Clinical trial NCT04214418
Conditions: Gastrointestinal Cancer
Sponsor: Columbia University
Start date: 2020-02-12; Completion date: 2022-07-01
Enrollment: 27 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This research study is for patients with an advanced cancer that carries a mutation in a gene called KRAS. Genes are parts of our DNA which carry instructions for a cell (the smallest component of an body part). In many cancers, the KRAS gene contains errors (mutations) which allows the tumors to grow. The purpose of this study is to determine if combination treatment with atezolizumab, cobimetinib, and hydroxychloroquine is safe, and if it will decrease the size of the tumor and prolong life in patients whose tumors contain this mutation. Cobimetinib and atezolizumab are both approved by the FDA for use in other cancers, but not in some cancer types being studied in this trial. Hydroxychloroquine is FDA approved to treat malaria and other conditions, but has also not been approved for these cancer types. Preliminary results have shown that this combination of drugs is effective at killing cancer cells and shrinking tumors in several KRAS-mutated cancers in animals.

Detailed description:
The overall objective of this study is to investigate the safety and preliminary efficacy of combination therapy with cobimetinib and hydroxychloroquine, with or without atezolizumab in patients with KRAS-mutated advanced malignancies. Given that the pre-clinical and clinical benefit from this combination is from within poorly differentiated endocrine carcinoma (PDAC) animal models and human subjects with PDAC and duodenal cancer, we will include at least 12 of the 18 evaluable subjects from PDAC and/or colorectal malignancies. The phase 2 portion of the study will be amended after preliminary safety and efficacy results from phase 1 and other ongoing clinical trials have been analyzed and a summary incorporated within the protocol as an amendment including a rationale of the cohorts to be tested.

Arms: arm 1: Subjects will be treated with combination therapy at the designated dose levels:

Dose 1 - Hydroxychloroquine 600mg twice per day, Cobimetinib 40mg, no Atezolizumab Dose 2 - Hydroxychloroquine 600mg twice per day, Cobimetinib 40mg, Atezolizumab 840mg Dose 3 - Hydroxychloroquine 600mg twice per day, Cobimetinib 60mg, Atezolizumab 840mg arm 2: Advanced Pancreatic Adenocarcinoma (N = 23-67) subjects will receive study treatment based on the MTD determined from Phase 1 arm 3: Advanced Colorectal Adenocarcinoma (N = 20-34) subjects will receive study treatment based on the MTD determined from Phase 1 arm 4: Histology Agnostic Adenocarcinoma (N = 23-56) subjects will receive study treatment based on the MTD determined from Phase 1
Interventions: intervention 1: Cobimetinib intervention 2: Hydroxychloroquine intervention 3: Atezolizumab
Intervention descriptions: intervention 1: (40-60 mg) orally once daily (morning) on days 1-21 of each 28-day selective small molecule inhibitor for MEK1 and MEK2 intervention 2: (600mg) orally twice daily on days 1-28 of each 28-day cycle intervention 3: 840 mg IV on Days 1 and 15 of each cycle humanized IgG1 monoclonal antibody (MAb)

Protocol documents:
Prot_SAP_000.pdf: 
Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer 
Center AAAS4165_Version Date: 07/07/2021 
NCT04214418
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TITLE:  MEKiAUTO: Phase 1/2 open-label study of combination therapy with the MEK 
inhibitor, cobimetinib, immune checkpoint blockade, atezolizumab, and the AUTOphagy 
inhibitor, hydroxychloroquine in KRAS-mutated advanced malignancies. 
Coordinating Center: 
Columbia University Medical Center 
Principal Investigator: 
Gulam Abbas Manji, M.D./Ph.D. 
161 Fort Washington Avenue 
New York, NY 10032 
Telephone: 212-212-304-6357 
Email address: gam2140@cumc.columbia.edu 
Statistician (Co-Investigator):   Shing M Lee, Ph.D. 
722 West 168th Street, 
6th Floor, Room 645 
New York, NY 10032  
Telephone: 212-342-1266 
Email address: sml2114@columbia.edu 
Herbert Irving Comprehensive 
Cancer Center 
Columbia University Irving Medical Center 
NewYork-Presbyterian 


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Regulatory Sponsor: 
Gulam Abbas Manji, M.D./Ph.D. 
161 Fort Washington Avenue 
New York, NY 10032 
Telephone: 212-304-6357 
Email address: gam2140@cumc.columbia.edu 
 
Funding Source: 
Genentech/F. Hoffmann-La Roche Ltd. 
Genentech protocol # ML41472 
Study Agent: 
Atezolizumab  
Cobimetinib  
Hydroxychloroquine 
Other Agent: 
N/A 
IND/IDE Status: 
IND  EXEMPT 
 
     
Affiliate Institutions: 
Site Principal Investigator and Contact Information: 
Other Investigators at Site 
Name of Institution: Rhode Island Hospital/Lifespan Cancer 
Institute 
Principal Investigator: Alexander Raufi, MD 
164 Summit Ave. Fain building 3rd floor 
Providence, RI 02906 
Telephone: 401-793-2920 
Fax: 401-793-7603 
Email address: ARaufi2@Lifespan.org 
Name  
 
 


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Initial version: 08/26/2019 
Amended: 
10/27/2019 
Amended:  
12/19/2019 
Amended:  
06/16/2020 
Amended:  
09/23/2020 
Amended: 
10/15/2020 
Amended: 
07/07/2021 
 
 


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PROTOCOL SIGNATURE PAGE 
 
I confirm that I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the applicable ICH guidelines for good 
clinical practices, and the applicable federal, state, and local laws, rules, and regulations relating 
to the conduct of the protocol. I have read and understand the information in the Investigators’ 
Brochure (or Manufacturer’s Brochure) regarding the risks and potential benefits. I will promptly 
submit the protocol to the applicable IRB for review and approval. Once the protocol has been 
approved by the IRB, I understand that any modification made during the course of the study must 
first be approved by the IRB, prior to implementation except when such modification is made to 
remove an immediate hazard to the subject. I certify that I, and the study staff, have received the 
requisite training to conduct this research protocol. I agree to maintain adequate and accurate 
records in accordance with Columbia University and Herbert Irving Comprehensive Cancer Center 
policies, Federal, state and local laws and regulations. I agree to maintain the confidentiality of all 
information received or developed in connection with this protocol. 
 
 
_________________________________                _______________ 
Signature of Principal Investigator  
               Date 
 
 
 
_________________________________                 
Site Principal Investigator Name (Print) 
 
 
 
 
_________________________________                 
Name of Institution
Instructions to Site Principal Investigator: Sign and Date this signature page and print your name. 
Return the original, completed and signed to the Clinical Protocol & Data Management Office. 
Retain a copy in the regulatory binder.  


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Protocol Synopsis  
 
Title 
MEKiAUTO: Phase 1/2 open label study of combination therapy with 
the MEK inhibitor, cobimetinib, immune checkpoint blockade, 
atezolizumab, and the AUTOphagy inhibitor, hydroxychloroquine in 
KRAS-mutated advanced malignancies. 
Short Title 
Cobimetinib + Atezolizumab + Hydroxychloroquine in KRAS-mutated 
advanced malignancies 
Protocol Number 
Genentech IST#: ML41472 
Phase 
Phase 1/2 
Study Duration 
18 months 
Study Center(s) 
Multicenter: Columbia University Medical Center, TBD 
Objectives 
PRIMARY OBJECTIVES 
Phase 1: To estimate the maximum tolerated dose of cobimetinib, 
atezolizumab, and hydroxychloroquine in KRAS-mutated advanced 
malignancies. 
Phase 2: To evaluate the preliminary efficacy based on the objective 
response by 16 weeks  of the combination of cobimetinib, 
atezolizumab, and hydroxychloroquine in KRAS-mutated advanced 
malignancies. 
 
SECONDARY OBJECTIVES 
Phase 1: To evaluate the safety profile of the combination of 
cobimetinib, atezolizumab, and hydroxychloroquine in KRAS-mutated 
advanced malignancies.  
Phase 2: To evaluate the progression free and overall survival, and the 
safety profile of cobimetinib, atezolizumab, and hydroxychloroquine 
combined treatment in KRAS-mutated advanced malignancies. 
 
Exploratory Objectives 
A. Determine MEK and autophagy pathway inhibition, and 
CD8+ T-cell infiltration within tumor specimens. 
B. Perform RNA seq analysis within tumor specimens. 
 


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Number of Subjects 
Phase 1:  KRAS-mutated histology (N=18)  
Phase 2:  KRAS-mutated histology pending results of phase 1 
Cohort 1 – Advanced Pancreas Adenocarcinoma (N = 23-67) 
Cohort 2 – Advanced Colorectal Adenocarcinoma (N = 20-34) 
Cohort 3 – Histology Agnostic Adenocarcinoma (N = 23-56) 
Study Product, 
Dose, Route, 
Regimen 
Dose Level 1: Cobimetinib (40mg) orally once daily (morning) on 
days 1-21 of each 28-day; Hydroxychloroquine (600mg) orally twice 
daily on days 1-28 of each 28-day cycle 
 
Dose Level 2: Cobimetinib (40mg) orally once daily (morning) on 
days 1-21 of each 28-day; Hydroxychloroquine (600mg) orally twice 
daily on days 1-28 of each 28-day cycle; Atezolizumab 840 mg IV on 
Days 1 and 15 of each cycle    
 
Dose Level 3: Cobimetinib (60mg) orally once daily (morning) on 
days 1-21 of each 28-day; Hydroxychloroquine (600mg) orally twice 
daily on days 1-28 of each 28-day cycle; Atezolizumab 840 mg IV on 
Days 1 and 15 of each cycle 28 day cycle.   
Duration of 
administration 
Continuous 28-day cycle 
Reference therapy 
N/A 
Statistical 
Methodology 
The MTD will be estimated using the time to event continual 
reassessment method (TITE-CRM). The MTD is defined as the dose 
combination at which 30% of the patients experience DLT by the end 
of Cycle 2. 
 
 
 
 
 


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Protocol Schema: 
 
 


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Contents 
Protocol Signature Page ................................................................................................................4 
INTRODUCTION........................................................................................................................16 
1. 
STUDY OBJECTIVES ....................................................................................................17 
2. 
BACKGROUND ..............................................................................................................19 
2.1 
Rationale for MEK1/2 and autophagy inhibitor combination therapy ..................19 
2.2 
Rationale for the addition of immune-checkpoint blockade to combination 
MEK1/2 and autophagy inhibitor therapy. ............................................................20 
2.3 
Current treatment outcomes in patients with KRAS-mutant cancers. ....................21 
3. 
INVESTIGATIONAL AGENT ......................................................................................24 
3.1 
Atezolizumab .........................................................................................................24 
3.1.1 Background ................................................................................................24 
3.1.2 Rationale for Treatment with Atezolizumab..............................................25 
3.1.3 Pharmacology of Atezolizumab .................................................................25 
3.1.4 Clinical Data to Date: Atezolizumab .........................................................26 
3.1.5 Tolerability profile during combination treatment ....................................27 
3.2 
Cobimetinib............................................................................................................27 
3.2.1 Background ................................................................................................27 
3.2.2 Toxicology .................................................................................................27 
3.2.3 Clinical Data ..............................................................................................28 
3.3 
Hydroxychloroquine ..............................................................................................28 
3.3.1 Background ................................................................................................28 
3.3.2 Clinical Data to Date ..................................................................................28 
3.3.3 Contraindications .......................................................................................28 
3.4 
Other Agent(s) .......................................................................................................29 
4. 
STUDY DESIGN ..............................................................................................................29 
4.1 
General Design.......................................................................................................29 


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4.1.1 Phase 1 .......................................................................................................29 
4.1.2 Phase 2 .......................................................................................................36 
4.2 
Number of Patients ................................................................................................37 
5. 
SUBJECT SELECTION AND WITHDRAWL ............................................................37 
5.1 
Inclusion Criteria ...................................................................................................37 
5.2 
Exclusion Criteria ..................................................................................................40 
5.3 
Inclusion of Women and Minorities ......................................................................45 
5.4 
Subject Recruitment ...............................................................................................46 
5.5 
Early Withdrawal of Subjects ................................................................................46 
5.5.1 When and How to Withdraw Subjects .......................................................46 
5.5.2 Data Collection and Follow-up for Withdrawn Subjects ...........................46 
6. 
REGISTRATION PROCEDURES ................................................................................47 
6.1 
CUIMC Research Participant Registration ............................................................47 
7. 
TREATMENT AND/OR IMAGING PLAN .................................................................48 
7.1 
Investigational Agent Administration ....................................................................48 
7.1.1 Atezolizumab .............................................................................................50 
7.1.2 Cobimetinib................................................................................................52 
7.1.3 Hydroxychloroquine ..................................................................................52 
7.1.4 Other Agent(s) ...........................................................................................52 
7.1.5 Other Modality(ies) or Procedures .............................................................52 
7.2 
General Concomitant Medication and Supportive Care Guidelines ......................52 
7.2.1 Medications to be given with precaution due to effects related to 
cytochrome P450 enzymes ........................................................................53 
7.2.2 Medications Prohibited ..............................................................................53 
7.3 
Duration of Therapy ...............................................................................................54 
7.4 
Duration of Follow Up ...........................................................................................54 
7.5 
Criteria for Removal from Study ...........................................................................54 
8. 
ADVERSE EVENTS AND DOSING DELAYS/MODIFICATIONS .........................55 
8.1 
General guidelines on dose delays and/or modifications .......................................55 


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8.2 
Drug-specific dose delays/modifications ...............................................................55 
8.2.1 Dose modifications: Atezolizumab ............................................................55 
8.2.2 Dose modifications: Cobimetinib ..............................................................56 
8.2.3 Dose modifications: Hydroxychloroquine .................................................56 
8.2.4 Dose modifications: Cobimetinib + Hydroxychloroquine with or 
without Atezolizumab therapy ...................................................................57 
8.3 
Management of adverse events ..............................................................................57 
8.3.1 Cobimetinib-associated adverse events .....................................................59 
9. 
ADVERSE EVENTS: REPORTING REQUIREMENTS ...........................................60 
9.1 
Definitions..............................................................................................................60 
9.1.1 Adverse Event: ...........................................................................................60 
9.1.2 Serious Adverse Event (SAE):...................................................................61 
9.1.3 Unanticipated Problem: .............................................................................62 
9.2 
Assessment .............................................................................................................62 
9.3 
Relationship to Study Intervention ........................................................................63 
9.4 
Recording and Reporting Adverse Events .............................................................65 
9.4.1 Specific Instructions for Recording Adverse Events .................................65 
9.4.2 Adverse Events of Special Interest to be Reported Immediately to 
the Collaborator: Genentech ......................................................................66 
9.4.3 Case Transmission Verification of Single Case Reports and 
Exchange of single case reports .................................................................67 
9.4.4 Reporting to Genentech .............................................................................68 
9.4.5 Reporting of Serious Adverse Events ........................................................69 
10. 
PHARMACEUTICAL INFORMATION ......................................................................73 
10.1 
Atezolizumab, Cobimetinib, and Hydroxychloroquine .........................................73 
10.1.1 Description .................................................................................................73 
10.1.2 Treatment Regimen ....................................................................................74 
10.1.3 Method for Assigning Subjects to Treatment Groups ...............................75 
10.1.4 Preparation and Administration of Study Drug .........................................75 
10.1.5 Subject Compliance Monitoring ................................................................76 


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10.1.6 Prior and Concomitant Therapy .................................................................76 
10.1.7 Packaging ...................................................................................................76 
10.1.8 Blinding of Study Drug ..............................................................................76 
10.1.9 Receiving, Storage, Dispensing and Return ..............................................76 
11. 
STUDY CALENDAR ......................................................................................................77 
11.1 
Pharmacokinetics Assessments ..............................................................................77 
12. 
MEASUREMENT OF EFFECT ....................................................................................82 
12.1 
Treatment Beyond Initial Radiographic Progression .............................................82 
12.2 
Rationale for the Use of Immune-Modified RECIST ............................................82 
12.3 
Immune-Modified Response Evaluation Criteria in Solid Tumors (Immune- 
Modified RECIST).................................................................................................83 
12.4 
Tumor measurability ..............................................................................................84 
12.4.1 Definition of measurable lesions ...............................................................85 
12.4.2 Definition of non-measurable lesions ........................................................85 
12.4.3 Special considerations regarding tumor measurability ..............................85 
12.4.4 Methods for assessing lesions ....................................................................86 
12.4.5 Assessment of tumor burden ......................................................................88 
12.4.6 Definition of target and non-target lesions ................................................88 
12.4.7 New lesions ................................................................................................88 
12.4.8 Calculation of sum of diameters ................................................................89 
12.5 
Missing assessments and not-evaluable designation .............................................91 
12.6 
Special notes on response assessment....................................................................91 
12.7 
Definitions..............................................................................................................91 
12.8 
Response Criteria ...................................................................................................92 
12.8.1 Evaluation of target lesions ........................................................................92 
12.8.2 Evaluation of Non-Target Lesions .............................................................93 
12.9 
Evaluation of Best Overall Response ....................................................................93 
12.10 Duration of Response .............................................................................................95 
12.10.1 
Duration of overall response ..........................................................95 
12.10.2 
Duration of stable disease ..............................................................95 


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12.11 Progression-Free Survival (PFS) ...........................................................................95 
12.12 Unblinding Procedures...........................................................................................95 
13. 
DATA REPORTING / REGULATORY REQUIREMENTS .....................................96 
13.1 
Data Collection ......................................................................................................96 
13.2 
Data Reporting .......................................................................................................96 
13.2.1 Lost to Follow-up .......................................................................................96 
13.3 
Data and Safety Monitoring Committee ................................................................97 
13.4 
Quality Assurance and Quality Control .................................................................97 
13.5 
Clinical Monitoring ................................................................................................97 
13.5.1 Internal On-site Monitoring: ......................................................................98 
13.5.2 Confidentiality ...........................................................................................99 
13.5.3 Source Documents .....................................................................................99 
13.5.4 Data Entry Procedures ...............................................................................99 
13.5.5 Records Retention ....................................................................................100 
14. 
TRANSLATIONAL SCIENCE ....................................................................................100 
14.1.1 PDAC Subtypes as Defined by Immune Cell Infiltrate and Gene 
Expression ................................................................................................100 
14.1.2 VECTRA Imaging of Human PDA .........................................................101 
14.1.3 Laser Capture Microdissection (LCM) and PDA ....................................101 
14.2 
Sample Processing of RNA-Seq Expression Data ...............................................103 
15. 
PROTECTION OF HUMAN SUBJECTS ..................................................................103 
16. 
STUDY FINANCES.......................................................................................................103 
16.1 
Conflict of Interest ...............................................................................................103 
17. 
GUIDELINES 
FOR 
AFFILIATE 
INSTITUTIONS 
IN 
MULTICENTER 
STUDIES ........................................................................................................................104 
17.1 
Multi-Site Communication: .................................................................................104 
17.2 
New Protocol Distribution, IRB Submission, Modifications, and Annual 
Renewals ..............................................................................................................104 
17.3 
Regulatory Documents.........................................................................................104 
17.3.1 Prior to Site Initiation: .............................................................................104 


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17.3.2 Ongoing Regulatory Documentation ......................................................105 
17.4 
Site Activation .....................................................................................................105 
17.5 
Central Registration Procedures--Affiliate Institution Research Participant 
Registration Process .............................................................................................106 
17.6 
Protocol Deviation request for Affiliate Sites: .....................................................107 
17.7 
Guidelines for Affiliate Site Monitoring ..............................................................108 
17.7.1 On-Site MCT Monitoring: .......................................................................108 
17.7.2 Remote MCT Monitoring: .......................................................................108 
17.8 
Adverse Event Reporting .....................................................................................110 
17.8.1 Sponsor Reporting: Notifying participating investigators at affiliate 
sites of adverse events ..............................................................................110 
17.8.2 Sub-Site SAE Reporting Procedures: ......................................................110 
17.8.3 Non-Serious Adverse Event Reporting ....................................................111 
17.9 
Reporting to the Institutional Review Board (IRB) and the Data and 
Safety Monitoring Committee: ...........................................................................111 
17.10 Guidelines for Processing IND Safety Reports ...................................................111 
17.11 Reporting to Hospital Risk Management .............................................................111 
17.12 Confidentiality .....................................................................................................111 
17.13 Data Reporting Plan .............................................................................................112 
17.14 Data Acquisition and Submission ........................................................................112 
17.15 Record Keeping and Record Retention................................................................112 
18. 
PUBLICATION PLAN .................................................................................................113 
19. 
REFERENCES ...............................................................................................................113 
20. 
ATTACHMENTS ..........................................................................................................121 
21. 
APPENDICES ................................................................................................................122 
21.1 
Appendix 1: Management of adverse events while administering 
atezolizumab, cobimetinib, and/or hydroxychloroquine .....................................122 
21.2 
Appendix 2: Strong CYP3A4 Inducers and Inhibitors ........................................150 
 
 
 


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Table of Figures 
Figure 1. Autophagy induction in hypoxic cells. .......................................................................... 19 
Figure 2. Proposed signal transduction cascade ........................................................................... 19 
Figure 3. Change in tumor volume over 60 days of treatment. .................................................... 20 
Figure 4. Change in plasma carcinoembryonic antigen and tomography images ........................ 21 
Figure 5. Simulated trial using time-to-event continuous reassessment method. ......................... 32 
Figure 6. VECTRA imaging of human PDA. ........................................................................... 1017 
Figure 7. Kaplan-Meier survival by molecular subtype. .......................................................... 1028 
 
Table of Tables 
Table 1. Cohort dose levels. ........................................................................................................ 309 
Table 2.  Selection probabilities and average expected number of patients assigned to each dose 
based on the two stage TITE-CRM (N=18) .................................................................................. 30 
Table 3. Accrual Targets ............................................................................................................. 454 
Table 4. Treatment schedule ....................................................................................................... 508 
Table 5. Atezolizumab administration ........................................................................................ 519 
Table 6. Cobimetinib dose modifications ................................................................................... 564 
Table 7. Hydroxychloroquine dose modidification .................................................................... 575 
Table 8. Adverse event severity scale for events not listed in NCI CTCAE ................................ 61 
Table 9. PK Assessments ............................................................................................................ 786 
Table 10. Schedule of Assessments ............................................................................................ 797 
Table 11. Comparison of RECIST v1.1 and Immune-Modified RECIST .................................... 80 
Table 12. Response assignment for participants with measurable disease ................................... 90 
Table 13. Response assignment for participants with non-measurable disease. ........................... 91 
 
 
 


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Table of Appendix Tables 
Table A1.1. Guidelines for managing IRRs, anaphylaxis, and hypersensitivity reactions in 
response to atezolizumab, cobimetinib, and/or hydroxychloroquine. ....................................... 1228 
Table A1.2. Guidelines for managing gastrointestinal events in response to atezolizumab, and/or 
cobimetinib. ............................................................................................................................... 1239 
Table A1.3. Guidelines for managing dermatologic events in response to atezolizumab, 
cobimetinib, and/or hydroxycholoroquine .............................................................................. 12521 
Table A1.4. Guidelines for managing hepatic events in response to atezolizumab, cobimetinib, 
and/or hydroxycholoroquine ................................................................................................... 12622 
Table A1.5. Guidelines for managing pulmonary events in response to atezolizumab, and/or 
cobimetinib ............................................................................................................................... 1295 
Table A1.6. Guidelines for managing endocrine disorders in response to atezolizumab, and/or 
cobimetinib ................................................................................................................................ 1317 
Table A1.7. Guidelines for managing pancreatic events in response to atezolizumab, and/or 
cobimetinib. ............................................................................................................................... 1339 
Table A1.8. Guidelines for managing neurologic disorders in response to atezolizumab, 
cobimetinib, and/or hydroxychloroquine. ................................................................................. 1362 
Table A1.9. Guidelines for managing ocular events in response to atezolizumab, cobimetinib, 
and/or hydroxychloroquine ....................................................................................................... 1384 
Table A1.10. Guidelines for managing cardiac events in response to atezolizumab, cobimetinib, 
and/or hydroxychloroquine ....................................................................................................... 1417 
Table A1.11. Guidelines for managing hemorrhage and other toxicities in response to atezolizumab 
and/or cobimetinib .................................................................................................................. 14440 
Table A1.12. Guidelines for managing electrocardiogram QT corrected interval prolonged in 
response to atezolizumab, cobimetinib, and/or hydroxychloroquine.. ..................................... 1502 
Table A1.13. Guidelines for managing rhabdomyolysis or CPK elevation in response to 
atezolizumab, cobimetinib, and/or hydroxychloroquine... ....................................................... 1503 
Table A1.14. Guidelines for managing Immune-related Myocarditis in response to atezolizumab, 
cobimetinib, and/or hydroxychloroquine. ................................................................................. 1504 
Table A1.15. Guidelines for managing Immune-related nephrotoxicity in response to 
atezolizumab, cobimetinib, and/or hydroxychloroquine.. ........................................................ 1505 
Table A2.1. Strong CYP3A4 Inducers and Inhibitors. ............................................................. 1506 


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INTRODUCTION 
Pancreas adenocarcinoma (PDAC) is an aggressive cancer for which little progress has been 
made towards effective treatment or cure. By 2030, PDAC is projected to be the second leading 
cause of cancer-related death in the United States (Siegel, Miller, & Jemal, 2016). Although 
‘modern’ combination therapies for metastatic PDA have improved survival by up to 5 months, 
the overall 5-year survival rate for these patients remains approximately 7%, highlighting the 
fact that novel therapies are desperately needed (Conroy et al., 2011; Rahib et al., 2014; Von Hoff 
et al., 2013). Currently, surgery remains the only curative option; however, the vast majority of 
patients diagnosed with PDAC either have locally advanced (~30%) or distant (~50%) disease, 
and are not candidates for resection (Howlader et al., 2017). Even in the those patients who receive 
surgery, recurrence remains high (> 60%) and median overall survival remains poor (23.6 months), 
despite adjuvant chemotherapy (Howlader  et al., 2017; Neoptolemos et al., 2010; Neoptolemos et 
al., 2004; Oettle et al., 2007; Regine et al., 2008). PRODIGE 24-ACCORD, a large randomized 
phase 3 study compared modified FOLFIRINOX (mFOLFIRINOX) to gemcitabine monotherapy 
in the adjuvant setting, and demonstrated a median overall survival benefit of 54.4 months 
compared to 35.0 months. The median disease-free survival was 21.6 months in the 
mFOLFIRINOX arm compared to 12.8 months in the gemcitabine monotherapy arm (Andre et al., 
2018; Conroy et al., 2018). Negative margins, smaller tumor size, and lack of lymph node 
involvement correlated with improved prognosis. Patients with metastasis to visceral organs, the 
peritoneum, or lymph nodes that are beyond the field of resection derive no benefit from surgery 
and are treated with systemic chemotherapy (Allison et al., 1998; Howard et al., 2006; Sohn et al., 
2000). 
The current standard of care for stage IV PDAC involves choosing between the two most active 
combination regimens, namely mFOLFIRNOX and gemcitabine/nab-paclitaxel. In 2011, Conroy 
et al (2018) published their landmark findings of a median survival of 11.1 months with 
FOLFIRINOX, compared to 6.8 months with gemcitabine alone (Conroy et al., 2011). Patients in 
the FOLFIRINOX group had higher rates of toxicity compared to gemcitabine. This  has prompted 
most clinicians in the United States to favor a dose-reduced ‘modified’ regimen, termed “modified 
FOLFIRINOX.” In 2013, the results of a large phase III trial, including 861 patients treated with 
either gemcitabine plus nab-paclitaxel or gemcitabine alone, were published (Von Hoff et al., 
2013). This combination demonstrated a median overall survival of 8.5 months compared to 6.7 
months for single agent gemcitabine.  
Immune checkpoint inhibitors, which have garnered much enthusiasm in numerous malignancies, 
but have limited efficacy in PDA. Although two early-phase clinical trials investigating single 
agent anti-CTLA-4 and anti-PD-1 antibodies in metastatic PDA produced limited responses, data 
presented from a study testing durvalumab, showed a more promising disease control rate of 21% 
(Brahmer et al., 2012; Royal et al., 2010; Segal NH) which led to the rationale of testing 
combination durvalumab (anti-PD-L1) and tremilimumab (anti-CTL-4) in advanced PDA. The 
combination failed to demonstrate meaningful responses or extension of life (O'Reilly EM et al., 
2019) 


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Whole-exome sequencing (WGS) studies have revealed several frequent somatic mutations in 
PDA, the most common of which include KRAS, TP53, CDKN2A, and SMAD4 (Dreyer, Chang, 
Bailey, & Biankin, 2017). The high frequency of KRAS mutations in patients with PDAC 
(approximately 95%) and its key role in activating the mitogen activated protein kinase (MAPK) 
pathway, make enzymes within this signal transduction cascade attractive targets. Recent data 
from a Phase 1b trial in which cobimetinib, a reversible MEK1 and 2 inhibitor, was administered 
in combination with atezolizumab, an anti-PD-L1 antibody, to patients with KRAS-mutated 
colorectal cancer demonstrated a clinical benefit in 37% of patients (Sieunarine et al., 2005). The 
majority of the 20% of patients who responded were MMR-P, suggesting that MEK inhibition 
interferes with an immunosuppressive mechanism, which allows atezolizumab to become 
effective. In addition, this combination led to the inhibition of phospho-ERK and increased CD8+ 
T-cell infiltration within the tumor, a potential correlative marker for predicting increased survival 
(Carstens et al., 2017). However, the randomized phase 3 (IMblaze370) study testing atezolizumab 
and cobimetinib versus atezolizumab or regorafenib failed to demonstrate an overall survival 
benefit compared to regorafenib alone (Bendell et al., 2018). 
Autophagy is a catabolic process through which a cell is capable of recycling cytoplasmic proteins 
and organelles so that they may serve as an alternative energy source (Bryant et al., 2019; Kinsey 
et al., 2019). Tumor cells can induce autophagy to maintain viability and homeostasis, particularly 
in the oxygen-deprived tumor microenvironment. Recent data has shown that autophagy is 
upregulated in cancers that harbor a kras mutation, and that this is essential for tumor cell growth 
(Yang et al., 2014; S. Yang et al., 2011). Furthermore, inhibition of KRAS or other proteins in the 
MAP kinase pathway, with MEK and ERK inhibitors, further increase, rather than suppress, 
autophagic flux in RAS-mutant melanoma and pancreatic cancer cells (Kinsey et al., 2019; Ma et 
al., 2014; Sanduja et al., 2016). A preclinical study published in early 2019 demonstated the 
effectiveness of a strategy combining an autophagy inhibitor and a MEK inhibitor in KRAS-driven 
cancer (Bryant et al., 2019; Kinsey et al., 2019).  
Here we propose a phase I/IIb study to investigate the novel combination of the autophagy 
inhibitor, hydroxychloroquine, with a MEK inibitor, cobimentinib, and an immune checkpoint 
inhibitor atezolizumab. 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312/812 and 
International Conference on Harmonization guidelines), applicable government regulations, and 
Columbia University Medical Center institutional research policies and procedures.  
 
1. 
STUDY OBJECTIVES 
The overall objective of this study is to investigate the safety and preliminary efficacy of  
combination therapy with cobimetinib and hydroxychloroquine, with or without atezolizumab in 
patients with KRAS-mutated advanced malignancies. Given that the pre-clinical and clinical 
benefit from this combination is from within PDAC animal models and human subjects with 
PDAC and duodenal cancer, we will include atleast 12 of the 18 evaluable subjects from PDAC 


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and/or colorectal  malignancies. The phase 2 portion of the study will be ammended after 
preliminary safety and efficacy results from phase 1 and other ongoing clinical trials have been 
analyzed and a summary encorporated within the protocol as an amendment including a rationale 
of the cohorts to be tested. The amendment will be submitted to the Scientfic Review Committee 
at CUIMC for approval prior to activation of phase 2 portion of the study. 
 
Specific objectives are: 
Phase 1:  
Primary: To estimate the maximum tolerated dose (MTD) of the combination of cobimetinib, 
atezolizumab, and hydroxychloroquine in KRAS-mutated advanced malignancies.  
Secondary: To evaluate the safety profile of the combination of cobimetinib, atezolizumab, and 
hydroxychloroquine in KRAS-mutated advanced malignancies. 
Phase 2: 
Primary: To evaluate preliminary efficacy based on the objective response by 16 weeks of the 
combination cobimetinib, atezolizumab, and hydroxychloroquine treatment in KRAS-mutated 
advanced malignancies. 
Secondary: To evaluate the progression-free time and overall survival and safety in patients treated 
with cobimetinib, atezolizumab, and hydroxychloroquine combined treatment in KRAS-mutated 
advanced malignancies. 
Exploratory analysis objectives: 
 Determine MEK and autophagy pathway inhibition and CD8+ T-cell infiltration within tumor 
specimens. 
 Perform RNA seq analysis within tumor specimens. 
 


