First 
reduction 
Second 
reduction 
Third 
reduction 
60 mg 
40 mg 
20 mg 
Discontinue 
Idasanutlin 
• All dose modifications should be based on the worst preceding toxicity. Once a dose has been reduced it will 
not be increased at a later time even if there is no toxicity. Patients who require dose reductions of Idasanutlin 
past the lowest dose level will be discontinued from study drugs treatment. 
• If a patient requires a dose delay of > 28 consecutive days from the intended day of the next scheduled dose 
of Idasanutlin, due to study related interventions, then the patient must be discontinued from the study 
treatment. 
• Patients that require a dose delay of > 28 days due to a cause unrelated to study participation will have the 
opportunity to continue study if deemed eligible to do so by the Protocol Chair of the study. 


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• Patients who discontinue from the study for a study-related adverse event (AE) or an abnormal laboratory 
value must be followed at least once a week for 4 weeks and subsequently at 4-week intervals, until 
resolution or stabilization of the event, whichever comes first, except specifically mentioned. 
Idasanutlin dose level reductions 
Starting dose 
First 
reduction 
Second 
reduction 
Third 
reduction 
Fourth reduction 
200 mg 
150 mg 
100 mg 
50 mg 
Discontinue 
150 mg 
100 mg 
50 mg 
Discontinue 
100 mg 
50 mg 
Discontinue 
Cardiac (Cobimetinib or Atezolizumab) 
Ejection fraction 
decrease or 
congestive heart 
failure 
Management of Asymptomatic LVEF Decrease from Baseline: 
• 
Withhold cobimetinib dosing for at least 2 weeks for either: 
– 
A drop in LVEF to  < 40% or 
– 
LVEF of 40% to 49% with a ≥ 10% absolute decrease below pretreatment values 
• 
If LVEF improves to ≥ 40% or to < 10% absolute decrease below pre-treatment 
values, resume cobimetinib at: 
– 
1st dose level down for first appearance of LVEF decline 
– 
2nd dose level down for second appearance of LVEF decline 
– 
Permanently discontinue cobimetinib for a third episode of LVEF decline 
– 
In patients restarting cobimetinib after a dose reduction or interruption, evaluate 
LVEF at approximately 2, 4, 10 and 16, and then as clinically indicated 
• 
If LVEF remains < 40% or ≥ 10% absolute decline below pretreatment values after 
withholding cobimetinib for at least 2 weeks, consider permanently discontinuing 
cobimetinib 
• 
Continue atezolizumab as clinically indicated 
Management of Symptomatic LVEF Decrease from Baseline: 
• 
Consider holding atezolizumab; discuss with Medical Monitor regarding resumption of 
atezolizumab 
• 
Cardiology consultation strongly recommended 
• 
Withhold cobimetinib dosing for at least 4 weeks for symptomatic LVEF decrease. 
• 
Permanently discontinue cobimetinib if after 4 weeks patient continues to have 
symptomatic heart failure despite maximal supportive care or if LVEF has not 
recovered to  ≥ 40% or to  < 10% absolute decrease below pretreatment values. 
• 
If heart failure symptoms have resolved following treatment break and LVEF has 
recovered to ≥ 40% or to < 10% absolute decrease below pretreatment values, 
resume cobimetinib at: 
– 
1st dose level down for first appearance of LVEF decline 
– 
2nd dose level down for second appearance of LVEF decline 
– 
Permanently discontinue cobimetinib for a third episode of LVEF decline 
Hematology (Cobimetinib or Idasanutlin) 
ANC decreased (Neutropenia) 
Grade 1 / 2 
Maintain dose level of Cobimetinib or Idasanutlin. 
Grade 3 
Omit dose of Cobimetinib or Idasanutlin until ANC ≥ 1000/mm3, then 
- If resolved in ≤ 7 days, then maintain dose level of Cobimetinib or Idasanutlin. 
- If resolved in > 7 days, then ↓ 1 dose level of Cobimetinib or Idasanutlin. 
Grade 4 
Omit dose of Cobimetinib until ANC ≥ 1000/mm3, then ↓ 1 dose level of Cobimetinib or 
Idasanutlin. 


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Anemia 
Grade 1 / 2 
Maintain dose level of Cobimetinib or Idasanutlin. 
Grade 3 
Omit dose of Cobimetinib or Idasanutlin until resolved to CTCAE Grade ≤ 1 or baseline 
Grade 4 
Discontinue Cobimetinib or Idasanutlin. 
Febrile neutropenia 
Grade 3 
Omit dose of Cobimetinib or Idasanutlin, then 
- If resolved by ≤ 7 days, then, ↓ 1 dose level of Cobimetinib or Idasanutlin. 
- If not resolved within 7 days discontinue Cobimetinib or Idasanutlin. 
Grade 4 
Discontinue Cobimetinib or Idasanutlin. 
Platelet count decreased (Thrombocytopenia) 
Grade 1 / 2 
Maintain dose level of Cobimetinib or Idasanutlin. 
Grade 3 
Omit dose of Cobimetinib or Idasanutlin until resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then ↓ 1 dose level of Cobimetinib or Idasanutlin. 
- If resolved in > 7 days and/or with signs of bleeding, then discontinue patient from 
Cobimetinib or Idasanutlin. 
Grade 4 
Discontinue Cobimetinib or Idasanutlin. 
Pulmonary (Cobimetinib or Atezolizumab) 
General 
guidance 
Mild-to-moderate events of pneumonitis have been reported with atezolizumab and 
cobimetinib. All pulmonary events should be thoroughly evaluated for other commonly 
reported etiologies such as pneumonia/infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary hypertension. 
For events concerning for pneumonitis, consider comprehensive infectious evaluation 
including viral etiologies. 
Pneumonitis, 
grade 1 
(asymptomatic) 
• Continue atezolizumab and cobimetinib. 
• Re-evaluate on serial imaging. 
• Consider patient referral to pulmonary specialist. 
• For recurrent pneumonitis, treat as Grade 3 or 4 event. 
Pneumonitis, 
grade 2 
• Withhold atezolizumab and cobimetinib. 
• Refer patient to pulmonary and infectious disease specialists and consider bronchoscopy 
or BAL. 
• If bronchoscopy is consistent with immune-related etiology, initiate treatment with 1−2 
mg/kg/day oral prednisone or equivalent. 
• Resume atezolizumab and cobimetinib if event resolves to Grade 1 or better within 12 
weeks. 
• Permanently discontinue atezolizumab and cobimetinib and contact Medical Monitor if 
event does not resolve to Grade 1 or better within 12 weeks. 
• For recurrent events, treat as a Grade 3 or 4 event. 
Pneumonitis, 
grade 3/4 
• Permanently discontinue atezolizumab and cobimetinib.c 
• Refer patient to pulmonary and infectious disease specialists and consider bronchoscopy 
or BAL. 
• If bronchoscopy is consistent with immune-related etiology, initiate treatment with 1−2 
mg/kg/day oral prednisone or equivalent. 
• If pulmonary event does not improve within 48 hr or worsens, consider adding an 
immunosuppressive agent (e.g., infliximab, cyclophosphamide, IV Ig, or mycophenolate 
mofetil). 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 


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Hepatic (Cobimetinib or Atezolizumab) 
AST/ALT > ULN 
to ≤ 3 × ULN with 
total 
bilirubin < 2 × ULN 
(Grade 1) 
• Continue atezolizumab and cobimetinib. 
• Continue with the standard monitoring plan (i.e., LFTs q4w before dosing). 
AST/ALT > 3 × baseli 
ne values 
to < 5 × ULN with 
total 
bilirubin < 2 × ULN 
(Grade 2) 
• Continue all study treatment. 
• Monitor LFTs at least weekly. 
• Consider referral to a hepatologist and liver biopsy. 
• For suspected immune related events of > 5 days duration 
o Consider withholding atezolizumab 
o Consider administering 1-2 mg/kg/day oral prednisone or equivalent followed by ≥ 
1 month taper 
o Restart atezolizumab if event resolves to Grade 1 or better within 12 weeks 
o Permanently discontinue atezolizumab and cobimetinib if event does not resolve 
to Grade 1 or better within 12 weeks 
AST/ALT > 5 × baseli 
ne values 
to < 10 × ULN with 
total 
bilirubin < 2 × ULN 
(Grade 3) 
• Continue all study treatment. 
• Monitor LFTs at least weekly. 
• Consider referral to a hepatologist and liver biopsy. 
• For suspected immune related events 
o Withhold atezolizumab 
o Consider administering 1-2 mg/kg/day oral prednisone or equivalent followed by ≥ 
1 month taper 
o 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. 
o Permanently discontinue atezolizumab and cobimetinib if event does not resolve 
to Grade 1 or better within 12 weeks Continue all study treatment. 
AST/ALT > 3 × ULN 
with 
bilirubin > 2  × ULN 
• Withhold atezolizumab and cobimetinib. 
• Consult hepatologist and consider liver biopsy. 
• Consider administering 1-2 mg/kg/day oral prednisone or equivalent followed by ≥ 1 
month taper (for possible autoimmune hepatitis). 
• If LFTs do not decrease within 48 hr after initiation of systemic steroids, consider 
adding an immunosuppressive agent (e.g., mycophenolate or TNF-α antagonist). 
• Monitor LFTs every 48−72 hr until decreasing and then follow weekly. 
• Restart atezolizumab at fixed dose and cobimetinib at 1 dose reduction after 
discussion with medical monitor if AST/ALT < 3 × ULN with bilirubin < 2 × ULN and 
steroid dose < 10 mg oral prednisone equivalent per day. 
• Permanently discontinue atezolizumab and cobimetinib for life-threatening hepatic 
events, and contact the Protocol Chair. 