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2. 
BACKGROUND 
2.1 
Rationale for MEK1/2 and 
autophagy 
inhibitor 
combination therapy 
Autophagy is a catabolic process which 
involves 
degradation 
of 
cytoplasmic 
proteins and organelles so that they may be 
recycled and serve as an alternative energy 
sources for a cell (Fig. 1; (Bryant et al., 
2019; Kinsey et al., 2019). Tumor cells, in a 
manner similar to that of healthy cells that 
have been stressed, can induce autophagy to 
maintain viability and homeostasis. The 
hypoxic tumor microenvironment of many 
solid tumors results in an increase in 
autophagy and produces an aggressive 
phenotype capable of resisting current 
anticancer therapies (Janji et al., 2016).  
The RAF-MEK-ERK-MAP kinase pathway 
plays a key role in cell replication, 
differentiation, 
invasion, 
tumor 
pathogenesis, and regulation of apoptosis 
(Downward, 2003; Roberts & Der, 2007). 
KRAS is a critical switch in this pathway, 
and when mutated, constitutively propagates 
signals 
to 
the 
the 
nucleus 
driving 
tumorogenesis. So-called “driver” mutations 
in this gene have been desribed in over 95% 
of pancreatic cancer, 25-52% of colorectal 
cancer, and 15-35% of non-small cell lung 
cancers (Bettegowda et al., 2014; Chapman, 
Sun, Ruestow, Cowan, & Madl, 2016; 
Dreyer et al., 2017; Tsilimigras et al., 2018). 
Although the development of KRAS 
inhibitors has been a focus of research for 
decades, no efficacious pharmacologic agent 
has been reported to date, and downstream 
inhibition of the pathway by targeting MEK 
alone has not resulted in any meaningful 
clinical benefit (Humphris et al., 2017; 
Infante et al., 2014).  
 
Figure 1. Autophagy induction in hypoxic cells.  
Under hypoxic conditions, stabilization of HIF-1α promotes its 
translocation to the nucleus and leads to a rapid induction of the BH3-
only proteins (BNIP3 and BNIP3L) through its binding to the hypoxia 
response element in the promoter of BNIP3. The induction of BNIP3 
and BNIP3L displaces Beclin1 from Bcl-2, leading to the induction of 
autophagy (Janji et al., 2016). 
 
 
Figure 2. Proposed signal transduction cascade.  
Signal transduction cascade of the proposed mechanism of action 
through which MAP kinase signaling may promote autophagic flux 
in pancreatic cancer cells (Kinsey et al., 2019) 


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Emerging data demonstrates that autophagy is upregulated in KRAS-mutant cancers and that it is 
critical for tumor cell growth (Yang et al., 2014; S. Yang et al., 2011). Interestingly, inhibition of 
KRAS or other proteins in the MAP kinase pathway with MEK and ERK inhibitors further 
increases, rather than decreases, autophagic flux in RAS-mutant melanoma and pancreatic cancer 
cells (Kinsey et al., 2019; Ma et al., 2014; Sanduja et al., 2016). The proposed mechanism is 
thought to be related to an increase in the LKB1  AMPK  ULK1/ATG1 signaling axis (Fig. 
2). Based on this premise, blocking MEK-inhibition driven autophagy presents a novel strategy to 
target RAS-driven cancer. 
Hydroxychloroquine is one 
of the best studied autophagy 
inhibitors 
but 
has 
demonstrated limited activity 
as a single agent (Boone et 
al., 2015; Wolpin et al., 
2014). 
Recently, 
several 
studies have shown that 
inhibition of MEK1/2 and 
autophagy 
(with 
hydroxychloroquine) 
promotes striking synergy 
and 
regression 
of 
xenografted patient-derived 
PDAC 
tumors 
in 
mice, 
NRAS-mutant 
melanoma, 
and BRAF-mutant CRC (Fig. 
3)  (Bryant et al., 2019; 
Kinsey et al., 2019).  
 
2.2 
Rationale for the addition of immune-checkpoint blockade to combination 
MEK1/2 and autophagy inhibitor therapy. 
Increased mutational burden within tumor DNA is hypothesized to lead to increased expression of 
antigenic peptides which drive the anti-tumor therapeutic immune response unleashed by immune 
checkpoint inhibitors (Azuma et al., 2014; Rizvi et al., 2015; Snyder et al., 2014). Several recently 
published studies have demonstrated synergistic effects of combination chemo-immunotherapy 
and targeted-immunotherapy in both non-small cell lung cancer and hepatocellular carcinoma 
(Gandhi et al., 2018; Ikeda et al., 2018). The mechanism by which combination therapies may 
synergize with immune check point blockade is currently unknown but exposure of neoantigens is 
 
 
Figure 3. Change in tumor volume over 60 days of treatment. 
Change in tumor volume over approximately 60 days in mice xenografted with either 
Mia-PaCa2 (a) or BxPC3 (b) cells and treated with: (1) vehicle (Control); (2) trametinib 
(1 mg/kg); (3) chloroquine (50 mg/kg); or (4) the combination of both agents at the 
aforementioned doses were assessed as indicated. Mia-PaCa2: control, n = 5, 
trametinib, n = 6, chloroquine, n = 5, combination of both agents, n = 4. BxPC3: n = 6 for 
all treatment groups. Center values are the mean; statistical testing was performed by 
two-sided t-test; ***P < 0.001 versus control; tttP < 0.001 versus trametinib. Error bars 
represent SD (Kinsey et al., 2019) 
a 
b 


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one 
of 
the 
leading 
hypotheses. In addition, 
hydroxychloroquine 
has 
been shown to enhance 
neo-antigen presentation 
and 
antigen 
cross-
presentation 
via 
MHC 
class I and thus promote 
antitumor 
immune 
responses (Liu et al., 
2018). 
Xenografted 
tumors from mice treated 
with MEK and autophagy 
inhibition 
demonstrated 
increased CD8+ T-cell 
infiltration. Furthermore, 
in 
preliminary 
results, 
addition of immune check 
point blockade to this 
combination resulted in 
further tumor response 
(Kinsey et al. unpublished 
data). Using this rationale, 
we 
administered 
hydroxycholorquine 
(HCQ) in combination 
with cobimetinib to a 63 year old male with recurrent stage IV KRAS G12R-mutated duodenal 
adenocarcioma with bilateral pulmonary metastasis who had progresed on all standard of care 
therapy. Mutation profiling of the tumor identified a number of mutations which would be 
consistent with that of a high mutation burden due to which Nivolumab was initiated. He next 
progressed on Nivolumab and required 4 to 6 liters of supplemental oxygen, but within one week 
of addition of HCQ and cobimetinib to nivolumab, his performance status improved, oxygen 
requirement resolved, and plasma carcinoembryonic antigen (CEA) declined from 90.5 to 74.9. 
CEA continued to decline the following week to 37.5 (Fig. 4a). He remained on treatment for six 
weeks and has tolerated therapy well, except for Grade 2 anorexia and Grade 1 diarrhea. CT of the 
chest four weeks after initiation of therapy identified pulmonary nodules which decreased in size 
with a response rate of -13% (Fig. 4b). Collectively, the preclinial and clinical data sumarized 
above justifies testing this combination in subjects with KRAS-mutated advanced adenocarcinoma 
as proposed in this clinical trial (GA Manji, unpublished data, Columbia University). 
2.3 
Current treatment outcomes in patients with KRAS-mutant cancers. 
Of all the oncogenes described in human cancer, RAS gene family members are the most prevalent, 
with approximately 20% of all tumors having undergone an activating RAS mutation (Downward, 
 
 
 
Figure 4. Change in plasma carcinoembryonic antigen and tomography images 
(a) Change in plasma carcinoembryonic antigen (CEA) in a patient with recurrent stage IV KRAS 
G12R mutated duodenal adenocarcioma treated with hydroxychloroquine (HCQ) in combination 
with cobimetinib and nivolumab. (b) Computed tomography depicting decrease in size of large right 
lung mass following the initiation of treatment. Manji GA, unpublished. 


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2003). There are three members within this family, namely HRAS, KRAS and NRAS, and all have 
been identified in a multitude of malignancies with various degrees of prevalence. RAS encodes a 
small GTPase that regulates normal cellular proliferation, which, when mutated, leads to 
deregulation of tumor-cell growth, cell death, and tumor invasion (Shields, Pruitt, McFall, Shaub, 
& Der, 2000).  
 
Pancreas Adenocarcinoma 
Whole exome sequencing (WES) studies have revealed several frequent somatic mutations in 
PDAC, the most common of which is KRAS which is seen in over 90% of patients (Dreyer et al., 
2017). The high frequency of KRAS mutations and its key role in PDAC pathogenesis make the 
pathway an attractive target. Again, we have seen limited success with this approach, and currently 
chemotherapy remains the mainstay of treatment in this aggressive disease. In general, pancreatic 
cancer patients tend to do poorly after progression on first-line therapy. The only FDA approved 
second-line regimen consists of fluorouracil, folinic acid, combined with nano-liposomal 
irinotecan (Garrido et al., 2017). In patients treated with this regimen the median overall survival 
is 6.1 months compared to 4.2 months with fluorouracil and folinic acid. Progression free survival 
(PFS) was improved with addition of nano-liposomal irinotecan with 3.1 months compared to 1.5 
months. Below we summarize some of the clinical outcomes in PDA which have resulted in either 
monotherapy or combination therapy targeting – PD-1, PD-L1, CTLA-4, autophagy, and/or the 
mitogen-activated protein kinase pathway. 
 Immunotherapy – 
Inhibition of programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), or 
anticytotoxic T-lymphocyte – associated antigen 4 (CTLA-4) have failed to result in 
appreciable responses in metastatic pancreas adenocarcinoma. Given that two of 29 subjects 
from a phase 1 expansion study with durvalumab (anti-PD-L1) monotherapy showed a partial 
response, a randomized study evaluating durvalumab in combination with tremilimumab (anti-
CTLA-4) was conducted (Segal, et al. 2014) . Unfortunately, combination therapy only 
resulted in a 3.1% response rate compared to no responses observed in the durvalumab arm. 
Both combination or monotherapy treatments failed to extent survival (3.1m versus 3.6m) 
(O’Reilly, et al. 2019). Taken together, these studies indicate that in a majority of PDAC 
patients, immunotherapy remains ineffective, despite suggestions that immune evasive 
mechanisms may contribute to PDAC being resistant to therapy. 
 Autophagy – 
Autophagy is a regulated process used by cells to recycle macromolecules and organelles and 
is used by some cancers for cell propagation. Hydroxychloroquine (HCQ) inhibits the fusion 
of the autophagosome to the lysosome, a critical step in autophagy. HCQ was tested in 
pretreated metastatic pancreas adenocarcinoma patients as monotherapy (up to 600mg twice 
daily), but failed to show an efficacy signal (Wolpin, et al. 2014). Although the autophagy 
pathway is active in PDAC, the preclinical studies described in sections 2.1 implicate that 


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autophagy is used to circumvent MEK inhibition to allow tumor growth and not the primary 
driver pathway for cell replication. Similarly, combination gemcitabine/nab-paclitaxel and 
hydroxychloroquine was tested in a randomized phase 2 study in advanced pancreas 
adenocarcinoma. Although the combination failed to prolong overall survival at 12 months 
compared to chemotherapy alone (Karasic et al. 2019), response rate was significantly higher 
with gemcitabine/nab-paclitaxel/HCQ compared to gemcitabine/nab-paclitaxel alone (38.2% 
versus 21.1%; P=0.047), suggestive of an efficacy signal which is not durable. Consistent with 
this finding, gemcitabine/nab-paclitaxel in combination with HCQ in the neoadjuvant setting 
demonstrated improvement in pathological responses (Miller-Ocuin et al. 2017). Similarly, 
combination of HCQ with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) and 
bevacizumab failed to prolong survival but resulted in an impressive response rate of 68%, 
including 11% complete response (O’Hara eta al. 2017). 
 
 Mitogen extracellular signal-related kinase Inhibition – 
The mitogen-activated protein kinase (MAPK) pathway is active in most pancreas cancer 
tumors given that an activated mutation within KRAS is identified in tumors from nearly 95% 
of patients. Trametenib, a reversible MEK1/2 inhibitor in combination with gemcitabine 
resulted in no progression free survival or overall survival (Infante et al. 2014).  Although 
median overall survival was 8.4m compared to 6.7m with gemcitabine alone, the improvement 
was not durable. 
 
Colorectal Adenocarcinoma 
In colon cancer, the frequency of KRAS mutations is over 45% and its presence is of clinical 
importance as it precludes the administration of epidermal growth factor receptor (EGFR)-directed 
therapies (Downward, 2003). Patients with colon cancer, regardless of having a RAS mutation, 
have several options after progressing on second-line therapy. For those patients who have 
progressed on fluoropyrpyrimidine-based combination therapy, with irinotecan and oxaliplatin, 
the most commonly used subsequent-line regimens in the United States include 
Trifluridine/Tipiracil (TAS-102), Regorafenib, immunotherapy for those with mismatch repair 
deficient (dMMR) disease or microsatellite instability (MSI-H). The phase 3 CORRECT study 
demonstrated a median overall survival (mOS) of 8.8 months [95% CI 7.3-9.8] in patients who 
received regorafenib versus 6.3 months [4.8-7.6] in those receiving placebo (Li et al., 2015) and a 
PFS benefit of 1.9 months compared to 1.7 months. Similarly, the phase 3 TERRA study showed 
a mOS of 7.8 months [95% CI, 7.1 to 8.8 months] with TAS-102 versus 7.1 months [95% CI, 5.9 
to 8.2 months] in those receiving placebo (Xu et al., 2018) with a PFS benefit of 2.0 months 
compared to 1.8 months. In an open-label, phase II trial by Overman et al., which provided 
nivolumab and ipilimumab to patients with dMMR/MSI-H metastatic colorectal cancer who had 
disease progression or were intolerant to ≥ one prior systemic treatment that included a 
fluoropyrimidine and oxaliplatin or irinotecan showed a significant response rate of 55% and mOS 
that had not reached at median follow-up of 13.4 months. Unfortunately, dMMR/MSI-H patients 


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only comprise about 4% of patients with metastatic colon cancer and therefore few patients are 
eligible for this combination. Attempts to treat patient whose tumors harbor KRAS mutation with 
either Trametinib or Selumetinib, oral selective inhibitors of MEK1/2 kinases, have yet to yield 
positive results (Gandara et al., 2017; Janne, Mann, & Ghiorghiu, 2016).  
 
Nonsmall Cell Lung Cancer (NSCLC) 
NSCLC patients with KRAS mutation are treated similarly to those without the mutation. Recent 
advances in NSCLC have overhauled treatment paradigms to include immunotherapy in the first-
line setting. This change in first line standard of care therapy has made ordering of subsequent 
lines of therapy, challenging. In patients who progress following first-line therapy, it is generally 
accepted that single agent chemotherapy, such as docetaxel or pemetrexed, or combination 
therapy, such as ramicurimab and docetaexl, or finally, immunotherapy, if it had not been used 
prior, be attempted. Docetaxel has been compared to pemetrexed in the second-line setting and no 
difference in the mOS was observed (8.3 versus 7.9 months (P = not significant) for pemetrexed and 
docetaxel, respectively) (Hanna et al., 2004). The REVEL study demonstrated a mOS of 10.5 
months in patients allocated to ramucirumab plus docetaxel, versus 9.1 months for patients who 
received placebo plus docetaxel in the second line setting (hazard ratio 0.86, 95% CI 0.75–0.98; 
p=0.023) (Garon et al., 2014). Several studies have looked into immunotherapy in the second and third 
line settings. The KEYNOTE-010 trial compared pembrolizumab to docetaxel in patients who were 
previously treated and found a mOS of 12.7 months with pembrolizumab vs 8.5 months with docetaxel 
(Herbst et al., 2016). Atezolizumab was evaluated in patients with NSCLC who had received one or 
more lines of prior chemotherapy in the phase III OAK trial. The investigators noted a median overall 
survival of 15.7 months with atezolizumab versus 10.3 months with docetaxel; HR 0·74 [95% CI 0.58–
0.93]; p=0.0102) (Rittmeyer et al., 2017). 
3. 
INVESTIGATIONAL AGENT  
3.1 
Atezolizumab 
3.1.1 
Background 
Atezolizumab (TECENTRIQ®), formerly known as MPDL3280A, is a humanized IgG1 
monoclonal antibody (MAb) consisting of two heavy chains (448 amino acids) and two light 
chains (214 amino acids), and is produced in Chinese hamster ovary cells. The antibody blocks 
interaction of PD-L1 to PD-1 receptor and CD80 (B7.1), which are inhibitory receptors on 
immune cells, including T cells. This inhibition is thought to enhance tumor specific T-cell 
function through enhanced priming, expansion, and effector function (Okazaki and Honjo 2007). 
Hence, disrupting this pathway with atezolizumab has been effective in various tumor subtypes.  
Atezolizumab lacks Fc-effector function, as it is engineered to be a non-glycosylated antibody, 
and hence does not function in antibody-dependent cell-mediated cytotoxicity or antibody-
mediated clearance of activated effector T cells. Atezolizumab has minimal binding to Fc 
receptors, thus eliminating detectable Fc-effector function and associated antibody-mediated 
clearance of activated effector T cells. Atezolizumab shows anti-tumor activity in both pre-clinical 


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models and in patients with cancer. It is being investigated as a potential therapy in a wide variety 
of malignancies. Atezolizumab is being studied as a single agent and in combination with 
chemotherapy in multiple tumor histologies. Studies demonstrate a clinical benefit in triple 
negative breast cancer (Schmid et al., 2018), extensive stage small cell lung cancer (Horn et al., 
2018), and non-small cell lung cancer (Socinski et al., 2018). Refer to the most current version of 
Atezolizumab Investigator's Brochure for details on non-clinical and clinical studies.  
3.1.2 
Rationale for Treatment with Atezolizumab  
Encouraging clinical data emerging in the field of tumor immunotherapy has demonstrated that 
therapies focused on enhancing T-cell responses against cancer can result in significant clinical 
benefit to patients across a broad array of advanced malignancies (Hodi et al., 2010; Kantoff et al., 
2010). The PD-L1 pathway serves as an immune checkpoint to dampen immune responses in states 
of chronic antigen stimulation, such as chronic infection or cancer. PD-L1 is an extracellular 
protein that downregulates immune responses through binding to its two receptors, PD-1 and B7-
1. PD-1 is an inhibitory receptor expressed on T cells following T-cell activation; expression is 
sustained in states of chronic stimulation (Blank, Gajewski, & Mackensen, 2005; Keir, Butte, 
Freeman, & Sharpe, 2008). B7-1 is a molecule expressed on antigen-presenting cells and activated 
T cells. Binding of PD-L1 to PD-1 and B7-1 inhibits T-cell proliferation and activation, cytokine 
production, and cytolytic activity, leading to the functional inactivation or exhaustion of T cells 
(Butte, Keir, Phamduy, Sharpe, & Freeman, 2007; J. Yang et al., 2011). Overexpression of PD-L1 
on tumor cells may impede anti-tumor immunity, resulting in immune evasion (Blank & 
Mackensen, 2007). Therefore, interrupting the PD-L1 pathway is an attractive strategy for 
restoring tumor-specific T-cell immunity.  
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients with 
advanced malignancies who have failed standard-of-care therapies. Objective responses have been 
observed across a broad range of malignancies, including non-small cell lung cancer (NSCLC), 
urothelial carcinoma, renal cell carcinoma (RCC), melanoma, colorectal cancer, head and neck 
cancer, gastric cancer, breast cancer, and sarcoma (see most current version of Atezolizumab 
Investigator's Brochure for detailed efficacy results). Atezolizumab has been generally well 
tolerated. Adverse events with potentially immune-related causes consistent with an 
immunotherapeutic agent, including rash, influenza-like illness, endocrinopathies, hepatitis or 
transaminitis, pneumonitis, colitis, and myasthenia gravis, have been observed (see most current 
version of Atezolizumab Investigator's Brochure for detailed safety results).  
3.1.3 
Pharmacology of Atezolizumab 
Atezolizumab is a humanized antibody containing heavy chain VHIII and light chain Vκl subgroup 
sequences. The antibody lacks the N-linked oligosaccharides due to an asparagine to alanine 
substitution at position 298 of each heavy chain, resulting in a non-glycosylated antibody. 
Atezolizumab is produced in Chinese hamster ovary (CHO) cells and is provided in 2-mL 
(Formulation F01 or early Phase I/II material) and 20-mL (Formulation F03 or late Phase I/II and 
Phase III material) glass vials. The diluent used with Formulation F01 is provided in 50-mL glass 
vials. The respective protein concentrations for Formulations F01 and F03 are 125 mg/mL and 60 


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mg/mL, respectively. Atezolizumab (F01 and F03) and diluent are in a solution containing 
histidine acetate, sucrose, and polysorbate 20. 
3.1.4 
Clinical Data to Date: Atezolizumab 
For most up to date information on clinical data available, refer to current version of Institutional 
Brochure. 
 
Effect of Atezolizumab in Humans 
As of the August 2018 Investigator’s Brochure (version 13), clinical data on atezolizumab as a 
single agent or in combination with chemotherapy or targeted agents are available from more than 
20 studies. Atezolizumab is approved in the United States for the treatment of patients with locally 
advanced or metastatic urothelial carcinoma who fit the following criteria:  1) are not eligible for 
cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-
infiltrating immune cells covering ≥ 5% of the tumor area), as determined by a US Food and Drug 
Administration (FDA)-approved test; or 2) are not eligible for any platinum-containing 
chemotherapy, regardless of PD-L1 status; or 3) have disease progression during or following any 
platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant 
chemotherapy. Atezolizumab is also approved for the treatment of previously treated locally 
advanced or metastatic non-small cell lung cancer (NSCLC). 
Pharmacokinetic, exposure-safety, and exposure-efficacy data analysis, as reported in the 
Atezolizumab Investigator's (version 13) identified that age, body weight, gender, albumin levels, 
tumor burden, renal impairment, mild hepatic impairment, level of PD-L1 expression, or Eastern 
Cooperative Oncology Group (ECOG) status had no clinically relevant effect. Positive anti-drug 
antibody (ADA) status against atezolizumab led to approximately 13% reduction in overall 
exposure. The effect of hepatic impairment (bilirubin or aspartate aminotransferase > upper 
limit of normal) on the pharmacokinetics of atezolizumab is unknown.  
 
Effect of atezolizumab in combination with cobimetinib  
The randomized phase 3 IMblaze370 study tested combination atezolizumab and cobimetinib 
versus atezolizumab or regorafenib alone in patients with advanced colorectal cancer who had 
progressed on or were intolerant of two lines of therapy. Of those treated with atezolizumab and 
cobimetinib, 61% experienced Grade 3/4 adverse events compared to 58% who were treated with 
regorafenib, an approved drug for metastatic colorectal adenocarcinoma. Diarrhea (11%), anemia 
(6%), increased blood creatine phosphokinase (7%), and fatigue (4%) were the most commonly 
observed all-cause Grade 3 – 4 toxicities in subjects treated with cobimetinib and atezolizumab 
(SAEs were reported in 40% subjects receiving combination therapy). Of the AEs, 26% of subjects 
experienced serious treatment-related AEs, 21% stopped treatment, and 61% required dose 
interruption or modification (Eng et al., 2019). 


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3.1.5 
Tolerability profile during combination treatment 
In studies investigating the combination of atezolizumab with other anti-cancer agents, the 
incidence of AEs in the treatment arms with combined use was consistent with the known safety 
profiles of the individual study drugs. Fatigue, decreased appetite, nausea and cough were adverse 
events reported in more than 10% of patients treated with atezolizumab monotherapy and in 
combination therapy. Through appropriate routine evaluations, investigational workup, and early 
mitigations, such as management guidelines, the majority of patients were able to continue 
atezolizumab therapy (see most current version of Atezolizumab Investigator's Brochure for 
detailed safety results).  
3.2 
Cobimetinib 
3.2.1 
Background 
Cobimetinib is a potent and highly selective small molecule inhibitor for MEK1 and MEK2, which 
are known key players of the RAS/RAF pathway (see Section 2.0). Inhibition of MEK1 and MEK2 
results in inhibition of ERK1/2 phosphorylation and thus decreased cell proliferation. Cobimetinib 
is a substrate of CYP3A4 and UGT2B7 and an inhibitor of isozymes CYP2D6 and CYP3A4. 
Cobimetinib accumulates in tumor xenografts and remains at high concentrations in the tumor 
after plasma concentrations have declined. 
The inhibition of ERK1 phosphorylation by cobimetinib correlates more closely with 
concentrations of cobimetinib in tumor tissues than in plasma; in general, there is a good 
correlation between reduced ERK1 phosphorylation and efficacy in tumor xenograft models.  
Nonclinical and in vitro metabolic profiling studies suggest that cobimetinib is a substrate for 
CYP3A4 and UGT2B7-mediated metabolism in human liver microsomes and recombinant 
enzymes; cobimetinib is an inhibitor of isozymes CYP2D6 and CYP3A4 in vitro. Cobimetinib is 
approximately 95% bound to human plasma proteins. The pharmacokinetics of cobimetinib has 
been characterized in multiple species, including mice, rats, dogs, and monkeys.  
3.2.2 
Toxicology 
The nonclinical toxicity of cobimetinib was characterized in single-dose and repeat-dose studies 
in rats and dogs, a repeat-dose toxicity study in juvenile rats, reproductive and developmental 
studies in rats, genotoxicity studies (including in vitro bacterial and mammalian genotoxicity 
bioassays and in vivo micronucleus assays) in rats, and in vitro (3T3 mouse fibroblasts) and in vivo 
(pigmented rats) phototoxicity studies. The nonclinical safety assessment for cobimetinib 
identified degenerative effects in multiple tissues that are clinically manageable, and the potential 
for reproductive toxicity at therapeutically relevant exposures. It was not phototoxic or genotoxic 
in vitro or in vivo. When considered together with the clinical safety database and the intended 
treatment population, the results of the nonclinical toxicity program provide a safety profile that 
supports the use of cobimetinib in the treatment of cancers. 


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3.2.3 
Clinical Data 
Cobimetinib has been approved in the United States for the treatment of advanced melanoma in 
tumors that encode a mutation in BRAF V600E or V600K in combination with vemurafinib. 
Cobimetinib is generally well tolerated, but common AEs include fatigue, rash, diarrhea, nausea, 
emesis, edema, ophthalmological disorders, and abdominal pain. For the most up to date 
information on clinical data, refer to current version of Institutional Brochure. Clinical information 
regarding combination cobimetinib and hydroxychloroquine is listed above (Section 2.2). 
3.3 
Hydroxychloroquine 
3.3.1 
Background 
Hydroxychloroquine sulfate is a colorless crystalline solid, soluble in water to at least 20%. 
Chemically, the drug is 2-[[4-[(7-Chloro-4-quinolyl)amino]pentyl]ethylamino] ethanol sulfate 
(1:1). The drug possesses antimalarial actions and also exerts a beneficial effect in lupus 
erythematosus (chronic discoid or systemic) and acute or chronic rheumatoid arthritis. The precise 
mechanism of action is not known. It is indicated for the suppressive treatment and treatment of 
acute attacks of malaria due to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of 
P. falciparum. It is also indicated for the treatment of discoid and systemic lupus erythematosus, 
and rheumatoid arthritis. The detailed mechanism by which hydroxychloroquine inhibits 
autophagy is currently unknown.  
3.3.2 
Clinical Data to Date 
Hydroxychloroquine sulfate (HCQ) is supplied in 200mg tablets, and when supplied to healthy 
males resulted in peak blood concentration of 129.6ng/mL in 3.26 hours. The half-life of HCQ is 
2963 hours (123.5 days). Renal clearance after 6 months of chronic exposure did not appear to 
change renal clearance. Dose adjust is not required for patients with renal impairment. In patients 
with rheumatoid arthritis (RA) there was large variability in the absorption of the drug. 
3.3.3 
Contraindications 
Hydroxychloroquine is contraindicated in patients with known hypersensitivity to 4-
aminoquinoline compounds.  
Adverse events noted from hydroxychloroquine include: 
Ocular -  
Irreversible retinal damage has been observed in some patients who have received 
hydroxychloroquine. Risk of this AE increases with dosage greater than 6.5mg/kg of actual body 
weight, use of durations greater than five years, subnormal glomerular filtration, use of some 
concomitant drug products, such as tamoxifen citrate, and concurrent macular disease. 
Cardiotoxicity and QT Prolongation – 


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Postmarketing cases of lifethreatening and fatal cardiomyopathy have been reported. Patients may 
present with atrioventricular block, pulmonary hypertension, sick sinus syndrome, or cardiac 
complications. ECG findings may include atrioventricular right or left bundle branch block. 
Worsening of psoriasis and porphyria – 
Use of hydroxychloroquine in patients with this condition may precipitate a severe attack.  
Proximal Myopathy and Neuropathy – 
Progressive muscle weakness and proximal muscle group atrophy have been reported, including 
depressed tendon reflexes and abnormal nerve conduction.  
Neuropsychiatric events, including suicidality – 
Suicidal behavior has been rarely reported in patients treated with hydroxychloroquine. 
Hypoglycemia – 
Hydroxychloroquine has been reported to cause severe hypoglycemia, including loss of 
consciousness, which can be life threatening in patients who may or may not be on anti-diabetic 
therapy. 
Other – 
Hydroxychloroquine should be used in caution with patients who have compromised hepatic or 
renal function. Blood counts should be monitored to ensure no myelosuppression. Dermatitis has 
been reported with the use of hydroxychloroquine. 
Drug Interactions – 
Digoxin, insulin or other antidiabetics, drugs that prolong QT interval, antiepileptics, 
methotrexate, cyclosporine, praziquantel, antacids, cimetidine, and ampicillin have significant 
interactions with hydroxychloroquine. 
3.4 Other Agent(s) 
N/A 
4. STUDY DESIGN 
4.1 
General Design 
4.1.1 
Phase 1 
The objective of this study is to determine the maximum tolerated dose (MTD) of the combination 
of cobimetinib, atezolizumab, and hydroxychloroquine. We will evaluate three dose combinations. 
Patients will be treated with combination therapy at the designated dose levels depicted in Table 
1, based on a 28 day cycle (Section 7.3). The MTD is defined as the dose associated with a target 
probability of dose limiting toxicity of 0.30.  The primary endpoint is DLT in the first cycle of 
treatment.   


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Given that cobimetinib is approved at a dose of 60 mg orally daily and hydroxychloroquine was 
well tolerated at 600 mg orally twice daily, we feel that the combination will be well tolerated 
(Wolpin et al., 2014). Cobimetinib and atezolizumab were tested in advanced colorectal cancer in 
IMblaze370, a large randomized phase 3 clinical trial (Eng et al., 2019) with proportion of patients 
experiencing grade 3 and over adverse events similar to those who received the FDA approved 
Regorafenib. Subjects will receive cobimetinib in cohort 1 and 2 at a lower dose (40mg oral daily) 
compared to that tested in IMblaze370 (60mg oral daily). Given that, other than ocular and hepatic 
toxicity, hydroxychloroquine has little to no overlapping adverse events with cobimetinib and 
atezolizumab, we do not anticipate significant toxicities with this combination at the doses being 
tested. Ocular toxicities with hydroxychloroquine are observed at high cumulative doses and will 
be monitored by required scheduled ophthalmological evaluations throughout the study period. 
We will initiate Phase 1 at dose level 1 using a combined 3+4 and time-to-event continual 
reassessment method (TITE-CRM). Table 1. Cohort dose levels. 
Patient 
No. 
Dose 
Level 
Hydroxychloroquine 
(mg) 
(oral; 1200mg/day; 
Days 1-28) 
Cobimetinib (mg) 
(oral; 40-60mg/day; 
Days 1-21) 
Atezolizumab (mg) 
(IV; 840mg every 
two weeks) 
1, 2, 3 
1 
600mg twice per day 
40mg 
 
4, 5, 6 
2 
600mg twice per day 
40mg 
840mg 
7, 8, 9 
10-18 
3 
600mg twice per day 
TITE-CRM 
60mg 
840mg 
Phase I Statistical Considerations 
The MTD will be estimated using a two-stage time to event continual reassessment method (TITE-
CRM), whereby in the first stage patients will be assigned to 3-patient cohorts (see table below) in 
the absence of DLT. However, once a DLT is observed, we will initiate the second stage and 
patients will be assigned using the TITE-CRM.  The initial design for the two stage was obtained 
using the method by Jia, et al (Jia, Ivanova, & Lee, 2017).   
 
Table 2.  Selection probabilities and average expected number of patients 
assigned to each dose based on the two stage TITE-CRM (N=18) 
Doses Level  
1 
2 
3 
Scenario 1 
DLT rate 
30% 
45% 
55% 
P(Selection) 
74% 
23% 
4% 
Average Number 
Assigned 
11 
4 
3 


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The advantage of the 
TITE-CRM is that it uses 
the 
patient’s 
partial 
information 
before 
a 
complete 
follow-up 
is 
achieved.  As a result, we 
can conduct the trial in a 
continuous 
fashion 
without having patients be 
turned 
away 
due 
to 
waiting time. The TITE-
CRM 
will 
use 
an 
empirical 
dose-toxicity 
model, with a sample size 
of 18. The prior distribution of the model parameter is assumed to be normal with a mean of 0 and 
a variance of 1.34.  The dose-toxicity model is calibrated such that the eventual dose yields 
between 18% and 32% DLT (Cheung & Chappell, 2002; Lee & Ying Kuen, 2009) and good 
operating characteristics across a wide range of potential scenarios of toxicity profiles. Given that 
the majority of the toxicities for the cobimetinib and atezolizumab trial occurred in the first cycle 
of treatment, the proposed toxicity evaluation period is 4 weeks. In the first stage, each cohort will 
be followed for the entire 4 weeks in the absence of a DLT. Once a DLT is observed, we will 
impose a minimum of 1 week of observation between patients in the second stage of the design.  
We do not allow for dose skipping during dose escalation or escalation immediately after a dose 
limiting toxicity. Patients who do not complete 80% of dosing due to reasons other than 
treatment-related toxicity (e.g. non-compliance) will need to be replaced. Moreover, patients 
who discontinue due to reasons other than treatment-related toxicity (i.e. progression or 
death) prior to completing 4 weeks of therapy without having experienced a DLT will be 
considered not evaluable and be replaced. Partial toxicity information from subjects that are 
greater than 80% compliant may be included for dose assignments and will continue to be used for 
future dose assignments unless the patient is not evaluable and/or discontinues prior to the 4 week 
DLT evaluation. To evaluate the performance of the method, 2000 simulations under these 
scenarios of toxicity profiles were done. The operating characteristics of our design under these 
scenarios are displayed in Table 2. Based on these simulation results, the 18-patient design selects 
the correct MTD with probabilities over 53% under all possible scenarios. These simulations 
assume that the patients arrive at a rate of 4 patients every 4 weeks (i.e., a patient every week) 
which is our full toxicity evaluation window, and that a DLT occurs randomly and uniformly 
Scenario 2 
DLT rate 
15% 
30% 
45% 
P(Selection) 
24% 
53% 
23% 
Average Number 
Assigned 
6 
6 
6 
Scenario 3 
DLT rate 
5% 
15% 
30% 
P(Selection) 
1% 
25% 
74% 
Average Number 
Assigned 
2 
5 
11 


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within the observation window. Moreover, based on the various simulation scenarios, we expect 
between 6 and 11 of the 18 patients will be assigned the MTD.   
 
To illustrate the method using an example, Figure 5 displays a simulation of a sample design using 
the method based on scenario 2 (see Table 2), where the true MTD is dose level 2.  In this simulated 
example, the recommended dose level is 2.  The first three patients are assigned to dose level 1 in 
weeks 1, 2, and 3.  By week 4 patient 1 has a DLT and we initiate the TITE-CRM with patients 4, 
5, 6, and 7 being assigned dose level 1.  With no DLTs, at week 7 the dose is escalated and patients 
8, 9, 10 and 11 are assigned to dose level 2.  With no DLTs, by week 12 the dose is escalated again 
and patient 12 is assigned to dose level 3.  Patient 12 has a DLT and the dose is de-escalated with 
patient 13 to 18 being assigned to dose level 2, with two DLTs being observed among them.  The 
estimated MTD is dose level 2 with an estimated probability of DLT of 0.27 and 90% probability 
interval of (0.12, 0.44). Two of the 10 patients assigned to dose level 2 have DLTs. With an accrual 
rate of 4 patients per month, this study takes a total of less than 6 months to complete.   
 
 
Figure 5. Simulated trial using time-to-event continuous reassessment method. 
 Each number represents an enrolled patient. Circled numbers depict time at which toxicity was experienced by that patient. 


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Dose Limiting Toxicities for Phase 1 
All patients who receive at least one dose of cobimetinib and hydroxychloroquine, with or without 
atezolizumab, will be evaluable for toxicity.  
In order for a patient to be evaluable for DLT assessments, the patient must either incur a DLT 
during the DLT evaluation period, or have received at least 80% of the planned doses of 
hydroxychloroquine, cobimetinib, and if applicable, atezolizumab. Patients who do not fulfill one 
of these criteria should be considered non-evaluable for DLT assessment purposes, and be 
replaced. 
A DLT is defined as an AE that is possibly, probably, or definitely related to study drug 
administration, and that is:  
 
 Not due to the underlying malignancy;  
 Has no clear evidence of an alternative etiology; and  
 Meets one of the following CTCAE v.5.0 criteria during the first 28 days of 
hydroxychloroquine, cobimetinib, and if applicable, atezolizumab administration:  
• 
Any Grade ≥ 4 hematologic toxicity, except grade 4 lymphopenia, lasting ≥ 7 consecutive 
days 
• 
Grade 3 neutropenia with fever 
• 
Grade 3 thrombocytopenia with clinically significant bleeding   
• 
Any circumstance that results in dose reduction 
• 
Any Grade ≥ 3 non-hematologic toxicity except:  
• 
Nausea, vomiting, and/or diarrhea of Grade 3 severity that resolves within 7 
consecutive days with optimal prophylaxis and/or treatment; 
• 
Grade 3 fatigue that resolves to Grade ≤ 2 within 7 consecutive days;  
• 
Grade ≥3 alkaline phosphatase that is related to underlying malignancy (eg, bone 
metastasis).  
• 
Grade  3 asymptomatic or mildly symptomatic rash will not be considered a DLT if 
the event can be adequately managed with supportive care, the event resolves to 
become asymptomatic and/or Grade  2 within 7 days, or the event continues for 
longer than 7 days in a patient who has not received appropriate supportive therapy. 
• 
Grade  3 elevation of serum creatine phosphokinase (CPK) level will not be 
considered a DLT if the event is asymptomatic (i.e., not accompanied by signs, 
symptoms, or other laboratory abnormalities associated with rhabdomyolysis or 
myocardial injury) and is deemed by the investigator to be clinically insignificant. 
• 
Grade 3 arthralgia will not be considered a DLT if the event can be adequately 
managed with supportive care or the event resolves to Grade  2 within 7 days. 
• 
Grade 3 fever (in the absence of any clinically significant source of fever) will not be 
considered a DLT if the event resolves to Grade  2 within 7 days or the event 
continues for longer than 7 days in a patient who has not received appropriate 
supportive care. 


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• 
Grade 3 laboratory abnormality will not be considered a DLT if the event is 
asymptomatic and is deemed by the investigator to be clinically insignificant. 
• 
Grade 3 autoimmune thyroiditis or other endocrine abnormality will not be considered 
a DLT if the event can be managed by endocrine therapy that would not necessitate 
initiation of systemic corticosteroids. 
• 
Grade ≥ 3 total bilirubin that is not attributed to disease progression 
• 
Grade ≥ 3 AST or ALT, but not isolated elevation in ALT (non-specific) in subjects 
without metastatic disease in the liver 
• 
AST or ALT ≥ 10X ULN in subjects with liver metastasis 
• 
QTc interval ≥ 501ms confirmed by a repeat ECG 
• 
Grade ≥ 3 Creatine Kinase with symptoms of myalgia 
• 
Grade ≥ 2 retinal events lasting greater than 14 days or Grade ≥ 3 retinal events that are 
confirmed by ophthalmologic examination 
• 
Grade ≥ 3 rash that persists despite optimal treatment, and that does not resolve to Grade 
≤ 2 within 7 days. 
Final decisions on determination of DLTs will be made in consultation with the Principal 
Investigator. The Principal Investigator may decide not to further dose escalate based on clinical 
judgement.  
DLTs are considered AEs of special interest, and require close monitoring and rapid 
communication with the Principal Investigator. An DLT may be serious or nonserious. The rapid 
reporting of DLTs allows ongoing surveillance of these events in order to prevent enrollment of 
subjects at inappropriate dose levels, therefore, DLTs will be required to be reported to the study 
email AAAS4165@lists.cumc.columbia.edu within 24 hours to the lead site by memo signed by 
the Affiliate Site PI/Treating Investigator. DLTs should also be reported in Velos. Please refer to 
Section 14.2 for Data Reporting Guidelines.  
 
Size/Accrual Rate 
The planned accrual size is 18 evaluable patients, with an accrual rate of 4 patients per month. 
 
Analysis of Primary Endpoints 
The TITE-CRM will be used to estimate the probability of DLT at each dose. It will be reported 
along with the 90% probability interval. Moreover, the observed rate of DLT will be reported by 
dose level.  
 
Analysis of Secondary and Exploratory Endpoints 
The frequency of radiographic response will be documented with summary statistics at the 
estimated MTD and by dose level. Best overall response rate (CR+PR) will be calculated along 
with a 95% confidence interval. 
Progression-free survival and overall survival curves will be generated using Kaplan-Meier 
methodology for all patients and those assigned to the estimated MTD at the end of the trial. 
Treatment-related toxicity will be reported by type, frequency, and severity according to the 


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National Cancer Institute Common Terminology Criteria for Adverse Events, version 5 (NCI, 
2017). 
Ten paired biopsies representing combination therapy with cobimetinib and hydroxychloroquine, 
with and without atezolizumab, will be performed. Once adequate tissue for exploratory analysis 
is procured from ten subjects, subsequent subjects may not need to undergo biopsies. Necessity 
will be determined by the principal investigator.  
Patients will be required to obtain research-specific biopsies as follows:  
 Baseline biopsy of a target lesion; 
 Repeat biopsy during week 3 of Cycle 1 (for pharmacodynamic analysis); 
 Optional biopsy at time of progression. 
All biopsies will attempt to obtain 4-6 cores. Each core biopsy obtained from a patient will only 
be performed if deamed safe by the interventional radiologist. The interventional radiologist will 
cease from obtaining biopsies if he/she deams that additional biopsies performed from pulmonary 
nodules would put the patient at significant increased risk for biopsy-related complications, in 
which case the core biopsies should be limited to 3 cores, if feasible. Two of the cores will be 
processed for formalin fixation, 2 will be frozen in liquid nitrogen, and if additional core tissue is 
available, samples will be processed for generation of organoids and/or single cell DNA 
analysisfor exploratory studies.  
Changes in CD8+ T-cells, FoxP3+ T-regs, autophagy and other markers from pre-treatment 
biopsies at baseline to on-treatment biopsies will be summarized and reported as means, medians, 
standard deviations, and ranges, and compared using the Wilcoxon signed rank test for patients 
assigned to the MTD. These correlative studies will be considered exploratory in nature. 
Statistical analysis of RNA-Seq expression data derived from samples of the treatment arms will 
be carried out in the R environment for statistical computing (RDC, 2016). In order to identify 
differentially expressed genes between the conditions, we will make use voom-limma 
framework (Ritchie et al., 2015). Briefly, linear models are fit for each gene to estimate the 
coefficients (= effect size) and their standard error. Empirical Bayes-moderated t-statistics and 
their associated p-values are then used to assess the significance of the observed expression 
changes. 
In order to evaluate concerted differences of biologically related genes, single sample gene set 
enrichment will be employed via the GSVA R package (Hanzelmann, Castelo, & Guinney, 2013) 
which produces a gene-set by sample matrix with approximately normally distributed enrichment 
scores which can then be compared between treatment arms using for example linear models. 
Detailed statistical plan is as described in the manuscript [Kenneth Olive, submitted]. 


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4.1.2 
Phase 2 
The phase 2 portion of the study will be amended after preliminary safety and efficacy results from 
phase 1 and other ongoing clinical trials have been analyzed and a summary incorporated within 
the protocol as an amendment including a rationale of the cohorts to be tested. The amendment 
will be submitted to the Scientific Review Committee (PRMC) and Institutional Review Board 
(IRB) at CUIMC for approval prior to activation of phase 2 portion of the study. 
Three separate phase 2 studies will be conducted based on the differences in baseline response rate 
by disease subtype:  
Cohort 1 – Advanced Pancreas Adenocarcinoma 
Cohort 2 – Advanced Colorectal Adenocarcinoma 
  Cohort 3 – Histology Agnostic Adenocarcinoma 
The primary outcome measure is best objective response by 16 weeks; that is, patients who achieve 
CR or PR within the first 16 weeks will be considered responders. Tumor response will be assessed 
by CT scans performed every 8 weeks using the Immune-Modified Response Evaluation Criteria 
in Solid Tumors (IM RECIST). We will use a Simon optimal 2-stage design for each disease 
subtype to allow for early stopping.   
Advanced Pancreas Adenocarcinoma 
For the advanced pancreas adenocarcinoma group, we assume an objective response rate of 16%, 
based on current therapy (Wang-Gillam et al., 2016). The study will enroll 23 patients in the first 
stage. If 5 or more patients respond in the first stage, the study will be expanded to a total of 67 
patients. If a total of 16 or more patients respond, the combination will be considered promising 
in patients with advanced pancreatic adenocarcinoma. This optimal two-stage design assumes for 
a type 1 error of 0.05 and type 2 error of 0.20 to detect a difference of 16%, versus 30% in the best 
objective response rate by 16 weeks.  
Metastatic Colorectal Adenocarcinoma 
For the advanced colorectal adenocarcinoma group, we assume an objective response rate of 2%, 
based on current therapy (Grothey et al., 2013; Mayer et al., 2015). The study will enroll 20 patients 
in the first stage. If 2 or more patients respond in the first stage, the study will be expanded to a 
total of 34 patients. If a total of 3 or more patients respond, the combination will be considered 
promising in patients with advanced colorectal adenocarcinoma. This optimal two-stage design 
assumes for a type 1 error of 0.05 and type 2 error of 0.20 to detect a difference of 2%, versus 15% 
in the best objective response rate by 16 weeks.  
Advanced Histology Agnostic Adenocarcinoma 
For the histology agnostic adenocarcinoma group, we assume an objective response rate of 5%, 
based on current therapy, and given the inclusion criteria that subjects must have progressed on or 
are intolerant of all standard of care therapies that result in a median progression free survival 
benefit of  ≥ 8 weeks or an overall response rate of > 5%.  The study will enroll 23 patients in the 
first stage. If 2 or more patients respond in the first stage, the study will be expanded to a total of 


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56 patients. If a total of 6 or more patients respond, the combination will be considered promising 
in patients with histology agnostic adenocarcinoma. This optimal two-stage design assumes for a 
type 1 error of 0.05 and type 2 error of 0.20 to detect a difference of 5% versus 15% in the best 
objective response rate by 16 weeks. 
 
Size/Accrual Rate 
The planned accrual size is 157 evaluable patients across the three cohorts of patients.  The 
expected accrual rate is 4 patients per month. However, given the possibility of early stopping, the 
sample size could be as low as 66 if all three cohorts stop in the first stage.   
 
Analysis of Primary Endpoints 
The frequency of best objective response (CR+PR) by 16 weeks will be calculated along with an 
exact 95% confidence interval.  
 
Analysis of Secondary and Exploratory Endpoints 
The frequency of radiographic response will be documented with summary statistics at the 
estimated MTD and by dose level. Best overall response rate (CR+PR) will be calculated along 
with a 95% confidence interval. 
Progression-free survival (PFS) and overall survival (OS) curves will be generated using Kaplan-
Meier methodology. PFS  is defined as the time from enrollment until disease progression or death 
from any cause. Patients who are alive and have not progressed will be censored at the date of their 
last follow-up. OS is defined as the time from enrollment until death from any cause.  Patients who 
are alive will be censored at their last follow-up.   
4.2 
Number of Patients 
Phase 1: N=18 
Phase 2: N=157 (66-157) 
5. 
SUBJECT SELECTION AND WITHDRAWL 
Each of the criteria in the following section must be met in order for a patient to be considered 
eligible for participation.  
5.1 
Inclusion Criteria 
For Phase 1 and 2, participants must have histologically confirmed KRAS-mutant malignancy that 
is metastatic or unresectable, and for which standard curative or meaningful life prolonging 
palliative measures do not exist or are no longer effective as described below (#3). Subjects with 
pancreas adenocarcinoma or colorectal adenocarcinoma have specific requirements. At least 12 
of the 18 evaluable patients within phase 1 should carry an active diagnosis of either pancreas 
or colorectal adenocarcinoma. 
Specific inclusion criteria are: 


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1. Histological or pathological confirmation of malignancy with a KRAS-activating mutation. 
Cytologic or histologic proof of malignancy needs to be verified by the treating institution 
pathologist, either from the initial diagnostic biopsy or from the required pre-treatment biopsy, 
prior to initiation of any study-related therapy. Tumor must contain an activating KRAS 
mutation as determined by an FDA or New York State approved non-significant risk assay 
(within exons 2, 3, and 4). Subjects may be enrolled using prior KRAS positive result by non-
FDA or New York State approved assay obtained per standard of care, but may not initiate 
treatment until KRAS mutation is confirmed by an FDA or New York State approved assay. FDA 
approved mutational analysis tests performed on blood which identify a KRAS mutation along 
with a biopsy which confirms tunmor histology will be sufficient to meet this criteria.  
Please note, there is specific interest in KRAS G12R mutated patients with pancreas cancer or 
colorectal cancer. 
 
2. Extent of disease 
Advanced disease for which no curable options are available, including but not limited to, surgery, 
radiation, or loco-regional therapy. Subjects who are not deemed candidates for these curative 
therapies will be eligible if they meet other criteria. 
3. Prior treatments 
 Pancreas adenocarcinoma 
Subjects must have progressed on or be intolerant of combination therapy containing 
either 5-Fluorouracil/Capecitabine- and/or gemcitabine-based therapy. Subjects who 
experienced disease recurrence while receiving adjuvant chemotherapy or within three 
months of completing adjuvant chemotherapy are eligible. 
 Colorectal adenocarcinoma 
Subjects must have progressed on or be intolerant of combination therapy containing 
5-Fluorouracil/Capecitabine, and must have received Oxaliplatin and Irinotecan. 
 
 MSI-H/dMMR or NTRK-fusion positive tumors 
Subjects must have received prior treatment with approved drugs for tumors harboring 
these aberrations. 
 Histology agnostic cancers other than pancreas and colorectal adenocarcinoma (see 
above; Phase 1 and 2) 
Subjects must have progressed on or be intolerant of all standard of care therapies that 
result in a median progression free survival benefit of  ≥ 8 weeks, or overall response 
rate of >5%. 


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4. ECOG performance status of 0 or 1 
5. Age ≥18 years 
6. Adequate hematological and end-organ function (test results from within 14 days prior to 
initiation of study treatment): 
 ANC ≥ 1.5 x 109/L without granulocyte colony-stimulating factor support 
 WBC count  2.5  109/L (2500/L)  
 Lymphocyte count  0.5  109/L (500/L) 
 Platelet count  100  109/L (100,000/L) without transfusion 
 Hgb > 9.0 g/dL  
 AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5X upper limit of normal (ULN), 
unless elevated secondary to biliary obstruction from the pancreas mass and amenable 
to decompression prior to initiation of therapy 
 Serum total bilirubin ≤ 1.5X ULN, unless in patients with known Gilbert disease (≤ 3X 
ULN), or unless elevated secondary to biliary obstruction from the pancreas mass and 
amenable to decompression prior to administration of investigational therapy 
 Albumin ≥ 3.0g/dL 
 Creatinine  within ULN or calculated creatinine clearance (CrCl)  >50 mL/min using 
the Cockcroft-Gault formula 
 INR and aPTT ≤ 1.5X ULN except for those who are on stable anticoagulation for at 
least three months. 
7. Measurable disease according to IM-RECIST and tumor accessible for fresh biopsy if ten 
adequate paired biopsied specimens have not been procured (Phase 1) 
8. Negative pregnancy test 
Women of childbearing potential must have a negative serum pregnancy test at screening and 
must agree to use an effective form of contraception from the time of the negative pregnancy 
test until a minimum of 3 months after the last dose of study drug. Effective forms of 
contraception include abstinence, hormonal contraceptive (injectable or implantable) in 
conjunction with a barrier method, or a double barrier method. Women of non-child-bearing 
potential must have been postmenopausal for ≥ 1 year or surgically sterile. 
9. Birth control agreement 
Fertile men must agree to use an effective method of birth control during the study and for up 
to 3 months after the last dose of study drug. 
10. Informed consent 
Participants must be willing and able to provide written informed consent prior to any study-
related procedures and to comply with all study requirements. 
11. Ability to comply 


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Participants must be able to comply with the study protocol, according to the investigator’s 
judgement. 
12. DVT testing 
Participants must have undergone lower extremity dopplers to rule out deep venous thrombosis 
(DVT) within the screening period, and undergo therapeutic anticoagulation if evidence of 
DVT is identified. 
13. VTE testing 
Patients deemed at increased risk of venous thromboembolism (VTE) based on primary cancer, 
which includes pancreas adenocarcinoma, gastric/GE junction adenocarcinoma, or CNS 
malignancy, and have not been taking anticoagulants, are to undergo prophylaxis 
anticoagulation with enoxaparin. Enoxaparin will be administered at a dose of 1mg/kg/day to 
mitigate the risk of VTE. Subjects who are unable to receive enoxaparin, but deemed at 
increased risk of VTE will not be eligible and consultation with the Principal Investigator is 
required. 
14. Anticoagulation treatment 
Subjects who are currently stable on full-dose anticoagulation medication for at least 8 weeks 
are considered eligible. However, subjects who have an increased clot burden on full-dose 
anticoagulation, such as central pulmonary embolism, or peripheral pulmonary embolism, and 
DVT within the extremities will be considered eligible only with the approval of the Principal 
Investigator. 
5.2 
Exclusion Criteria 
Specific exclusion criteria are: 
1. Prior treatment with investigational therapy. 
Participants may not have had any treatments with investigational therapy within the 28 days prior 
to initiation of study treatment. 
2. Prior radiation therapy 
Participants may not have had radiation therapy within 2 weeks prior to initiation of study 
treatment. Participants may not have had previous radiotherapy to 25% or more of the bone 
marrow. 
3. Prior Therapy 
Participants may not have had systemic chemotherapy within 14 days or 5 half-lives of the drug 
(whichever is longer) prior to initiation of study treatment.  
In addition, the following prior treatment is not allowed during Phase 1 of the study:  
 Receptor tyrosine kinase inhibitors targeting MAP kinase pathway; 


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 Any pharmacological agents inhibiting the autophagy pathway. 
In addition, the following prior treatment is not allowed during Phase 2 of the study: 
 T-cell co-stimulating agents or immune checkpoint blockade therapies, including but 
not limited to anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies; 
 Receptor tyrosine kinase inhibitors targeting MAP kinase pathway; 
 Any pharmacological agents inhibiting the autophagy pathway. 
4. Adverse events from prior anti-cancer therapy 
Participants may not initiate treatment if they have adverse events from prior anti-cancer therapy 
that have not resolved to Grade ≤ 1 or better, with the exception of Grade ≤ 2 peripheral neuropathy 
or any grade alopecia. 
5. Patients currently receiving any other investigational agents  
6. Concomitant treatment with other anti-neoplastic agents (hormone therapy acceptable) 
7. Uncontrolled pleural effusion, pericardial effusion, or ascites 
8. Patients with symptomatic brain metastases 
Subjects with untreated brain metastasis ≤ 1 cm can be considered eligible if deemed asymptomatic 
by the investigator upon consultation with the medical monitor, and do not require immediate 
radiation or steroids. Subjects with brain metastasis that is treated and stable for 1 month may be 
considered eligible if they are asymptomatic and on stable dose of steroids, or if they do not require 
steroids following successful local therapy. 
9. Uncontrolled hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12mg/dL, or 
corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use 
of bisphosphonate therapy. 
10. Recent major surgery or significant traumatic injury 
Participants may not have undergone major surgery or experienced significant traumatic injury 
within 14 days prior to initiating study treatment, or be recovering from a procedure related to 
adverse events of ≤ Grade 1. 
11. Active or history of autoimmune disease or immune deficiency 
Includes, but is not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody 
syndrome, Wegener granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions: 
 Patients with a history of autoimmune-related hypothyroidism who are on stable 
thyroid-replacement hormone are eligible for the study. 
 Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen 


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are eligible for the study. 
 Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met: 
- 
Rash must cover <10% of body surface area; 
- 
Disease is well-controlled at baseline and requires only low-potency topical 
corticosteroids; 
- 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months. 
12. History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia 
(e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or 
evidence of active pneumonitis on screening chest computed tomography scan [history of 
radiation pneumonitis in the radiation field (fibrosis) is permitted]. 
13. Positive for HIV at screening or any time prior to screening 
Patients without prior positive HIV test result will undergo an HIV test at screening, unless not 
permitted under local regulations. 
14. Active Hepatitis B virus (HBV) infection (chronic or acute) 
Defined as having a positive hepatitis B surface antigen (HBsAg) test at screening. Patients with 
a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total 
hepatitis B core antibody test at screening, are eligible for the study. 
15. Active hepatitis C virus (HCV) infection 
Defined as positive HCV antibody test followed by a positive HCV RNA test at screening. The 
HCV RNA test will be performed only for patients who have a positive HCV antibody test. 
16. Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, fatty 
liver disease, and inherited liver disease 
17. Active tuberculosis 
18. Severe infection 
Patients may not have had a severe infection within 4 weeks prior to initiation of study treatment. 
This includes, but is not limited to, hospitalization for complications of infection, bacteremia, or 
severe pneumonia. However, patients who were admitted for biliary tract infection due to bile duct 
obstruction at time of diagnosis must have a functioning biliary stent (as evidenced by declining 
total bilirubin and ≤ 2X ULN) and resolved infection (defined by normalization of elevated white 
blood cell count, absence of signs of infection) and completion of an antibiotic course (at least a 
seven-day course) prior to initiation of therapy. 


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19. Recent antibiotic treatment  
Patients may not have been treated with therapeutic oral or intravenous (IV) antibiotics within 2 
weeks prior to initiation of study treatment, except for biliary tract infection due to bile duct 
obstruction from the pancreas mass. Patients receiving prophylactic antibiotics (e.g., to prevent a 
urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the 
study.  
20. Significant cardiovascular disease 
Patient may not have significant cardiovascular disease (such as New York Heart Association 
Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 
12 months prior to initiation of study treatment, seizure disorder, uncontrolled hypertension, or 
unstable arrhythmia or unstable angina within 3 months prior to initiation of study treatment. 
21. Left ventricular ejection fraction below institutional lower limit of normal or below 50%, 
whichever is lower 
22. Baseline QTcF ≥ 450 ms (males) or ≥ 470 ms (females) 
23. Grade  3 hemorrhage or bleeding event within 28 days prior to initiation of study 
treatment 
24. Prior autologous stem cell, allogeneic stem cell, or solid organ transplantation 
25. History of malignancy 
Patient may not have a history of malignancy other than PDA within 2 years prior to screening, 
with the exception of those with a negligible risk of metastasis or death (e.g., 5-year overall 
survival of  90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. 
26. Recent vaccination 
Patients may not have been treated with a live, attenuated vaccine within 4 weeks prior to initiation 
of study treatment, or anticipate the need for such a vaccine during treatment with atezolizumab 
or within 5 months after the last dose of atezolizumab. 
27. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins 
28. Known allergy or hypersensitivity to 4-aminoquinoline compounds or any of the study 
drug excipients 
29. Recent immunosuppressive treatment 
Patients may not have been treated with systemic immunosuppressive medication (including, but 
not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study treatment, or 


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anticipate the need for systemic immunosuppressive medication during the course of the study, 
with the following exceptions: 
 Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for 
orthostatic hypotension or adrenal insufficiency are eligible for the study if receiving 
equivalent to < 10mg of prednisone daily. 
 Patients who received a one-time pulse dose of systemic immunosuppressant 
medication are eligible for the study after approval from the Principal Investigator.  
30. Inability to swallow medication or malabsorption condition that would alter the absorption 
of orally administered medications 
31. History of retinal pathology 
Patients may not have a history of or evidence of retinal pathology on ophthalmologic examination 
that is considered a risk factor for neurosensory retinal detachment, central serous 
chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration. 
Specifically, patients will be excluded from study participation if they currently are known to have 
any risk factors for RVO, including: 
 Glaucoma with intraocular pressure  21 mmHg; 
 Grade  2 serum cholesterol; 
 Grade  2 hypertriglyceridemia; 
 Grade  2 uncontrolled hypertension (patients with a history of hypertension controlled 
with anti-hypertensive medication to Grade  1 are eligible). 
32. Pregnancy 
Pregnant women are excluded from this study because there is an unknown, but potential risk for 
AEs in nursing infants secondary to treatment of the mother with these agents; breastfeeding 
should be discontinued. 
33. Other contraindicated conditions 
Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory 
finding that contraindicates the use of an investigational drug, may affect the interpretation of the 
results, or may render the patient at high risk from treatment complications in the opinion of the 
treating investigator. 
34. Concomitant strong CYP3A4 inhibitors and inducers  
Refer to list of common CYP3A4 inhibitors and inducers (Appendix 2). These include 
anticonvulsants, mycin antimicrobials, and antiretrovirals. Some common examples include 
inhibitors, such as erythromycin, fluoxetine, gemfibrozil, and inducers, such as rifampicin, 
carbamazepine, phenytoin, efavirenz, and nevirapine. Concomitant treatment is permitted if the 


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medication is not expected to interfere with the evaluation of safety or efficacy of the study drug. 
During the study, if the use of any concomitant treatment becomes necessary (e.g., for treatment 
of an adverse event), the treatment must be recorded on the eCRF, including the reason for 
treatment, generic name of the drug, dosage, route, and start and stop dates of administration. 
35. Uncontrolled psoriasis, porphyria, proximal myopathy or neuropathy 
36. Severe depression 
Subjects hospitalized for depression within the past 2 years, or who have prior suicidal attempts 
will be excluded. 
37. Gluocose-6-phosphate dehydrogenase (G-6-PD) deficiency 
38. History of connective tissue disorders (e.g., lupus, scleroderma, arteritis nodosa) 
39. Subjects on greater than once daily dose of antacid therapy 
40. Concomitant use of any of the following drugs: 
 Digoxin  
 Pharmacological agents known to prolong QT interval  
 Mefloquine or other agents which may lower the convulsive threshold 
 Antiepileptics 
 Methotrexate 
 Cyclosporine 
 Ampicillin 
 Cimetidine 
5.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. See Table 3 below 
for specific accrual targets. 
 
Table 3. Accrual Targets 
 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
2 
+ 
2 
= 
4 
Not Hispanic or Latino 
5 
+ 
9 
= 
14 
TOTAL 
7 
+ 
11 
= 
18 
Racial Category 
 


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American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
0 
+ 
0 
= 
0 
Black or African American 
1 
+ 
1 
= 
2 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
6 
+ 
10 
= 
16 
TOTAL 
7 
+ 
11 
= 
18 
 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
5.4 
Subject Recruitment  
Patients will be recruited for the study from investigator or co-investigator clinical practices and 
referring physicians. 
5.5 
Early Withdrawal of Subjects  
5.5.1 
When and How to Withdraw Subjects 
 If at any time the patient develops progressive disease, he/she will be taken off treatment 
and referred for alternative therapy. 
 If at any time the patient develops unacceptable toxicity, he/she will be removed from 
study treatment. 
 If at any time the patient is found to not meet key eligibility Criteria for Patient/Subject 
Eligibility (e.g., a change in diagnosis), the patient will be removed from study. 
 If the patient fails to comply with the defined treatment plan and follow-up evaluations, 
the patient will be removed from the study treatment. 
 If the patient withdraws consent for continued participation, he/she will be removed 
from study treatment. Patient may agree to be contacted for follow up data. 
5.5.2 
Data Collection and Follow-up for Withdrawn Subjects 
If a patient withdraws consent to participate in the study treatment administration, every attempt 
will be made to follow up for survival data. 


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6. 
REGISTRATION PROCEDURES 
6.1 
CUIMC Research Participant Registration  
All participants must be centrally registered through the Central Registration Office within Herbert 
Irving Comprehensive Cancer Center at CUMC prior to initiation of study treatment. 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST (excluding 
holidays and weekends). Same-day subject registrations (and after hour registrations) will be 
accommodated on a case-by-case basis, provided that the study team has expressed all time 
sensitive registration concerns/cases in a timely manner to the Central Registration Office. 
The following requirements exist for participant registration: 
 Confirm eligibility, as defined in the section entitled Criteria for Subject Eligibility. 
 Obtain informed consent by following procedures defined in section entitled Informed 
Consent Procedures, along with applicable institutional policies and federal regulations. 
 Only Investigators/Research personnel properly trained and delegated to consent 
subjects for this protocol will participate in the consenting process. Furthermore, 
properly delegated/trained Physician Investigators (e.g., MD, MD PhD) are required to 
sign/verify a protocol specific Eligibility Checklist for each subject enrolled on the 
study, in addition to providing the relevant source documentation confirmation subject 
eligibility. 
CPDM Central Registration Procedures: 
Within 48 hours of obtaining consent (excluding holidays and weekends), a completed/signed 
IRB-approved informed consent HIPAA form, and demographics forms must be submitted to the 
CPDM Central Registration Office via an email to CPDMRegistration@cumc.columbia.edu or fax 
to 212.305.5292, with the subject line “AAAS4165 Pending Subject Registration Request (PHI)”.  
Upon receipt, applicable subject information as well as a “pending eligibility” status will be 
entered into HICCC’s institutional database. This status will remain until further source 
documentation is made available to confirm overall patient eligibility. Required materials for all 
pending registration submissions are as follows: 
 
Completed/signed IRB approved/stamped Informed Consent Forms, including additional 
study ICFs (e.g., tissue, DNA, etc.), as applicable. 
 
The completed/signed IRB approved HIPAA Authorization form 
 
Completed/signed CPDM ICF checklist 
 
Completed/signed HICCC personal census form 
 
Completed/signed CPDM Demographics Note to File 


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In order to confirm eligibility status, Investigators/designees (e.g., study specific Clinical Research 
Coordinator/Research Nurse, etc.) must submit the following documentation to the Central 
Registration Office via email or fax: 
 
Completed/signed study-specific Eligibility Checklist (signed by Physician level Investigator) 
 
Copies of source documentation necessary for each item to be verified on the CPDM specific 
Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., hematology, serum chemistry, 
pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) or other appropriate medical records capturing the consent process 
information, along with providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms (e.g., positive 
investigator statements of unique eligibility items not captured via other direct source 
documentation, concomitant medication lists, etc.) 
Subject line of email or fax should read: “AAAS4165 Complete Subject Registration Request 
(PHI)”. 
Upon receipt of documentation, participant eligibility information will be verified by a qualified 
Central Registration Registrar. If any questions arise during the review process, email queries to 
the applicable study team personnel for clarification prior to enrollment. All applicable finalized 
registration/eligibility information will then be entered into HICCC’s institutional CTMS database 
by the Central Registration Registrar. Upon completion, an official subject registration notification 
email will be sent to the PI/research team to include eligibility/enrollment status and subject ID 
information. Protocol therapy may not be initiated prior to receipt of this notification. 
All screen fail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office in a 
manner analogous to the procedures noted above. Applicable source documentation will be 
required within the corresponding submissions. 
7. 
  TREATMENT AND/OR IMAGING PLAN 
7.1 
   Investigational Agent Administration 
Treatment will be on an outpatient basis. Reported AEs and potential risks for cobimetinib, 
hydroxychloroquine, and atezolizumab are described below (Section 8, Appendix 1).  Appropriate 
dose modifications are described in Section 9. No investigational or commercial agents or 
therapies other than those described below may be administered to treat the patient's malignancy. 
Patients will receive treatment as outlined in Table 4 below until unacceptable toxicity or loss of 
clinical benefit, as determined by the investigator after an integrated assessment of radiographic 


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and biochemical data, local biopsy results (if available), and clinical status (e.g., symptomatic 
deterioration such as pain secondary to disease). 