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AST/ALT > 10 × ULN 
• Permanently discontinue atezolizumab and cobimetinib. 
• Consult hepatologist and consider liver biopsy. 
• Consider administering 1−2 mg/kg/day oral prednisone or equivalent (for possible 
autoimmune hepatitis). If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ _1 month. 
• If LFTs do not decrease within 48 hr after initiation of systemic steroids, addition of 
an alternative immunosuppressive agent (e.g., mycophenolate or TNF-α antagonist) 
or dose escalation of corticosteroids may be considered. 
• Monitor LFTs every 48−72 hr until decreasing and then follow weekly. 
Endocrine (Atezolizumab) 
Asymptomatic 
hyperthyroidism 
• 
Withhold Atezolizumab 
• 
Resume Atezolizumab at the same doses when symptoms are controlled and 
thyroid function is improving. 
• 
TSH < 0.1 mU/L: Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
hyperthyroidism 
• Withhold Atezolizumab 
• Resume Atezolizumab when symptoms are controlled and thyroid function is 
improving. 
• Permanently discontinue Atezolizumab for life-threatening immune-related 
hyperthyroidism. 
Symptomatic adrenal 
insufficiency, Grade 
2, 3, or 4 
• Withhold Atezolizumab 
• Resume Atezolizumab if event resolves to Grade 1 or better within 12 weeks 
• Permanently discontinue Atezolizumab if event does not resolve to Grade 1 or 
better within 12 weeks 
Hyperglycemia, 
Grade 3 or 4 
• 
Withhold Atezolizumab 
• Resume Atezolizumab when symptoms resolve and glucose levels are stable. 
Ocular (Cobimetinib or Atezolizumab) 
General guidance 
• An ophthalmologist should evaluate visual complaints. 
• Uveitis or episcleritis and other immune−mediated ocular disease may be 
associated with atezolizumab and may be treated with topical corticosteroid eye 
drops. Atezolizumab should be permanently discontinued for immune-related ocular 
event that is unresponsive to local immunosuppressive therapy. 
• Serous retinopathy is associated with cobimetinib. In clinical trials, most events were 
Grade 1 (asymptomatic) or 2 (symptomatic).  Most events in clinical trials resolved 
or improved to asymptomatic grade 1 following dose interruption or reduction. If 
serous retinopathy is diagnosed, cobimetinib should be withheld until visual 
symptoms improve to Grade ≤1.   Serous retinopathy can be managed with 
treatment interruption, dose reduction or with treatment discontinuation. 
• Retinal vein occlusion (RVO) has been reported in patients treated with MEK 
inhibitors other than cobimetinib. 
Serous retinopathy 
Severity grade 
assessment based 
on NCI CTCAE v4 
“Eye Disorders – 
Other” scale 
Serous retinopathy, Grade 1  or 2 (tolerable): 
• Continue cobimetinib and atezolizumab without dose change. 
• Continue ophthalmology follow-up as clinically indicated. 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
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Serous retinopathy, Grade 2 (intolerable) or 3/4: 
• Interrupt cobimetinib until grade ≤1. 
• Continue atezolizumab as clinically indicated. 
• Consult ophthalmology and undergo complete ophthalmologic examination, which 
includes visual acuity testing, intra-ocular pressure measurements, slit lamp 
ophthalmoscopy, indirect ophthalmoscopy, visual field, and OCT. Consider a 
fluorescein angiogram and/or indocyanine green angiogram, if clinically indicated. 
• Cobimetinib should be dose reduced by 1 dose level when restarting. 
Consider permanent discontinuation of cobimetinib if serous retinopathy recurs 
despite 2 dose level reductions 
Retinal vein 
occlusion (any 
grade) 
• If RVO (any grade) is diagnosed, cobimetinib dosing should be permanently 
discontinued and RVO treated per institutional guidelines. 
• Continue atezolizumab. 
Potential immune- 
related ocular toxicity 
(e.g., uveitis, iritis, 
episcleritis, or 
retinitis) 
Grade 1: continue atezolizumab (if symptoms persist, treat as grade 2) 
Grade 2: 
• hold atezolizumab 
• resume atezolizumab if event resolves to grade 1 or better within 12 weeks 
• permanently discontinue atezolizumab if event does not resolve to grade 1 or better 
within 12 weeks 
Grade 3 or 4: permanently discontinue atezolizumab 
CK/ CPK elevation (Cobimetinib or Atezolizumab) 
General guidance 
• Rule out cardiac cause (check ECG, serum cardiac troponin, and CPK-isoforms M 
and B fraction) and rule out rhabdomyolysis (clinical examination; serum creatinine, 
potassium, calcium, phosphorus, uric acid, and albumin; and urine myoglobin). 
• Assess patient for any history of strenuous physical activity, blunt trauma, or recent 
IM injections. 
For Grade ≤ 3 CPK 
elevations that are 
asymptomatic and 
deemed not clinically 
significant 
• Cobimetinib and atezolizumab dosing does not need to be modified or interrupted to 
manage asymptomatic Grade ≤ 3 creatine phosphokinase (CPK) elevations. 
• Recheck CPK at least once a week. 
For Grade 4 CPK 
elevations that are 
asymptomatic and 
deemed not clinically 
significant 
• Interrupt cobimetinib and atezolizumab treatment. 
• If improved to Grade ≤ 3 within 4 weeks, restart cobimetinib at a dose reduced by 20 
mg, if clinically indicated. 
• If CPK elevations do not improve to Grade ≤3 within 4 weeks following dose 
interruption, permanently discontinue cobimetinib treatment. 
• Resumption of atezolizumab may be considered in patients who are deriving 
benefit. 
Rhabdomyolysis or 
symptomatic CPK 
elevations 
• Interrupt cobimetinib and atezolizumab treatment. 
• If severity is improved by at least one grade and symptoms resolve within 4 weeks, 
restart cobimetinib at a dose reduced by 20 mg, if clinically indicated. 
• If rhabdomyolysis or symptomatic CPK elevations do not improve within 4 weeks, 
permanently discontinue cobimetinib treatment 
• Resumption of atezolizumab may be considered in patients who are deriving benefit 
after discussion with the Protocol Chair. 


BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
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Gastrointestinal (Cobimetinib or Atezolizumab or Idasanutlin) 
Diarrhea 
General Guidance 
• All events of diarrhea or colitis should be thoroughly evaluated for more common 
etiologies other than drug induced effects. 
• For events of significant duration or severity or associated with signs of systemic 
inflammation or acute phase reactants, check for immune-related colitis. 
• Administer anti-diarrheal agents and other maximal supportive care per institutional 
guidelines such as: at the first report of watery diarrhea or loose stool, initiate 
maximal anti-diarrheal supportive care (Lomotil and loperamide). 
• Suggested regimen: 
o Loperamide: Initiate dose with 4 mg, then 4 mg/6 hr around the clock, alternating 
with Lomotil. 
o Lomotil (diphenoxylate and atropine): 2 tablets (diphenoxylate 5 mg, atropine 
0.05 mg) every 6 hr around the clock 
o Continue Lomotil and loperamide until no loose stools for 24 hours. 
o If Grade ≤ 2 diarrhea persists after 48 hr total treatment with Lomotil and  
loperamide, consider second-line agents (e.g., octreotide, budesonide, tincture 
of opium).  
• Oral supplementation: 
o Initiate oral supplementation of potassium and/or magnesium if serum levels are 
< LLN. 
o Consider oral rehydration therapy (e.g., Pedialyte) for Grade ≥ 1 diarrhea or  
vomiting.  
• Dietary modifications: 
o Stop all lactose-containing products and eat small meals. 
o The BRAT (banana, rice, apples, toast) diet, without fiber (other vegetables and 
fruits), may be helpful. 
o Encourage adequate hydration with salt-containing liquids, such as broth or 
Gatorade. 
Diarrhea, Grade 1 or 
Grade 2 (tolerable) 
• Continue atezolizumab, idasanutlin and cobimetinib. 
• Initiate supportive care and monitor patient closely. 
• Investigate etiology, referring patient to GI specialist for evaluation of possible colitis 
if appropriate. 
Diarrhea, Grade 2 
(intolerable) or 
Grade 3 
• Withhold atezolizumab, idasanutlin and cobimetinib. 
• Initiate supportive care and monitor patient closely. 
• Discontinue medications that may exacerbate colitis (e.g., NSAIDS) while 
investigating etiology. 
• Investigate etiology, referring patient to GI specialist for evaluation of possible 
colitis, including biopsy if appropriate. 
• If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at fixed 
dose.  If not, permanently discontinue atezolizumab, idasanutlin and cobimetinib. 
• If event resolves to Grade 1 or better within 28 days, resume cobimetinib and 
idasanutlin with dose reduced by one level. If not, permanently discontinue 
cobimetinib and idasanutlin. 


BRE 17107: Atezolizumab, Idasanutlinand Cobimetinib inmetastatic ER+breast cancer 
Protocol Chair.  Ingrid Mayer 
 
VAN   D E 1tn  1 LT V 
u  N 1V E R S 1 T Y 
MliOICAI.. G ENT ER 
 
 
Diarrhea, Grade4 
• Permanently discontinueatezolizumab, idasanutlin and cobimetinib, and contact 
Medical Monitor.c 
• Initiate supportive care and monitor patient closely. 
• Discontinue medications that may exacerbate colitis (e.g., NSAIDS) while 
investigating etiology. 
• Rule out bowel perforation. 
• Investigate etiology, referring patient to GI specialist for evaluation of possible 
colitis, including biopsy if appropriate. 
Colitis, Grade 1 
• Continue atezolizumab, idasanutilin and cobimetinib. 
• Initiate supportive care and monitor patient closely. 
• Discontinue medications that may exacerbate colitis (e.g., NSAIDS). 
• Refer patient to gastrointestinal specialist for evaluation and confirmatory biopsy if 
symptoms persist for > 7 days. 
Colitis, Grade 2 
• Withhold atezolizumab, idasanutilin and cobimetinib. 
• Initiate supportive care and monitor patient closely. 
• Discontinue medications that may exacerbate colitis (e.g., NSAIDS). 
• Refer patient to gastrointestinal specialist for evaluation and confirmatory biopsy. 
• For recurrent events or events that persist D 5 days, initiate treatment with 1- 2 
mg/kg/day oral prednisone or equivalent. 
• If event resolves to Grade 1 or better within 12 weeks, resume atezolizumab at fixed 
dose. If not, permanently discontinue atezolizumab, idasanutilin and cobimetinib 
• If event resolves to Grade 1 or better within 28 days, resume cobimetinib and 
idasanutilin with dose reduced by one level. If not, permanently discontinue 
cobimetinib and idasanutilin. 
Colitis, Grade 3 
• Withhold atezolizumab, idasanutlin and cobimetinib. 
• Initiate supportive care and monitor patient closely. 
• Discontinue medications that may exacerbate colitis (e.g., NSAIDS). 
• Refer patient to gastrointestinal specialist for evaluation and confirmatory biopsy. 
• Initiate treatment with 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 resolves to Grade 1 or better within 12 weeks, resume atezolizumab at fixed 
dose. If not, permanently discontinue atezolizumab, cobimetinib and idasanutlin 
• If event resolves to Grade 1 or better within 28 days, resume cobimetinib with dose 
reduced by one level. If not, permanently discontinue cobimetinib and idasanutlin. 
Colitis, Grade 4 
• Permanently discontinue atezolizumab, idasanutlin and cobimetinib, and contact 
Medical Monitor. 
• Initiate supportive care and monitor patient closely. 
• Discontinue medications that may exacerbate colitis (e.g., NSAIDS). 
• Refer patient to gastrointestinal specialist for evaluation and confirmatory biopsy. 
• Initiate treatment with 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. 
 
Protocol Version 3114/2019 
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BRE 17107: Atezolizumab, Idasanutlin and Cobimetinib in metastatic ER+ breast cancer 
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Nausea and Vomiting (Cobimetinib or Idasanutlin) 
Grade 1 / 2 
Continue Cobimetinib or Idasanutlin at same doses. 
Begin maximum supportive care and adequate anti-emetic treatments 
Grade 3 / 4 
Begin maximum supportive care and adequate combination anti-emetic treatments, 
including ondansetron and aprepitant. 
May delay Cobimetinib or Idasanutlin dosing (up to 28 days) until Grade ≤ 1 on 
maximum supportive care and then restart but decrease dose one level. 
Permanently discontinue if after restarting, the patient experiences persistent nausea 
and/or vomiting despite prophylaxis and treatment requiring need to withhold 
treatment. 
Pancreatic toxicity (Atezolizumab) 
Amylase or 
lipase elevation, 
Grade 3 or 4 
• Withhold Atezolizumab. 
• Resume Atezolizumab if event resolves to Grade 1 or better within 12 weeks 
• Permanently discontinue Atezolizumab if event does not resolve to Grade 1 or 
better within 12 weeks 
• For recurrent events, permanently discontinue Atezolizumab 
Immune-related 
pancreatitis, Grade 2 
or 3 
• Withhold Atezolizumab 
• Resume Atezolizumab if event resolves to Grade 1 or better within 12 weeks 
• Permanently discontinue Atezolizumab if event does not resolve to Grade 1 or 
better within 12 weeks 
• For recurrent events, permanently discontinue Atezolizumab 
Immune-related 
pancreatitis, Grade 4 
Permanently discontinue Atezolizumab. 
Skin and subcutaneous  (Cobimetinib or Atezolizumab) 
General guidance 
A dermatologist should evaluate persistent and/or severe rash or pruritus. A biopsy 
should be considered unless contraindicated. 
Dermatologic event, 
Grade 1/2 
• Continue atezolizumab and cobimetinib. 
• Initiate supportive care (e.g., antihistamines, topical corticosteroids). If event does 
not improve, consider treatment with higher-potency topical corticosteroids. 
• For grade 2 rash, consider referral to dermatologist. 
Acneiform rash: 
• Consider topical corticosteroids (e.g., hydrocortisone 2.5%, alclometasone) and oral 
antibiotics (minocycline, doxycycline, or antibiotics covering skin flora) as clinically 
indicated. 