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Table 4. Treatment schedule 
 
Cycle 
Cycle 
Length 
Dose, Route and Regimen 
(drugs listed in order of administration) 
Cycle 1 and beyond 
28 days 
 
Cobimetiniba orally once daily (morning) on 
Days 1-21 of each 28-day  
 
Hydroxychloroquine: 600mg orally twice daily 
on Days 1-28 of each 28-day cycle 
 
Atezolizumab None or 840 mg IV on Days 1 and 
15 of each cycle 
aDose will be determined via dose levels 
If one study drug is discontinued, the other study drug(s) can be continued if the patient is likely 
to derive clinical benefit, as determined by the investigator in consultation with the Principal 
Investigator.   
7.1.1 
Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of 
each 28-day cycle (Section 7.3). 
Administration of atezolizumab will be performed in a monitored setting where there is immediate 
access to trained personnel and adequate equipment and medicine to manage potentially serious 
reactions. 
Atezolizumab administration will be according to Table 5 below. Please note that 
Hydroxychloroquine and Cobimetinib could be administered in the morning, prior to Atezo.  
 
 
 


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Table 5. Atezolizumab administration 
 
 
First Infusion  
Subsequent Infusions 
• No premedication is permitted prior to the 
atezolizumab infusion.  
• Vital signs (pulse rate, respiratory rate, blood 
pressure, pulse oximetry, and temperature) 
should be recorded within 60 minutes prior to 
the infusion.  
• Atezolizumab should be infused over 60 (± 
15) minutes.  
• If clinically indicated, vital signs should be 
recorded every 15 (± 5) minutes during the 
infusion and 30 (± 10) minutes after the 
infusion.  
• Patients should be informed about the 
possibility of delayed post-infusion symptoms 
and instructed to contact their study physician 
if they develop such symptoms. 
• If the patient experienced an infusion-related 
reaction 
with 
any 
previous 
infusion, 
premedication 
with 
antihistamines, 
antipyretics, 
and/or 
analgesics 
may 
be 
administered for subsequent doses at the 
discretion of the investigator.  
• Vital signs should be recorded within 60 
minutes prior to the infusion.  
• Atezolizumab should be infused over 30 (± 
10) minutes if the previous infusion was 
tolerated without an infusion-related reaction, 
or 60 (± 15) minutes if the patient experienced 
an infusion-related reaction with the previous 
infusion.  
• If the patient experienced an infusion-related 
reaction with the previous infusion, or if 
clinically indicated, vital signs should be 
recorded during the infusion and at 30 (± 10) 
minutes after the infusion. 
 
Atezolizumab treatment may be interrupted for reasons other than toxicity (e.g., surgical 
procedures) with Principal Investigator approval. The Investigator and Principal Investigator will 
determine the acceptable length of treatment interruption. 
 
Premedication 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered for the 
second and subsequent atezolizumab infusions only, at the discretion of the investigator. 
Hematopoietic growth factors are not to be administered prophylactically prior to the first dose of 
therapy. In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice. Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, 
and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local 
standard practice. Serious infusion-associated events manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies, as clinically indicated (e.g., supplemental oxygen and ß2- 
adrenergic agonists; see Appendix 1. 


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7.1.2 
Cobimetinib 
In this study, cobimetinib will be administered orally once daily (morning) on Days 1-21 of each 
28-day cycle. Cobimetinib will be supplied as 20-mg, film-coated tablets packaged in blister packs 
(21 tablets per pack; 3 packs per box) for oral administration. Cobimetinib should be taken 
approximately the same time in the morning, and no later than 4 hours after the scheduled time. 
Cobimetinib may be taken with or without a meal. Cobimetinib should be swallowed whole with 
a glass of water and should not be chewed, cut, or crushed. If a dose of cobimetinib is missed (i.e., 
not taken within 12 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. For information on the 
formulation and handling of cobimetinib, see the pharmacy manual and the Cobimetinib 
Investigator's Brochure. 
7.1.3 
Hydroxychloroquine 
In this study, Hydroxychloroquine will be administered orally twice daily on Days 1-28 of each 
28-day cycle with a meal or a glass of milk.  Hydroxychloroquine should be swallowed whole with 
a glass of water (with meals) or milk and should not be chewed, cut, or crushed. If a dose of 
Hydroxychloroquine is missed (i.e., not taken within 6 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. 
Hydroxychloroquine treatment may be suspended for reasons other than toxicity with Principal 
Investigator approval. 
7.1.4 
Other Agent(s) 
N/A 
7.1.5 
Other Modality(ies) or Procedures 
N/A 
7.2 
General Concomitant Medication and Supportive Care Guidelines 
The following are permitted therapies while receiving investigational agents. 
 Oral contraceptives  
 Hormone-replacement therapy 
 Been stable on anticoagulation therapy (at a stable dose or low-molecular-weight heparin) that 
was initiated at least two months prior to initiation of study treatment.  
 Inactivated influenza vaccinations  
 Mineralocorticoids (e.g., fludrocortisone)  
 Inhaled corticosteroids administered for chronic obstructive pulmonary disease or asthma  
 Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 


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insufficiency amounting to less than 10mg of prednisone daily, and with the approval of the 
Principal Investigator.  
 Hormonal therapy with gonadotropin-releasing hormone agonists or antagonists for prostate 
cancer 
 Nerve blocks for pain control with adequate pain management  
7.2.1 
Medications to be given with precaution due to effects related to cytochrome P450 
enzymes 
Concomitant treatment is permitted if the medication is not expected to interfere with the 
evaluation of safety or efficacy of the study drug. During the study, if the use of any concomitant 
treatment becomes necessary (e.g., for treatment of an adverse event), the treatment must be 
recorded on the eCRF, including the reason for treatment, generic name of the drug, dosage, route, 
and start and stop dates of administration. 
Concomitant use of strong and moderate inhibitors of CYP3A (e.g., clarithromycin, 
itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole; see Appendix 2) 
should be avoided during cobimetinib treatment because cobimetinib is a sensitive substrate of 
CYP3A, and exposures will be increased in t h e  presence of these agents (approximately 7-
fold increase in presence of itraconazole in healthy subjects). Consumption of grapefruit 
juice, a potent CYP3A4 enzyme inhibitor, is prohibited during the study and for 30 days after 
the last dose of study treatment. 
Strong and moderate CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine, and 
phenobarbital; see Appendix 2) should be avoided during cobimetinib treatment because they 
increase the metabolism of cobimetinib. Strong inducers of CYP3A4 should be avoided, or 
selection of an alternate concomitant medicinal product with no or minimal potential to induce 
CYP3A4 should be considered. 
The above lists of cautionary medications are not necessarily comprehensive. The Investigator 
should consult the prescribing information when determining whether a concomitant medication 
can be safety administered with study treatment. In addition, the Investigator should contact the 
Principal Investigator if questions not listed above arise regarding medications. 
7.2.2 
Medications Prohibited 
 Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to initiation of 
study treatment, during treatment with atezolizumab, and for 5 months after the last dose of 
atezolizumab. 
 Systemic immunostimulatory agents (including, but not limited to, interferons and interleukin 
2) are prohibited within 12 weeks or five half-lives of the drug, whichever is longer, prior to 
initiation of study treatment and during study treatment because these agents could potentially 
increase the risk for autoimmune conditions when given in combination with atezolizumab. 
 Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, 


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azathioprine, methotrexate, and thalidomide) are prohibited during study treatment because 
these agents could potentially alter the efficacy and safety of atezolizumab. 
7.3 
  Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for 1 cycle or 
until one of the following criteria applies: 
 Confirmed disease progression 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse event(s) 
 Patient decides to withdraw from the study treatment 
 General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the Investigator 
7.4 
  Duration of Follow Up 
Participants will be followed for up to 5 years after completion or removal from study treatment 
or until death, whichever occurs first. Participants removed from study treatment for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event. A post-study 
follow-up contact via phone by site staff will be conducted every 3 months during years 1 and 2, 
then every 6 months thereafter to obtain information on any new anti-cancer therapy received and 
survival status. 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 2 weeks, 
counsel the participant on the importance of maintaining the assigned visit schedule, and ascertain 
if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the Investigator or designee will make every 
effort to regain contact with the participant (where possible, at least 3 telephone attempts). These 
contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
7.5 
 Criteria for Removal from Study 
Participants will be removed from study when any of the criteria listed in Section 7.4 applies.  The 
reason for study removal and the date the patient was removed will be documented in the Case 
Report Form. 


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8. 
ADVERSE EVENTS AND DOSING DELAYS/MODIFICATIONS 
8.1 
General guidelines on dose delays and/or modifications 
Dose Modifications – 
Dose reductions during the DLT period are not allowed, unless a DLT is confirmed. If the subject 
experiences a DLT, they should be removed from the study unless the subject is deriving clinical 
benefit, as determined by the Investigator in consultation with the Principal Investigator.  
Dose modifications will be allowed if subject does not tolerate therapy after the DLT period, as 
described (Section 8.2).  
Dose Interruptions – 
Dose interruptions are allowed during the DLT period as long subjects receive 90% of the 
scheduled doses. Doses held due to toxicity will not be replaced within the same cycle. If a drug 
is held due to toxicity, the other drug(s) may be administered as scheduled. If hydroxychloroquine 
and/or cobimetinib is held for longer than 28 days, all treatments should be permanently 
discontinued and the patient removed from study, unless the subject is deriving clinical benefit as 
determined by the Investigator in consultation with the Principal Investigator. If atezolizumab is 
held for longer than 105 days, atezolizumab should be permanently discontinued; however, 
hydroxychloroquine and cobimetinib may be continued.  
8.2 
Drug-specific dose delays/modifications 
8.2.1 
Dose modifications: Atezolizumab 
There will be no dose modifications for atezolizumab in this study. Atezolizumab treatment may 
be temporarily suspended in patients experiencing toxicity considered to be related to study 
treatment. If corticosteroids are initiated for treatment of the toxicity, they must be tapered over 
≥1 month to ≤10 mg/day oral prednisone or equivalent before atezolizumab can be resumed. If 
atezolizumab is withheld for >105 days, the patient will be discontinued from atezolizumab. 
However, atezolizumab may be withheld for >105 days to allow for patients to taper off 
corticosteroids prior to resuming treatment. Atezolizumab can be resumed after being withheld for 
>105 days if the Principal Investigator agrees that the patient is likely to derive clinical benefit. 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice. Additional tests, such as autoimmune serology or biopsies, 
should be used to evaluate for a possible immunogenic etiology. Although most immune-related 
adverse events 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, or other immunosuppressive agents. The investigator should consider the 
benefit-risk balance a given patient may be experiencing prior to further administration of 
atezolizumab. In patients who have met the criteria for permanent discontinuation, resumption of 
atezolizumab may be considered if the patient is deriving benefit and has fully recovered from the 


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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 Principal 
Investigator. Please refer to Appendix 1 for management of atezolizumab-related adverse events. 
8.2.2 
Dose modifications: Cobimetinib 
Allowable dose modifications for Cobimetinib are described in Table 6. Cobimetinib treatment 
may be temporarily suspended in patients who experience toxicity considered to be related to study 
treatment. After dose reduction, the dose of cobimetinib may be escalated by a maximum of one 
dose level (20 mg) increments at the Investigator's discretion in consultation with the Principal 
Investigator, provided there are no safety concerns.  If cobimetinib has been withheld for >28 days 
because of toxicity, the patient should be discontinued from cobimetinib, unless resumption of 
treatment is approved following Investigator discussion with the Principal Investigator. The 
Principal Investigator should be consulted for any major surgery (e.g., involving a body cavity), 
and cobimetinib should generally be withheld for 12 hours prior to the procedure and for 2 weeks 
thereafter. 
 
Table 6. Cobimetinib dose modifications 
 
Dose Level 
Cobimetinib  (mg) TDD 
-1 
40mg (orally in AM) 
-2 
20mg (orally in AM) 
8.2.3 
Dose modifications: Hydroxychloroquine 
Allowable dose modifications for Hydroxychloroquine are described in Table 7. 
The 4-aminoquinoline compounds are very rapidly and completely absorbed after ingestion. In 
accidental overdosage, or rarely with lower doses in hypersensitive patients, toxic symptoms may 
occur within 30 minutes. The symptoms of overdosage may include headache, drowsiness, visual 
disturbances, cardiovascular collapse, convulsions, hypokalemia, rhythm and conduction 
disorders, including QT prolongation, torsades de pointes, ventricular tachycardia and ventricular 
fibrillation, followed by sudden, potentially fatal respiratory and cardiac arrest. Treatment is 
symptomatic and must be prompt. Immediate gastric lavage until the stomach is completely 
emptied is indicated. After lavage, activated charcoal is introduced by the stomach tube within 30 
minutes of ingestion of the drug may inhibit further intestinal absorption. To be effective, the dose 
of activated charcoal should be at least five times the estimated dose of hydroxychloroquine 
ingested.  
Consideration should be given to administering diazepam parenterally since studies suggest that it 
may be beneficial in reversing chloroquine and hydroxychloroquine cardiotoxicity.  
Respiratory support and shock management should be instituted as necessary.  
Exchange transfusions are used to reduce the level of 4-aminoquinoline drug in the blood.  


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A patient who survives the acute phase and is asymptomatic should be closely observed for at least 
six hours. Fluids may be forced and sufficient ammonium chloride (8 g daily in divided doses for 
adults) may be administered for a few days to acidify the urine. This will promote urinary excretion 
in cases of both overdosage and sensitivity. However, caution must be exercised in patients with 
impaired renal function and/or metabolic acidosis. 
  
Table 7. Hydroxychloroquine dose modification 
 
Dose Level 
Hydroxychloroquine (mg) TDD 
-1 
1000mg (400mg AM and 600mg PM orally) 
-2 
800mg (400mg BID orally) 
-3 
600mg (200mg AM and 400mg PM orally) 
 
8.2.4 
Dose modifications: Cobimetinib + Hydroxychloroquine with or without 
Atezolizumab therapy 
Dose modification may be made for Cobimetinib and/or Hydroxychloroquine, as necessary, 
according to the guidelines described (Table 6 and 7), as guided in Appendix 1. If further dose 
reduction of cobimetinib is indicated after two dose reductions, the patient must discontinue 
cobimetinib. Similarly, if further dose reduction of hydroxychloroquine is indicated after three 
dose reductions, the patient must discontinue hydroxychloroquine. Subjects may continue 
treatment if being administered two of the three study drugs, but may not continue on study with 
either cobimetinib, hydroxychloroquine, or atezolizumab alone, unless with the approval of the 
Principal Investigator deeming the subject to be deriving clinical benefit. 
8.3 
Management of adverse events 
The following categories of adverse events have been associated with one or more of the study 
drugs:  
 Infusion related reactions (IRRs), anaphylaxis, and hypersensitivity reactions 
 Gastrointestinal toxicity 
 Dermatologic toxicity 
 Hepatic toxicity 
 Pulmonary events 
 Endocrine disorders 
 Pancreatic events 


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 Neurologic disorders 
 Ocular toxicity 
 Cardiotoxicity 
 Hemorrhage 
 Myositis  
Specific actions to be taken in each case as described in Appendix 1.  
Adverse events of special interest must be reported by the investigator to the Principal Investigator 
immediately (i.e., no more than 24 hours after learning of the event; see Section 9.5 for reporting 
instructions). Adverse events of special interest for this study include the following: 
 
Non-Drug Specific Adverse Events of Special Interest:  
 Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law. 
 Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
 Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 Suspected transmission of an infectious agent by the study treatment. 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 
study 
treatment 
is 
suspected.  
 
Atezolizumab Specific Adverse Events of Special Interest 
 Pneumonitis 
 Colitis  
 Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, or hyperthyroidism 
and hypophysitis 
 Hepatitis, or AST or ALT >10 x ULN  
 Systemic lupus erythematosus  
 Neurologic: Guillain-Barré syndrome, myasthenia gravis or myasthenic syndrome, 
meningoencephalitis  


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 Nephritis  
 Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release syndrome, 
influenza-like illness and systemic inflammatory response syndrome. 
 Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)  
 Myositis  
 Myopathies, including rhabdomyolysis 
 Grade ≥2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 Vasculitis 
 Autoimmune hemolytic anemia 
 Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
 
Cobimetinib Specific Adverse Events of Special Interest  
 Any grade Retinal vein occlusion 
 Any grade serous retinopathy including 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 
 Symptomatic heart failure or Grade ≥ 2 left ventricular dysfunction 
 Pneumonitis 
 AST and/or ALT > 10 X ULN 
8.3.1 
Cobimetinib-associated adverse events 
For specific guidelines on how to respond to adverse events associated with cobimetinib, see 
Appendix 1.  
The following adverse events are classified as identified risks associated with cobimetinib: serious 
retinopathy, left ventricular dysfunction, severe hemorrhage, rhabdomyolysis, and pneumonitis. 
The following adverse events are classified as potential risks for cobimetinib: severe 
hepatotoxicity (Grade ≥3), impaired female fertility, and teratogenicity and developmental 
toxicity. In addition, there is the possibility of drug-drug interactions in patients treated with 
cobimetinib. Clinical and safety data were reported that included monotherapy and combination 


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studies, of which key adverse events are summarized here, but for a complete review of the safety 
data please refer to the most current IB version.  
Common (>10%) adverse events observed with Cobimetinib included bleeding, serious 
retinopathy, diarrhea, nausea, emesis, rash, pyrexia, chills, anemia, increased liver function 
enzymes, increased creatinine phosphokinase, and photosensitivity. Less common (1% - 10%) 
adverse events included decreased left ventricular ejection, risk of basal and squamous cell 
carcinoma, kertocanthoma, dehydration, hyponatremia, hypophosphatemia, hyperglycemia, and 
pneumonitis. Guidelines for treatment interruption or discontinuation in the case of adverse events 
are described in Appendix 1. 
 
Cobimetinib should be permanently discontinued for: 
 
Grade 4 hemorrhage events attributed to cobimetinib 
 
Symptomatic or asymptomatic decrease of LVEF < 40% or ≥ 10% absolute decrease from 
baseline after treatment break or recurrent symptomatic absolute decrease of LVEF < 10% 
(See Table 1 for details) 
 
Rhabdomyolysis or symptomatic CPK elevations not improving within 4 weeks of dose 
interruption 
 
Liver laboratory abnormalities not resolving to Grade ≤1 within 4 weeks of dose 
interruption or if Grade 4 liver laboratory abnormalities recur after initial improvement 
 
QTc increase meets values of both > 500 ms and > 60 ms change from pre-treatment values 
or 3rd occurrence of QTc > 500 ms during treatment and change from pre-treatment value 
remains ≤ 60ms 
 
9. 
ADVERSE EVENTS: REPORTING REQUIREMENTS  
9.1 
Definitions 
9.1.1 
Adverse Event: 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human patient, 
including abnormal sign, symptom or disease, temporally associated with the patient’s 
participation in research, whether or not considered related to the patient’s participation in the 
research. Abnormal results of diagnostic procedures are considered to be AEs if the 
abnormality: 
 
Results in study withdrawal; 
 
Is associated with a serious adverse event; 
 
Is associated with clinical signs or symptoms; 
 
Leads to additional treatment or to further diagnostic tests;  


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 
Is considered by the investigator to be of clinical significance, including: 
o AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with pancreatic adenocarcinoma 
that were not present prior to the AE reporting period; 
o Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures, such as cardiac catheterizations); 
o  If applicable, AEs that occur prior to assignment of study treatment that are associated 
with medication washout, no treatment run-in, or other protocol-mandated intervention; 
o  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. 
Please note:  This study will utilize Common Terminology Criteria for Adverse Events 
(CTCAE) v.5 (NCI, 2017) for all AE reporting criteria. (See Section 9.2 for adverse event 
severity grading scale for events not specifically listed in NCI CTCAE)  
The maximum severity grade of AEs or the worsening of a pre-existing medical condition 
occurring during the study should be recorded, regardless of relationship to study medication. 
For the purposes of this study, progression of the subject’s underlying disease (“disease 
progression”) is an efficacy assessment and should not be reported as an AE or SAE. However, if 
the investigator determines that there is evidence suggesting a causal relationship between the 
event and the study medication, the event should be reported immediately to the safety contact and 
recorded as an AE or SAE. 
9.1.2 
Serious Adverse Event (SAE): 
AEs are classified as serious or non-serious. A serious adverse event is any AE that is: 
 
Fatal; 
 
Life-threatening; 
 
Requires inpatient hospitalization/prolongation of existing hospitalization, unless: 
o Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition (procedures such as central line placements, 
paracentesis, pain control); 
o Elective or pre-planned treatment for a preexisting condition that is unrelated to 
the indication under study; 
o Treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of an SAE given above/below and not resulting in hospital 
admission; 


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o Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition; 
 
Results in persistent or significant disability or incapacity; 
 
A congenital anomaly or birth defect; 
 
An important medical event (i.e., those that may not be immediately life threatening, but are 
clearly of major clinical significance. For example, drug overdose or abuse, seizure that 
does not result in inpatient hospitalization, or intensive treatment of bronchospasm in an 
emergency department). 
 
Any AE that does not meet any of the above criteria should be regarded as non-serious 
adverse events. 
9.1.3 
Unanticipated Problem: 
An unanticipated problem (UP) is any incident, experience, or outcome involving risks to patients 
or others in any human patient/patient research that meets all of the following criteria: 
 
Unexpected (in terms of nature, severity, or frequency) given: (a) the research procedures 
that are described in the IRB-approved protocol and informed consent document, and (b) the 
characteristics of the patient population being studied; 
 
Related or possibly related to participation in such research (e.g., there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in such research); and 
 
Suggests that the research places patients or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
9.2 
Assessment 
At each contact with the subject, the investigator must seek information on AEs through specific 
questioning and, as appropriate, by examination. Information on all AEs should be recorded 
immediately in the source document, and also in the appropriate AE module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results 
should be recorded in the source document; they should be grouped under one diagnosis. 
A consistent methodology for eliciting AEs at all patient 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?” 
All AEs occurring during the study period must be recorded. The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study 


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treatment or participation is not the cause. Serious AEs that are still ongoing at the end of the study 
period must be followed up to determine the final outcome.  Any SAE that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation should 
be recorded and reported immediately.   
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), study collaborators, 
and Genentech, Inc., in accordance with CFR 312.32 [Investigational New Drug (IND) Safety 
Reports].  
Safety assessments will consist of monitoring and reporting AEs and SAEs, per protocol. This 
includes all events of death, and any study specific issue of concern. The AE severity grading scale 
for the NCI CTCAE (v. 5) will be used for assessing AE severity. To assess severity of AEs that 
are not specifically listed in the NCI CTCAE, see Table 8. 
 
Table 8. Adverse event severity scale for events not listed in NCI CTCAE 
 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE 5.0, which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
b. Examples of self-care activities of daily living include bathing, dressing and undressing, feeding 
oneself, using the toilet, and taking medications, as performed by patients who are not bedridden. 
c. 
If an event is assessed as a "significant medical event," it must be reported as a serious adverse 
event  
d. Grade 4 and 5 events must be reported as serious adverse events  
9.3 
Relationship to Study Intervention 
All AEs and SAEs, whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means, will be 
reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and 


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end dates), regulatory seriousness criteria if applicable, suspected relationship to atezolizumab 
and/or cobimetinib (see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration of 
cobimetinib and hydroxychloroquine either alone or with atezolizumab, and the AE cannot be 
readily explained by the patient’s clinical state, intercurrent illness, or concomitant therapies; 
and/or the AE follows a known pattern of response to the study drug; and/or the AE abates or 
resolves upon discontinuation of the study drug or dose reduction and, if applicable, reappears 
upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than that from cobimetinib and 
hydroxychloroquine, either alone or with atezolizumab (e.g., preexisting medical condition, 
underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no 
plausible temporal relationship to the administration of the study drugs (e.g., cancer diagnosed 2 
days after first dose of study drug). 
Expectedness 
Expected adverse reactions are AEs that are known to occur for the study intervention being 
studied and should be collected in a standard, systematic format using a grading scale based on 
functional assessment or magnitude of reaction. Identify the source of the reference safety 
information used to determine the expectedness of the AE (e.g., IB, approved labeling). 
Expectedness is assessed based on the awareness of AEs previously observed, not on the basis of 
what might be anticipated from the properties of the study intervention.  
An AE or suspected adverse reaction is considered "unexpected" if it is not listed in the IB, package 
insert, or device labeling, or is not listed at the specificity or severity that has been observed; or, if 
an IB is not required or available, or is not consistent with the risk information described in the 
protocol, as amended. For example, under this definition, hepatic necrosis would be unexpected 
(by virtue of greater severity) if the IB or package insert referred only to elevated hepatic enzymes 
or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the IB or package insert listed only cerebral vascular accidents. 
"Unexpected," as used in this definition, also refers to AEs or suspected adverse reactions that are 
mentioned in the IB, package insert, or device labeling as occurring with a class of drugs (or other 
medical products) or as anticipated from the pharmacological properties or other characteristics of 
the study intervention, but are not specifically mentioned as occurring with the particular study 
intervention under investigation. 
The Investigator will be responsible for determining whether an AE is expected or unexpected.  
An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention. 


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9.4 
Recording and Reporting Adverse Events 
 
9.4.1 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
 
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. 
 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 9.4.7.1), 
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”. 
 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be re-
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important to 
convey the concept that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
 
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 patient is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be reported 
as the SAE. For example, if a patient is hospitalized to undergo coronary bypass surgery, record 
the heart condition that necessitated the bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
 
Diagnostic or elective surgical procedures for preexisting conditions; 
 
Efficacy measurement for the study; or 
 
Scheduled therapy of the target disease of the study. 


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Pregnancy 
If a female patient becomes pregnant while receiving the study drug or within 5 months after the 
last dose of study drug, a report should be completed and expeditiously submitted to Columbia 
University who will report on behalf of all sites to its collaborators, Genentech, Inc., and 
Halozyme.. 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 patient exposed to the cobimetinib, atezolizumab and/or Hydroxychloroquine should 
be reported as an SAE. 
 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a patient has completed or 
discontinued study participation if attributed to prior exposure to cobimetinib, atezolizumab and/or 
Hydroxychloroquine . If the investigator should become aware of the development of cancer or a 
congenital anomaly in a subsequently conceived offspring of a female patient who participated in 
the study, this should be reported as an SAE. 
For studies involving collection of survival data and follow up until progression-free period, the 
investigator, after the end of the AE reporting period (defined as 30 days after the last dose of 
study drug) should report all deaths, (regardless of cause), and any SAE, including development 
of cancer or a congenital anomaly in a subsequently conceived offspring of a female subject, 
including pregnancy occurring in the partner of a male study subject who participated in the study 
that is believed to be related to prior exposure to study drug 
Case Transmission Verification will be performed by both parties during this period to ensure 
successful transmission of Single Case Reports. 
 
Abnormal Laboratory Values 
All abnormal laboratory values that are gradable per National Cancer Institute (NCI) CTCAE 
criteria; will be documented as toxicities regardless of grade, attribution, or clinical significance. 
They must be documented in the medical record directly, to include the CTCAE grade and 
applicable attribution pertaining to the investigational products. If the laboratory abnormality 
suggests a disease and/or organ toxicity and/or requires active management, the suspected cause 
and course of management should also be documented. 
9.4.2 
Adverse Events of Special Interest to be Reported Immediately to the Collaborator: 
Genentech 
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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Affiliate sites should report directly to CUMC, who will report to Genentech on behalf of 
Affiliate sites.  
See section 8.3 for AEs which are considered of special interest and must be reported to the 
Principal-Investigator by the affiliated sites within 24 hours of the awareness date and must 
be reported to the Genentech Drug Safety expeditiously, irrespective of regulatory seriousness 
criteria within 15 calendar days of awareness date.  (See section 9.4.5 for AESI reporting 
timeline) 
9.4.3 
Case Transmission Verification of Single Case Reports and Exchange 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 Investigator emailing Genentech 
a Quarterly line-listing documenting single case reports sent by Sponsor Investigator to Genentech 
in the preceding time period.  
The periodic line-listing will be exchanged within seven (7) calendar days of the end of the agreed 
time period. Confirmation of receipt should be received within the time period mutually agreed 
upon. 
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-by-case 
basis until satisfactory resolution.  The sponsor shall receive reconciliation guidance documents 
within the ‘Activation Package’. 
Following Case Transmission Verification, single case reports which have not been received by 
Genentech shall be forwarded by Sponsor Investigator to Genentech within five (5) calendar days 
from request by Genentech. 
At the end of the study, a final cumulative Case Transmission Verification report will be sent to 
Genentech. 
Investigator will track all protocol-defined AE, AESI, Product Complaints (with or without an 
AE) and Special Situation Reports (including pregnancy reports) originating from the Study for 
atezolizumab and cobimetinib. Investigators must report all SAEs, protocol-defined AE, AESI, 
Product Complaints (with or without an AE)  and Special Situation Reports (including pregnancy 
reports) to Columbia University within the timelines described below, using the HICCC DSMC 
SAE Report Form. The completed SAE report form should be sent immediately upon completion 
to Columbia University. Affiliate sites should report directly to CUMC, who will report 
simultaneously to Genentech Drug Safety at: 
 (fax) 650-238-6067 or (email) usds_aereporting-d@gene.com. 
All Product Complaints without an AE should be sent to: 
             Email: kaiseraugst.global_impcomplaint_management@roche.com 
 


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Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available and/or upon request by Genentech 
9.4.4 
Reporting to Genentech 
Adverse events, serious adverse events (SAEs), AEs of Special Interest (AESIs), pregnancy reports 
(including pregnancy occurring in the partner of a male study subject),  Product Complaints (with 
or without an AE) and other Special Situation Reports where the patient has been exposed to the 
Genentech Product, will be sent on a MedWatch form or CIOMS I form or on Genentech approved 
reporting forms to  Genentech Drug Safety. Transmission of these reports (initial and follow-up) 
will be sent either electronically or by fax and within the timelines specified below: 
• 
Serious Adverse Drug Reactions (SADRs) 
Serious AE reports that are related to the Product shall be transmitted to Genentech within fifteen 
(15) calendar days of the awareness date. 
• 
Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech within thirty 
(30) calendar days of the awareness date. 
• 
Pregnancy reports 
While such reports are not serious AEs or ADRs per se, as defined herein, any reports of 
pregnancy, where the fetus may have been exposed to the Product, shall be transmitted to 
Genentech within thirty (30) calendar days of the awareness date. Pregnancies will be followed up 
until the outcome of the pregnancy is known, whenever possible, based upon due diligence taken 
to obtain the follow-up information. 
 
AESI reporting to Genentech 
AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the awareness date.  
 
 
Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to Genentech within fifteen 
(15) calendar days of the awareness date. 
A Product Complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial. 
Special situation reports 
In addition to all AEs, pregnancy reports and AESIs, the following Special Situations Reports 
should be collected and transmitted to Genentech even in the absence of an Adverse Event within 
thirty (30) calendar days: 


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 
Data related to the Product usage during breastfeeding 
 
Data related to overdose, abuse, off-label use, misuse, or medication error (including 
potentially exposed or intercepted medication errors) 
 
In addition, reasonable attempts should be made to obtain and submit the age or age group of 
the patient, in order to be able to identify potential safety signals specific to a particular 
population). 
Occasionally Genentech may contact the reporter 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 regard to 
obtaining follow-up information on incomplete AE, Special Situations and pregnancy reports. 
9.4.5 
Reporting of Serious Adverse Events 
 
Adverse Event Reporting Period 
The recording of AEs will begin at the start of the administration of the first dose of a study 
medication, with the exception of study-procedure-associated SAEs. Any AE that occurs after 
the time of ICF signature will be recorded as an SAE if the event is associated with a study 
procedure and meets criteria of seriousness, even if the subject has not yet received any study 
medication. For this study, the study treatment follow-up is defined as 30 days following the last 
administration of study treatment, or 30 days following the decision to remove the patient 
from study treatment, whichever is earliest for all non-serious and serious adverse events. 
After this period, investigators will follow subjects for SAEs and AESI activity up to 90 days 
from last does of atezolizumab. After that period of time, investigators should only report SAEs 
that are attributed to prior study treatment. 
 
IRB Notification by Sponsor-Investigator 
Reports of all events (including follow-up information) that meet the definition of an unanticipated 
problem posing risk to subjects or others must be submitted to the IRB within one week (5 business 
days) following the occurrence of the unanticipated problem or the principal investigator’s 
acquiring knowledge of the unanticipated problem  in accordance with IRB policy. Additionally, 
the sponsor-investigator will submit a summary of all Unanticipated problems that occurred since 
the beginning of the study at the time of continuing review. Copies of each report and 
documentation of IRB notification and receipt will be kept in the Regulatory binder. 
 