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Dermatologic event, 
Grade 3 
• Withhold atezolizumab and cobimetinib. 
• Refer patient to dermatologist.  A biopsy should be performed if appropriate. 
• Consider initiating treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 1−2 mg/kg/day if event does not improve within 48−72 hours. 
• If event resolves to Grade 2 or better within 12 weeks, resume atezolizumab at fixed 
dose.  If not, permanently discontinue atezolizumab and cobimetinib 
• Permanently discontinue atezolizumab and cobimetinib and contact Medical Monitor 
if event does not resolve to Grade 1 or better within 12 weeks. 
• If event resolves to Grade 2 or better within 28 days, resume cobimetinib with dose 
reduced by one level.  If not, permanently discontinue cobimetinib. 
Acneiform rash: 
Consider continuation of topical corticosteroids (e.g., 2.5% alclometasone) and oral 
antibiotics (e.g., minocycline, doxycycline or antibiotics covering skin flora) when 
restarting cobimetinib. 
Dermatologic event, 
Grade 4 
Permanently discontinue atezolizumab and cobimetinib, and contact Medical Monitor. 
General (Cobimetinib or Idasanutilin) 
Fatigue/ asthenia 
Grade 1 / 2 
Maintain dose level of Cobimetinib or Idasanutlin. 
Grade 3 
Omit dose of Cobimetinib or Idasanutlin until resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, maintain dose level of Cobimetinib or Idasanutlin. 
- If resolved in > 7 days, discontinue patient from Cobimetinib or Idasanutlin. 
Neurologic (Atezolizumab) 
Immune-related 
neuropathy, Grade 2 
• Withhold Atezolizumab. 
• Resume Atezolizumab if event resolves to Grade 1 or better within 12 weeks 
• Permanently discontinue Atezolizumab if event does not resolve to Grade 1 or 
better within 12 weeks 
Immune-related 
neuropathy, Grade 3 
or 4 
Permanently discontinue Atezolizumab 
Myasthenia gravis 
and Guillain-Barré, 
all grades 
Permanently discontinue Atezolizumab 
Immune-related 
meningoencephalitis, 
all grades 
Permanently discontinue Atezolizumab 
Other AEs 
Grade 1 / 2 
Maintain dose level of Atezolizumab, Cobimetinib or Idasanutlin 
Grade 3 
Omit dose of Atezolizumab, Cobimetinib or Idasanutlin until resolved to CTCAE Grade 
≤ 1 within 28 days, then ↓ dose level of Cobimetinib. If adverse event persists > 28 
days, permanently discontinue Cobimetinib or Idasanutlin 
Grade 4 
Discontinue Atezolizumab, Cobimetinib or Idasanutlin. 


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8.6. Special Considerations 
• 
For toxicities which are considered by the treating investigator unlikely to develop into serious 
or life–threatening events (e.g. alopecia, altered taste etc.), treatment may be continued at 
the same dose without reduction or interruption. 
• 
The treating investigator may reduce a subject’s dose for a toxicity of any grade/duration 
where s/he believes it to be in the best interests of the subject. 
 Any consideration to modification of the above dose modification guidelines should be 
discussed with the Principal Investigator for approval or disapproval in advance. 
 If a toxicity requiring Cobimetinib or Idasanutlin permanent drug interruption occurs, 
Atezolizumab can be continued as a single-agent 
 If a toxicity requiring Atezolizumab permanent drug interruption occurs, patients will come off 
both study drugs 
 
Diagnostic Criteria and Recommended Management for Systemic Immune Activation 
(applicable only when alternative etiologies have been excluded) 
Major Criteria 
Minor Criteria 
• Fever ≥ 38.5°C on more than one occasion 
• Ferritin ≥ 3000 ng/mL 
• Cytopenias (Grade ≥ 2 in two or more 
lineages) 
• Age-adjusted soluble IL-2 receptor 
elevated by ≥ 2 standard deviations 
• Severe dysfunction in two or more organs 
• Decreased fibrinogen 
• Splenomegaly 
• Hemophagocytosis in bone marrow, spleen, or lymph 
nodes 
• Elevated GGT or LFTs (AST, ALT, or total bilirubin) 
• Elevated triglycerides 
• Elevated LDH 
• Decreased natural killer cell activity 
Diagnosis and Management of Systemic Immune Activation 
Number of 
Criteria 
Diagnosis 
Action to Be Taken 
≥ 4 major criteria 
Consistent 
with 
systemic 
immune 
activation 
• Permanently discontinue atezolizumab. 
• Consider treatment with an immunosuppressive agent 
(i.e., tocilizumab, infliximab, cyclosporine A, or etoposide) and IV 
corticosteroids (i.e., methylprednisolone 1 g once daily or equivalent). 
• Consider HLH-94 protocol if there is no clinical improvement. 
3 major criteria 
OR 
2 major plus 
≥ 3 minor criteria 
Probable 
systemic 
immune 
activation 
• Depending on clinical severity, follow guidelines for “Consistent with 
systemic immune activation” or “Possible systemic immune 
activation” diagnosis. 
2 major plus 
≤ 2 minor criteria 
OR 
1 major plus 
≥ 4 minor criteria 
Possible 
systemic 
immune 
activation 
• Withhold atezolizumab. 
• Consider treatment with IV corticosteroids. 
• Follow guidelines for “Consistent with systemic immune activation” 
diagnosis if there is no clinical improvement or if clinical worsening 
occurs. 
• If clinical improvement occurs, atezolizumab may be resumed 
following a benefit-risk assessment. 


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9. DRUG FORMULATION/STORAGE/SUPPLY 
 
9.1. Cobimetinib 
 
9.2. 
Supply 
Cobimetinib is an investigational agent and will be supplied free-of-charge from Genentech. 
 
9.2.1. 
Formulation 
The 20-mg Cobimetinib drug product is a film-coated, immediate release tablet. The white tablet 
is round with the engraving “ROCHE” on one side. Cobimetinib will be packaged in both bottles 
and blister packs. The inactive ingredients in Cobimetinib are as follows: lactose monohydrate, 
microcrystalline cellulose, croscarmellose sodium, and magnesium stearate for the tablet core. 
The tablet coating consists of polyvinyl alcohol-part hydrolyzed, titanium dioxide, polyethylene 
glycol 3350, and talc. For further details, see the Cobimetinib Investigator’s Brochure. 
 
9.2.2. Dosage, Administration, and Storage 
Cobimetinib should not be stored above 25°C (77°F). If study drug is stored outside of the 
permitted temperature ranges, quarantine the affected supply and contact the Coordinating 
Center (who will contact Genentech, the drug supplier). The dose level of Cobimetinib to be tested 
in this study is 60 mg PO by self-administration daily on days 1 – 21 of each cycle, every 28 days. 
 
9.3. Idasanutlin 
 
9.3.1. Supply 
Idasanutlin is an investigational agent and will be supplied free-of-charge from Genentech. 
 
9.3.2. Formulation 
The 50 mg, 200 mg, 300 mg, and 400 mg film−coated tablets with idasanutlin (SDP) that have 
been optimized for use in current and future studies and as market formulation contain the 
excipients copovidone, microcrystalline cellulose, croscarmellose sodium, crospovidone, colloidal 
silicon dioxide, magnesium stearate, and a film coat. The film coat of the 50 mg as well as 200 
mg tablets consists of polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide 
yellow, iron oxide red, and iron oxide black. The film coat of the 300 mg dose strength consists of 
polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. The film coat of the 400 mg dose 
strength consists of polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide 
yellow. 
 
9.3.3. Dosage, Adminitration, and Storage 
Idasanutlin should not be stored above 25°C (77°F). The dose levels of Idasanutlin to be tested 
in this study are 300 - 500 mg PO by self-administration daily on days 1 – 5 of each cycle, every 
28 days. 
 
9.4. Atezolizumab 
 
9.4.1. Supply 
Atezolizumab (MPDL3280A) is an investigational agent and will be supplied free-of-charge from 
Genentech. 


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9.4.2. Formulation 
The Atezolizumab drug product is provided in a single-use, 20-cc USP/Ph. Eur. Type 1 glass vial 
as a colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution intended for IV 
administration. The vial contains ~20 mL (1200 mg) of Atezolizumab solution. The Atezolizumab 
drug product is formulated as 60 mg/mL Atezolizumab in 20 mM histidine acetate, 120 mM 
sucrose, 0.04% polysorbate 20, pH 5.8. 
Atezolizumab must be refrigerated at 2°C–8°C (36°F–46°F) upon receipt until use. Vials should 
not be used beyond the expiration date provided by the manufacturer. No preservative is used in 
the Atezolizumab drug product; therefore, each vial is intended for single use only. Discard any 
unused portion of drug left in a vial. Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. For further details on the storage and preparation of Atezolizumab, 
see the Investigator’s Brochure. 
 
9.4.3. Dosage, Administration, and Storage 
The dose level of Atezolizumab to be tested in this study is 840 mg administered by IV infusion 
every 2 weeks (14 [± 2] days). Atezolizumab will be delivered in infusion bags with IV infusion 
lines that have product contacting surfaces of polyvinyl chloride (PVC) or polyolefin and 0.2 µm 
in-line filters (filter membrane of polyethersulfone [PES]). No incompatibilities have been 
observed between Atezolizumab and PVC or polyolefin infusion materials (bags or infusion lines). 
 
9.5. Drug Accountability 
Clinical drug supply must be accounted for and patients will be asked to return all unused study 
drug and packaging on a regular basis, at the end of the study or at the time of study drug 
discontinuation. Accountability for the drug at all study sites is the responsibility of the principal 
investigator and designated Pharmacy representative. The investigator will ensure that the 
investigational drug is used only in accordance with this protocol. Drug accountability records 
indicating the drug’s delivery date to the site, inventory at the site, use by each patient, and 
destruction/disposal per institutional policy will be maintained by the clinical site. Accountability 
records will include dates, quantities, lot numbers, expiration dates, and patient numbers. 
At the conclusion of the study, and, as appropriate during the course of the study, the investigator 
will return all used and unused study drug, packaging, drug labels, and a copy of the completed 
drug accountability ledger to Genentech. 
 
10. CORRELATIVE/SPECIAL STUDIES 
 
10.1. 
Overview 
The correlative studies will focus on: 
1) Pharmacodynamic evaluation of the effect of Cobimetinib and Idasanutlin using paired 
biopsies; 
2) Evaluation of the effects of MEK and MDM2 inhibition on the tumor-immune microenvironment 
prior to initiating Atezolizumab; 
3) Evaluation of the effects of MEK and MDM2 inhibition on the peripheral blood T cell repertoire 
and immunophenotype before and after initiating Atezolizumab; and 
4) Correlation of items (1 - 3) with clinical response of the combination. 


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10.2. 
Blood Samples 
Tubes should be packed according to the Lab manual and sent immediately (within 24 h). 
 
10.2.1. Specimen collection 
Peripheral blood will be collected in patients prior to initiating Cobimetinib or Idasanutlin (PRE- 
Bx), and after 7-14 days of Cobimetinib or Idasanutlin, prior to adding on Atezolizumab (POST- 
Bx).  The molecular correlates for each biological sample/time point are listed below. 
 
Parameter 
Cycle 1 
Day 1 
(PRE) 
Cycle 1 
Day 15 
(POST) 
Cycle 3 
Day 1 
End of 
Treatment 
cfDNA 
X 
X 
X 
X 
Flow Cytometry 
X 
X 
X 
X 
HLA Typing 
X 
Exome-seq (germline) 
X 
 
Details on specimen handling can be found in the Lab Manual. 
 
10.2.2. Specimen processing 
 
Correlate 
Sample Source 
Test 
Needs immediate 
specialized 
processing 
Needs 
immediate 
shipping 
Exome-seq 
Buffy coat 
WBC DNA/NGS 
NO 
NO 
HLA-typing 
WBC DNA/NGS 
CyTOF/Flow 
cytometry 
Cyropreserved 
Ficoll-separated 
blood 
PBMCs 
YES (refer to Lab 
Manual) 
cfDNA 
Blood, platelet 
poor plasma 
(PPP) 
Cell free 
DNA/NGS 
 
 
10.2.3. Specimen shipment 
Ship specimens along with Tissue/Blood Registration Form directly to: 
Justin M. Balko, Pharm.D. Ph.D 
658 Preston Research Building 
Vanderbilt Ingram Cancer Center 
2220 Pierce Avenue 
Nashville, TN 37232-6307 
Office Phone: 615-875-8666 
Research Lab Phone: 615-936-2205 


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**Specimens should be mailed to arrive from Monday 8AM through Friday 1PM** 
 
10.3. 
Tissues Samples 
At screening: patients will provide a signed informed consent form prior to any study related 
activities. Patients with known TP53 mutation status (by previously performed NGS or cfDNA) will 
not be required to wait to initiate study treatment provided all other screening procedures have 
been completed. For patients without known TP53 mutation status, an archival tissue (FFPE from 
primary or metastatic lesion) should be sent to the Sponsor (see sections 10.3.1 – 10.3.3 for 
details on tissue submission requirements and testing procedures), and once tissue is received, 
results for TP53 status will take an average of 2 weeks and will be communicated to the site. 
On study: Fresh tumor biopsies will be collected in patients (a) prior to initiating Cobimetinib or 
Idasanutlin (PRE-Bx), and (b) after 15 days of Cobimetinib or Idasanutlin but prior to adding on 
Atezolizumab (POST-Bx). One tumor core will be fixed for IHC analysis, while two additional cores 
will be snap-frozen for RNA and DNA extraction where feasible. The fresh biopsies will follow 
guidelines as listed in the Lab Manual. The molecular correlates for each biological sample/time 
point are listed below. 
 
Correlate 
Sample 
Source 
Test 
Needs 
immediate 
specialized 
processing 
Needs 
immediate 
shipping 
TILs 
FFPE tumor 
biopsy 
IHC/multiplexed IF 
NO 
NO 
CD8 
CD4 
HLA-A (MHC-I) 
IHC 
HLA-DR (MHC-II) 
IHC 
FoxP3 
PD-L1 
RNA-seq 
Fresh frozen 
tumor biopsy 
RNA 
Exome-seq 
DNA 
 
 
Parameter 
Prior to Cycle 1 
Day 1 
Cycle 1 
Day 15 
Immunohistochemistry (IHC) Analysis 
X 
X 
RNA-seq 
X 
X 
Exome-seq (tumor) 
X 
TCR Sequencing 
X 
X 
 
Tissue specimen labeling, documentation and shipment 
• 
Label ALL specimens before freezing 
• 
If sample comes in contact with contaminate, make note in information section of paperwork. 
• 
Enter time core biopsy was collected on paperwork. 
• 
Label each collection containers with Patient ID sequence number/code letter, Medical 
Record #, site and location of biopsy, date and time. 
• 
Ship specimens along with Tissue/Blood Registration Form directly to: 


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Justin M. Balko, Pharm.D. Ph.D 
658 Preston Research Building 
Nashville, TN 37232-6307 
Office Phone: 615-875-8666 
Research Lab Phone: 615-936-2205 
The specimens will be logged in as a consented specimen and either be stored frozen or as 
paraffin-embedded tissue and available for molecular pathology studies. 
***All frozen tissue should be sent in a cooler with ample volume of dry ice. 
***All formalin-fixed paraffin embedded tissue and/or slides should be sent in a cooler with 
cold packs (except in winter months) to avoid melting of the paraffin leading to the tissue 
falling off the slides. 
**These procedures are essential to prevent compromise of the tissue analyses. 
**Specimens should be mailed to arrive from Monday 8AM through Friday 1PM** 
 
10.4. 
Quality control 
First, Dr. Melinda Sanders or her designee (Pathology) will be examining tumor content of the 
frozen tissue by cutting a frozen H&E section from the tissue. To be adequate for the correlative 
studies, the invasive tumor area should be at least 5 mm x 5 mm and contain 20% tumor 
cellularity. If the biopsy contains tumor/immune content >40%, entire 10um sections will be used 
for RNA purification using the Promega Maxwell 16 automated method. 
Purified RNA will be subjected to RNA-sequencing for whole-transcriptome profiling. Biopsies 
containing <40% will be macrodissected from sequential slides to enrich for the tumor portion, 
and RNA purified as above. 
For DNA extraction, there are no expected tumor changes at the exome level, and so only one 
time point will be analyzed, preferably PRE-Bx. Tumor content >80% will be targeted, using the 
whole section/macrodissection scheme above. 
 
10.5. 
Genetic Testing 
Participants will be given information as part of the informed consent process that samples will be 
used for research tests that will include genetic studies and testing. The intent is not to give 
participants (or his/her medical providers) the results of any testing done for research purposes; 
however, incidental germline (heritable) mutations may be identified of which a participant may or 
may not already be aware. In the case that an incidental genetic finding is identified, the Protocol 
Chair of this project will be notified. The possible decisions for handling incidental findings may 
include notification of the participant (and provider); recommendation for genetic counseling, 
which may or may not include genetic testing (e.g., if the finding was not done in a CLIA certified 
laboratory); or, neither. In general, a member of the participant’s treating team will be given the 
information to help with notification. In all cases, the current policy of the local/participating site 
IRB, as applicable, will be followed and any additional approvals that may be required prior to 
participant notification will be secured in advance. 


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11. SPECIMEN BANKING 
 
The study Protocol Chair and collaborators have approval to use all research bio-specimens 
collected during the conduct of this trial to address the research questions described in the 
protocol document. All future use of residual or repository specimens collected in this trial for 
purposes not prospectively defined will require review and approval by the Protocol Chair, 
whether the specimens are stored in a central site or at a local institution in a virtual repository. 
 
12. MEASUREMENT OF EFFECT 
For the purposes of this study, patients should be re-evaluated for response after every two 
cycles. Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) Committee 
(version 1.1)73. Changes in only the largest diameter (unidimensional measurement) of the tumor 
lesions are used in the RECIST criteria. 
 
12.1. 
Definitions 
 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
administration of study treatment drugs. 
 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. 
 
12.2. 
Disease Parameters 
 
12.2.1. Measurable 
 
Tumor lesions: Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
 
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest X-ray 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, 
a lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm). At baseline and in follow- 
up, only the short axis will be measured and followed. 
 
12.2.2. Non-measurable 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph 
nodes of ≥10 to <15 mm in the short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
and abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 


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12.2.3. Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
 
12.2.4. Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above 
• 
Blastic bone lesions are non-measurable 
 
12.2.5. Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non cystic 
lesions are present in the same patient, these are preferred for selection as target lesions 
 
12.3. 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco- 
regional therapy, are usually not considered measurable unless disease progression there 
has been demonstrated 
12.3.1. Specifications by methods of measurements 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
 
12.3.2. Method of assessment 
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 should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but is/are assessable by clinical exam. 
• 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules). For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the lesion 
is suggested. When lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may also be reviewed at the 
end of the study. 
 Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important  endpoint,  since  CT  is more sensitive than X-ray,  particularly in  identifying  new 


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lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
 CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. Guidelines have defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement. Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI 
may be used instead of CT in selected instances. 
 Endoscopy, laparoscopy: The utilisation of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
 Tumor markers: Tumor markers alone cannot be used to assess objective tumor response.  
If markers are initially above the upper normal limit, however, they must normalise for a patient 
to be considered in complete response. 
 Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol (for example, residual lesions in tumor types such as germ 
cell tumors, where known residual benign tumors can remain). When effusions are known to 
be a potential adverse effect of treatment (e.g. with taxanes or angiogenesis inhibitors), the 
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered, if measurable lesions have met criteria for response or stable 
disease, in order to differentiate between response (or stable disease) and progressive 
disease. 
 
12.4. 
Response Criteria 
 
12.4.1. Target lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. This means 
that in instances where patients have only one or two organ sites involved, a maximum of two 
and four lesions, respectively, will be recorded. 
 
12.4.1.1. 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum must 


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also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one 
or more new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum of diameters while on study. 
 
12.4.2. Non-target lesions: 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or, in rare cases ‘unequivocal progression’. 
In addition, it is possible to record multiple 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’). 
 
12.4.2.1. 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker levels. All lymph nodes must be non-pathological in size (<10 mm in their 
short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker levels above the normal limits. 
 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression). 
 
12.4.3. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocol must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of new 
lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in non-randomized trials where response is 
the primary endpoint, confirmation of PR or CR is needed to deem either one as the ‘best overall 
response’. 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non CR/Non PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non PD or not all evaluated 
No 
PR 
SD 
Non PD or not all evaluated 
No 
SD 
Not all evaluated 
Non PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 


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CR=complete response, PR=partial response, PD=progressive disease, SD=stable disease, 
NE=not evaluable. 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration”. In these patients, every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
13. Immune-Related Response Criteria (irRC) 
 
13.1. 
Introduction 
Increasing clinical experience indicates that traditional response criteria (e.g., Response 
Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1] and World Health Organization 
[WHO]) may not be sufficient to characterize fully activity in the new era of target therapies and/or 
biologics. In studies with cytokines, cancer vaccines, and monoclonal antibodies, complete 
response, partial response, or stable disease has been shown to occur after an increase in tumor 
burden as characterized by progressive disease by traditional response criteria. Therefore, 
conventional response criteria may not adequately assess the activity of immunotherapeutic 
agents because progressive disease (by initial radiographic evaluation) does not necessarily 
reflect therapeutic failure. Long-term effect on the target disease must also be captured. The 
immune-related response criteria (irRC) are criteria that attempt to do that by enhancing 
characterization of new response patterns that have been observed with immunotherapeutic 
agents (i.e., ipilimumab). (Note:  The irRC only index and measurable new lesions are taken  
into account.) 
 
13.2. 
Glossary 
 
Term 
Definition 
SPD 
sum of the products of the two largest perpendicular diameters 
Tumor burden 
SPDindex lesions + SPDnew, measurable lesions 
Nadir 
minimally recorded tumor burden 
irCR 
immune-related complete response 
irPD 
immune-related progressive disease 
irPR 
immune-related partial response 
irSD 
immune-related stable disease 
irBOR 
immune-related best overall response 
 
 
13.3. 
Baseline Assessment Using irRC 
Step 1. Identify the index lesions  (five  lesions  per  organ,  up  to  ten  visceral  lesions  and 
five cutaneous lesions). 
Step 2. Calculate the SPD of all of these index lesions: SPD = Σ (Largest diameter of lesion 
i) × (Second largest diameter of lesion i). 


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13.4. 
Post-baseline Assessments using irRC: 
Step 1. Calculate the SPD of the index lesions. 
Step 2. Identify new, measurable lesions (≥ 5 × 5 mm; up to five new lesions per organ: five new 
cutaneous lesions and ten visceral lesions). 
Step 3. Calculate the SPD of the new, measurable lesions. 
Step 4. Calculate the tumor burden: Tumor burden =  SPDindex lesions + SPDnew, measurable lesions 
Step 5. Calculate the change in tumor burden relative to baseline and the change in tumor burden 
relative to nadir. 
Step 6. Derive the overall response using the table below. 
 
Overall 
Response 
Criterion 
irCR 
Complete disappearance of all lesions (whether measurable or not, and no new 
lesions) confirmed by a repeat, consecutive assessment ≥ 4 weeks from the 
date first documented 
irPR 
Decrease in tumor burden ≥ 50% relative to baseline confirmed by a 
consecutive assessment ≥ 4 weeks from the date first documented 
irSD 
Criteria for irCR, irPR, and irPD are not met; does not require confirmation 
irPD 
Increase in tumor burden ≥ 25% relative to nadir confirmed by a consecutive 
assessment ≥ 4 weeks from the date first documented 
irCR = immune-related complete  response;  irPD = immune-related  progressive  disease; 
irPR = immune-related partial response; irSD = immune-related stable disease. 
 
13.5. 
Determination of Immune-Related Best Overall Response (irBOR) 
Once a patient has completed all tumor assessments, his/her irBOR may be determined: 
 
Condition 
irBOR 
At least one irCR 
irCR 
At least one irPR and no irCR 
irPR 
At least one irSD and no irCR and no irPR 
irSD 
At least one irPD and no irCR, no irPR, and no irSD 
irPD 
irBOR = immune-related best overall response; irCR = immune-related complete response; 
irPD = immune-related  progressive   disease;   irPR = immune-related   partial   response; 
irSD = immune-related stable disease. 
 
14. Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment   started). 


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The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started. 
 
 
15. ADVERSE EVENT REPORTING REQUIREMENTS 
 
15.1. 
General 
Adverse event collection and reporting is a routine part of every clinical trial. This study will use 
the descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events version 5.0 (CTCAE v5.0) that is available at http://ctep.cancer.gov/reporting//ctc.html. 
Information on all adverse events, whether reported by the participant, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, recorded, 
followed and reported as described in the following sections. 
Adverse events experienced by participants will be collected and reported from initiation of study 
medication, throughout the study, and within 28 days (+/- 7 days) of the last dose of study 
medication. Participants who experience an ongoing adverse event related to a study procedure 
and/or study medication beyond 28 days (+/- 7 days) will continue to be contacted by a member 
of the study team weekly until the event is resolved, stabilized, or determined to be irreversible 
by the participating investigator. 
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study. The investigator should notify the IRB (as per institutional 
guidelines) and any other applicable regulatory agency of any unanticipated death or adverse 
event occurring after a participant has discontinued or terminated study participation that may 
reasonably be related to the study drugs. 
 
15.2. 
Definitions 
 
15.2.1. Adverse Event (AE) 
 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal product 
(IMP)      or      other      protocol-imposed      intervention,      regardless      of       attribution. 
This includes the following: 
 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with metastatic ER+ breast 
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. 