FDA Notification by Sponsor-Investigator 
The Columbia University Medical Center Sponsor-Investigator, as holder of the IND, will be 
responsible for all communication with the FDA. Columbia University Medical Center Principal 
Investigator will report to the FDA, regardless of the site of occurrence, any adverse event that is 


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serious, unexpected, and there is evidence to suggest a causal relationship between the drug and 
the adverse event. These must be reported to the FDA and any affiliate sites as soon as possible, 
but in no case later than 15 calendar days after the sponsor determines that the information qualifies 
for reporting. 
Sponsor-Investigator, 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 
 
The Sponsor-Investigator will also submit an IND annual report to the FDA in accordance with 
21.CFR 312.33. 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. 
The Columbia University Medical Center Sponsor Investigator must report to the FDA and any 
affiliate site investigators as follows:  
 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 
cobimetinib and hydroxychloroquine either alone or with atezolizumab. An unexpected 
adverse event is one that is not already described in cobimetinib, hydroxychloroquine and 
atezolizumab’s Investigator Brochure. Such reports are to be telephoned or faxed to the 
FDA and Genentech within 7 calendar days of first learning of the event. 
 Any findings from epidemiological studies, pooled analysis of multiple studies, or clinical 
studies, whether or not conducted under an IND, and whether or not conducted by the sponsor-
investigator, that suggest a significant risk in humans exposed to the drug, must be reported 
as soon as possible, but no later than 15 calendar days after the sponsor-investigator 
determines that the information qualifies for reporting. 
 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 cobimetinib and hydroxychloroquine either alone or with 
atezolizumab. An unexpected adverse event is one that is not already described in cobimetinib, 
hydroxychloroquine or atezolizumab’s 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, 
Genentech, and all participating investigators within 15 calendar days of first learning of the 
event.  


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 Any findings from animal or in vitro testing, whether or not conducted under an IND, and 
whether or not conducted by the sponsor-investigator, that suggest a significant risk in humans 
exposed to the drug must be reported as soon as possible, but no later than 15 calendar days 
after the sponsor-investigator determines that the information qualifies for reporting. 
 Any clinically important increase in the rate of a serious suspected adverse reaction over that 
listed in the protocol or Investigator Brochure. 
 Expected SAEs and AEs will be included in the IND Annual Reports. 
Follow-up information to a safety report should be submitted as soon as the relevant information 
is available. However, if the results of a sponsor’s investigation show that an adverse drug 
experience not initially determined to be reportable are so reportable, the sponsor investigator must 
report such experience as soon as possible, but no later than 15 calendar days after the 
determination is made. 
All other serious unexpected experiences associated with the use of the study treatment will be 
reported to FDA as soon as possible but in no event later than 15 calendar days after initial receipt 
of the information. 
 
DSMC Reporting by the Sponsor Investigator 
Serious adverse events not constituting unanticipated problems are to be reported to the HICCC 
DSMC. Reporting must occur within 24 hours of knowledge of the SAE occurring at our institution 
or affiliate sites. 
All SAEs must be reported using the HICCC DSMC Serious Adverse Event Reporting Form and 
submitted to the central HICCC DSMC email at: HICCC_DSMC@lists.cumc.columbia.edu.   
Any events that qualify for FDA reporting to the applicable IND/IDE, must be vetted through the 
CPDM IND officer, in collaboration with the applicable regulatory staff. 
All serious adverse events (SAEs) will be followed until satisfactory resolution, or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting 
documentation of the event may be requested by the HICCC DSMC and should be provided as 
soon as possible. 
 
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 
 
Reporting to Drug Manufacturer by Sponsor-Investigator 
Investigators must report all SAEs to Columbia University/Sponsor/Investigator within the 
timelines described below, using the HICCC DSMC SAE Report Form. The completed SAE report 
form should be sent immediately upon completion to Columbia University. Affiliate sites should 


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report directly to CUMC, who will report simultaneously to Genentech Drug Safety at: (fax) 
650-238-6067 or (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. SAEs, pregnancy reports and adverse events of special 
interest (AESIs), where the patient has been exposed to the Product, will be sent on a DSMC SAE 
Report Form or equivalent to the Roche contact. Transmission of these reports (initial and follow-
up) will be sent either electronically or by fax and within the timelines specified above for both 
Genentech. 
 
Sponsor-Investigator will forward a copy of the Final Study Report to Genentech upon completion 
of the Study.  
 
Copies of such reports should be emailed to Genentech at:  Genentech Drug Safety CTV mail 
box: ctvist_drugsafety@gene.com 
Genentech 
For questions related to safety reporting, please contact Genentech Drug Safety: 
 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
 
STUDY CLOSE-OUT 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study report). 
Additionally, any literature articles that are a result of the study should be sent to Genentech. 
Copies of such reports should be emailed to the assigned Clinical Operations contact for the study: 
 
imCORE-USMA-OPS-d@gene.com  
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
 
QUERIES 
 
Queries related to the Study will be answered by Sponsor-Investigator. However, responses to all  
safety  queries  from  regulatory  authorities  or  for publications will be discussed and coordinated 
between the Parties. The Parties agree that Genentech shall have the final say and control over 
safety queries relating to the Product. Sponsor-Investigator agrees that it shall not answer such 
queries from regulatory authorities and other sources relating to the Product independently but 
shall redirect such queries to Genentech. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent requests 
for information or review of data are met. The Parties will clearly indicate on the request the reason 
for urgency and the date by which a response is required. 
 


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SAFETY CRISIS MANAGEMENT 
 
In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), on 
the conduct of the Study, may lead to labeling changes or regulatory actions that limit or restrict 
the way in which the Product is used, or where there is media involvement, the Party where the 
crisis originates will contact the other Party as soon as possible. 
 
The Parties agree that Genentech shall have the final say and control over safety crisis management 
issues relating to the Product. Sponsor-Investigator agrees that it shall not answer such queries 
from media and other sources relating to the Product but shall redirect such queries to Genentech. 
 
 
10. 
PHARMACEUTICAL INFORMATION 
10.1 
Atezolizumab, Cobimetinib, and Hydroxychloroquine 
10.1.1 
Description 
Atezolizumab 
Atezolizumab is a monoclonal antibody which binds to PD-L1. The antibody lacks the N-linked 
oligosaccharides due to an asparagine to alanine substitution at position 298 of each heavy chain 
resulting in a non-glycosylated antibody. 
Injection for intravenous use is a sterile, preservative-free, colorless-to-slightly-yellow solution in 
single-dose vials. Each mL of TECENTRIQ contains 60 mg of atezolizumab and is formulated in 
glacial acetic acid (16.5 mg), L-histidine (62 mg), sucrose (821.6 mg), polysorbate 20 (8 mg), pH 
5.8. 
 
Cobimetinib 
Cobimetinib is a small molecule inhibitor of MEK that is being developed as an anti-cancer 
therapeutic intended for oral administration. Cobimetinib is approved in multiple countries 
including United States, European Union, Switzerland, and across the world for use with 
vemurafenib for the treatment of advanced BRAF-mutated melanoma. Cobimetinib Drug Product 
is supplied as a 20 mg film coated, immediate-release tablet. Furthermore, a powder for oral 
suspension, 250 mg formulation (corresponding to a cobimetinib concentration of 4.8 mg/ml after 
reconstitution), filled in multi-dose containers is provided for pediatric patients and adults facing 
difficulties in swallowing tablets. 
Food-effect studies demonstrated that cobimetinib pharmacokinetics were not altered in the fed 
state when compared to the fasted state. High-fat meal or proton pump inhibitors did not affect 
cobimetinib pharmacokinetics. CYP3A4 inhibitors, such as itraconazole, significantly altered 
cobimetinib elimination with an approximately 7-fold increase in cobimetinib maximum 
concentration. Additionally, because cobimetinib is a sensitive substrate of CYP3A, it is likely that 


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cobimetinib exposures will be significantly lower in the presence of CYP3A inducers. Patients 
with severe hepatic impairment led to a reduction in total cobimetinib exposure, which is not 
considered to be clinically significant.  
 
Hydroxychloroquine 
Hydroxychloroquine is a small water soluble compound (MW 433.95) that is dispensed in 200 mg 
tablets for oral administration. In healthy males, peak blood concentration was reached in 3.26 
hours with a half life of 537 hours (22.4 days). The plasma peak concentration was reached in 3.74 
hours with a half life of 2,963 hours (123.5 days). The long half-life can be attributed to extensive 
tissue uptake rather than through decreased excretion. In subjects taking the drug chronically for 
six months, renal clearance of the drug appeared similar.  
Hydroxychloroquine is prescribed for Malaria, Rheumatoid Arthritis, and Systemic Lupus 
Erythematosus by an unknown mechanism. 
 
10.1.2 
Treatment Regimen 
Atezolizumab 
Atezolizumab 840 mg over 60 mins (+ 15 mins) IV on days 1 and 15 every 28 day cycle.  
 
Cobimetinib 
To be taken by mouth once daily with or without meal at the recommended daily dose on days 1 
through 21 every 28 days. 
Patients will receive cobimetinib at the recommended daily dose orally once daily (20 mg tablets) 
in the morning on Days 1-21 of each 28-day cycle. Cobimetinib should be taken approximately the 
same time each day, and no later than 4 hours after the scheduled time. Cobimetinib may be 
taken with or without a meal. Cobimetinib should be swallowed whole with a glass of water and 
should not be chewed, cut, or crushed.  If a dose of cobimetinib is missed (i.e., not taken within 
12 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. 
 
Hydroxychloroquine 
Hydroxychloroquine should be taken by mouth twice daily (200 mg tablets) with meals or with a 
glass of milk at the recommended daily dose. Hydroxychloroquine should be taken approximately 
at the same time each day, and no later than 4 hours after the scheduled time. Hydroxychloroquine 
should be swallowed whole with a glass of water (with meals) or milk and should not be chewed, 
cut, or crushed.  If a dose of Hydroxychloroquine is missed (i.e., not taken within 6 hours after 


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the scheduled dosing time), the patient should resume dosing with the next scheduled dose.  
Missed or vomited doses will not be made up. 
10.1.3 
Method for Assigning Subjects to Treatment Groups 
Phase 1 – Hybrid 3+3 and TITE CRM (see Section 4.1) 
10.1.4 
Preparation and Administration of Study Drug 
Atezolizumab 
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 is designed to deliver 20 mL (1200 mg) of atezolizumab solution but 
may contain more than the stated volume to enable delivery of the entire 20 mL volume. 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 stored per the manufacturer’s label upon receipt until use. Atezolizumab 
vials should not be used beyond the expiration date provided by the manufacturer. No preservative 
is used in the atezolizumab drug product; 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, see the current Atezolizumab Investigator’s Brochure. 
The dose level of atezolizumab to be tested in this study is 840 mg (equivalent to an average body 
weight-based dose of 15 mg/kg) administered by IV infusion every 2 weeks for two doses pre- 
surgery and 4 doses post-surgery. 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 m in-line filters (filter membrane of polyethersulfone [PES]). No incompatibilities have been 
observed between atezolizumab and PVC or polyolefin infusion materials (bags or infusion lines). 
Administration of atezolizumab will be performed in a setting with emergency medical facilities 
and staff who are trained to monitor for and respond to medical emergencies. 
The initial dose of atezolizumab will be delivered over 60 (+/- 15) minutes (see Table 5). If the 
first infusion is tolerated without infusion-associated AEs, the second infusion may be delivered 
over 30 (+/- 10) minutes. If the 30 minute infusion is well tolerated, all subsequent infusions 
may be delivered over 30 (+/- 10) minutes. For the first infusion, the patient’s vital signs (heart 
rate, respiratory rate, blood pressure, and temperature) should be determined within 60 minutes 
before, during (every 15 [+/- 5] minutes), and 30 (+/- 10) minutes after the infusion. For subsequent 
infusions, vital signs will be collected within 60 minutes before and within 30 minutes after the 
infusion. Vital signs should be collected during the infusion only if clinically indicated. Patients 
will be informed about the possibility of delayed post-infusion symptoms and instructed to contact 
their study physician if they develop such symptoms. 


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Describe in detail all the steps necessary to properly prepare the investigational agent.  Include 
whether the drug preparation will be done in a pharmacy or by a study team member.  Fully 
describe how the study treatment is to be administered.  If study drug is stored, mixed/prepared or 
dispensed from the CUMC Research Pharmacy, that should be noted here, including the contact 
number to that service office. 
Cobimetinib 
Dispense in a tight, light-resistant container as defined in the USP/NF. Keep out of the reach of 
children. Store at room temperature [20° to 25°C (68° to 77°F), allows excursions between 15° 
and 30°C (59° and 86°F)]. 
Hydroxychloroquine 
Dispense in a tight, light-resistant container as defined in the USP/NF. Keep out of the reach of 
children. Store at room temperature [20° to 25°C (68° to 77°F), allows excursions between 15° 
and 30°C (59° and 86°F)]. 
10.1.5 
Subject Compliance Monitoring 
Oral study drugs (if applicable) will be provided only to eligible patients under the supervision of 
the investigator or identified sub-investigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing. Any discrepancy regarding the dose administered, 
and the reason for the discrepancy, will be recorded in the eCRF. At each clinic visit, patients will 
be questioned about their compliance with study drug administration, and their dosing diary should 
be reviewed. 
10.1.6 
Prior and Concomitant Therapy 
Refer to Inclusion/Exclusion criteria (Sections 5.1 - 5.2). 
10.1.7 
Packaging 
Please refer to the package insert or the most current version of the Investigator Brochure for 
details. 
10.1.8 
Blinding of Study Drug 
N/A 
10.1.9 
Receiving, Storage, Dispensing and Return 
 
Receiving 
Study drug must be received by a designated person at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the investigator and designated assistants 
have access. 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug 
receipt log filled out and signed by the person accepting the shipment. It is important that the 


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designated study staff counts and verifies that the shipment contains all the items noted in the 
shipment inventory. Any damaged or unusable study drug in a given shipment (active drug or 
comparator) will be documented in the study files. The investigator must notify agent manufacturer 
of any damaged or unusable study treatments that were supplied to the investigator’s site. 
 
Storage 
Please refer to the package insert or the most current version of the Investigator Brochure for 
details. 
 
Dispensing of Study Drug 
The Study drug provided in accordance with this Protocol will be kept in a secure place, and will 
only be supplied to patients participating in this Study. The PI is accountable for all Study drug 
supplied by Genentech in accordance with this Protocol. In addition, the PI must keep accurate 
and up-to-date dispensation records. Any Study drug accidently or deliberately destroyed must be 
recorded in a timely fashion, including an explanation for the destruction in writing. Any 
discrepancies between the amounts of Study drug dispensed and returned must also be explained 
in writing. All such records of drug accountability must be entered on the corresponding Patient 
CRF’s. 
 
Destruction of Study Drug 
All unused and partially used Study drug must be sealed and returned to the PI or his/her designee, 
or destroyed on Site in accordance with the established procedures for drug destruction, and with 
approval by the PI or his/her designee. Details of destruction, including, but not limited to, the 
number of boxes destroyed, batch number, and the date and method of destruction must be 
recorded on the Study drug destruction logs. 
11. 
STUDY CALENDAR 
The schedule of assessments is detailed in Table 10 below.  
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans 
must be done ≤ 2 weeks prior to the start of therapy. In the event that the patient’s condition is 
deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the 
next cycle of therapy. 
Unless otherwise noted below, all assessments (e.g., labs, imaging, physical exam, vitals, etc.) will 
follow the CPDM departmental SOP “Guidelines for Timing of Protocol Required Procedures”. 
Any activities that would fall within those pre-determined windows will not be considered 
deviations/violations of protocol procedures. 
11.1 
Pharmacokinetics Assessments  
On days with PK assessments, patients should not eat breakfast or take cobimetinib or 
hydroxychloroquine at home. Upon arrival to the clinic after undergoing pre-dose PK draw, they 
will take medications with a glass of milk and eat breakfast, as instructed by clinic staff. 


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Table 9. PK Assessments 
a Hydroxychloroquine (HCQ) will be measured in whole blood and Cobimetinib will be measured in plasma 
b Pre-dose levels should be drawn just prior to administration of Cobimetinib (Cobi) and Hydroxychloroquine (HCQ) 
c Unscheduled doses related to other issues will be sequentially numbered as shown 
 
Treatment 
Cycle 
Day 
PK Sample # 
Hydroxychloroquine 
(HCQ) a 
(Whole Blood) 
PK Sample # 
Cobimetinib 
(Cobi) a 
(Plasma) 
Time Relative 
to Dose 
1 
1 
101 
201 
Pre-doseb 
1 
1 
102 
202 
1hr ± 5 min 
1 
1 
103 
203 
2hr ± 5 min 
1 
1 
104 
204 
4hr ± 5 min 
1 
8 
105 
205 
Pre-doseb 
1 
8 
106 
206 
1hr ± 5 min 
1 
8 
107 
207 
4hr ± 5 min 
1 
15 
108 
208 
Pre-dose 
1 
15 
109 
209 
1hr ± 5 min 
1 
15 
110 
210 
4hr ± 5 min 
2 
1 
111 
211 
Pre-dose 
2 
1 
112 
212 
1hr ± 5 min 
2 
1 
113 
213 
4hr ± 5 min 
 
 
 
 
 
N/A 
N/A 
5101+ 
5201+ 
Anytimec 
 


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Table 10. Schedule of Assessments 
Procedure 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and on 
(every 28 days) 
EOS2 
Follow
-up3 
(21 days)1 
D1 
(±3d) 
D8 
(±3d) 
D15 
(±3d) 
D22 
(±3d)  
D1 
(±3d) 
D15 
(±3d) 
D1 
(±3d) 
D15 
(±3d) 
D1 
(±3d) 
D15 
(±3d) 
Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Medical history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Cytology/pathology/mol. 
conf.4 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Physical exam5, vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Height 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
ECOG perf. status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
ECG6 
X 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
LE Doppler Ultrasound 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGA7 
X 
  
  
  
  
X 
  
  
  
  
  
X 
  
CBC with differential8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Comprehensive metab. 
panel8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Opthalmalogic exam9 
X 
  
  
  
  
  
  
X 
  
X 
  
X 
  
PT/PTT 
X 
  
  
X 
  
  
  
  
  
  
  
  
  
Fresh tumor biopsy10 
X 
  
  
X 
  
  
  
  
  
  
  
X 
  
TSH, free T4, cortisol11 
X 
  
  
  
  
X 
  
X 
  
X 
  
X 
  
Viral Serology12 
X 
  
  
  
  
  
  
  
  
  
  
  
  
C-reactive protein 
X 
  
  
  
  
  
  
  
  
  
  
  
  
LDH 
X 
  
  
  
  
  
  
  
  
  
  
  
  


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CPK 
X 
  
  
  
  
X 
  
X 
  
X 
  
X 
  
Ca 19-9 and/or CEA 
X 
  
  
  
  
X 
  
X 
  
X 
  
X 
  
Pregnancy test13 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Urinalysis 
X 
  
  
  
  
  
  
  
  
  
  
  
  
PBMC samples14 
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
Tumor response 
assessment15 
X 
  
  
  
  
  
  
X 
  
  
  
X 
  
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Adverse Events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Atezolizumab 
administration16 
  
X 
  
X 
  
X 
X 
X 
X 
X 
X 
  
  
Dispense cobimetinib 
  
X 
  
  
  
X 
  
X 
  
X 
  
  
  
Dispense 
hydroxychloroquine 
  
X 
  
  
  
X 
  
X 
  
X 
  
  
  
Dispense Enoxpaparin 
  
X 
  
  
  
X 
  
X 
  
X 
  
  
  
Review of dosing diary  
  
  
X 
X 
X 
X 
  
X 
  
X 
  
X 
  
Survival follow-up 
  
  
  
  
  
  
  
  
  
  
  
  
X 
Blood sampling for PK/PD17 
  
X 
X 
X 
  
X 
  
  
  
  
  
  
  
 
1. 
Protocol-specified screening procedures that are performed as part of standard of care and within 21 days of Day 1 of Cycle 1 may be used for screening purposes. Clinical laboratory studies and 
baseline CT scan must be performed within the 14-day period before Day 1 of Cycle 1. Screening labs may be used for Cycle 1 Day 1 if performed within 72 hours prior to study visit. 
2. 
The End-of-Study (EOS) visit should be scheduled within the 28-day period after the last dose of study drug and before starting any new anti-neoplastic therapy.  
3. 
A post-study follow-up contact by phone by site staff will be conducted every 3 months during years 1 and 2, then every 6 months thereafter to obtain information on any new anti-cancer therapy 
received and survival status. 
4. 
Initial diagnosis of adenocarcinoma and KRAS mutation status needs to be confirmed by a CLIA certified pathology. 
5. 
A complete physical examination will be performed at screening. All subsequent physical examinations will be disease-specific on Cycle 1 days 1, 8, 15, 22; Cycle 2 and 3 days 1 and 15; day 1 and 15 on 
each subsequent cycle, and at the End-of-Study visit. 
6. 
ECG will be performed after the patient has been in a supine position for at least 5 minutes. It will be performed at screening, cycle 1 day 15, day 1 of every subsequent cycle, and at the End-of-Study 
visit. 
7. 
ECHO or MUGA scan should be performed at screening, day 1 of cycle 2, every 3 months (+ 1 week) thereafter and at the end of study visit. 


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8. 
A complete blood count with differential and comprehensive metabolic panel including glucose, calcium, albumin, total protein, sodium, potassium, CO2 (carbon dioxide, bicarbonate), chloride, BUN 
(blood urea nitrogen), creatinine, ALP (alkaline phosphatase), ALT (alanine amino transferase), AST (aspartate amino transferase) and bilirubin will be performed on Cycle 1 days 1, 8, 15, and 22; Cycle 2 
and 3 days 1 and 15; on day 1 and 15 of each subsequent cycle, and at the End-of-Study visit. 
9. 
An Ophthalmologic examination should be performed during the screening period, and on cycle 3 day 1 (+ 7 days), every 12 weeks (+ 7 days) thereafter, and at the End-of-Study visit if not performed 
within 6 weeks. The baseline exam should include: best corrected distance visual acuity (BCVA), an automated threshold visual field (VF) of the central 10 degrees (with retesting if an abnormality is 
noted), and spectral domain ocular coherence tomography (SD-OCT). Each subsequent examinations should include BCVA, VF and SD-OCT. In patients of Asian descent, it is recommended that visual 
field testing be performed in the central 24 degrees instead of the central 10 degrees. 
10. Fresh core tumor biopsy will be performed: (1) within 14 days of starting therapy but at least three days prior to starting therapy; (2) Cycle 1 week 3 (day 15-21); and (3) If the patient allows, at 
progression (within 4 days of discontinuation of therapy). 
11. TSH, free T4, and AM cortisol will be assessed at screening, Day 1 of each cycle starting at C2, at end of study, and as clinically appropriate. 
12. At screening, patients without a prior positive HIV test result will undergo an HIV test, unless not permitted per local regulations. Patients will also be tested for HBsAg, HBsAb, total HBcAb, and HCV 
antibody. If a patient has a negative HBsAg test and a positive total HBcAb test at screening, an HBV DNA test should be performed. If a patient has a positive HCV antibody test at screening, an HCV 
RNA test must also be performed to determine if the patient has an active HCV infection. 
13. For women of child-bearing potential, a screening serum pregnancy test must be negative within 7 days of Day 1 of Cycle 1. 
14. 14. Peripheral blood mononuclear cells will be collected during screening, cycle 1 day 15, cycle 3 day 1, every eight weeks (+ 7 days), and at End-of-Service visit. 
15. CT scan with contrast of the chest, abdomen, pelvis or CT chest and MRI of abdomen/pelvis, PET/CT, or appropriate imaging of disease site to assess tumor status will be performed. Imaging should be 
performed at the designated time for tumor assessment +/- 7 days. End of study needs not be performed if patient has radiological evidence confirming progression, but needs to be performed if 
patient coming off study for other reasons, except due to fatality. 
Phase 1 –Imaging to be performed every 8 weeks (+ 7 days) 
Phase 2 – Pancreas adenocarcinoma –Imaging to be performed every 8 weeks (+ 7 days) 
Colorectal adenocarcinoma – Imaging to be performed every 12 weeks (+ 7 days) 
Histology agnostic adenocarcinoma – Imaging to be performed every 8 weeks (+ 7 days) 
16. The initial dose of atezolizumab will be delivered over 60 (+/- 15) minutes. Subsequent infusions will be delivered over 30 (+/-10) minutes if the previous infusion was tolerated without infusion-
associated adverse events, or 60 (+/- 15) minutes if the patient experienced an infusion-associated adverse event with the previous infusion. 
17. For pharmacokinetic (PK) analysis, whole blood for hydroxychloroquine and plasma for cobimetinib will be obtained on – 
Cycle 1 Day 1 - Pre-morning dose, 1, 2, and 4 hours post-morning dose. 
Cycle 1 Day 8 - Pre-morning dose, 1, and 4 hours post-morning dose. 
Cycle 1 Day 15- Pre-morning dose, 1, and 4 hours post-morning dose. 
Cycle 2 Day 1 - Pre-morning dose, 1, and 4 hours post-morning dose. 
 
 
 
 


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12. 
MEASUREMENT OF EFFECT 
For the purposes of this study, patients should be re-evaluated for progression, as indicated in 
the schedule of assessments. 
12.1 
Treatment Beyond Initial Radiographic Progression 
In studies of immunotherapeutic agents, complete response, partial response, and stable disease 
have each been shown to occur after radiographic evidence of an apparent increase in tumor 
burden. This initial increase in tumor burden caused by immune cell infiltration in the setting of 
a T-cell response has been termed pseudo-progression (Hales et al., 2010). In Study PCD4989g, 
evidence of tumor growth followed by a response was observed in several tumor types. In 
addition, in some responding patients with radiographic evidence of progression, biopsies of new 
lesions or areas of new growth in existing lesions revealed immune cells and no viable cancer 
cells. Because of the potential for a response after pseudo-progression, this study will allow 
patients randomly assigned to immunotherapy-based treatment arms to continue combination 
treatment after apparent radiographic progression, per immune-modified Response Evaluation 
Criteria in Solid Tumors (RECIST), provided the benefit-risk ratio is judged to be favorable by 
the investigator in consultation with the Principal Investigator, and they meet all of the following 
criteria: 
 Evidence of clinical benefit, as determined by the investigator following a review of 
all available data; 
 Absence of symptoms and signs (including laboratory values, such as new or 
worsening hypercalcemia) indicating unequivocal recurrence of disease; 
 Absence of decline in ECOG Performance Status that can be attributed to disease 
recurrence; 
 Absence of tumor recurrence at critical anatomical sites (e.g., leptomeningeal disease) 
that cannot be managed by protocol-allowed medical interventions; 
 Patient's written consent to acknowledge deferring other treatment options in favor of 
continuing study treatment at the time of initial apparent disease recurrence. 
 
12.2 
Rationale for the Use of Immune-Modified RECIST 
Increasing clinical experience indicates that traditional response criteria (e.g., RECIST v1.1 and 
World Health Organization [WHO] criteria) may not adequately assess the activity of 
immunotherapeutic agents because initial radiographic evidence of disease progression (or 
in this case, disease recurrence) does not necessarily reflect therapeutic failure. Patients can 
experience a response in the presence of new lesions or after an increase in tumor burden. Thus, 
this study will employ immune-modified RECIST for tumor assessments to account for the 
possible appearance of new lesions and allow radiographic recurrence to be confirmed at a 
subsequent assessment. It is required that radiographic recurrence be confirmed at a subsequent 


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tumor assessment to take into account the potential for pseudo-recurrence (caused by immune 
cell infiltration). Given the proposed immunomodulatory mechanism of action of atezolizumab, 
and the possibility of observing delayed responses, use of immune-modified RECIST will allow 
for the capture of a greater proportion of potential responses and allow patients to derive 
maximum clinical benefit. Immune-modified Response Evaluation Criteria in Solid Tumors 
(RECIST), as described here, were adapted from RECIST, Version 1.1 (v1.1) (Eisenhauer et al., 
2009) in the same manner that immune- related response criteria were adapted from WHO 
criteria (Wolchok et al., 2009) and RECIST v1.0 (Nishino, Hatabu, Johnson, & McLoud, 2014). 
When not otherwise specified, RECIST v1.1 conventions will apply. Differences between 
immune-modified RECIST and RECIST v1.1 are summarized in Table 11. 
12.3 
Immune-Modified Response Evaluation Criteria in Solid Tumors (Immune- 
Modified RECIST) 
Conventional response criteria may not be adequate to characterize the anti-tumor activity of 
immunotherapeutic agents, like atezolizumab, which can produce delayed responses that may 
be preceded by initial apparent radiographic progression, including the appearance of new 
lesions. Therefore, immune-modified response criteria have been developed to incorporate 
new lesions into the assessment of total tumor burden and to allow radiographic progression to 
be confirmed at a subsequent assessment. Immune-modified Response Evaluation Criteria in 
Solid Tumors (RECIST), as described within this appendix, were adapted from RECIST, 
Version 1.1 (v1.1), in the same manner that immune-related response criteria were adapted 
from WHO criteria and RECIST v1.0 (Hanzelmann et al., 2013; Ritchie et al., 2018). When 
not otherwise specified, RECIST v1.1 conventions will apply. Differences between immune-
modified RECIST and RECIST v1.1 are summarized in Table 11. 
 
 
 


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12.4 
Tumor measurability 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable, 
as described below. All measurable and non-measurable lesions should be assessed at screening 
and at subsequent protocol-specified tumor assessment time points. Additional assessments 
may be performed as clinically indicated when recurrence is suspected. 
Table 11. Comparison of RECIST v1.1 and Immune-Modified RECIST 
 
RECIST v1.1 
Immune-Modified RECIST 
Measurable new lesions 
Always represent progression 
Incorporated into the total tumor burden 
1 and followed 
Non-measurable new 
lesions 
Always represent progression 
Do not represent progression, but 
preclude CR 
Non-target lesions 
Contribute to defining CR, PR, 
SD, and PD 
Contribute to defining CR only 
CR 
Disappearance of all lesions 
Disappearance of all lesions 
PR 
≥ 30% decrease in sum of 
diameters of target lesions, in the 
absence of CR, new lesions, and 
unequivocal progression in non- 
target lesions 
≥30% decrease in tumor burden, 1 in the 
absence of CR 
PD 
≥20% increase in sum of diameters 
of target lesions, unequivocal 
progression in non- target lesions, 
and/or appearance of new lesions 
≥20% increase in tumor burden 1 
SD 
Neither sufficient shrinkage to 
qualify for CR or PR nor 
sufficient increase to qualify for 
PD 
Neither sufficient shrinkage to qualify 
for CR or PR nor sufficient increase to 
qualify for PD 
CR  complete response; PD  progressive disease; PR  partial response; RECIST  Response 
Evaluation Criteria in Solid Tumors; SD  stable disease. 
1Tumor burden is the sum of diameters of target lesions and measurable new lesions. 


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12.4.1 
Definition of measurable lesions 
 
Tumor Lesions 
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 as follows: 
 
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval   5 mm); 
 
10-mm caliper measurement by clinical examination (lesions that 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  15 mm in the 
short axis when assessed by CT scan (  5 mm CT scan slice thickness recommended). At 
baseline and follow-up, only the short axis will be measured and followed. Additional 
information on lymph node measurement is provided below (see "Identification of Target and 
Non-Target Lesions," "New Lesions," and "Calculation of Sum of Diameters"). 
12.4.2 
Definition of non-measurable lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or pathological 
lymph nodes with short axis  10 mm but   15 mm), 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, 
peritoneal spread, and abdominal mass/abdominal organomegaly identified by physical 
examination that is not measurable by reproducible imaging techniques. 
12.4.3 
Special considerations regarding tumor measurability  
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment, as outlined below. 
 
Bone Lesions: 
 Technetium-99m bone scans, sodium fluoride PET scans, and plain films are not 
considered adequate imaging techniques for measuring 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 scan or MRI can 
be considered measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
 Blastic bone lesions are non-measurable. 


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Cystic Lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) because they are, 
by definition, simple cysts. 
 Cystic lesions thought to represent cystic metastases can be considered 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. 
 
Lesions with Prior Local Treatment: 
Tumor lesions situated in a previously irradiated area or in an area patiented to other loco- 
regional therapy are usually not considered measurable unless there has been demonstrated 
progression in the lesion. 
 
12.4.4 
Methods for assessing 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. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during the study. Imaging-based evaluation should 
always be the preferred option. 
 
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. 
 
Chest X-ray 
Chest CT scan is preferred over chest X-ray, particularly when recurrence is an important 
endpoint, because CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
 
CT and MRI scans 
CT is the best currently available and reproducible method to measure lesions selected for response 
assessment. In this guideline, the definition of measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is  5 mm. When CT scans have slice thickness of  5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV contrast 


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because of allergy or renal insufficiency, the decision as to whether a non-contrast CT scan or 
MRI (without IV contrast) will be used to evaluate the patient at baseline and during the study 
should be guided by the tumor type under investigation and the anatomic location of the disease. 
For patients who develop contraindications to contrast after baseline contrast CT scan is done, the 
decision as to whether non-contrast CT scan or MRI (enhanced or non-enhanced) will be performed 
should also be based on the tumor type and the anatomic location of the disease, and should be 
optimized to allow for comparison with the prior studies if possible. Each case should be discussed 
with the site- designated radiologist to determine if substitution of these other approaches is 
possible. If not, the patient should be considered not evaluable from that point forward. Care must 
be taken in measuring target lesions and interpreting non-target disease or new lesions on a 
different modality, because the same lesion may appear to have a different size using a new 
modality. 
 
FDG-PET  
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of recurrence 
(particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
progressive disease (PD) based on a new lesion. 
 No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT scan, this is PD, 
which should be confirmed by a biopsy. If the positive FDG-PET at follow-up is not 
confirmed as a new site of disease on CT, additional follow-up CT scans are needed to 
determine if there is truly progression occurring at that site (if so, the date of PD will be the 
date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of 
the anatomic images, this is not PD. 
 FDG-PET may be used to upgrade a response to a complete response (CR) in a manner 
similar to a biopsy in cases where a residual radiographic abnormality is thought to 
represent fibrosis or scarring. The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical literature 
for the indication. However, it must be acknowledged that both approaches may lead to 
false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note: A ‘positive’ FDG-PET scan lesion means one that is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 


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Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, histology  
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be utilized 
for objective tumor evaluation. 
12.4.5 
Assessment of tumor burden 
To assess recurrence, it is necessary to estimate the overall tumor burden at baseline and use this 
as a comparator for subsequent measurements. 
12.4.6 
Definition of target and non-target lesions  
Baseline scan should be that which is considered optimal for the particular histology.  
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and 
be representative of all involved organs, but in addition should lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement, in which case the next largest lesion that can be measured 
reproducibly should be selected.  
Lymph nodes merit special mention because they are normal anatomical structures that may be 
visible by imaging, even if not involved by tumor. As noted above, pathological nodes that are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of  15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline 
sum. The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Lymph node size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT, this is almost always the axial plane; for MRI, the plane of 
acquisition may be axial, sagittal, or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node that is reported as being 20 mm  30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis  10 mm but  15 mm) 
should be considered non-target lesions. Nodes that have a short axis of  10 mm are considered 
non-pathological and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or non-measurable), 
including pathological lymph nodes, should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required. It is possible to record multiple non-target 
lesions involving the same organ as a single item on the CRF (e.g., "multiple enlarged pelvic 
lymph nodes" or "multiple liver metastases"). 
12.4.7 
New lesions 
New lesions identified after baseline will be evaluated for measurability with use of the same 
criteria applied to prospective target lesions at baseline per RECIST [e.g., non-lymph node lesions 
must be ≥10 mm on the longest diameter; new lymph nodes must be ≥15 mm on the short axis 
(see note below)]. All new lesions (measurable or non-measurable) must be assessed and recorded 
at the time of identification and at all subsequent tumor assessment time points. 


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Up to a maximum of five measurable new lesions total (and a maximum of two lesions per organ) 
can be included in the calculation of tumor burden that is performed as part of the tumor response 
evaluation. New lesion types that would not qualify as target lesions per RECIST cannot be 
included in the calculation of tumor burden and thus will not affect overall tumor response 
evaluation. New lesions that are not measurable at first appearance but meet measurability criteria 
at a subsequent time point can be included in the tumor response evaluation from that point on, if 
the maximum number of measurable new lesions has not been reached. 
Note regarding new lymph node lesions: If at first appearance the short axis of a lymph node 
lesion is ≥15 mm, it will be considered a measurable new lesion. If at first appearance the short 
axis of a lymph node lesion is ≥10 mm and  15 mm, the lymph node will not be considered 
measurable, but will still be considered a new lesion and should be identified as a non-measurable 
new lesion. If at first appearance the short axis of a lymph node is  10 mm, the lymph node should 
not be considered pathological and should not be considered a new lesion. A lymph node can 
subsequently become measurable, when the short axis is ≥15 mm. 
12.4.8 
Calculation of sum of diameters  
A sum of the diameters (longest diameter for non-lymph node lesions, short axis for lymph node 
lesions) will be calculated for all target lesions at baseline as a measure of tumor burden. At each 
subsequent tumor assessment, a sum of the diameters (longest diameter for non-lymph node 
lesions, short axis for lymph node lesions) will be calculated for all target lesions plus measurable 
new lesions (up to five new lesions, with a maximum of two new lesions per organ) that have 
emerged after baseline. Hence, each net percentage change in tumor burden per assessment 
accounts for the size and growth kinetics of both old lesions and new lesions as they appear. 
 
Measuring Lymph Nodes 
If at first appearance the short axis of a new lymph node lesion is  15 mm, it will be considered a 
measurable new lesion and may be included in the sum of the diameters. If the new lymph node 
lesion is included in the sum of diameters, it will continue to be measured and included in the sum 
of diameters at subsequent time points, even if the short axis decreases to  15 mm (or even 
 10 mm). However, if it subsequently decreases to  10 mm and all other lesions are no longer 
detectable or have also decreased to a short axis of  10 mm (if lymph nodes), a response 
assessment of complete response may be assigned. 
Lymph nodes should always have the actual short axis measurement recorded (measured in the 
same anatomical plane as the baseline examination), even if the node regresses to  10 mm during 
the study. Thus, when lymph nodes are included in the sum of diameters, the sum may not be zero 
even if complete response criteria are met, because a normal lymph node is defined as having a 
short axis of  10 mm. 
 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions and up to five measurable new lesions (lymph node and 
non-lymph node) should have their actual measurements recorded at each subsequent evaluation, 


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even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes become so faint 
on CT scan that the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure. When this occurs, it is important that a value be 
recorded on the CRF, as follows: 
 If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
 If the lesion is believed to be present, but too small to measure, a default value of 5 mm 
should be assigned and "too small to measure" should be ticked. (Note: It is less likely 
that this rule will be used for lymph nodes because they usually have a definable size 
when normal and are frequently surrounded by fat, such as in the retroperitoneum; 
however, if a lymph node is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned in this circumstance as well, and 
"too small to measure" should also be ticked). 
 
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
measurement should be recorded, even if it is  5 mm, and in that case "too small to 
measure" should not be ticked. 
 
Measuring lesions that split or coalesce on treatment 
When non-lymph node lesions fragment, the longest diameters of the fragmented portions should 
be added together to calculate the sum of diameters. Similarly, as lesions coalesce, a plane 
between them may be maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they are 
no longer separable, the vector of the longest diameter in this instance should be the maximum 
longest diameter for the coalesced lesion. 
 
Evaluating non-target lesions and non-measurable new lesions  
Measurements are not required for non-target lesions or non-measurable new lesions. Non-target 
lesions should be noted at baseline, and non-measurable new lesions should be noted at the time 
of identification. At subsequent evaluations, non-target lesions and non-measurable new lesions 
will be categorized as "present" or "absent." 
After baseline, changes in non-target lesions or non-measurable new lesions (or measurable new 
lesions in excess of 5 total or 2 per organ) will contribute only in the assessment of complete 
response (i.e., a complete response is attained only with the complete disappearance of all tumor 
lesions, including non-target lesions and non-measurable new lesions) and will not be used 
to assess progressive disease. 
 


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12.5 
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable 
at that time point. If measurements are made on only a subset of target or measurable new lesions 
at a time point, usually the case is also considered not evaluable at that time point, unless 
a convincing argument can be made that the contribution of the individual missing lesions would 
not change the assigned time point response. This would be most likely to happen in the case of 
treatment beyond recurrence. For example, if a patient had a recurrence sum of 50 mm with three 
measured lesions, and during the study only 2 lesions were assessed, but those gave a sum of 80 
mm, the patient will have achieved confirmed recurrence status, regardless of the contribution of 
the missing lesion. 
12.6 
Special notes on response assessment 
Patients with a global deterioration in health status requiring discontinuation of treatment without 
objective evidence of disease recurrence at that time should be reported as having "symptomatic 
deterioration." Every effort should be made to document objective recurrence even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response; it is a reason for stopping study therapy. The objective response status of such patients 
is to be determined by evaluation of target and non-target lesions, as well as new lesions. 
12.7 
Definitions 
Evaluable for toxicity: All Participants will be evaluable for toxicity from the time of their first 
treatment with study drug. 
Evaluable for objective response: Only those Participants who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These Participants will have their response classified 
according to the definitions stated below. (Note: Participants who exhibit objective disease 
progression prior to the end of cycle 1 or who die prior to tumor assessment will also be considered 
non- responders). 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal 
lesions) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical 
exam. All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area are not considered 
measurable.   
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 


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Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered non-measurable. 
Note:  Cystic 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. 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, and be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement, in which circumstance the next largest lesion that can 
be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum. The baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions: All other lesions (or sites of disease), including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be recorded 
at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up.  
12.8 
Response Criteria 
12.8.1 
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 the diameters of target lesions, taking 
as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (including the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: 1 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 diameters while on study. 


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12.8.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the Principal Investigator. 
12.9 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria (Tables 12-13). 
 
 


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Table 12. Response assignment for participants with measurable disease 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*  
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**  
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 
 
 


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Table 13. Response assignment for participants with non-measurable disease. 
 
Non-Target Lesions New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
12.10 
 Duration of Response 
12.10.1 
Duration of overall response  
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
12.10.2 
Duration of stable disease  
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started, including the 
baseline measurements.  
12.11 
Progression-Free Survival (PFS) 
Progression-free survival is defined as the duration from start of treatment to time of progression 
or death, whichever occurs first. 
12.12 
Unblinding Procedures 
N/A 


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13. 
DATA REPORTING / REGULATORY REQUIREMENTS 
A list of adverse events (AEs) can be found in Appendix 1. Guidelines, and instructions for AE 
reporting can be found in Section 10. The Data Safety Monitoring Plan is described in Section 
14.3. 
13.1 
Data Collection 
The Herbert Irving Comprehensive Cancer Center has an electronic clinical trials and data 
management system (CTMS) that will be used for data collection. CRFs for the study will be built 
into the CTMS for data entry. The system has full auditing capabilities, and is web-based and 
housed on a server in a fully HIPAA-compliant server room with restricted access and video 
camera monitoring. All users must login with their own application username and password.  Users 
off campus must first access the Virtual Private Network with their assigned campus username 
and password and then use their application credentials. Users are only able to see study 
information if they are indicated as study personnel in our electronic IRB system. Users are limited 
to access based on the role assigned in their corresponding protocol. Subject data is entered directly 
into the system, which (in the case of Columbia subjects) confirms the correct identity of 
Participants via an interface with the electronic medical patient index. Staff with the appropriate 
IRB-defined roles can run reports within the system for reporting purposes. 
13.2 
Data Reporting 
Case Report Forms will be completed for each subject enrolled in the clinical study through the 
CTMS. It is the investigator’s responsibility to ensure that all clinical and laboratory data entered 
on the corresponding CRFs are complete, accurate, and authentic. 
13.2.1 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits, 
and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
 The site will attempt to contact the participant, reschedule the missed visit, counsel the 
participant on the importance of maintaining the assigned visit schedule, and ascertain if 
the participant wishes to and/or should continue in the study; 
 Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls). These 
contact attempts should be documented in the participant’s medical record or study file; 
 Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 


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13.3 
Data and Safety Monitoring Committee 
The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert Irving 
Comprehensive Cancer Center (HICCC) will monitor every subject who receives treatment on this 
protocol for toxicity. This protocol will adhere to the policies of the currently-approved HICCC 
Data and Safety Monitoring Plan (DSMP), which is in accordance with NCI and CUMC-IRB 
policy and guidelines.  The committee chair is appointed by the HICCC Director. The committee 
consists of HICCC faculty and staff with expertise in oncology, research pharmacy, research 
nursing, and data management. The DSMC convenes twice a month to review patient safety and 
the conduct of the trial. The PI will submit data and safety monitoring reports to the DSMC at a 
frequency to be determined by the DSMC, based on risk to the subjects. 
At the time of renewal, the study team will submit the most recent DSMC approval letter for safety 
review to the CUMC IRB. Any modifications that are required by the DSMC to ensure patient 
safety will be submitted to the IRB. All protocol deviations, violations, and eligibility waivers will 
be submitted to and approved by the DSMC prior to being reported to the IRB. All study data 
reviewed and discussed during these meetings will be kept confidential.  
For multicenter research, the Sponsor/Principal Investigator will assure that there is a mechanism 
in place to distribute the report to all participating investigators for submission to their local IRB.  
The report will document that a review of data and outcomes across all centers took place on a 
given date. It will summarize the DSMC’s review of the cumulative toxicities reported from all 
participating sites without specific disclosure by treatment arm. It will also inform site 
investigators of the study of the DSMC’s conclusion with respect to progress or need for 
modification of the protocol.   
13.4 
Quality Assurance and Quality Control   
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion, according to site policies and procedures. 
The monitors will verify that the clinical trial is conducted and data are generated and biological 
specimens are collected, documented (recorded), and reported in compliance with the protocol, 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable 
regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices 
(GMP)).  
The investigational site will provide direct access to all trial-related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
13.5 
Clinical Monitoring 
An ssDSMP is required for all investigator initiatied trials, wherein CUIMC HICCCC DSMC is 
serving as the DSMC of record. 
Ongoing monitoring of the clinical study for protocol and GCP compliance will be conducted on 
a quarterly basis by the CPDM Compliance Core on behalf of the HICCC DSMC. Quarterly 


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monitoring will ensure data quality and verify source documents for all enrolled subjects related 
to dose limiting toxicity, all response assessments and RECIST/imRECIST forms, study drug 
administration including, but not limited to pill accountability, duration of response, date of disease 
progression, resolution of treated related AEs, subsequent treatments, and survival. This report 
will be submitted to the Sponsor-Investigator and study statistician on a quarterly basis. Delinquent 
or discrepant data will be rectified within 4 weeks of notification and the quarterly report amended 
and resubmitted by the DSMP office. Additionally, the Compliance Oversight Committee of the 
IRB at Columbia University Medical Center may audit the study at any time per institutional 
policies and procedures. The investigator-sponsor and Columbia University Medical Center will 
permit direct access of the study monitors and appropriate regulatory authorities to the study data 
and to the corresponding source data and documents to verify the accuracy of this data. 
A risk-based approach will be used by the Compliance Core to determine the frequency, number 
of subject charts, and data elements to be monitored. This trial will utilize a study-specific Data 
Safety Monitoring Plan (which is to be reviewed and acknowledged by the HICCC DSMC).  
The Compliance Coordinator will review the study status and summarize enrollment, toxicities, 
SAEs/UPs, dose escalation, statistical endpoints (e.g., stopping rules), etc. for the full DSMC 
membership at the regularly scheduled meetings.   
13.5.1 
Internal On-site Monitoring: 
 Initial, recurrent, and close-out on-site monitoring visits will also be conducted at remote 
clinical sites, as appropriate/feasible. Other sites will have monitoring performed remotely 
(see below for further details). 
 The Compliance Coordinator will communicate with the site coordinator/site Principle 
Investigator to schedule the monitoring visits and arrange for access to study materials 
and documentation. 
 In accordance with the ssDSMP and RBM methologies, the assigned Compliance 
Coordinator will monitor IIT trials throughout the life of the study to ensure that the study 
is being conducted in accordance with the protocol, GCP, applicable federal and local 
regulations, and per all applicable SOPs. The Compliance Coordinator is responsible for 
notifying the PI and CRNP/CRN/CRC of upcoming monitor visits, and for conveying 
what information and documentation will be required for the visit(s). The Compliance 
Coordinator is responsible for verifying that informed consent is properly obtained, 
eligibility is met (via the central registration process), and all study procedures are 
conducted according to the study protocol. The Compliance Coordinator will also verify 
that the data reported in the CRF’s accurately reflect source documents, that all toxicities 
have been reported to date, and that all SAE’s/UPs/deviations/violations have been 
reported according to local IRB and HICCC DSMC requirements. The Compliance 
Coordinator will issue queries and ensure resolution in a timely and efficient manner.  The 
Compliance Coordinator will also monitor for applicable regulatory compliance and 
research pharmacy compliance (if applicable) and communicate any deficiencies, as 
appropriate. 


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13.5.2 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following:  
 
What protected health information (PHI) will be collected from subjects in this study; 
 
Who will have access to that information and why; 
 
Who will use or disclose that information; 
 
The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (e.g., that the subject is alive) at the end 
of their scheduled study period. 
The subject binders will be maintained with in the CPDM offices, a secured floor within the 
Herbert Irving Pavilion and only the investigator  and study staff will have access to the file. 
13.5.3 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents.  Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
Source documents including, but not limited to, those needed to establish subject eligibility, 
response scans, dose limiting toxicity, imRECIST, and pill accountability will be made available 
to the Principal Investigator on at least a quarterly basis.  
13.5.4 
Data Entry Procedures 
The Herbert Irving Comprehensive Cancer Center has an electronic CTMS that will be used 
for data collection. CRFs for the study will be built into the CTMS for data entry. The system 
has full auditing capabilities which is web-based and housed on a server in a fully HIPAA-
compliant server room with restricted access and video camera monitoring. All users must 
login with their own application username and password. Users off campus must first 
access the Virtual Private Network with their assigned campus username and password and 
then use their application credentials. Users are only able to see study information if they are 
indicated as study personnel in our electronic IRB system. Users are limited to access based on 
the role assigned in their corresponding protocol. Patient data is entered directly into the 


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system, which (in the case of Columbia patients) confirms the correct identity of patients via an 
interface with the electronic medical patient index. Staff with the appropriate IRB-defined roles 
can run reports within the system for reporting purposes. 
13.5.5 
Records Retention 
Records relating to a specific research activity, including research records collected by 
investigators, must be maintained for at least 3 years after completion of the research (45 CFR 
46.115(b); 21 CFR 56.115(b); 21 CFR 312.62). This minimum retention period applies whether 
or not any subjects were enrolled in the study. 
If the research is FDA regulated, records should be retained for at least 2 years after approval of 
the investigational agent by FDA; if it is not approved, records should be retained at least 2 years 
after the study is terminated and FDA is notified (note the additional requirement below for clinical 
research studies);  
Clinical records, including consent forms that document clinical intervention or clinical diagnostic 
procedure research-related procedures, must be retained in medical records by the institution for 
at least 7 years, per CUMC and NYP policy, which is based on state law. 
14. 
TRANSLATIONAL SCIENCE 
14.1.1 
PDAC Subtypes as Defined by Immune Cell Infiltrate and Gene Expression 
 
CD8+ T-Cell Infiltration and Survival 
CD8+ TILs, which are known anti-tumor effector cells, are less frequently found in the PDA 
tumor microenvironment (TME) as compared to the more ‘inflamed’ TMEs of melanoma, non-
small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) (Vonderheide & Bayne, 2013). In 
part, this may be explained by the unique desmoplastic stroma that typically surrounds PDAC 
epithelial cells. This has been hypothesized to act as a physical barrier to T-cell infiltration, but 
recent data has challenged this theory (Carstens et al., 2017; Ene-Obong et al., 2013). The PDA 
stroma is typically infiltrated by significant numbers of immunosuppressive leukocytes, 
including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), 
and regulatory T-cells (Clark et al., 2007; Hiraoka, Onozato, Kosuge, & Hirohashi, 2006) . Recent 
evidence has surfaced supporting a correlation between increased CD8+ lymphocyte infiltration 
and improved prognosis, suggesting CD8+ infiltration may serve as a good surrogate for 
response to therapy (Cheng, Sato, Kohi, & Yamaguchi, 2013; Deng et al., 2016). In an effort to 
better-characterize the TME of solid tumors, several novel technologies have been developed. 
Quantitative multiplex immunofluorescence (qmIF) represents one such platform and allows for 
simultaneous identification of multiple distinct epitopes on a single formalin-fixed, paraffin-
embedded tissue section using a unique tyramide signal amplification technique (Stack, Wang, 
Roman, & Hoyt, 2014). This technology is only available at a few institutions and is rapidly 
becoming an accepted method for studying the TME in many cancers (Carstens et al., 2017; 
Schalper et al., 2015; Tumeh et al., 2014). Using qmIF, Carstens et al. demonstrated that high 


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infiltration of CD8+ and CD4+ T-cells correlated with improved survival, whereas infiltration of 
regulatory T cells or other T cell subtypes was not. In addition, increased infiltration of intra-
tumoral CD8+ T cells within a 20M radius of tumor cells also correlated with prolonged patient 
survival (Deng et al., 2016). An example of work performed at Columbia University Irving 
Medical Center (CUIMC) is shown in Figure 6.  
14.1.2 
VECTRA Imaging of Human PDA 
A detailed protocol of tissue processing is provided in the laboratory manual. After the Manji 
laboratory has been contacted and approval given, tissue samples are to be sent to the address 
below to ensure receipt and processing on delivery. Specimens should be shipped either on a 
Monday or Tuesday of a non-holiday week to accommodate possible shipment delays and ensure 
timely delivery of biospecimens. 
Attention to: 
Gulam Abbas Manji, MD/PhD 
Herbert Irving Comprehensive Cancer Center Columbia University 
1130 Saint Nicholas Avenue, ICRC 207 New York, NY 10032 
Phone:   
212-304-6357 
Alternate:  518-488-4704 
14.1.3 
Laser Capture Microdissection (LCM) and PDA 
We believe that the combinations being tested, including atezolizumab, hydroxychloroquine, and 
cobimetinib, 
will 
change 
the 
regulatory context of the PDAC 
TME from an immunotherapy-
resistant to an immunotherapy-
sensitive phenotype. Fresh frozen 
tissue will be sectioned for laser 
capture microdissection of the 
neoplastic epithelial and stromal 
components for RNA extraction. 
PDAC are characterized by two 
main components: the epithelium, 
formed from aggregates of tumor 
cells, and the surrounding stroma. 
Moffitt et al. (2015) performed 
virtual microdissection on gene 
expression 
microarray 
data 
obtained from 145 PDA patients, 
and 
identified 
two 
distinct 
epithelial-specific subtypes. One 
 
 
Figure 6. VECTRA imaging of human PDA. 
7-color IP: DNA (DAPI), cytotoxic T-cells (CD8), macrophage (CD68), helper T-cells 
(CD4), regulatory T-cells (FOXP3), pan-T-cells (CD3), and proliferation (Ki67). 


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subtype contained genes enriched for extracellular matrix (ECM) deposition and remodeling, 
which they termed ‘basal-like’, while the other was enriched in immune and interleukin pathways, 
termed ‘classical’. Distinct gene signatures represented by 25 distinct genes were able to 
distinguish these two phenotypes. The classical molecular subtype represented a patient population 
with an improved median OS compared to that of the basal-like subtype (Moffitt et al., 2015). 
The Olive lab here at CUIMC has performed LCM on over 200 human pancreatic tumors and 
RNA-seq to a depth of 30 million 100 base pair single-end reads. Their analyses showed clean 
separation of the two compartments. Hierarchical clustering, using Neutral Matrix Factorization 
of the top 1000 variable genes of the stromal RNA-seq data, found two distinct clusters. One cluster 
was enriched for inflammatory genes, while the other was enriched in both immune effector and 
immunosuppressive signatures; these groups were classified “classical” and “basal-like” subtypes, 
respectively [Kenneth Olive, 
submitted]. 
Furthermore, 
supervised clustering analysis 
of the RNA-seq data, using the 
same 
epithelial 
classifier 
signatures described by Moffitt 
et al., confirmed the prognostic 
value 
of 
PDA 
molecular 
subtypes in the CUMC cohort. 
As shown in Figure 7, patients 
with the classical epithelial 
phenotype have significantly 
better prognoses as compared 
to those with the basal-like 
phenotype 
[Kenneth 
Olive, 
submitted]. 
We 
hypothesize 
that 
the 
combination of atezolizumab, 
hydroxychloroquine, 
and 
cobimetinib, will result in gene 
regulation that enriches the 
immune 
and 
interleukin 
pathways, which reflect classical/immune subtype compared to the basal-like/ECM subtype. 
In order to test this hypothesis, the epithelium compartment will be isolated using LCM from 
each resected tumor specimen on which RNA-seq analysis will be performed. Using epithelial 
classifiers, as described above, samples from distinct treatment groups will be compared to 
determine if certain treatments are able to alter the PDA epithelial gene expression from 
‘basal/ECM-like’ to ‘classical/immune’ subtype, which may confer a prognostic advantage. If 
a treatment(s) leads to enrichment of classical/immune subtype and improved outcomes, the 
regulated pathways that associate with improved disease-free survival will need to be validated 
in a larger sample, and those pathways further exploited to convert the tumor into one that is 
 
 
Figure 7. Kaplan-Meier survival by molecular subtype. 
VECTRA imaging of human PDA. Analysis of RNA-seq data from patients with resected 


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more susceptible to immunotherapy. These studies will complement the 
multiplex 
immunofluorescence (IF) studies described above and will hopefully identify key regulatory 
pathways affected by distinct therapies. 
14.2 
Sample Processing of RNA-Seq Expression Data 
A detailed protocol of tissue processing is provided in the laboratory manual. Briefly, fresh frozen 
tissue will be obtained from EUS-guided biopsy and surgically resected tissue and immediately 
sectioned and microscopically evaluated. Suitable samples will be transferred into OCT medium 
(Tissue Tek) and snap frozen in a 2-methylbutane dry ice slurry. The tissue blocks will be stored 
at -80oC until further processing at Manji’s laboratory, as per established protocol. Frozen blocks 
are to be sent to Dr. Manji’s laboratory using the address listed below after the laboratory has been 
contacted and approval given to ship the specimens to ensure receipt and processing on delivery. 
Specimens should be shipped either on a Monday or Tuesday of a non-holiday week to 
accommodate possible shipment delays and ensure timely delivery of biospecimens. 
Attention to: 
Gulam Abbas Manji, MD/PhD 
Herbert Irving Comprehensive Cancer Center Columbia University 
1130 Saint Nicholas Avenue, ICRC 207 New York, NY 10032 
Phone:   
212-304-6357 
Alternate:  518-488-4704 
15. 
PROTECTION OF HUMAN SUBJECTS  
This study is to be conducted in accordance with applicable government regulations and 
Institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted Institutional Review 
Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  
The decision of the IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be obtained before commencement of this study.  
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB. 
The formal consent of a subject, using the IRB-approved consent form, must be obtained before 
that subject is submitted to any study procedure. This consent form must be signed by the subject 
or legally acceptable surrogate, as outlined in the IRB-approved protocol, and the investigator-
designated research professional obtaining the consent.  
16. 
STUDY FINANCES 
16.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 


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reviewed by the Columbia University Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved prior to participation in this study.  
All CUMC investigators will follow the University conflict of interest policy. 
17. 
GUIDELINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER 
STUDIES 
17.1 
Multi-Site Communication: 
The CPDM Office at CUMC provides administration, data management, and organizational 
support for the affiliate sites in the conduct of a multicenter clinical trial. The CPDM Office will 
coordinate regularly scheduled conference calls with affiliate sites. 
The following issues will be discussed, as appropriate: 
 Enrollment information; 
 Cohort updates (e.g., DLTs); 
 Adverse events (e.g., new AEs and updates on unresolved AEs and new safety 
information); 
 Protocol violations; 
 Other issues affecting the conduct of the study. 
 
17.2 
New Protocol Distribution, IRB Submission, Modifications, and Annual 
Renewals 
 Protocol-specific documents are distributed to affiliate sites once CUMC IRB approval has 
been obtained. 
 The affiliate site must submit a draft of site-specific revisions to protocol and/or consent 
form documents for review and approval by the Sponsor Investigator prior to submission 
to the local IRB. Draft documents should be sent to the studyspecific email address. The 
site will be provided confirmation that they are approved to submit to their local IRB. 
 Protocol amendments must be approved by the affiliate site’s local IRB within 90 days of 
distribution to the site by the Sponsor-Investigator. 
 
17.3 
Regulatory Documents  
17.3.1 
Prior to Site Initiation: 
The Sponsor Investigator will ensure that proper requests are made of sites and that the 
following documentation is collected, prior to the initiation of an affiliate site. 
 Curriculum vita (CV) of site’s Principal Investigator, Co-Investigators, and other research 
staff listed on FDA 1572 (signed and dated copy within 2 years); 


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 Medical licenses of PI and Co-Investigators (current copy); 
 Human patients training certificates for Principal Investigator and Co-Investigators; 
 CLIA/laboratory certifications for local laboratories listed on FDA 1572; 
 Local laboratory Director’s CV and license; 
 Local laboratory reference ranges; 
 IRB roster or statement of compliance; 
 FDA Form 1572, if applicable (wet ink originals required); 
 Financial disclosure forms for all members listed on FDA 1572 (wet ink originals 
required). 
17.3.2 
Ongoing Regulatory Documentation  
Sponsor-Investigator will ensure that proper requests are made of sites and that the following 
documentation is collected throughout the course of the study: 
 IRB approval letters for all protocol modifications and all renewals; 
 IRB-approved consent forms; 
 Current IRB roster, if statement of compliance is not provided as part of site initiation; 
 FDA Form 1572, if applicable as updates are required; 
 Updated investigator and site information where relevant (e.g., CV, medical licensure and 
Financial Disclosure for new sub-investigator, local laboratory information). 
Regulatory documents may be sent to AAAS4165@lists.cumc.columbia.edu or to the following 
address if wet ink originals are required: 
Clinical Protocol & Data Management Office  
161 Fort Washington Ave. 
Herbert Irving Pavilion  
Mezzanine Level, M-203  
New York, NY 10032 
17.4 
Site Activation 
Columbia University will schedule a site initiation visit once IRB approval has been submitted 
from the affiliate site. 


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17.5 
Central Registration Procedures--Affiliate Institution Research Participant 
Registration Process 
All Affiliate Institutions must register patients with the coordinating center (CUMC) prior to any 
administration of study drug/intervention/local institution registration. Please see instructions 
below: 
1. Within 48 hours of obtaining consent (excluding holidays and weekends), the Affiliate 
Institution CRN and/or CRC is required to submit the following documents to the 
coordinating center’s Multicenter Core and the study email 
AAAS4165@lists.cumc.columbia.edu. The coordinating center’s designee will review 
the documents for accurateness, and subsequently submit the documents to the CPDM 
Central Registration Office via email with a request to register the patient “pending 
eligibility”. The title of the email should read, “AAAS4165 Pending Patient Registration 
Request (PHI)”. The following documents should be submitted with the pending registration 
request, as applicable: 
 Redacted Completed/signed IRB approved/stamped Informed Consent Forms, including 
additional study ICFs (e.g., tissue, DNA, etc.), as applicable; 
 Redacted Signed HIPAA (or institutional equivalent); 
 MCT CPDM Velos Note to File form. 
2. The Affiliate Institution’s investigator/research nurse/data manager/coordinator must 
contact the coordinating center’s designee (CUMC Multicenter Core) via telephone or 
email to communicate the following: 
 Notify of pending registration request 
 Confirm method of registration request submission (email or fax) 
 Communicate expected time-line of registration request submission (e.g., same day, next 
day, within the hour, etc.) 
3. To complete registration, the Affiliate Institution’s investigator/research nurse/data 
manager/coordinator should then submit the following documents to the CUMC 
Multicenter Core/designee: 
 A signed Affiliate Site Eligibility Checklist (signed by the investigator); 
 Copies of redacted source documentation necessary for each item to be verified on 
the CUMC-specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., hematology, 
serum chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, 
etc.); 
o Copy of pathology and surgical reports; 
o Copy of clinic note(s) capturing the consent process information, along with 
providing source documentation of any other items needed for 


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screening/eligibility that are not captured in other source document forms. (e.g., 
positive investigator statements of unique eligibility items not captured via 
other direct source documentation, concomitant medication lists, etc.). 
Please note: subject line of email or fax should include the following: “AAAS4165 Complete 
Patient Registration Request (PHI)”. 
4. Upon receipt of the above-mentioned documents, the designated study-specific Clinical 
Research Coordinator will review all documents and verify patient eligibility. If any 
questions arise during the review process, queries in the form of emails will be addressed to 
the applicable affiliate site study team personnel for clarification prior to enrollment. Upon 
verification, the CUMC study-specific designee will then forward all documents to the 
CPDM Central Registration Office for central registration (as described above). The CPDM 
Central Registration Registrar will review all applicable documents and communicate to the 
CUMC study-specific designee in order to clarify any items. The CUMC study specific 
designee will communicate with the applicable site study team personnel for additional 
clarifications as necessary prior to enrollment. 
5. Upon receipt of the patient registration notification email, the CUMC study-specific 
designee will forward the notification email (which will include the study-specific patient 
ID) to the affiliate site’s PI, Consenting Professional, and applicable research personnel. 
This notification should be filed in the patient research binder accordingly. Protocol therapy 
may not be initiated prior to receipt of this notification from the coordinating center. 
6. All screen-fail/ineligible patients, as well as patients who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration 
Office in a manner analogous to the procedures noted above. Applicable source 
documentation will be required within the corresponding submissions. 
 
17.6 
Protocol Deviation request for Affiliate Sites: 
The Affiliate site must submit a prospective deviation request to the CUMC lead PI for review 
and submission to the HICCC DSMC and CUMC IRB. Approvals must be obtained from all 
entities prior to implementation at the Affiliate site. If a prospective protocol deviation request is 
submitted for review (from an Affiliate site), the PI/site memo(s), HICCC DSMC approval(s) and 
correspondence and CUMC IRB deviation approval letter(s) should be forwarded to the Affiliate 
site for documentation. The Affiliate site is also required to obtain prospective local IRB approval 
as per institutional policies/procedures prior to implementing the proposed deviation. All 
documents and determinations must be clearly documented in the study patient’s medical record, 
research chart, and regulatory binder, as described. 
The HICCC DSMC and PRMC will no longer accept eligibility deviations, but will still continue 
to accept deviations not related to eligibility. 