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15.2.2. Serious adverse event (SAE) 
An AE should be classified as an SAE if 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). 
 
Events not considered to be serious adverse events are hospitalizations for: 
 routine treatment or monitoring of the studied indication, not associated with any deterioration 
in condition, or for elective procedures 
 elective or pre-planned treatment for a pre-existing condition that did not worsen 
 emergency outpatient treatment for an event not fulfilling the serious criteria outlined above 
and not resulting in inpatient admission 
 respite care 
 
 
15.3. 
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). 
 
15.3.1. Adverse Event Reporting Period 
The study period during which AEs and SAEs as described in section 13.2 where the 
patient has been exposed to Genentech product 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. 
 
15.3.2. 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, cobimetinib or idasanutlin (see 
following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 
 
Yes 


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There is a plausible temporal relationship between the onset of the AE and 
administration of atezolizumab, cobimetinib or idasanutlin, 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 atezolizumab, cobimetinib or idasanutlin; and/or the AE abates or resolves 
upon discontinuation of atezolizumab, cobimetinib or idasanutlin or dose 
reduction and, if applicable, reappears upon re- challenge. 
 
No 
Evidence exists that the AE has an etiology other than atezolizumab, 
cobimetinib or idasanutlin (e.g., preexisting medical condition, underlying 
disease, intercurrent illness, or concomitant medication); and/or the AE has 
no plausible temporal relationship to atezolizumab, cobimetinib or 
idasanutlin 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. 
 
15.3.3. Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
 
• 
Definite – The AE is clearly related to the study treatment 
• 
Probable – The AE is likely related to the study treatment 
• 
Possible – The AE may be related to the study treatment 
 Unlikely - The AE is doubtfully related to the study treatment 
 Unrelated - The AE is clearly NOT related to the study  treatment 
 
16. Adverse Events of Special Interest (AESI - Immediately Reportable) 
All AESIs must be reported to the Coordinating Center according to the SAE reporting 
guidelines. Coordinating Center will be responsible for reporting to Genentech within 24 hours of 
the Coordinating Center becoming aware of it. 
 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the 
product, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor 
is required. Such an event might require further investigation in order to characterize and 
understand it. Depending on the nature of the event, rapid communication by the trial Sponsor to 
other parties (e.g., Regulatory Authorities) may also be warranted. 


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16.1. 
Non-drug specific AESI 
 Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law and 
based on the following observations: 
o Treatment-emergent ALT or AST > 3 x baseline value in combination with total bilirubin 
> 2 x ULN (of which > 35% is direct bilirubin) 
o Treatment-emergent ALT or AST > 3 x baseline value in combination with clinical 
jaundice 
 
16.2. 
Cobimetinib 
The following events are adverse events of special interest and will need to be reported to 
Genentech expeditiously (i.e. no more than 1 business day after learning of the event), 
irrespective of regulatory seriousness criteria: 
 Retinal vein occlusion 
 Any retinal detachment, retinal pigment epithelium detachment, neurosensory retinal 
detachment or central serous chorioretinopathy 
 Rhabdomyolysis or Grade 3+ CPK elevation 
 Grade 3+ hemorrhage or any grade cerebral hemorrhage 
 Grade 3+ rash 
 Grade 3+ diarrhea 
 Significant liver toxicity: AST and/or ALT > 10 x upper limit of normal, potential drug-induced 
liver injury as defined by Hy's law 
 Symptomatic heart failure or Grade 2+ left ventricular ejection fraction reduction 
 Pneumonitis 
 
16.3. 
Idasanutlin 
The following events are adverse events of special interest and will need to be reported to 
Genentech expeditiously (i.e., no more than 1 business day after learning of the event), 
irrespective of regulatory seriousness criteria: 
 TLS of any grade, irrespective of causality 
• 
Febrile neutropenia, Grade ≥ 3 neutropenia, Grade ≥ 3 thrombocytopenia or Grade 2 
thrombocytopenia if associated with hemorrhage/bleeding 
• 
Diarrhea (Grade ≥ 3) 
• 
Grade ≥ 2 Clostridium difficile infection 
• 
Grade ≥ 3 infection 
• 
Grade ≥ 3 vomiting 
• 
Grade ≥ 2 thromboembolic event 
 Supraventricular arrhythmias (any grade) 
 
16.4. 
Atezolizumab 
Adverse events of special interest are required to be reported by the investigator to Genentech 
immediately (i.e., no more than 24 hours after learning of the event). Adverse events of special 
interest for this study include the following conditions which may be suggestive of an autoimmune 
disorder: 
 Pneumonitis 
 Colitis 


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 Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, and 
hypophysitis 
 Vasculitis 
 Hepatitis 
o Grade ≥ 2 transaminitis (AST or ALT > 3 ×ULN and bilirubin > 2 ×ULN or AST/ALT > 
10 ×ULN) 
 Systemic lupus erythematosus 
• 
Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, 
and meningoencephalitis 
 Nephritis 
 Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 Myositis 
 Myopathies, including rhabdomyolysis 
 Grade > 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 Events suggestive of hypersensitivity, cytokine release syndrome, influenza-like illness, 
systemic inflammatory response syndrome (SIRS), or infusion-reaction syndromes, systemic 
immune activation 
 Autoimmune Hemolytic Anemia 
 Severe cutaneous reactions (e.g. Stevens-Johnson Syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
 
17. Reporting Procedures 
 
17.1. 
General Considerations 
All adverse events will be captured on a centralized electronic case report form called ON-line 
Clinical Oncology Research Environment = Oncore 
(http://www.vicc.org/ct/research/oncore.php). 
Oncore is a highly secure, web based, cancer specific, and customizable system that provides 
fully integrative clinical data management and study administration capabilities developed in an 
ongoing collaborative effort with NCI designated Comprehensive Cancer Centers. It fully 
integrates study administration functionality including protocol tracking, patient registration, NCI 
reporting, review committee tracking, and SAE tracking, with clinical data management 
functionality including electronic case report forms (eCRF) design, clinical data capture, protocol 
and regulatory compliance monitoring. Specified members at each participating site will submit 
all regulatory documents to the Coordinating Center. 
 
17.2. 
Procedures for Eliciting, Recording and Reporting Adverse Events 
 
17.2.1. 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?” 
 
17.2.2. Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 


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Avoid colloquialisms and abbreviations. 
 
a. 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. 
b. Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section I), 
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”. 
c. 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. W hen 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”). 
d. 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 the study 
e. Assessment of Severity of Adverse Events 
 
The adverse event severity grading scale for the NCI CTCAE v5.0 will be used for assessing 
adverse event severity. Below Table should be used for assessing severity for adverse events 
that are not specifically listed in the NCI CTCAE. 
 
 
 
 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 


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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 
 
f. Pregnancy 
If a female subject becomes pregnant while receiving the study drug or within 5 months after the 
last dose of study drug, (add the following if applicable or if the female partner of a male study 
subject becomes pregnant while the study subject is receiving the study drug or within five months 
after the last dose of study drug), a report should be completed and expeditiously submitted to 
Genentech, Inc. Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, 
whether accidental, therapeutic, or spontaneous, should always be classified as serious, and 
expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to 
a female subject exposed to the study drug should be reported as an SAE. 
 
 
17.3. 
Serious Adverse Events 
All serious adverse events, regardless of causality to study drug, will be reported to the Principal 
Investigator and/or the Study Coordinator at each institution, and also to the Coordinating Center. 
All serious adverse events must be reported to the Coordinating Center within 1 business day 
after the investigator becomes aware of the event. Events should be reported using the Vanderbilt 
SAE form. 
 
The Vanderbilt Coordinating Center SAE form is part of the packet of supplemental forms and 
must be fully completed and emailed (preferred), faxed, or scanned to: 
 
ATTN:  VICC CTSR Personnel 
EMAIL: coordinating.center@vumc.org 


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FAX:  (615) 875-0040 
 
If SAE documents are faxed, the Coordinating Center must be notified via email as well. Follow- 
up information must also be reported within 1 business day of receipt of the information by the 
investigator. 
The Coordinating Center will disseminate information regarding serious adverse events to the 
participating sites as described in FDA guidance only in the case that the event(s) is/are believed 
to be related (i.e., possibly, probably or definitely) to the study medication. The Coordinating 
Center will be responsible for reporting of events to the FDA and supporters, as appropriate 
(outlined below). 
 
17.3.1. Institutional Review Board 
All adverse events and serious adverse events will be reported to the IRB per current institutional 
standards. If an adverse event requires modification of the informed consent, these modifications 
will be provided to the IRB with the report of the adverse event. If an adverse event requires 
modification of the study protocol, these modifications will be provided to the IRB as soon as is 
possible. 
 
17.3.2. Food and Drug Administration (FDA) 
In this trial, unexpected serious adverse events believed to be definitely, probably, or possibly 
related to the study treatment will be reported to the FDA via MedWatch 3500A (available at 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf. 
Submissions by the sponsor can also be submitted via fax or email and must be addressed to 
Regulatory Project Manager and the Chief, Project Management Staff in the FDA review division 
that has responsibility for review of the IND. The Coordinating Center will be responsible for 
correspondence regarding adverse events with the FDA for all participating sites. 
 
17.3.3. Genentech 
The Sponsor will be responsible for collecting all protocol-defined Adverse Events (AEs) and 
Special Situation Reports (including pregnancy reports) originating from the Study for the 
Product. 
 
The Sponsor must report all Adverse Events/Serious Adverse events (SAEs), AEs of Special 
Interest (AESIs) and Special Situation Reports (including pregnancy reports) adequately to 
Genentech within the timelines described below. The completed MedWatch or CIOMS I form 
or Genentech approved reporting forms should be faxed immediately upon completion to 
Genentech Drug Safety at: 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available and/or upon request. 
 
All SAEs, pregnancy reports (if applicable, including pregnancy occurring in the partner of a male 
study subject), AESI reports, and other Special Situation Reports where the patient has been 
exposed to the Genentech Product(s), shall be transmitted to Genentech on the Vanderbilt 
Coordinating SAE form or Medwatch or CIOMS I form within 1 business day of the Awareness 
Date. 


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 
All non-serious Atezolizumab, Idasanutlin or Cobimetinib AEs originating from the study will 
be forwarded Genentech quarterly by the Sponsor. 
Note:  Investigators should also report events to their IRB as required. 
 
17.4. 
Other Special Situation Reports 
In addition to all SAEs, pregnancy reports and AESIs, the following other Special Situations 
Reports should be collected and transmitted to the Coordinating Center even in the absence of 
an Adverse Event within 1 business day of the Awareness Date: 
 
Data related to product usage during breastfeeding 
 
Data related to overdose, abuse, misuse ormedication error (including potentially exposed or 
intercepted medication errors) 
 
Drug interaction 
 
Use of a Medicinal Product in a Pediatric and Elderly population (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) 
 
Data related to a 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 
 
The Coordinating Center will transmit to Genentech within 1 business day of Awareness. 
In addition, reasonable attempts should made to obtain and submit the age or age group of the 
patient, in order to be able to identify potential safety signals specific to a particular population 
 
Occasionally Genentech may contact the Coordinating Center for additional information, 
clarification, or current status of the patient for whom an adverse event was reported. 
 
It is understood and agreed that the Sponsor will perform adequate due diligence with regardto 
obtaining follow-up information on incomplete AE, Special Situations and pregnancy reports. 
 
 
17.5. 
Aggregate Reports 
17.5.1. IND Annual Reports 
 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. 
 
Copies of such reports should be emailed to Genentech at: Genentech Drug Safety CTV mail 
box: ctvist_drugsafety@gene.com 
 
17.5.2. Other Reports 
The Sponsor will forward a copy of the Final Study Report to Genentech/Roche upon completion 
of the Study. 
 
OR 


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Sponsor will forward a copy of the Publication to Genentech/Roche upon completion of the 
Study. 
 
17.6. 
Safety Reconciliation 
17.6.1. 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 Sponsor emailing Genentech a 
Quarterly line-listing documenting single case reports sent by 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 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 
Genentech. 
 
 
17.6.2. MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (item 5) of the 
MedWatch 3500A form: 
 
Protocol description (and number, if assigned) 
 
Description of event, severity, treatment, and outcome if known 
 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the AE to each investigational product and 
suspect medication 
17.6.2.1. 
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 


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 
Summarizing new information and submitting it with a cover letter including patient identifiers 
(i.e., date of birth, initial, patient number), protocol description and number, if assigned, brief 
AE description, and notation that additional or follow-up information is being submitted. (The 
patient identifiers are important so that the new information is added to the correct initial 
report.) 
 