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17.7 
Guidelines for Affiliate Site Monitoring 
17.7.1 
On-Site MCT Monitoring: 
 Initial, recurrent, and close-out on-site monitoring visits will also be conducted at Affiliate 
sites, as appropriate/feasible. Other sites will have monitoring performed remotely (see 
below for further details). 
 The Compliance Coordinator will communicate with the Affiliate site coordinator/Site 
Principle Investigator to schedule the monitoring visit and arrange for access to study 
materials and documentation. 
 The Compliance Coordinator will monitor IIT trials within 1 month after the first patient 
is enrolled at the Affiliate site and throughout the life of the study to ensure that the study 
is being conducted in accordance with the protocol, GCP, applicable federal and local 
regulations, and per all applicable SOPs. The Compliance Coordinator is responsible to 
notify the participating site PI and CRNP/CRN/CRC of upcoming monitor visits and 
convey what information and documentation will be required for the visit(s). The 
Compliance Coordinator is responsible for verifying that informed consent is properly 
obtained, eligibility is met (via the central registration process), and all study procedures 
are conducted according to the study protocol. The Compliance Coordinator will also 
verify that the data reported in the CRFs accurately reflect source documents, that all 
toxicities have been reported to date, and that all SAE’s/UPs/deviations/violations have 
been reported, according to Coordinating Center, local IRB and HICCC DSMC 
requirements. The Compliance Coordinator will issue queries and ensure resolution in a 
timely and efficient manner. The Compliance Coordinator will also monitor for applicable 
regulatory compliance and research pharmacy compliance (if applicable) and communicate 
any deficiencies, as appropriate. 
 A site initiation visit (SIV) (or) teleconference will be scheduled and conducted prior to 
study drug being made available (if applicable) and before any patients are enrolled on a 
study at the Affiliate site. 
 
17.7.2 
Remote MCT Monitoring: 
 When necessary (due to logistical constraints), Affiliate sites will be monitored remotely 
by a designated Compliance Coordinator. Sites will be informed of this remote 
monitoring process on a site-by-site basis. 
 Affiliate sites will be monitored by the Compliance Coordinator on both a regulatory 
level, as well as a clinical data/source documentation review level. 


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 Redacted source documents (applicable to supporting the protocolspecific CRF data 
requirements) will be sent to the designated Compliance Coordinator via fax or secure 
email for all patients enrolled at Affiliate sites. Timelines for submission procedures will 
be defined on a case-by-case basis. 
 The Compliance Coordinator will review all submitted redacted source documents 
against the data entered on the protocol specific CRFs. The Compliance Coordinator will 
issue queries when/if necessary. 
 The Affiliate site research staff will respond to queries within 30 days. If queries remain 
outstanding, the Compliance Coordinator will send a delinquent query reminder for the 
outstanding items. 
 The remote monitoring procedures will include review of applicable redacted source 
documentation and supporting applicable documents to determine compliance regarding: 
o Informed consent procedures; 
o Eligibility criteria; 
o Protocol-specific treatment compliance; 
o Protocol-specific toxicity/outcome documentation/compliance; 
o Protocol-specific schedule of events (e.g., baseline visits, pre-treatment, on study, 
follow-up); 
o Participating site IRB documents (e.g., IRB amendment approvals, annual 
renewals, SAE/UP submissions, violation/deviation submissions, IND Safety 
Reports submissions, etc.); 
o Required specimen submissions (e.g., tissue specimens, research blood specimens, 
etc.); 
o Pharmacy accountability records; and 
o Adherence to the CRF submission timeframes to CUMC (within the protocol 
specified timeframes). 
 Affiliate site remote monitoring reports will be sent to the lead Principal Investigator, 
HICCC DSMC, and Affiliate sites after each remote monitoring review. Reports will 
include information regarding data submission timeliness/accuracy, protocol adherence 
items, query resolution status, regulatory status, and overall Affiliate site performance. 
These reports will be generated by the Compliance Coordinator and reviewed with the 
Compliance Core Manager prior to dissemination. 


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17.8 
Adverse Event Reporting 
17.8.1 
Sponsor Reporting: Notifying participating investigators at affiliate sites of adverse 
events 
It is the responsibility of the study Sponsor to notify all affiliate sites, in a written IND safety report, 
of any AE associated with the use of the drug that is both serious and unexpected, as well as 
any finding from tests in laboratory animals that suggest a significant risk for human patients. 
Additionally, Sponsors are also required to identify in IND safety reports all previous reports 
concerning similar AEs, and to analyze the significance of the current event in light of the 
previous reports. 
17.8.2 
Sub-Site SAE Reporting Procedures: 
Each participating investigator is required to abide by the reporting requirements set by Columbia 
University Medical Center. The study must be conducted in compliance with FDA regulations, 
local safety reporting requirements, and reporting requirements of the Principal Investigator. 
Participating investigators must report each SAE to the Columbia University Medical Center 
Overall Principal Investigator within 24 hours of learning of the occurrence using the SAE Report 
Form. In the event that the participating investigator does not become aware of the 
SAE 
immediately (e.g., participant sought treatment elsewhere), the participating investigator is to 
report the event within 24 hours after learning of it and document the time of his or her first 
awareness of the AE. Report SAEs by telephone, email, or facsimile to: 
Gulam Abbas Manji, M.D/Ph.D.  
161 Fort Washington Avenue  
New York, NY 10032 
Telephone: 212-304-6357 (Multicenter Trial Number)  
Fax: 212-304-6330 (Multicenter Trial Fax) 
Email:  CPDM Multicenter Trials Core (AAAS4165@lists.cumc.columbia.edu) 
The participating investigator must provide follow-up information on the SAE until resolution of 
the event. Follow-up information should describe whether the event has resolved or continues, if 
and how the event was treated, and whether the participant will continue or discontinue study 
participation.  
Follow-up information is sent to the same person to whom the original SAE Report Form was sent, 
using a new SAE Report Form stating that this is a follow-up to the previously reported SAE and 
giving the date of the original report. Each re-occurrence, complication, or progression of the 
original event should be reported as a follow-up to that event regardless of when it occurs. The 
follow-up information should describe whether the event has resolved or continues, if and how it 
was treated, whether the patient continued or withdrew from study participation, and if study 
drug was interrupted or discontinued. 


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If the SAE is not previously documented in the Investigator’s Brochure for the study drug (new 
occurrence) and is thought to be related to the investigational agent, the Sponsor-Investigator may 
urgently require further information from the investigator for reporting to Health Authorities. 
17.8.3 
Non-Serious Adverse Event Reporting 
Non-serious adverse events will be reported to the Columbia University Medical Center Overall 
PI on the toxicity Case Report Forms. 
17.9 
Reporting to the Institutional Review Board (IRB) and the Data and Safety 
Monitoring Committee: 
All UPs will be reported to the CUMC IRB. SAEs not constituting UPs will be reported to the 
HICCC DSMC. 
Each affiliate site will be responsible for safety reporting to their local IRB. Investigators are 
responsible for complying with their local IRB’s reporting requirements, though must submit the 
required reports to their IRB no later than 7 calendar days following the occurrence of the UP or 
the Principal’s Investigator’s acquiring knowledge of the UP. Copies of each report and 
documentation of IRB notification and receipt must be included in the regulatory binder. 
17.10 
Guidelines for Processing IND Safety Reports 
The FDA regulations require Sponsors of clinical studies to notify the FDA and all participating 
investigators of any serious and unexpected adverse experiences that are possibly related to the 
investigational agent. The CUMC Principal Investigator will review all applicable IND Safety 
Reports and has the responsibly to forward the IND Safety Reports to the Affiliate Institutions. 
The Affiliate Institution investigators are to review, send a copy to their IRB according to their 
local IRB’s policies and procedures, and file a copy with their regulatory documents. All 
Affiliate site IND Safety Reports submissions, along with IRB acknowledgment (per local 
policies and procedures) are to be forwarded to CUMC for placement within the trial master file. 
17.11 
Reporting to Hospital Risk Management 
Affiliate Site investigators will report to their local Risk Management Office any patient safety 
reports or sentinel events that require reporting according to institutional policy. 
17.12 
Confidentiality 
Each affiliate site will be assigned a site number. Each patient that signs consent should be assigned 
a unique code number consisting of site number followed by a number with each new patient being 
assigned the next sequential number (e.g., 04-10). All sites will be required to enter their data in 
the Velos eResearch, the Clinical Trial Management System used for all Cancer-related clinical 
research at CUMC. All users must login with their own application username and password. Users 
off campus must first access the Virtual Private Network with their assigned campus username 
and password and then use their application credentials. 


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Patient confidentiality must be maintained according to HIPAA regulations and GCP 
recommendations. Except when required by law, study information shared with persons and 
organizations outside of CUMC must not identify the patient by name, social security number, 
address, telephone number, or any other direct personal identifier. 
If the results of this research project are published or presented at a scientific or medical meeting, 
the patient must not be identified. Otherwise, all results will be kept confidential and will not be 
divulged (except as required by law) without permission. 
17.13 
Data Reporting Plan 
CUMC is deeply committed to research integrity and strong credibility when it comes to the 
discovery of new treatment concepts, implementation of new clinical research techniques, and 
acceptance of its researcher's findings by the medical establishment. In accord with these 
ethics, CUMC encourages and supports its investigators in the sharing of final research data and/or 
details of newly developed clinical treatments. 
CUMC's policies that pertain to patient data sharing conform to CUMC IRB rules, local and state 
laws, and HIPAA privacy regulations. The primary reason for this is to protect the privacy of 
patients who participate in clinical trials. The data can be made available for continuing review by 
federal agencies upon request and for ongoing study safety reviews by the PI, Statistician, Data 
Safety and Monitoring Board (DSMB), and, in other instances, the CUMC IRB. 
Data collected during the course of this clinical trial will primarily be shared with other 
investigators and University staff, the IRB, FDA, and other reporting agencies, and/or transferred 
to other collaborators. Prior to transfer, the data collected must comply with, and must be limited 
by, the CUMC's guidelines for Protecting the Rights and Privacy of Human Patients. 
17.14 
Data Acquisition and Submission 
Informed consent, including HIPPA authorization, must be obtained on all patients prior to their 
participation. Always keep the original signed and dated consent form, with the redacted source 
documents and eligibility checklist. Velos eResearch will be used as the electronic clinical trials 
and data management system. Affiliate sites will enter data directly into Velos eResearch via 
customized case report forms for the study. The research staff will generate reports from Velos 
eResearch to ensure timely submission of data by affiliate sites. This resource allows for the timely 
analysis of particular data sets for safety analysis. 
17.15 
Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by patients, as well as written records of the disposition of the 
drug when the study ends. 
The PI is required to prepare and maintain adequate and accurate case histories that record all 
observations and other data pertinent to the investigation on each individual administered 
the investigational drug or employed as a control in the investigation. Case histories include the 


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case report forms and supporting data including, for example, signed and dated consent forms and 
medical records including, for example, progress notes of the physician, the individual's hospital 
chart(s), and the nurses' notes. The case history for each individual shall document that informed 
consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed, or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 
18. 
PUBLICATION PLAN 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test results 
and all data derived from the study. 
19. 
REFERENCES 
Allison, D. C., Piantadosi, S., Hruban, R. H., Dooley, W. C., Fishman, E. K., Yeo, C. J., . Cameron, 
J. L. (1998). DNA content and other factors associated with ten-year survival after 
resection of pancreatic carcinoma. J Surg Oncol, 67(3), 151-159.  
Andre, T., Vernerey, D., Mineur, L., Bennouna, J., Desrame, J., Faroux, R., . . . Unicancer. (2018). 
Three Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With 
Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, 
International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial. J Clin Oncol, 
36(15), 1469-1477. doi:10.1200/JCO.2017.76.0355 
Azuma, K., Ota, K., Kawahara, A., Hattori, S., Iwama, E., Harada, T., . . . Okamoto, I. (2014). 
Association of PD-L1 overexpression with activating EGFR mutations in surgically 
resected 
nonsmall-cell 
lung 
cancer. 
Ann 
Oncol, 
25(10), 
1935-1940. 
doi:10.1093/annonc/mdu242 
Bendell, J., Segal, N., Sobrero, A., Uyei, A., Chang, I., Roberts, L., . . . Kozloff, M. (2018). LBA-
004Efficacy and safety results from IMblaze370, a randomised Phase III study comparing 
atezolizumab+cobimetinib 
and 
atezolizumab 
monotherapy 
vs 
regorafenib 
in 
chemotherapy-refractory metastatic colorectal cancer. Annals of Oncology, 29(suppl_5). 
doi:10.1093/annonc/mdy208.003 
Bettegowda, C., Sausen, M., Leary, R. J., Kinde, I., Wang, Y., Agrawal, N., . . . Diaz, L. A., Jr. 
(2014). Detection of circulating tumor DNA in early- and late-stage human malignancies. 
Sci Transl Med, 6(224), 224ra224. doi:10.1126/scitranslmed.3007094 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
AAAS4165_Version Date: 07/07/2021 
 
114 
 
Blank, C., Gajewski, T. F., & Mackensen, A. (2005). Interaction of PD-L1 on tumor cells with 
PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor 
immunotherapy. Cancer Immunol Immunother, 54(4), 307-314. doi:10.1007/s00262-004-
0593-x 
Blank, C., & Mackensen, A. (2007). Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: 
an update on implications for chronic infections and tumor evasion. Cancer Immunol 
Immunother, 56(5), 739-745. doi:10.1007/s00262-006-0272-1 
Boone, B. A., Bahary, N., Zureikat, A. H., Moser, A. J., Normolle, D. P., Wu, W. C., . . . Zeh, H. 
J., 3rd. (2015). Safety and Biologic Response of Pre-operative Autophagy Inhibition in 
Combination with Gemcitabine in Patients with Pancreatic Adenocarcinoma. Ann Surg 
Oncol, 22(13), 4402-4410. doi:10.1245/s10434-015-4566-4 
Brahmer, J. R., Tykodi, S. S., Chow, L. Q., Hwu, W. J., Topalian, S. L., Hwu, P., . . . Wigginton, 
J. M. (2012). Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. 
N Engl J Med, 366(26), 2455-2465. doi:10.1056/NEJMoa1200694 
Bryant, K. L., Stalnecker, C. A., Zeitouni, D., Klomp, J. E., Peng, S., Tikunov, A. P., . . . Der, C. 
J. (2019). Combination of ERK and autophagy inhibition as a treatment approach for 
pancreatic cancer. Nat Med. doi:10.1038/s41591-019-0368-8 
Butte, M. J., Keir, M. E., Phamduy, T. B., Sharpe, A. H., & Freeman, G. J. (2007). Programmed 
death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T 
cell responses. Immunity, 27(1), 111-122. doi:10.1016/j.immuni.2007.05.016 
Carstens, J. L., Correa de Sampaio, P., Yang, D., Barua, S., Wang, H., Rao, A., . . . Kalluri, R. 
(2017). Spatial computation of intratumoral T cells correlates with survival of patients with 
pancreatic cancer. Nat Commun, 8, 15095. doi:10.1038/ncomms15095 
Chapman, A. M., Sun, K. Y., Ruestow, P., Cowan, D. M., & Madl, A. K. (2016). Lung cancer 
mutation profile of EGFR, ALK, and KRAS: Meta-analysis and comparison of never and 
ever smokers. Lung Cancer, 102, 122-134. doi:10.1016/j.lungcan.2016.10.010 
Cheng, X. B., Sato, N., Kohi, S., & Yamaguchi, K. (2013). Prognostic impact of hyaluronan and 
its regulators in pancreatic ductal adenocarcinoma. PLoS One, 8(11), e80765. 
doi:10.1371/journal.pone.0080765 
Cheung, Y. K., & Chappell, R. (2002). A simple technique to evaluate model sensitivity in the 
continual reassessment method. Biometrics, 58(3), 671-674.  
Clark, C. E., Hingorani, S. R., Mick, R., Combs, C., Tuveson, D. A., & Vonderheide, R. H. (2007). 
Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer 
Res, 67(19), 9518-9527. doi:10.1158/0008-5472.CAN-07-0175 
Conroy, T., Desseigne, F., Ychou, M., Bouche, O., Guimbaud, R., Becouarn, Y., . . . Intergroup, 
P. (2011). FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J 
Med, 364(19), 1817-1825. doi:10.1056/NEJMoa1011923 
Conroy, T., Hammel, P., Hebbar, M., Abdelghani, M. B., Wei, A. C.-c., Raoul, J.-L., . . . Bachet, 
J.-B. (2018). Unicancer GI PRODIGE 24/CCTG PA.6 trial: A multicenter international 
randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in 
patients with resected pancreatic ductal adenocarcinomas. Journal of Clinical Oncology, 
36(18_suppl), LBA4001-LBA4001. doi:10.1200/JCO.2018.36.18_suppl.LBA4001 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
AAAS4165_Version Date: 07/07/2021 
 
115 
 
Deng, R., Bumbaca, D., Pastuskovas, C. V., Boswell, C. A., West, D., Cowan, K. J., . . . Iyer, S. 
(2016). Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor 
penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor. MAbs, 
8(3), 593-603. doi:10.1080/19420862.2015.1136043 
Downward, J. (2003). Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer, 3(1), 
11-22. doi:10.1038/nrc969 
Dreyer, S. B., Chang, D. K., Bailey, P., & Biankin, A. V. (2017). Pancreatic Cancer Genomes: 
Implications for Clinical Management and Therapeutic Development. Clin Cancer Res, 
23(7), 1638-1646. doi:10.1158/1078-0432.ccr-16-2411 
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., . . . Verweij, 
J. (2009). New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer, 45(2), 228-247. doi:10.1016/j.ejca.2008.10.026 
Ene-Obong, A., Clear, A. J., Watt, J., Wang, J., Fatah, R., Riches, J. C., . . . Kocher, H. M. (2013). 
Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the 
juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology, 145(5), 
1121-1132. doi:10.1053/j.gastro.2013.07.025 
Gandara, D. R., Leighl, N., Delord, J. P., Barlesi, F., Bennouna, J., Zalcman, G., . . . Blumenschein, 
G., Jr. (2017). A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed 
in Patients With Advanced Non-Small Cell Lung Cancer. J Thorac Oncol, 12(3), 556-566. 
doi:10.1016/j.jtho.2016.11.2218 
Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., . . . Garassino, 
M. C. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung 
Cancer. 
New 
England 
Journal 
of 
Medicine, 
378(22), 
2078-2092. 
doi:10.1056/NEJMoa1801005 
Garon, E. B., Ciuleanu, T. E., Arrieta, O., Prabhash, K., Syrigos, K. N., Goksel, T., . . . Perol, M. 
(2014). Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line 
treatment of stage IV non-small-cell lung cancer after disease progression on platinum-
based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet, 
384(9944), 665-673. doi:10.1016/s0140-6736(14)60845-x 
Garrido, P., Olmedo, M. E., Gómez, A., Paz Ares, L., López-Ríos, F., Rosa-Rosa, J. M., & Palacios, 
J. (2017). Treating KRAS-mutant NSCLC: latest evidence and clinical consequences. 
Therapeutic 
advances 
in 
medical 
oncology, 
9(9), 
589-597. 
doi:10.1177/1758834017719829 
Grothey, A., Van Cutsem, E., Sobrero, A., Siena, S., Falcone, A., Ychou, M., . . . Group, C. S. 
(2013). Regorafenib monotherapy for previously treated metastatic colorectal cancer 
(CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. 
Lancet, 381(9863), 303-312. doi:10.1016/S0140-6736(12)61900-X 
Hales, R. K., Banchereau, J., Ribas, A., Tarhini, A. A., Weber, J. S., Fox, B. A., & Drake, C. G. 
(2010). Assessing oncologic benefit in clinical trials of immunotherapy agents. Ann Oncol, 
21(10), 1944-1951. doi:10.1093/annonc/mdq048 
Hanna, N., Shepherd, F. A., Fossella, F. V., Pereira, J. R., De Marinis, F., von Pawel, J., . . . Bunn, 
P. A. (2004). Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
AAAS4165_Version Date: 07/07/2021 
 
116 
 
Non–Small-Cell Lung Cancer Previously Treated With Chemotherapy. Journal of Clinical 
Oncology, 22(9), 1589-1597. doi:10.1200/JCO.2004.08.163 
Hanzelmann, S., Castelo, R., & Guinney, J. (2013). GSVA: gene set variation analysis for 
microarray and RNA-seq data. BMC Bioinformatics, 14, 7. doi:10.1186/1471-2105-14-7 
Herbst, R. S., Baas, P., Kim, D. W., Felip, E., Perez-Gracia, J. L., Han, J. Y., . . . Garon, E. B. 
(2016). Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced 
non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 
387(10027), 1540-1550. doi:10.1016/s0140-6736(15)01281-7 
Hiraoka, N., Onozato, K., Kosuge, T., & Hirohashi, S. (2006). Prevalence of FOXP3+ regulatory 
T cells increases during the progression of pancreatic ductal adenocarcinoma and its 
premalignant lesions. Clin Cancer Res, 12(18), 5423-5434. doi:10.1158/1078-0432.CCR-
06-0369 
Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., . . . Urba, 
W. J. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. N 
Engl J Med, 363(8), 711-723. doi:10.1056/NEJMoa1003466 
Horn, L., Mansfield, A. S., Szczesna, A., Havel, L., Krzakowski, M., Hochmair, M. J., . . . Group, 
I. M. S. (2018). First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-
Cell Lung Cancer. N Engl J Med, 379(23), 2220-2229. doi:10.1056/NEJMoa1809064 
Howard, T. J., Krug, J. E., Yu, J., Zyromski, N. J., Schmidt, C. M., Jacobson, L. E., . . . Lillemoe, 
K. D. (2006). A margin-negative R0 resection accomplished with minimal postoperative 
complications is the surgeon's contribution to long-term survival in pancreatic cancer. J 
Gastrointest 
Surg, 
10(10), 
1338-1345; 
discussion 
1345-1336. 
doi:10.1016/j.gassur.2006.09.008 
Howlader N, N. A., Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis 
DR, Chen HS, Feuer EJ, Cronin KA (eds). (2017). SEER Cancer Statistics Review, 1975-
2014. Retrieved from: https://seer.cancer.gov/csr/1975_2014/ 
Humphris, J. L., Patch, A. M., Nones, K., Bailey, P. J., Johns, A. L., McKay, S., . . . Biankin, A. 
V. (2017). Hypermutation In Pancreatic Cancer. Gastroenterology, 152(1), 68-74.e62. 
doi:10.1053/j.gastro.2016.09.060 
Ikeda, M., Sung, M. W., Kudo, M., Kobayashi, M., Baron, A. D., Finn, R. S., . . . Okusaka, T. 
(2018). A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) 
with unresectable hepatocellular carcinoma (uHCC). Journal of Clinical Oncology, 
36(15_suppl), 4076-4076. doi:10.1200/JCO.2018.36.15_suppl.4076 
Infante, J. R., Somer, B. G., Park, J. O., Li, C. P., Scheulen, M. E., Kasubhai, S. M., . . . Le, N. 
(2014). A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK 
inhibitor, in combination with gemcitabine for patients with untreated metastatic 
adenocarcinoma 
of 
the 
pancreas. 
Eur 
J 
Cancer, 
50(12), 
2072-2081. 
doi:10.1016/j.ejca.2014.04.024 
Janji, B., Viry, E., Moussay, E., Paggetti, J., Arakelian, T., Mgrditchian, T., . . . Chouaib, S. (2016). 
The multifaceted role of autophagy in tumor evasion from immune surveillance. 
Oncotarget, 7(14), 17591-17607. doi:10.18632/oncotarget.7540 
Janne, P. A., Mann, H., & Ghiorghiu, D. (2016). Study Design and Rationale for a Randomized, 
Placebo-Controlled, Double-Blind Study to Assess the Efficacy and Safety of Selumetinib 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
AAAS4165_Version Date: 07/07/2021 
 
117 
 
in Combination With Docetaxel as Second-Line Treatment in Patients With KRAS-Mutant 
Advanced Non-Small Cell Lung Cancer (SELECT-1). Clin Lung Cancer, 17(2), e1-4. 
doi:10.1016/j.cllc.2015.12.010 
Jia, X., Ivanova, A., & Lee, S. M. (2017). Selection of the initial design for the two-stage continual 
reassessment 
method. 
J 
Biopharm 
Stat, 
27(3), 
495-506. 
doi:10.1080/10543406.2017.1290650 
Kantoff, P. W., Higano, C. S., Shore, N. D., Berger, E. R., Small, E. J., Penson, D. F., . . . 
Investigators, I. S. (2010). Sipuleucel-T immunotherapy for castration-resistant prostate 
cancer. N Engl J Med, 363(5), 411-422. doi:10.1056/NEJMoa1001294 
Karasic, T.B., O'Hara, M.J., Loaiza-Bonilla, A., Reiss, K.A., Teitelbaum, U.R., Borazanci, E., … 
Effect of Gemcitabine and nab-Paclitaxel With or Without Hydroxychloroquine on 
Patients With Advanced Pancreatic Cancer: A Phase 2 Randomized Clinical Trial. JAMA 
Oncol. 2019 Jul 1;5(7):993-998. doi:10.1001/jamaoncol.2019.0684. 
Keir, M. E., Butte, M. J., Freeman, G. J., & Sharpe, A. H. (2008). PD-1 and its ligands in tolerance 
and 
immunity. 
Annu 
Rev 
Immunol, 
26, 
677-704. 
doi:10.1146/annurev.immunol.26.021607.090331 
Kinsey, C. G., Camolotto, S. A., Boespflug, A. M., Gullien, K. P., Foth, M., Truong, A., . . . 
McMahon, M. (2019). Protective autophagy elicited by RAF→MEK→ERK inhibition 
suggests a treatment strategy for RAS-driven cancers. Nat Med. doi:10.1038/s41591-019-
0367-9 
Lee, S. M., & Ying Kuen, C. (2009). Model calibration in the continual reassessment method. Clin 
Trials, 6(3), 227-238. doi:10.1177/1740774509105076 
Li, J., Qin, S., Xu, R., Yau, T. C., Ma, B., Pan, H., . . . Kim, T. W. (2015). Regorafenib plus best 
supportive care versus placebo plus best supportive care in Asian patients with previously 
treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-
controlled, phase 3 trial. Lancet Oncol, 16(6), 619-629. doi:10.1016/s1470-
2045(15)70156-7 
Liu, J., Liu, X., Han, Y., Zhang, J., Liu, D., Ma, G., . . . Kong, D. (2018). Nanovaccine Incorporated 
with Hydroxychloroquine Enhances Antigen Cross-Presentation and Promotes Antitumor 
Immune 
Responses. 
ACS 
Appl 
Mater 
Interfaces, 
10(37), 
30983-30993. 
doi:10.1021/acsami.8b09348 
Ma, X. H., Piao, S. F., Dey, S., McAfee, Q., Karakousis, G., Villanueva, J., . . . Amaravadi, R. K. 
(2014). Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in 
melanoma. J Clin Invest, 124(3), 1406-1417. doi:10.1172/jci70454 
Mayer, R. J., Van Cutsem, E., Falcone, A., Yoshino, T., Garcia-Carbonero, R., Mizunuma, N., . . . 
Group, R. S. (2015). Randomized trial of TAS-102 for refractory metastatic colorectal 
cancer. N Engl J Med, 372(20), 1909-1919. doi:10.1056/NEJMoa1414325 
Miller-Ocuin  JL, Bahary  NS, Singhi  AD,  et al.  Inhibition of autophagy improves pathologic 
and biomarker response to preoperative gemcitabine/nab-paclitaxel in potentially 
resectable pancreatic cancer: a phase II randomized controlled trial.  Ann Surg Oncol. 
2017;24:S6-S7. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
AAAS4165_Version Date: 07/07/2021 
 
118 
 
Moffitt, R. A., Marayati, R., Flate, E. L., Volmar, K. E., Loeza, S. G., Hoadley, K. A., . . . Yeh, J. 
J. (2015). Virtual microdissection identifies distinct tumor- and stroma-specific subtypes 
of pancreatic ductal adenocarcinoma. Nat Genet, 47(10), 1168-1178. doi:10.1038/ng.3398 
NCI. (2017). Common Terminology Criteria for Adverse Events Version 5.   Retrieved from 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quic
k_reference_8.5x11.pdf 
Neoptolemos, J. P., Stocken, D. D., Bassi, C., Ghaneh, P., Cunningham, D., Goldstein, D., . . . 
European Study Group for Pancreatic, C. (2010). Adjuvant chemotherapy with fluorouracil 
plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized 
controlled trial. JAMA, 304(10), 1073-1081. doi:10.1001/jama.2010.1275 
Neoptolemos, J. P., Stocken, D. D., Friess, H., Bassi, C., Dunn, J. A., Hickey, H., . . . European 
Study Group for Pancreatic, C. (2004). A randomized trial of chemoradiotherapy and 
chemotherapy after resection of pancreatic cancer. N Engl J Med, 350(12), 1200-1210. 
doi:10.1056/NEJMoa032295 
Nishino, M., Hatabu, H., Johnson, B. E., & McLoud, T. C. (2014). State of the art: Response 
assessment in lung cancer in the era of genomic medicine. Radiology, 271(1), 6-27. 
doi:10.1148/radiol.14122524 
O'Hara  MH, Karasic  TB, Vasilevskaya  I,  et al.  Phase II trial of the autophagy inhibitor 
hydroxychloroquine with FOLFOX and bevacizumab in front line treatment of metastatic 
colorectal cancer.  J Clin Oncol. 2017;35(15_suppl):3545. 
O'Reilly, EM., Oh, D.Y., Dhani, N., Renoug, D.J., Lee, M.A., Sun, W., ... Durvalumab With or 
Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: 
A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019 Jul 18. doi: 
10.1001/jamaoncol.2019.1588. 
Oettle, H., Post, S., Neuhaus, P., Gellert, K., Langrehr, J., Ridwelski, K., . . . Riess, H. (2007). 
Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-
intent resection of pancreatic cancer: a randomized controlled trial. JAMA, 297(3), 267-
277. doi:10.1001/jama.297.3.267 
Rahib, L., Smith, B. D., Aizenberg, R., Rosenzweig, A. B., Fleshman, J. M., & Matrisian, L. M. 
(2014). Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, 
liver, and pancreas cancers in the United States. Cancer Res, 74(11), 2913-2921. 
doi:10.1158/0008-5472.CAN-14-0155 
RDC. (2016). R: A Language and Environment for Statistical Computing. R Foundation for 
Statistical Computing. Vienna, Austria. Retrieved from https://www.R-project.org/ 
Regine, W. F., Winter, K. A., Abrams, R. A., Safran, H., Hoffman, J. P., Konski, A., . . . Rich, T. 
A. (2008). Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based 
chemoradiation following resection of pancreatic adenocarcinoma: a randomized 
controlled trial. JAMA, 299(9), 1019-1026. doi:10.1001/jama.299.9.1019 
Ritchie, G., Gasper, H., Man, J., Lord, S., Marschner, I., Friedlander, M., & Lee, C. K. (2018). 
Defining the Most Appropriate Primary End Point in Phase 2 Trials of Immune Checkpoint 
Inhibitors for Advanced Solid Cancers: A Systematic Review and Meta-analysis. JAMA 
Oncol, 4(4), 522-528. doi:10.1001/jamaoncol.2017.5236 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
AAAS4165_Version Date: 07/07/2021 
 
119 
 
Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015). limma 
powers differential expression analyses for RNA-sequencing and microarray studies. 
Nucleic Acids Res, 43(7), e47. doi:10.1093/nar/gkv007 
Rittmeyer, A., Barlesi, F., Waterkamp, D., Park, K., Ciardiello, F., von Pawel, J., . . . Gandara, D. 
R. (2017). Atezolizumab versus docetaxel in patients with previously treated non-small-
cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. 
Lancet, 389(10066), 255-265. doi:10.1016/s0140-6736(16)32517-x 
Rizvi, N. A., Hellmann, M. D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J. J., . . . Chan, T. 
A. (2015). Cancer immunology. Mutational landscape determines sensitivity to PD-1 
blockade 
in 
non-small 
cell 
lung 
cancer. 
Science, 
348(6230), 
124-128. 
doi:10.1126/science.aaa1348 
Roberts, P. J., & Der, C. J. (2007). Targeting the Raf-MEK-ERK mitogen-activated protein kinase 
cascade 
for 
the 
treatment 
of 
cancer. 
Oncogene, 
26(22), 
3291-3310. 
doi:10.1038/sj.onc.1210422 
Royal, R. E., Levy, C., Turner, K., Mathur, A., Hughes, M., Kammula, U. S., . . . Rosenberg, S. A. 
(2010). Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or 
metastatic 
pancreatic 
adenocarcinoma. 
J 
Immunother, 
33(8), 
828-833. 
doi:10.1097/CJI.0b013e3181eec14c 
Sanduja, S., Feng, Y., Mathis, R. A., Sokol, E. S., Reinhardt, F., Halaban, R., & Gupta, P. B. 
(2016). AMPK promotes tolerance to Ras pathway inhibition by activating autophagy. 
Oncogene, 35(40), 5295-5303. doi:10.1038/onc.2016.70 
Schalper, K. A., Brown, J., Carvajal-Hausdorf, D., McLaughlin, J., Velcheti, V., Syrigos, K. N., . . . 
Rimm, D. L. (2015). Objective measurement and clinical significance of TILs in non-small 
cell lung cancer. J Natl Cancer Inst, 107(3). doi:10.1093/jnci/dju435 
Schmid, P., Adams, S., Rugo, H. S., Schneeweiss, A., Barrios, C. H., Iwata, H., . . . Investigators, 
I. M. T. (2018). Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast 
Cancer. N Engl J Med, 379(22), 2108-2121. doi:10.1056/NEJMoa1809615 
Segal NH, H. O., Hwu W, et al. . A phase I multi-arm dose-expansion study of the anti-
programmed cell death-ligand-1 (PD-L1) antibody MEDI4736: Preliminary data. Ann 
Oncol. 2014;25(suppl 4):iv365.  
Shields, J. M., Pruitt, K., McFall, A., Shaub, A., & Der, C. J. (2000). Understanding Ras: 'it ain't 
over 'til it's over'. Trends Cell Biol, 10(4), 147-154.  
Siegel, R. L., Miller, K. D., & Jemal, A. (2016). Cancer statistics, 2016. CA Cancer J Clin, 66(1), 
7-30. doi:10.3322/caac.21332 
Sieunarine, K., Hakim, N. S., Corless, D. J., Noakes, D. E., Ungar, L., Del Priore, G., & Smith, J. 
R. (2005). Is it feasible to use a large vessel patch with a uterine allograft en bloc for uterine 
transplantation? Int Surg, 90(5), 257-261.  
Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky, J. M., Desrichard, A., . . . Chan, T. A. 
(2014). Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J 
Med, 371(23), 2189-2199. doi:10.1056/NEJMoa1406498 
Socinski, M. A., Jotte, R. M., Cappuzzo, F., Orlandi, F., Stroyakovskiy, D., Nogami, N., . . . Group, 
I. M. S. (2018). Atezolizumab for First-Line Treatment of Metastatic Nonsquamous 
NSCLC. N Engl J Med, 378(24), 2288-2301. doi:10.1056/NEJMoa1716948 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
AAAS4165_Version Date: 07/07/2021 
 