MedWatch 3500A (Mandatory Reporting) form is available at: 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsFo       rms/Forms/UCM048334.pdf 
 
 
17.7. 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
Vanderbilt University Medical Center, as the Sponsor of the Study, will be responsible for the 
expedited reporting of safety reports originating from the Study to the Regulatory Authorities 
(FDA) where it has filed a clinical trial approval, in compliance with local regulations. 
Vanderbilt University Medical Center will be responsible for the distribution of safety information 
to its own investigators, where relevant 
 
17.7.1. Additional Reporting Requirements for IND Holders (if applicable): 
 
For Investigator-Initiated IND Studies, some additional reporting requirements for the FDA apply 
in accordance with the guidance set forth in 21 CFR § 
600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug Administration 
(FDA) as expedited IND Safety Reports according to the following guidance and timelines: 
 
• 
7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the Investigator to be possibly related to the use of atezolizuma, 
cobimetinib, or idasanutlin. An unexpected adverse event is one that is not already described in 
the atezolizuma, cobimetinib, and idasanutlin Investigator Brochure. Such reports are to be 
telephoned or faxed to the FDA and Genen within 7 calendar days of first learning of the event. 
 
• 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly 
related to the use of atezolizumab,cobimetinib, or idasanutlin. An unexpected adverse event is 
one that is not already described in the atezolizumab,cobimetinib, and idasanutlin investigator 
brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in light of the 
previous, similar reports commented on. 
 
Written IND  safety reports with  Analysis of  Similar Events are  to  be  submitted to  the    FDA, 


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Genentech, and all participating investigators within 15 calendar days of first learning of the event. 
The FDA prefers these reports on a MedWatch 3500 form, but alternative formats are acceptable 
(e.g., summary letter). 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
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 
 
And Vanderbilt University Medical Center will be responsible for the distribution of safety information to 
the participating sites for submission to their IRBs per their local IRB reporting  requirements. 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
 
17.8. 
STUDY CLOSE-OUT 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech/Roche. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech/Roche. Copies of such reports should be mailed to the assigned Clinical Operations 
contact for the study: 
 
Anti-pdl-1-mpd3280a-gsur@gene.com 
Attention: Heather Ronemus 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
 
17.9. 
QUERIES 
 
Queries related to the Study will be answered by the Vanderbilt Coordinating Center. 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 the Product. The Vanderbilt Coordinating Center 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. 


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17.10. 
Safety Crisis Management 
 
In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), 
on the conduct of the Study, may lead to labeling changes or regulatory actions that limit or restrict 
the way in which the Product is used, or where there is media involvement, the Party where the 
crisis originates will contact the other Party as soon as possible. 
 
The Parties agree that Genentech shall have the final say and control over safety crisis 
management issues relating to the Product. Vanderbilt University Medical Center agrees that it 
shall not answer such queries from media and other sources relating to the Product but shall 
redirect such queries to Genentech. 
 
18. DATA AND SAFETY MONITORING 
 
18.1. 
Data Management and Reporting 
Data will be collected using a centralized electronic case report form called ON-line Clinical 
Oncology Research Environment (Oncore), located at 
< http://www.vicc.org/ct/research/oncore.php >. 
Oncore allows the investigator to define specific protocol requirements and generate data 
collection forms. Creation of the data collection form is done with a single button click after the 
parameters of an individual protocol have been specified. Oncore also permits specification of 
study protocols, management of patient enrollment, clinical data entry and viewing, and the 
generation of patient or study-specific reports based on time stamping. OnCore is embedded with 
a comprehensive domain repository of standard reference codes and forms to promote 
standardization. The sources for the repository include CDUS, CTC, CDEs from NCI, ICD, 
MedDRA and various best practices from contributing NCI-designated Comprehensive Cancer 
Centers. OnCore provides several reporting features specifically addressing NCI Summary 3 and 
Summary 4 and other reporting requirements. Data may also be exported in a format suitable for 
import into other database, spreadsheets or analysis systems (such as SPSS). This system will 
be used to manage all VICCC clinical trials data. OnCore is maintained and supported in the VICC 
Clinical and Research Informatics Resource. 
Specified site members will submit all pertinent regulatory documents to the Coordinating Center 
Data Manager, who will store it in a secure location. 
The Principal Investigator or designee will inform Genentech as defined in established Safety and 
Data Exchange Agreement (SDEA) of any serious adverse event, and will inform the Vanderbilt 
IRB in accordance with IRB policy. The Principle Investigator is responsible for the detection and 
documentation of events meeting the criteria and definition of an AE or SAE, as specified in this 
protocol. Whenever there is a safety evaluation during the study, the treating investigator or site 
staff will be responsible for detecting, documenting and reporting AEs and SAEs, as detailed in 
the protocol. If any problem is identified related to the conduct of this research, the VICC Data 
Safety and Monitoring Committee (DSMC) will be formally asked to review the study and the 
situation that required DSMC intervention. 
 
19. Data Handling and Record Keeping 
An electronic case report form (Oncore eCRF) is required and must be completed for each 
included participant. 


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The investigator or designee may maintain records separate from the case report forms in the 
forms of clinic charts, medical records, original laboratory, radiology and pathology reports, 
pharmacy records, etc. The investigator will document in the clinic chart or medical record the 
date on which the patient signed informed consent prior to the patient’s participation in the trial. 
Source documents must completely reflect the nature and extent of the patient’s medical care, 
and must be available for source document verification against entries in the case report forms. 
Source documents regarding procedures such as scans and laboratory evaluations performed as 
part of the standard of care prior to consent, but within the protocol specified screening period 
can be used to fulfill certain screening and baseline assessments. All information obtained from 
source documents will be kept in strict confidentiality. Source data sent as supporting 
documentation to regulatory authorities for serious adverse events will be de-identified to preserve 
confidentiality. 
To enable evaluations and/or audits from Health Authorities and Vanderbilt the investigator 
agrees to keep records including: The identity of all participants (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, all source documents, 
and detailed records of drug disposition. To comply with international regulations, the records 
should be retained by the investigator in compliance with regulations. 
 
19.1. 
Data Verification 
 
Data will be collected via eCRFs and entered into the database per Coordinating Center 
guidelines. The Coordinating Center will check data accuracy by performing source data 
verification. Source data verification is a direct comparison of the entries made on the CRFs 
against the appropriate source documentation. This will be conducted remotely, with the 
possibility of on-site verification periodically. Discrepancies in the data will be brought to the 
attention of the Investigator and/or the Investigator’s staff. A summary report (QC Report) of 
these checks together with any queries resulting from manual review of the eCRFs will be 
generated and transmitted to the site by the assigned monitor. Any necessary corrections will be 
made directly to the eCRFs or via queries by the Investigator and/or the Investigator’s staff. This 
will be done on an ongoing basis. 
 
 
20. Meetings 
This trial will be monitored by the VICC Breast Cancer Research Team. The Breast Cancer 
Research Team is composed of the Clinical Core Director of the Breast Cancer Program and 
Team Leader, surgical oncologists, radiation oncologists, medical oncologists, research nurses, 
data managers, and our regulatory specialist. The Breast Cancer Research Team meets 
informally weekly and officially on a monthly basis to discuss all AEs/SAEs, accrual, compliance, 
safety issues, adherence to protocol, data reviews, etc. pertaining to all breast cancer clinical 
trials. This particular study will be thoroughly reviewed during these meetings. The monthly 
meetings have minutes recorded each time, those are also reviewed on a monthly basis by the 
Breast Cancer Research Team Physician Leader. 
Teleconferences between participating sites and the Breast Cancer research team at Vanderbilt 
will be held monthly, to discuss all issues related to the trial (AEs/SAEs, accrual, compliance, 
safety issues, adherence to protocol, data reviews, etc.). 


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21. Monitoring and Quality Assurance 
This trial will be monitored continuously by the Protocol Chair and the Breast Cancer Research 
Team (weekly and monthly). Additionally, the Vanderbilt-Ingram Cancer Center (VICC) oversees 
patient safety and data monitoring for its investigator-initiated and NIH-NCI funded clinical trials 
through its Data and Safety Monitoring Committee (DSMC). The purpose of the DSMC is to 
ensure the efficient implementation and management of VICC Data and Safety Monitoring Plan 
(DSMP). The Committee maintains authority to intervene in the conduct of studies as necessary 
to ensure clinical research performed at VICC achieves the highest quality standards. 
The VICC DSMC meets on a quarterly basis and ad hoc to discuss data and safety monitoring of 
clinical trials and to oversee the VICC DSMP. Internal audits for compliance with adverse event 
reporting, regulatory and study requirements, and data accuracy and completion are conducted 
according to the VICC DSMP according to study phase and risk. The committee reviews all 
serious adverse events (SAE) on Vanderbilt sponsored, investigator-initiated studies on a 
quarterly basis and provides DSMC SAE review reports to the Vanderbilt IRB. 
The investigator will allow the VICC-DSMC designee access to all pertinent medical records, as 
required by federal regulations, in order to allow for the verification of data gathered in the 
electronic data case report forms (eCRFs) and for the review of the data collection process. The 
VICC-DSMC designee will review various aspects of the trial including, but not limited to: 
screening and enrollment logs; compliance with the protocol and with the principles of Good 
Clinical Practice; completion of case report forms; source data verification; study drug 
accountability and storage; facilities and staff. The investigator and the investigational site staff 
must be available to meet with the VICC-DSMC designee in order to discuss the progress of the 
trial, make necessary corrections to case report form entries, respond to data clarification 
requests and respond to any other trial-related inquiries of the Research Compliance Coordinator. 
Additionally, the Coordinating Center has responsibilities to health authorities to take all 
reasonable steps to ensure the proper conduct of the study as regards to ethics, protocol 
adherence, integrity, validity of the data recorded on the CRFs, and adherence to regulations 
regarding    Good    Clinical    Practice    (GCP)    and    the    protection    of    human  subjects. 
 
In accordance with applicable regulations, GCP, and Coordinating Center procedures, sites will 
be contacted prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and Coordinating Center 
requirements. 
 
During the course of the study, the Coordinating Center will routinely monitor sites for protocol 
compliance, compare CRFs with individual subjects’ original source documents, assess drug 
accountability, and ensure that the study is being conducted according to the pertinent regulatory 
requirements. The review of subjects’ medical records will be performed in a manner to ensure 
that subjects’ confidentiality is maintained. Monitoring visits will primarily be conducted remotely, 
and sites are required to provide the appropriate source documentation in order to allow for proper 
oversight per GCP. Investigators must agree to cooperate with the Coordinating Center to ensure 
that any problems detected are resolved. 
In addition to the above, the FDA may review the conduct or results of the study at the 
investigational site. 
In accordance with HIPAA and associated privacy regulations, a subject’s authorization to use 
personally identifiable health information may be required from each subject before 
commencement of research activities. This authorization document must clearly specify what 


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parties will have access to a subject’s personal health information, for what purpose and for 
what duration. 
 
22. REGULATORY CONSIDERATIONS 
 
22.1. 
Pre-Study Documentation 
Prior to initiating the trial, the sponsor will collect all relevant regulatory documents, including but 
not limited to  the following documents: 
 A copy of the signed FDA Form 1572 
 A current curriculum vitae of the Principal Investigator and each sub-investigator listed on the 
FDA Form 1572 
 A copy of the current medical licenses of the Principal Investigator and all sub-investigators 
listed on the FDA 1572 
 A copy of the Protocol Acceptance Page signed and dated by the Principal Investigator 
 A letter from the IRB stipulating approval of the protocol, the informed consent document and 
any other material provided to potential trial participants with information about the trial (e.g. 
advertisements) 
 A copy of the informed consent document approved by both the sponsor and local IRB 
 The current IRB membership list for the reviewing IRB 
 A completed financial disclosure form for the investigator and all sub- investigators listed on 
the FDA 1572 
 Current laboratory certification for the reference laboratory and curriculum vitae of the 
laboratory director 
 A list of current laboratory normal values for the reference laboratory 
 A copy of the signed Delegation of Authority Log 
 Protocol training documentation for study staff 
 The drug destruction SOP for each participating site 
 A copy of the fully executed contract must be on record 
 
22.2. 
Protocol Review and Amendments 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per the current institutional standards of each participating center. Any changes to 
the protocol will be made in the form of an amendment and must be approved by the IRB of each 
institution prior to implementation at that institution. Documentation of these approvals must be 
sent to the Coordinating Center upon receipt. 
The Protocol Chair (or his designee) is responsible for the coordination and development of all 
protocol amendments, and will disseminate this information to the participating centers. 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee (IRB/IEC/REB). Any amendments to the protocol, other 
than administrative ones, must be approved by this committee. 
Amendments significantly affecting the safety of subjects, the scope of the investigation or the 
scientific quality of the study, require additional approval by the IRB/IEC/REB. Amendments 
affecting only administrative aspects of the study do not require formal protocol amendments or 
IRB/IEC/REB approval but the IRB/IEC/REB of each center must be kept informed of such 
administrative changes. 


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22.3. 
Informed Consent 
The investigator (or his/her designee) will explain to each subject the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits involved 
and any discomfort it may entail. Each subject will be informed that participation in the study is 
voluntary, that s/he may withdraw from the study at any time, and that withdrawal of consent will 
not affect her subsequent medical treatment or relationship with the treating physician(s) or 
institution. The informed consent will be given by means of a standard written statement, written 
in non-technical language, which will be IRB approved. The subject should read and consider 
the statement before signing and dating it, and will be given a copy of the signed document. No 
subject will enter the study or have study-specific research procedures performed before his/her 
informed consent has been obtained. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the written 
informed consent document (or a separate document to be given in conjunction with the consent 
document) will include a subject authorization to release medical information to the study sponsor 
and supporting agencies and/or allow these bodies, a regulatory authority, or Institutional Review 
Board access to subjects’ medical information that includes all hospital records relevant to the 
study, including subjects’ medical history. 
 
22.4. 
Confidentiality and Disclosure 
The investigator agrees to keep all information provided by this study in strict confidence and to 
request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents provided 
(protocols, investigators' brochures, CRFs and other material) will be stored appropriately to 
ensure their confidentiality. 
Patient medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited. Upon the patient’s permission, medical information 
may be given to his or her personal physician or other appropriate medical personnel responsible 
for his or her welfare. This medical information must be made available to the IRB and DSMC, 
upon request, for source verification of study documentation. Data generated by this study must 
be available for inspection upon request by representatives of the U.S. Food and Drug 
Administration, the Federal Government Office for Human Research Protections, National Cancer 
Institute, the Vanderbilt University Institutional Review Board, local health authorities, Dr. Ingrid 
Mayer and her authorized representative(s), collaborators and licensees, Genentech and its 
authorized representatives, and the IRB for each study site, if appropriate. We will make all 
reasonable efforts to keep patient’s protected health information (PHI) private and confidential. 
We will only utilize or relinquish this kind of information according to federal privacy guidelines. 
There are many safeguards in place to prevent the unintentional disclosure of information 
obtained for or produced by this study. Research data, including the data collected from the 
medical charts will be entered into a password-protected database. Any publications or public 
disclosure of data relating to the patient’s tumor will be done without any identifying information. 
PHI will be collected and stored in the ONCORE research database. The coordinating center will 
have access to all research data, which will be kept for at least 2 years after the study is 
completed. Any research data entered in a patient medical record will be stored for an indefinite 
amount of time. There are no plans to destroy data at this time. 
Confidentiality and security will be maintained for the tissue collection within this study. All tissue 
samples obtained for this study will be assigned a code and this code used to identify the sample. 
The samples will not be labeled with the patient’s name, address or other information that would 
identify them. All information will be coded to maintain privacy. Research data, including the data 


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collected from the medical charts will be entered into a password-protected database. The 
database (Breast Cancer Program Database) in which this study data are going to be stored has 
a firewall (in addition to the institutional firewall) with the highest level of protection, i.e. the same 
level of protection as the on-line hospital information system at Vanderbilt. This means that users 
must log on to a web server that sits between the institutional firewall and the firewall to the 
database, and only this application server is allowed to query the database. Information, including 
the identifier and password for the authorized users, is transmitted via a secure shell protocol 
using 128k encryption. Only Dr. Ingrid Mayer, the PI, and the Breast Team Data Manager, 
approved through our IRB will be allowed access to patient identifiers. Other levels of 
authorization may exist for approved users, e.g. access to de-identified data. This database will 
store a de-identified link to the patient data and will not otherwise store patient data, even de- 
identified data. The safety monitoring will be performed by the groups deemed appropriate by 
the Vanderbilt University Medical Center IRB for reviewing the clinical trials procedure. Safety 
monitoring for the database is also performed by the Networking and Security Services of the 
Vanderbilt University Medical Center. Audit trails for access to the web server and the databases 
behind the dual firewall system are maintained in accordance with the practices of the Networking 
and Security Services of the Vanderbilt University Medical Center. 
The investigator agrees to keep all information provided by Genentech in strict confidence and to 
request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents provided 
by Genentech (investigators' brochures and other material) will be stored appropriately to ensure 
their confidentiality. The information provided by Genentech to the investigator may not be 
disclosed to others without direct written authorization from Genentech, except to the extent 
necessary to obtain informed consent from patients who wish to participate in the trial. 
 
22.5. 
Records Retention 
The investigator will retain the records of the clinical trial (including, but not necessarily limited to, 
CRFs, source documents, informed consent forms, drug accountability records, IRB 
correspondence, etc.) for at least 2 years after all investigations have been discontinued. Study 
records must be stored in a safe and secure location permitting timely retrieval, if necessary. 
Study records that must be retained include case report forms, signed informed consents, 
correspondence with the IRB, study drug dispensing and inventory records, source documents 
(clinic charts, medical records, laboratory results, radiographic reports) and screening/ enrollment 
logs. 
 
22.6. 
Study Termination 
The investigator reserves the right to terminate the study at any site and at any time. Reasons 
for study termination may include, but are not limited to, the following: 
 Investigator non-compliance with the protocol, GCP or regulatory requirements 
 Insufficient enrollment 
 Safety concerns 
 Decision by Genentech to modify or discontinue the development or manufacturing of 
erdafitinib 
 A request to discontinue the study by the IRB or FDA 
The investigator will promptly notify Genentech, the IRB and FDA if the study is terminated for 
any reason. 


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22.7. 
Ethics and GCP 
This study will be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
 ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996 
 US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations) 
 Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding 
Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended 
Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996) 
The investigator agrees to adhere to the instructions and procedures described in it and thereby 
to adhere to the principles of Good Clinical Practice to which it conforms. 
 
22.8. 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted will 
allow subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and study site contact information. 
 
 
23. MULTI-CENTER GUIDELINES 
 
23.1. 
Study Documentation 
Each participating site is responsible for submitting copies of all relevant regulatory 
documentation to the Coordinating Center. The required documents include, but are not limited 
to the following: local IRB approvals (i.e., protocol, consent form, amendments, patient brochures 
and recruitment material, etc.), each participant’s informed consent, enrollment form, eligibility 
checklist and tissue block registration, summary of unanticipated problems or protocol deviations, 
and documentation of expertise of the investigators. The Coordinating Center will provide each 
participating site with a comprehensive list of the necessary documents. It is the responsibility of 
the participating sites to maintain copies of all documentation submitted to the Coordinating 
Center. 
The requirements for data management, submissions, and monitoring are outlined below. The 
participating sites will submit all the research related information (source documents and research 
records – IRB approval documents, patient registration list, CRF info, toxicity assessments, tumor 
measurements/ responses, etc.) within 2 weeks of the patient’s visit to the assigned Coordinating 
Center Monitor. The Coordinating Center Monitor will check if data was entered into Oncore within 
1 week of receiving the information. Personnel from the VICC Clinical Trial Shared Resource will 
monitor the trial and may periodically visit the investigative site to assure proper conduct of the 
trial and proper collection of the data. The investigators at other sites will allow the monitor to 
review all source documents used in the preparation of the case reports. 
 
23.2. 
Records Retention 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 


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laboratory test results, and medication inventory records, must be retained by each Principal 
Investigator for 2 years after marketing application approval. If no application is filed, these 
records must be kept 2 years after the study is discontinued and the U.S. FDA and the applicable 
national and local health authorities are notified. 
Following closure of the study, each participating center will maintain a copy of all site study 
records in a safe and secure location. The Coordinating Center will inform the investigator at each 
site at such time that the records may be destroyed. 
 
23.3. 
Publication 
It is understood that any manuscript or releases resulting from the collaborative research will be 
circulated to all participating sites prior to submission for publication or presentation. 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Genentech and prior to any outside submission. Genentech will receive copies of 
any intended communication in advance of publication (at least twenty-one working days for 
presentational materials and abstracts and thirty working days for manuscripts). Principal 
Investigator/Institution shall have the final authority to determine the scope and content of its 
publications, provided such authority shall be exercised with reasonable regard for the interests 
of Genentech and, in accord with the trial contract shall not permit disclosure of Genentech 
confidential or proprietary information. 
 
24. STATISTICAL CONSIDERATIONS 
This two-part study consists of 1) a Phase Ib dose-escalation study of Idasanutlin in combination 
with Atezolizumab to determine an RP2D in patients with TP53-wt ER+ mBC, followed by 2) a 
Phase II open-label, multi-arm, multicenter clinical trial to determine whether whether Cobimetinib 
or Idasanutlin in combination with Atezolizumab improves anti-tumor effect relative to a historical 
control of Atezolizumab alone in patients with ER+ mBC. 
 
24.1. 
Phase Ib Trial of Idasanutlin and Atezolizumab 
For the dose-escalation study, a standard 3 + 3 dose escalation scheme will be utilized to evaluate 
the primary objective of determining a RP2D (Recommended Phase II Dose) for Idasanutlin in 
combination with Atezolizumab. Three dosing cohorts of Idasanutlin will be evaluated in 
combination with Atezolizumab (dosage will be held constant at 840 mg) to determine the RP2D 
and will occur in accordance with the dose escalation rule below. 
 
1 Cycle = 28 days 
N of pts. 
Dose Level 
Atezolizumab 
(IV q15 days) 
Idasanutlin 
(PO daily x 5 out of 28 days) 
3-6 
3 
840 mg 
200 mg 
3-6 
2 
840 mg 
150 mg 
3-6 
1 
840 mg 
100 mg 
3-6 
–1 
840 mg 
50 mg 
 
DLTs are defined in section 7.5 and will be assessed during a DLT assessment window, which is 
during the first cycle of therapy.      The RP2D from this study will be utilized in the Idasanutlin + 


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Atezolizumab arm in the Phase II portion of this study. The determination of the MTD and RP2D 
are reviewed in the following table. Of note, the PI may adjust the RP2D based on overall 
tolerability after cycle 1 at their discretion after discussion with all study PI’s. 
 
Number of Patients 
with DLT at a given 
dose level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
If dose level 3 is reached without DLT, then dose level 3 will be 
considered the MTD and RP2D. 
>= 2 
Dose escalation will be stopped. This dose level will be declared the 
maximally administered dose (highest dose administered), exceeding 
the MTD. Three (3) additional patients will be entered at the next 
lowest dose level if only 3 patients were treated previously at that 
dose. 
If this occurs at dose level 1, then 3-6 additional patients will be 
enrolled on dose level -1, based on toxicity occurring at that dose 
level. If ≥ 2 patients experience DLT at dose level -1, then the study 
is considered a failure. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
If 0 of these 3 patients experience DLT, proceed to the next dose 
level. In the event that enrollment is on dose level 3 when this 
occurs, then dose level 3 is considered the MTD and the RP2D. 
If 1 or more of this group suffer DLT, then dose escalation is stopped, 
and this dose is declared the maximally administered dose. Three 
(3) additional patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest 
dose level below the 
maximally 
administered dose 
This is generally the MTD and RP2D. At least 6 patients must be 
entered at the recommended phase 2 dose. These patients will also 
be considered evaluable in the phase II portion of the study. 
 
24.2. 
Phase II Trial of Atezolizumab with Cobimetinib or Idasanutlin Study Design 
Subsequent to the completion of the Phase Ib dose escalation portion for the Idasanutlin arm of 
this study, the Phase II portion of the Idasanutlin arm of this trial will open. The Phase II portion 
of the Cobimetinin arm will start once the study is activated, as no Phase I is necessary for that 
combination. Patients will be allocated based on TP53 mutational status and treated with a 15 
day lead-in of Cobimetinib or Idasanutlin, followed by combination therapy with Atezolizumab until 
progressive disease or intolerable toxicity. Tumor tissue and blood will be obtained at study start 
and before initiation of Atezolizumab. Additional blood samples will be obtained after the first cycle 
of combination therapy and at disease progression. 
The primary endpoint of this study is Progression-Free Survival (PFS); imaging will be performed 
at 8-week intervals. To observe a definitive outcome (success or failure), we will define treatment 
success as being progression-free at 16 weeks when the subjects will have the second imaging. 
Patients will be followed for a minimum of 12 months from time of study initiation, and their actual 
progression-free survival time will be recorded. There will be two treatment groups; however, 
these two groups will not be compared, rather each arm will be compared to historic control. 


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Secondary endpoints include ORR defined by iRecist, Clinical benefit rate (lack of disease 
progression at 6 months), Duration of Response (DOR), Overall Response Rate (ORR by 
RECIST 1.1), and percentage of patients alive (OS) at 12 months, and will be similarly 
summarized with 95% CI by arm. Patients will be followed for a minimum of 12 months from time 
of study initiation. 
Safety will be evaluated by estimating the percentage of patients who experience a clinically 
relevant toxicity (both patient and physician reported) for each arm. Additionally, continuous 
monitoring for toxicity will be employed. 
 
24.3. 
Sample Size/ Accrual Rate 
 
24.3.1. Primary Endpoint/ Sample Size 
In recently reported trials of PD-L1 therapies, the median progression-free survival (PFS) rates of 
8 weeks were observed in ER+ mBC22. Assuming an exponential survival model, this corresponds 
to the hazard rate of 0.0866 and progression-free survival of 25% and 13% at 16 and 24 weeks, 
respectively. For the new treatment arms, we expect the median PFS to be 16 weeks, which 
corresponds to the hazard rate of 0.0433. The table below summarizes the two survival curves. 
 
Group 
Median 
Survival 
Hazard Rate 
Proportion Surviving 
8 weeks 
16 weeks 
24 weeks 
Historical Control 
8 weeks 
0.0866 
50% 
25% 
13% 
Cobimetinib / Idasanutlin 
16 weeks 
0.0433 
71% 
50% 
35% 
 
Our proposed phase II trial results will serve as a proof-of-concept for future immunotherapy 
combination strategies in these patients. In view of the overall low PFS in ER+ mBC treated with 
single-agent immune checkpoint inhibitors, we opted for an open-label design without an 
Atezolizumab only control arm, and will use the 16-week PFS (Yes/No) as the primary endpoint. 
“Response” (16-week PFS and 8-week PFS) will be estimated and reported along with a 95% 
exact confidence interval. Progression-free survival will be estimated using the Kaplan-Meier 
method with censoring used as needed (e.g. if a patient is lost to follow-up, or analysis is done 
before all patients have had the event of interest). Median time to event and corresponding 95% 
CI will be reported along with Kaplan-Meier curves. The duration of PFS for patients who progress 
and then subsequently die will be the number of days between initiation of the study treatment 
and the date of when disease progression is first observed. 
We propose to use a Simon’s Minimax design with stage I and II sample sizes of 16 and 17, 
respectively (maximum total of 33 patients per arm), to ensure that the total number of patients 
exposed to Atezolizumab + Cobimetinib or Idasanutlin is minimized in each of the arms in the 
trial. The futility boundary at the end of stage I is 4, that is if we have 4 of fewer “responses”, then 
the trial will be terminated. At the end of the trial if there are 13 or more “responses”, we will 
conclude clinical benefit of Cobimetinib or Idasanutlin. This design has 4.5% type I error rate at 
response rate of 25%, and 90% power if the true “response” rate is 50% or higher. At the end of 
stage I, patient accrual will not be halted; accrual will be stopped after the data from the 16th 
patient are available and the number of responders is below the threshold. The patients who are 
already accrued at the time of interim decision will be followed and their data will be included in 
all the subsequent analysis. 


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24.3.2. Accrual Rate 
We expect to accrue a minimum of 4 patients per month (all participating sites combined). 
Assuming a linear increase over the first 6 months to target accrual, approximately 24 months of 
patient accession is anticipated, with an additional 12 months needed for follow-up. 
 
24.3.3. Secondary Endpoints 
Secondary endpoints defined in terms of percentages such as Immune related response criteria 
(irRC), Clinical Benefit Rate (CBR), Overall Response Rate (ORR), and rate of Overall Survival 
(OS) at 12 months will be summarized by cohort and 95% CI for each percentage will be reported. 
Safety will be evaluated by estimating the percentage of patients who experience a clinically 
relevant toxicity with 95% CI. All adverse events will be tabulated and summarized with 
descriptive statistics. The distribution of OS per each cohort will be estimated using the Kaplan- 
Meier method with censoring used as needed (e.g. if a patient is lost to follow-up, or analysis is 
done before all patients have had the event of interest). Median time to event and corresponding 
95% CI will be reported along with Kaplan-Meier curves. Demographic and clinical characteristics 
will be summarized for all patients overall and by cohort as percentages for categorical variables 
and as mean, standard deviation, median, minimum and maximum for continuous measures. 
Data will be collected using a centralized electronic case report form called ON-line Clinical 
Oncology Research Environment = Oncore (http://www.vicc.org/ct/research/oncore.php). 
 
24.3.4. Correlative Science Endpoints 
Each biomarker will be compared to each clinical endpoint, particularly the primary endpoint of 
overall response rate, overall response by iRecist, and PFS. These exploratory analyses will be 
performed using the baseline biopsy, and also using correlative science assay values obtained 
from the Cycle 1 Day 1 time point biopsy. 
Biomarkers will be categorized as continuous variables (gene expression values, expression 
signatures, IHC staining intensity, FAC based cell type counts, Neoantigen burden, etc.), or as 
dichotomous variables (somatic mutation in gene X yes or no, DNA copy number change Y, etc.). 
Many continuous variable scores will be also examined as dichotomous, but given the exploratory 
nature of these the precise cut points are not yet determined. Some specific assays are listed 
below, and when it says response it is understood to mean testing each assay result versus all 
response endpoints, both using the baseline biopsy and the C1/intermediate time biopsy. 
A paired t-test (or the non-parametric equivalent if needed) will be used to determine if the 
proposed endpoints are significantly increased in paired biopsy in either arm. In exploratory 
analyses, patients will also be stratified by clinical response to determine if the change in endpoint 
is associated with patient-specific clinical response. 
 
25. Reporting and Exclusions 
All patients included in the study must be assessed for safety, tolerability, and response to 
treatment, even if there are major protocol treatment deviations or if they are ineligible. Each 
patient will be assigned one of the following categories: 1) complete response, 2) partial response, 
3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death 
from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient 
data). All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate. 
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression). Thus, an incorrect treatment schedule  or drug  administration  does  not result  in 


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exclusion from the analysis of clinical endpoints (e.g. overall response rate and clinical benefit 
rate). 
 
 
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33. 
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type breast cancer cells. PLoS One 9, e88557 (2014). 


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53. 
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71. 
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1-10 (1989). 


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27. APPENDIX A:  ECOG PERFORMANCE STATUS SCALE 
 
 
Score 
Definition 
Karnofsky Equivalent 
0 
Asymptomatic 
100 
1 
Symptomatic, fully ambulatory 
80 – 90 
2 
Symptomatic, in bed less than 50% of day 
60 – 70 
3 
Symptomatic, in bed more than 50% of day, 
but not bedridden 
40 – 50 
4 
Bedridden 
20 – 30 


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28. APPENDIX B: CONTRACEPTIVE GUIDELINES 
 
Women Not of Childbearing Potential are Defined as Follows: 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed by follow up hormone level assessment 
is she considered not of child bearing potential. 
 
Contraceptive Guidelines for Women of Child-Bearing Potential: 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use at least two methods of acceptable contraception from 15 days prior to first 
trial treatment administration until at least 5 months after final dose of study treatment. The highly 
effective contraception is defined as either: 
1. Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least six weeks ago. [In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment.] 
2. Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). For female subjects on the study, the vasectomized male 
partner should be the sole partner for that patient. 
3. Use of a combination of two of the following: 
a) Barrier methods with spermicide 
• 
condom (male or female) 
• 
occlusive cap (diaphragm or cervical/vault caps/shield) 
• 
use of two barrier methods is acceptable (i.e. male condom + diaphragm or 
equivalent) 
b) Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
c) Hormonal implants or combined oral contraceptives 
 
The following are unacceptable forms of contraception for women of childbearing potential: 
• 
Natural family planning (rhythm method) or breastfeeding 
• 
Fertility awareness 
• 
Withdrawal 
• 
Abstinence 


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29. APPENDIX C: PROHIBITED AND CAUTIONARY CONCOMITANT MEDICATIONS 
 
 
PROHIBITED AND CAUTIONARY CONCOMITANT MEDICATIONS 
Herbal preparations are not allowed throughout the study. These herbal preparations 
include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Patients should 
stop using these herbal preparations 7 days prior to first dose of study drug. 
 
 
INHIBITORS 
Inhibitors compete with other drugs for a particular enzyme thus affecting the optimal level of
metabolism of the substrate drug, which in many cases affects the individual's response to that
particular medication, e.g. making it ineffective. 
A Strong inhibitor is one that causes a > 5-fold increase in the plasma AUC values or more 
than 80% decrease in clearance. 
A Moderate inhibitor is one that causes a > 2-fold increase in the plasma AUC values or 
50-80% decrease in clearance. 
A Weak inhibitor is one that causes a > 1.25-fold but < 2-fold increase in the plasma AUC 
values or 20-50% decrease in clearance. 
FDA preferred1 and acceptable2 inhibitors for in vitro experiments*. 
CYP2C9 (for idasanutlin only) 
CYP3A4 (for cobimetinib only) 
fluconazole2 
amiodarone 
efavirenz 
fenofibrate 
fluconazole 
fluvastatin 
fluvoxamine2 
isoniazid 
lovastatin 
metronidazole 
paroxetine 
phenylbutazone 
probenicid 
sertraline 
sulfamethoxazole 
sulfaphenazole1 
indinavir 
nelfinavir 
ritonavir 
clarithromycin 
itraconazole1 
ketoconazole 
nefazodone 
saquinavir 
suboxone 
telithromycin 
aprepitant 
erythromycin 
fluconazole 
grapefruit juice 
verapamil2 
diltiazem 


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teniposide 
voriconazole 
zafirlukast 
cimetidine 
amiodarone 
NOT azithromycin 
chloramphenicol 
boceprevir 
ciprofloxacin 
delaviridine 
diethyl-dithiocarbamate 
fluvoxamine 
gestodene 
imatinib 
mibefradil 
mifepristone 
norfloxacin 
norfluoxetine 
starfruit 
telaprevir 
voriconazole 
INDUCERS 
CYP2C9 (for idasanutlin only) 
CYP3A4 (for cobimetinib only) 
Carbamazepine 
Enzalutamide 
Nevirapine 
Phenobarbital 
Rifampin 
Secobarbital  
St. John's Wort 
efavirenz 
nevirapine 
barbiturates 
carbamazepine 
enzalutamide 
glucocorticoids 
modafinil 
oxcarbazepine 
phenobarbital2 
phenytoin2 
pioglitazone 
rifabutin 
rifampin1 
St. John's Wort 
troglitazone1 


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OATP INHIBITORS – to be used with caution in patients in the idasanutlin arm 
 
o 
Statins 
o 
Atazanavir (Reyataz®) 
o 
Clarithromycin (Biaxin®) 
o 
Cobicistat (part of Stribild®) 
o 
Cyclosporine (Neoral®, Gengraf®, Sandimmune®) 
o 
Daclatasvir (Daklinza™) 
o 
Eltrombopag (Promacta®) 
o 
Erythromycin (E-mycin®) 
o 
Gemfibrozil (Lopid®) 
o 
Lopinavir/Ritonavir (Kaletra®) 
o 
Paritaprevir (Viekira Pak™, Technivie™) 
o 
Ritonavir/Lopinavir (Kaletra®) 
o 
Sacubitril (Entresto®) 
o 
Saquinavir (Invirase®) 
o 
Simeprevir (Olysio®) 
o 
Telithromycin (Ketek®) 
o 
Tipranavir (Aptivus®) 
o 
Rifampin 
o 
Velpatasvir (Epclusa®)