120 
 
Sohn, T. A., Yeo, C. J., Cameron, J. L., Koniaris, L., Kaushal, S., Abrams, R. A., . . . Lillemoe, K. 
D. (2000). Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and 
prognostic indicators. J Gastrointest Surg, 4(6), 567-579.  
Stack, E. C., Wang, C., Roman, K. A., & Hoyt, C. C. (2014). Multiplexed immunohistochemistry, 
imaging, and quantitation: a review, with an assessment of Tyramide signal amplification, 
multispectral 
imaging 
and 
multiplex 
analysis. 
Methods, 
70(1), 
46-58. 
doi:10.1016/j.ymeth.2014.08.016 
Tsilimigras, D. I., Ntanasis-Stathopoulos, I., Bagante, F., Moris, D., Cloyd, J., Spartalis, E., & 
Pawlik, T. M. (2018). Clinical significance and prognostic relevance of KRAS, BRAF, 
PI3K and TP53 genetic mutation analysis for resectable and unresectable colorectal liver 
metastases: A systematic review of the current evidence. Surg Oncol, 27(2), 280-288. 
doi:10.1016/j.suronc.2018.05.012 
Tumeh, P. C., Harview, C. L., Yearley, J. H., Shintaku, I. P., Taylor, E. J., Robert, L., . . . Ribas, 
A. (2014). PD-1 blockade induces responses by inhibiting adaptive immune resistance. 
Nature, 515(7528), 568-571. doi:10.1038/nature13954 
Von Hoff, D. D., Ervin, T., Arena, F. P., Chiorean, E. G., Infante, J., Moore, M., . . . Renschler, 
M. F. (2013). Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. 
N Engl J Med, 369(18), 1691-1703. doi:10.1056/NEJMoa1304369 
Vonderheide, R. H., & Bayne, L. J. (2013). Inflammatory networks and immune surveillance of 
pancreatic carcinoma. Curr Opin Immunol, 25(2), 200-205. doi:10.1016/j.coi.2013.01.006 
Wang-Gillam, A., Li, C. P., Bodoky, G., Dean, A., Shan, Y. S., Jameson, G., . . . Group, N.-S. 
(2016). Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic 
pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, 
randomised, open-label, phase 3 trial. Lancet, 387(10018), 545-557. doi:10.1016/S0140-
6736(15)00986-1 
Wolchok, J. D., Hoos, A., O'Day, S., Weber, J. S., Hamid, O., Lebbe, C., . . . Hodi, F. S. (2009). 
Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related 
response criteria. Clin Cancer Res, 15(23), 7412-7420. doi:10.1158/1078-0432.CCR-09-
1624 
Wolpin, B. M., Rubinson, D. A., Wang, X., Chan, J. A., Cleary, J. M., Enzinger, P. C., . . . 
Kimmelman, A. C. (2014). Phase II and pharmacodynamic study of autophagy inhibition 
using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. 
Oncologist, 19(6), 637-638. doi:10.1634/theoncologist.2014-0086 
Xu, J., Kim, T. W., Shen, L., Sriuranpong, V., Pan, H., Xu, R., . . . Li, J. (2018). Results of a 
Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Trifluridine/Tipiracil 
(TAS-102) Monotherapy in Asian Patients With Previously Treated Metastatic Colorectal 
Cancer: The TERRA Study. J Clin Oncol, 36(4), 350-358. doi:10.1200/jco.2017.74.3245 
Yang, A., Rajeshkumar, N. V., Wang, X., Yabuuchi, S., Alexander, B. M., Chu, G. C., . . . 
Kimmelman, A. C. (2014). Autophagy is critical for pancreatic tumor growth and 
progression in tumors with p53 alterations. Cancer Discov, 4(8), 905-913. 
doi:10.1158/2159-8290.Cd-14-0362 
Yang, J., Riella, L. V., Chock, S., Liu, T., Zhao, X., Yuan, X., . . . Sayegh, M. H. (2011). The 
novel costimulatory programmed death ligand 1/B7.1 pathway is functional in inhibiting 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
AAAS4165_Version Date: 07/07/2021 
 
121 
 
alloimmune 
responses 
in 
vivo. 
J 
Immunol, 
187(3), 
1113-1119. 
doi:10.4049/jimmunol.1100056 
Yang, S., Wang, X., Contino, G., Liesa, M., Sahin, E., Ying, H., . . . Kimmelman, A. C. (2011). 
Pancreatic cancers require autophagy for tumor growth. Genes Dev, 25(7), 717-729. 
doi:10.1101/gad.2016111 
 
 
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21. 
APPENDICES 
 
21.1 
Appendix 1: Management of adverse events while administering atezolizumab, 
cobimetinib, and/or hydroxychloroquine 
 
Table A1.1. Guidelines for managing IRRs, anaphylaxis, and hypersensitivity reactions in 
response to atezolizumab, cobimetinib, and/or hydroxychloroquine. 
Event 
Action  
IRR, Grade 1 
 Reduce infusion rate to half the rate at 
time of event onset, and continue for 30 
min; 
 If the reduced rate infusion is tolerated 
for 30 min after symptoms have 
resolved, resume infusion at higher 
rate.  
IRR, Grade 2 
 Interrupt infusion; 
 Administer aggressive symptomatic 
treatment (e.g., oral/IV antihistamine, 
epinephrine, oxygen); 
 After symptoms have resolved, resume 
infusion at half rate; 
 Administer oral premediation with 
antihistamine and anti-pyretic prior to 
subsequent infusions and monitor 
closely for IRRs. 
IRR, Grade 3 or 4 
 Stop infusion; 
 Administer aggressive symptomatic 
treatment (e.g., oral/IV antihistamine, 
epinephrine, oxygen); 
 Permanently discontinue the drug and 
contact PI. 
 
 
 


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Table A1.2. Guidelines for managing gastrointestinal events in response to atezolizumab, 
and/or cobimetinib. 
Event 
Action  
General guidance 
 All GI events should be evaluated for 
more common etiologies; 
 For events of significant duration or 
magnitude, perform sigmoidoscopy (or 
colonoscopy) with colonic biopsy to 
check 
for 
inflammation 
and 
lymphocytic infiltrates to confirm 
colitis diagnosis; 
 Administer all anti-diarrheal agents 
and 
other 
supportive 
care 
per 
institutional guidelines. 
Diarrhea or colitis, Grade 1 
 Continue atezolizumab (if applicable) 
and cobimetinib; 
 Initiate symptomatic treatment; 
 Recommend endoscopy if symptoms 
persist >7 days; 
 Monitor closely. 
Diarrhea or colitis, Grade 2-3 
 Withhold atezolizumab (if applicable) 
and cobimetinib; 
 Initiate symptomatic treatment; 
 Discontinue medications that may 
exacerbate colitis while investigating 
etiology; 
 Refer 
patient 
to 
GI 
specialist 
(recommended); 
 If Received Atezolizumab – 
 If event recurs, or persists >5 days, 
initiate 
treatment 
with 
1-2 
mg/kg/day 
oral 
prednisone 
or 
equivalent. 
 Resume atezolizumab at fixed dose 


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if event resolves to Grade 1 or better 
within 12 weeks; 
 Resume 
Cobimetinib 
with 
dose 
reduced by 1 level if event resolves to 
Grade 1 or better within 28 days 
 If event does not resolve, permanently 
discontinue 
atezolizumab 
(if 
applicable) 
and 
cobimetinib 
and 
contact PI. 
Diarrhea colitis, Grade 4 
 Permanently discontinue atezolizumab 
(if applicable) and cobimetinib and 
contact PI; 
 Refer 
patient 
to 
GI 
specialist 
(confirmation and biopsy); 
 Discontinue medications that may 
exacerbate colitis while investigating 
etiology; 
 If Received Atezolizumab – 
 
Initiate 
treatment 
with 
1-2 
mg/kg/day 
oral 
prednisone 
or 
equivalent. Convert to 1-2 mg/kg/day 
oral prednisone or equivalent upon 
improvement; 
 
If event does not improve within 48 
hrs 
after 
starting 
corticosteroids, 
consider immunosuppressive agent; 
 
If event resolves to Grade 1 or 
better, taper corticosteroids over ≥1 
month. 
 
 


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Table A1.3. Guidelines for managing dermatologic events in response to atezolizumab, 
cobimetinib, and/or hydroxychloroquine 
Event 
Action  
General guidance 
 Seek dermatologic evaluation for 
persistent and/or severe rash or pruritis 
 Consider biopsy unless contraindicated 
Grade 1 or 2 
 Continue atezolizumab (if applicable), 
cobimetinib, and hydroxychloroquine 
 Initiate supportive care. If event does 
not improve, consider treatment with 
higher potency topical steroids. 
 For Grade 2, consider referral to 
dermatologist 
 For acneiform rash: consider initiating 
treatment with topical corticosteroids 
and oral antibiotics, as clinically 
indicated. 
Grade 3  
 Withhold atezolizumab (if applicable), 
cobimetinib, and hydroxychloroquine; 
 Refer patient to dermatologist; 
 If Received Atezolizumab – 
 
If event resolves to Grade 2 or 
better within 12 weeks, resume 
atezolizumab at fixed dose. If not, 
discontinue 
atezolizumab 
and 
cobimetinib and contact PI. 
 If event resolves to Grade 2 or better 
within 28 days, resume cobimetinib 
with dose reduced by 1level. If not, 
permanently discontinue cobimetinib. 
 For acneiform rash: consider initiating 
treatment with topical corticosteroids 
and oral antibiotics, as clinically 


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indicated. 
Grade 4 
 Permanently discontinue atezolizumab 
(if 
applicable), 
cobimetinib, 
and 
hydroxychloroquine and contact PI. 
 
Table A1.4. Guidelines for managing hepatic events in response to atezolizumab, 
cobimetinib, and/or hydroxychloroquine 
Event 
Action  
Elevations in ALT, AST, and/or bilirubin 
AST/ALT > 3xULN with total bilirubin >ULN 
to ≤ 2xULN 
 Continue atezolizumab (if applicable), 
cobimetinib, and hydroxychloroquine, 
and contact PI. 
AST/ALT > 3 x ULN to 5 x ULN with total 
bilirubin > ULN to ≤ 2xULN 
 Continue atezolizumab (if applicable), 
cobimetinib, and hydroxychloroquine, 
and contact PI. 
 Monitor LFT weekly; 
 Consider referral to hepatologist and 
liver biopsy; 
 If Received atezolizumab – 
 
For 
suspected 
immune-related 
events lasting >5 days: 
o Consider 
withholding 
atezolizumab; 
o Consider initiating 1-2mg/kg/day 
prednisone or equiv.; 
o If atezolizumab is withheld and 
event resolves to AST/ALT ≤ 2 
x ULN within 12 weeks, resume 
at 
fixed 
dose. 
Otherwise, 
discontinue atezolizumab and 
cobimetinib, and contact PI.a,b,c 
AST/ALT > 5 x ULN to < 10 x ULN with total 
 Continue atezolizumab (if applicable), 


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bilirubin > ULN to ≤ 2xULN 
cobimetinib, and hydroxychloroquine, 
and contact PI. 
 Monitor LFT weekly; 
 Consider referral to hepatologist and 
liver biopsy; 
 If Received Atezolizumab – 
 
For 
suspected 
immune-related 
events lasting >5 days: 
o Consider 
withholding 
atezolizumab; 
o Consider initiating 1-2mg/kg/day 
prednisone or equiv.; 
o If atezolizumab is withheld and 
event resolves to AST/ALT ≤ 2 
x ULN within 12 weeks, resume 
at 
fixed 
dose. 
Otherwise, 
discontinue atezolizumab and 
cobimetinib, and contact PI.a,b,c 
AST/ALT > ULN to ≤ 3 x ULN with total 
bilirubin > 2 x ULN 
 Investigate 
causes 
for 
elevated 
bilirubin and initiate treatment per 
institutional guidelines; 
 Use best medical judgement as to 
whether to continue study treatment. 
AST/ALT > 3 x ULN with total bilirubin > 2 x 
ULN 
 Withhold atezolizumab (if applicable), 
cobimetinib, and hydroxychloroquine. 
 Monitor LFTs every 48-72 hrs until 
decreasing; then monitor weekly. 
 Refer to hepatologist and consider liver 
biopsy. 
 If Received atezolizumab – 
 
Consider initiating 1-2 mg/kg.day 
oral 
prednisone 
treatment 
(or 
equivalent). 
 
If corticosteroids are initiated and 
event does not improve within 48 hrs, 


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consider adding immunosuppressive 
agent. 
 
If event resolves to AST/ALT ≤ 2 
x ULN within 12 weeks, resume at 
fixed dose. Otherwise, discontinue 
atezolizumab and cobimetinib, and 
contact PI.a,b,c 
 
If event resolves to AST/ALT ≤ 2 
x ULN within 28 days, resume 
cobimetinib and hydroxychloroquine 
with dose reduced by one level. If not, 
premanently discontinue cobimetinib 
and hydroxychloroquine. 
 
Permanently 
discontinue 
atezolizumab, 
cobimetinib, 
and 
hydroxychloroquine 
for 
life-
threatening hepatic events and contact 
the PI. 
AST/ALT > 10 x ULN 
 Permanently discontinue atezolizumab 
(if 
applicable), 
cobimetinib, 
and 
hydroxychloroquine and contact PI. 
 Monitor LFTs every 48-72 hrs until 
decreasing; then monitor weekly. 
 Refer to hepatologist and consider liver 
biopsy. 
 If Received atezolizumab – 
 
Consider initiating 1-2 mg/kg.day 
oral 
prednisone 
treatment 
(or 
equivalent). 
 
If corticosteroids are initiated and 
event does not improve within 48 hrs, 
consider adding immunosuppressive 
agent. 
 
If event resolves to AST/ALT ≤ 3 
x ULN with total bilirubin ≤ 2 x ULN, 


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taper corticosteroids over ≥1 month. 
LFT = liver function test; ULN = upper limit of normal. 
a  Corticosteroids must be tapered over ≥1 month to ≤ 10 mg/kg/day oral prednisone or 
equivalent before atezolizumab may be resumed. 
b Atezolizumab may be withheld for more than 12 weeks to allow for corticosteroid treatment 
tapering. Course must be agreed upon by the investigator and PI. 
c Resuming atezolizumab may be considered in patients who are deriving benefit an have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab 
only after approval from both the investigator and the PI.  
 
 
 
Table A1.5. Guidelines for managing pulmonary events in response to atezolizumab, and/or 
cobimetinib. 
Event 
Action  
General guidance 
 All pulmonary events would be 
thoroughly 
evaluated 
for 
other 
commonly reported etiologies. 
Grade 1 
 Continue atezolizumab (if applicable) 
and cobimetinib. 
 Re-evaluate on serial imaging; 
 Consider 
referral 
to 
pulmonary 
specialist; 
Grade 2 
 Withhold atezolizumab (if applicable)  
and cobimetinib. 
 Refer patient to pulmonary and 
infectious disease specialist; 
 Consider bronchoscopy or BAL; 
 If results are consistent with immune-
related etiology or pneumonitis, initiate 
treatment with 1-2 mg/kg/day oral 
prednisone or equivalent; 
 Resume atezolizumab (if applicable) at 
fixed dose if event resolves to Grade 1 
or better within 12 weeks; 


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 If event does not resolve, permanently 
discontinue 
atezolizumab 
(if 
applicable) 
and 
cobimetinib 
and 
contact PI.a,b,c 
 Treat recurrent events as Grade 3 or 4. 
Grade 3 or 4 
 Permanently discontinue atezolizumab 
(if applicable) and cobimetinib and 
contact PI.c 
 Bronchoscopy 
or 
BAL 
is 
recommended; 
 If results are consistent with immune-
related etiology or pneumonitis, initiate 
treatment with 1-2 mg/kg/day oral 
prednisone or equivalent.  
 If event does not improve within 48 
hrs, 
or 
worsens, 
after 
starting 
corticosteroids, 
consider 
immunosuppressive agent; 
 If event resolves to Grade 1 or better, 
taper corticosteroids over ≥1 month. 
BAL = brochoscopic alveolar lavage 
a  Corticosteroids must be tapered over ≥1 month to ≤ 10 mg/kg/day oral prednisone or 
equivalent before atezolizumab may be resumed. 
b Atezolizumab may be withheld for more than 12 weeks to allow for corticosteroid treatment 
tapering. Course must be agreed upon by the investigator and PI. 
c Resuming atezolizumab may be considered in patients who are deriving benefit an have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab 
only after approval from both the investigator and the PI.  
 


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Table A1.6. Guidelines for managing endocrine disorders in response to atezolizumab, and/or 
cobimetinib. 
Event 
Action  
Asymptomatic hypothyroidism 
 Continue atezolizumab (if applicable) 
and cobimetinib; 
 Initiate thyroid hormone replacement 
treatment; 
 Monitor TSH weekly. 
Symptomatic hypothyroidism 
 Withhold atezolizumab (if applicable); 
 Continue cobimetinib; 
 Initiate thyroid replacement hormone 
treatment; 
 Monitor TSH weekly; 
 Consider referral to endocrinologist; 
 Resume treatment when symptoms are 
controlled and thyroid function is 
improving. 
*Asymptomatic hyperthyroidism 
If TSH ≥0.1mU/L and <0.5 mU/L: 
 Continue atezolizumab (if applicable) 
and cobimetinib; 
 Monitory TSH every 4 weeks. 
If TSH <0.1mU/L 
Follow 
guidelines 
for 
symptomatic 
hyperthyroidism; 
Symptomatic hyperthyroidism 
 Withhold atezolizumab (if applicable); 
 Continue cobimetinib; 
 For life-threatening immune-related 
hyperthyroidism, 
withhold 


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cobimetinib. 
If 
event 
becomes 
clinically manageable within 28 days, 
resume cobimetinib with dose reduced 
1 level. If not, permanently discontinue 
cobimetinib. 
 Initiate treatment with anti-thyroid 
drug, 
such 
as 
methimazole 
or 
carbimazole, as needed; 
 Consider referral to endocrinologist; 
 Resume treatment when symptoms are 
controlled and thyroid function is 
improving; 
 If 
condition 
is 
life-threatening, 
permanently discontinue atezolizumab 
(if applicable) and contact PI. 
Symptomatic adrenal insufficiency, Grade 2-4 
 Withhold atezolizumab (if applicable); 
 Continue cobimetinib. 
 Refer patient to endocrinologist; 
 Perform appropriate imaging; 
 If Received atezolizumab – 
 Initiate 
1-2 
mg/kg/day 
IV 
methylprednisolone 
or 
equivalent; 
convert 
to 
1-2 
mg/kg/day 
oral 
prednisone 
or 
equivalent 
upon 
improvement; 
 Resume 
atezolizumab 
(if 
applicable) treatment if event resolves 
to Grade 1 or better within 12 weeks; 
 If event does not resolve to Grade 1 
or better within 12 weeks, or patient is 
not stable on replacement therapy, 
permanently discontinue atezolizumab 
(if applicable) treatment and contact PI. 
Hyperglycemia, Grade 1 or 2 
 Continue atezolizumab (if applicable) 
and cobimetinib; 


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 Initiate treatment with insulin, as 
needed; 
 Monitor for glucose control. 
Hyperglycemia, Grade 3 or 4 
 Withhold atezolizumab (if applicable); 
 Continue cobimetinib. 
 Initiate treatment with insulin; 
 Monitor for glucose control; 
 Resume atezolizumab (if applicable) 
when symptoms resolve and glucose 
levels are stable. 
TSH = tyhyroid stimulating hormone 
a  Corticosteroids must be tapered over ≥1 month to ≤ 10 mg/kg/day oral prednisone or 
equivalent before atezolizumab may be resumed. 
b Atezolizumab may be withheld for more than 12 weeks to allow for corticosteroid treatment 
tapering. Course must be agreed upon by the investigator and PI. 
c Resuming atezolizumab may be considered in patients who are deriving benefit an have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab only 
after approval from both the investigator and the PI. 
 
Table A1.7. Guidelines for managing pancreatic events in response to atezolizumab, and/or 
cobimetinib. 
Event 
Action  
Amylase and/or lipase elevation Grade 1 
 Continue atezolizumab (if applicable) 
and cobimetinib. 
 Monitor amylase and lipase prior to 
dosing. 
Amylase and/or lipase elevation Grade 2 
 Continue atezolizumab (if applicable) 
and cobimetinib. 
 Monitor amylase and lipase weekly. 
 For prolonged elevation (> 3 weeks), 
consider 10 mg/day oral prednisone or 
equivalent. 
Amylase and/or lipase elevation, Grade 3 or 4 
 Withhold atezolizumab (if applicable). 
 Continue cobimetinib. 


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 Monitor amylase and lipase every other 
day. 
 If Received atezolizumab – 
 
If no improvement, consult GI and 
consider 
1-2 
mg/kg/day 
oral 
prednisone or equivalent. 
 
Resume atezolizumab if event 
resolves to Grade 1 or better within 12 
weeks. a,b 
 
Permanently 
discontinue 
atezolizumab and contact PI if event 
does not resolve to Grade 1 or better 
within 12 weeks. a,b,c 
 
For recurrent events, permanently 
discontinue cobimetinib, and contact 
PI. 
Immune-related pancreatitis Grade 2 
 Withhold atezolizumab (if applicable). 
 Continue cobimetinib. 
 Refer patient to GI specialist. 
 If Received atezolizumab – 
 
Upon improvement, initiate 1-2 
mg/kg/day IV methylprednisone or 
equivalent. Convert to 1-2 mg/kg/day 
oral prednisone upon improvement. 
 
Resume atezolizumab if event 
resolves to Grade 1 or better within 12 
weeks. a,b 
 
Permanently 
discontinue 
atezolizumab and contact PI if event 
does not resolve to Grade 1 or better 
within 12 weeks. a,b,c 
 
 For recurrent events, permanently 
discontinue atezolizumab, and contact 
PI. 
Immune-related pancreatitis Grade 3 
 Withhold cobimetinib. 


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 Follow guidelines for atezolizumab (if 
applicable) for Grade 2 event. 
Immune-related pancreatitis Grade 4 
 Permanently discontinue atezolizumab 
(if 
applicable) 
and 
consider 
permanently 
discontinuing 
cobimetinib. Contact PI.c 
 If cobimetinib is withheld and event 
resolves to Grade 1 or better within 28 
days, resume treatment at current dose. 
If event does not resolve to Grade 1 or 
better within 28 days, permanently 
discontinue treatment. 
 Refer patient to GI specialist. 
 If Received atezolizumab – 
 
Upon improvement, initiate 1-2 
mg/kg/day IV methylprednisone or 
equivalent. Convert to 1-2 mg/kg/day 
oral prednisone upon improvement. 
 
If event does not improve within 48 
hrs 
of 
initiating 
corticosteroid 
treatment, 
consider 
adding 
an 
immunosuppressive agent. 
 
If event resolves to Grade 1 or 
better, taper corticosteroids over ≥1 
month. 
a  Corticosteroids must be tapered over ≥1 month to ≤ 10 mg/kg/day oral prednisone or 
equivalent before atezolizumab may be resumed. 
b Atezolizumab may be withheld for more than 12 weeks to allow for corticosteroid treatment 
tapering. Course must be agreed upon by the investigator and PI. 
c Resuming atezolizumab may be considered in patients who are deriving benefit an have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab only 
after approval from both the investigator and the PI. 
 


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Table A1.8. Guidelines for managing neurologic disorders in response to atezolizumab, 
cobimetinib, and/or hydroxychloroquine. 
Event 
Action  
Neuropathy Grade 1 
 Continue atezolizumab (if applicable) 
and cobimetinib. 
 Withhold hydroxychloroquine. 
 Investigate etiology. 
Neuropathy Grade 2 
 Withhold atezolizumab (if applicable) 
and hydroxychloroquine; 
 Continue cobimetinib. 
 Investigate etiology. 
 Initiate 
treatment 
according 
to 
institutional guidelines. 
 Resume atezolizumab (if applicable) 
if event resolves to Grade 1 or better 
within 12 weeks. a,b 
 Permanently 
discontinue 
atezolizumab (if applicable) and 
contact PI if event does not resolve to 
Grade 1 or better within 12 weeks. a,b,c 
Neuropathy Grade 3 
 Permanently 
discontinue 
atezolizumab (if applicable) and 
contact PI. 
 Withhold hydroxychloroquine. 
 Continue cobimetinib. 
 Initiate 
treatment 
according 
to 
institutional guidelines. 
Neuropathy Grade 4 
 Permanently 
discontinue 
atezolizumab (if applicable) and 
contact PI. 
 Withhold 
cobimetinib 
and 
hydroxychloroquine. 
 Initiate 
treatment 
according 
to 
institutional guidelines. 


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 If patient stabilizes within 28 days, 
consider resuming cobimetinib at 
current 
dose 
and 
resuming 
hydroxychloroquine at 1 dose level 
lower. If not, permanently discontinue 
treatment with these drugs. 
Myasthenia 
gravis 
or 
Guillain-Barré 
syndrome, Grade 4 
 Permanently 
discontinue 
atezolizumab (if applicable). 
 Withhold 
cobimetinib 
and 
hydroxychloroquine. 
 Refer patient to neurologist. 
 Initiate 
treatment 
according 
to 
institutional guidelines. 
 If Received atezolizumab – 
 Consider 1-2 mg/kg/day oral or IV 
prednisone or equivalent. 
 If patient stabilizes within 28 days, 
resume cobimetinib at current dose, 
and resume hydroxychloroquine at 1 
dose level lower. If not, permanently 
discontinue 
cobimetinib 
and 
hydroxychloroquine. 
Meningoencephalitis, all grades 
 Permanently 
discontinue 
atezolizumab (if applicable) and 
contact PI. a 
 Withhold 
cobimetinib 
and 
hydroxychloroquine. 
 Refer patient to neurologist. 
 If Received atezolizumab – 
 Initiate 
1-2 
mg/kg/day 
IV 
methylprednisone 
or 
equivalent. 
Convert 
to 
1-2mg/kg/day 
oral 
prednisone 
or 
equivalent 
upon 
improvement. 
 If event does not improve within 


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48 hrs of initiating corticosteroids, 
consider 
adding 
an 
immunosuppressive agent. 
 If patient stabilizes within 28 days, 
resume cobimetinib at current dose, 
and resume hydroxychloroquine at 1 
dose level lower. If not, permanently 
discontinue 
cobimetinib 
and 
hydroxychloroquine. 
a Resuming atezolizumab may be considered in patients who are deriving benefit an have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab 
only after approval from both the investigator and the PI. 
 
Table A1.9. Guidelines for managing ocular events in response to atezolizumab, cobimetinib, 
and/or hydroxychloroquine. 
Event 
Action  
General guidance 
 Refer patient to ophthalmologist. 
Serious retinopathy, Grade 1 
 Continue atezolizumab (if applicable), 
cobimetinib, and hydroxychloroquine; 
 Refer to ophthalmologist; 
Serious retinopathy, Grade 2 (tolerable) 
 Continue atezolizumab (if applicable) 
and cobimetinib. 
 Withhold hydroxychloroquine. 
 If event resolves to Grade 1, resume 
hydroxychloroquine at one dose level 
lower. 
 Refer to ophthalmologist. 
Serious retinopathy, Grade 2 (intolerable), 
Grade 3 or Grade 4 
 Withhold 
cobimetinib 
and 
hydroxychloroquine. 
 Continue atezolizumab (if applicable). 
 Complete 
ophthalmologic 
examination. 
 If even improves by at least one grade 


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within 28 days, resume cobimetinib 
and hydroxychloroquine at 1 dose level 
lower. If not, permanently discontinue 
cobimetinib and hydroxychloroquine. 
Retinal vein occlusion 
 Permanently discontinue cobimetinib 
and hydroxychloroquine. 
 Continue atezolizumab (if applicable). 
 Treatment 
as 
per 
institutional 
guidelines. 
Potential immune-related ocular toxicity, 
Grade 1 
 Continue atezolizumab (if applicable), 
cobimetinib, and hydroxychloroquine. 
 Complete 
ophthalmologic 
examination. 
 Initiate topical corticosteroid eye drops 
and 
topical 
immunosuppressive 
therapy. 
 If symptoms persist, treat as Grade 2. 
Potential immune-related ocular toxicity, 
Grade 2 
 Withhold atezolizumab (if applicable). 
 Continue 
cobimetinib 
and 
hydroxychloroquine. 
 Initiate topical corticosteroid eye drops 
and 
topical 
immunosuppressive 
therapy. 
 If event resolves to Grade 1 or better 
within 12 weeks, resume atezolizumab 
(if applicable). If not, permanently 
discontinue 
atezolizumab 
(if 
applicable), hydroxychloroquine, and 
cobimetinib and contact PI. a,b,c 
Potential immune-related ocular toxicity, 
Grade 3 or 4 
 Permanently 
discontinue 
atezolizumab, 
cobimetinib, 
and 
hydroxychloroquine, and contact PI.c 
a  Corticosteroids must be tapered over ≥1 month to ≤ 10 mg/kg/day oral prednisone or 


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equivalent before atezolizumab may be resumed. 
b Atezolizumab may be withheld for more than 12 weeks to allow for corticosteroid treatment 
tapering. Course must be agreed upon by the investigator and PI. 
c Resuming atezolizumab may be considered in patients who are deriving benefit an have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizuman only 
after approval from both the investigator and the PI. 
 


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Table A1.10. Guidelines for managing cardiac events in response to atezolizumab, 
cobimetinib, and/or hydroxychloroquine. 
Event 
Action  
Asymptomatic LVEF increase from baseline. 
LVEF  ≥ 50% or LVEF 40-49% with <10% 
absolute decrease from baseline 
 Continue cobimetinib, atezolizumab 
(if 
applicable), 
and 
hydroxychloroquine. 
LVEF < 40% or LVEF 40-49% with  ≥ 10% 
absolute decrease from baseline 
 Withhold 
cobimetinib 
and 
hydroxychloroquine. 
Continue 
atezolizumab 
(if 
applicable) 
as 
clinically indicated. 
 Reevaluate LVEF at 14 days. 
 If patient has <10% absolute decrease 
from 
baseline 
LVEF, 
resume 
cobimetinib and hydroxychloroquine 
with dose level reduced by 1. 
Reevaluate after 2, 4, 10, and 16 
weeks, and then every 12 weeks 
thereafter, or as clinically indicated. 
 If patient has LVEF <40% or a  ≥ 10% 
absolute decrease from baseline, 
permanently discontinue cobimetinib 
and 
hydroxychloroquine. 
Assess 
LVEF every 6 weeks, or as clinically 
indicated, until LVEF recovers to 50% 
or lower limit of normal. 
Symptomatic LVEF decrease from baseline 
 Withhold 
cobimetinib 
and 
hydroxychloroquine for at least 4 
weeks.  
 Consider withholding atezolizumab 
(if applicable). 
 Refer patient to cardiologist. 
 If atezolizumab is withheld (if 
applicable), contact the PI to discuss 


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resuming treatment. 
 Reevaluate LVEF at 28 days. 
 If patient is asymptompatic after 
treatment break: 
o Resume 
cobimetinib 
and 
hydroxychloroquine with dose 
reduced 1 level if <10% 
absolute 
decrease 
from 
baseline LVEF. 
o Permanently 
discontinue 
cobimetinib 
and 
hydroxychloroquine if <40% 
or  ≥10% asolute decrease 
from baseline. Continue to 
assess LVEF every 6 weeks. 
 If patient is symptomatic following 
treatment 
break, 
permanently 
discontinue 
cobimetinib 
and 
hydroxychloroquine. Assess LVEF 
every 6 weeks until LVEF recovers to 
50% or to the lower limit of normal, or 
until symptoms resolve. 
Rhabdomyolysis or CPK elevation 
General guidance 
 Evaluate for cardiac cause and 
rhabdomyolysis. 
 Assess patient for any history of 
strenuous physical activity, blunt 
trauma, or recent IM injections. 
Asymptomatic CPK elevation, Grade 1-3 
 Continue atezolizumab (if applicable)  
and cobimetinib. 
 Recheck CPK at least 1/wk 
Asymptomatic CPK elevation, Grade 4 
 Withhold 
atezolizumab 
(if 
applicable), 
cobimetinib, 
and 
hydroxychloroquine. 


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 If resolved to Grade 3 or better within 
28 days, resume cobimetinib and 
hydroxychloroquine 
with 
dose 
reduced by one level. 
If not, 
permanently discontinue cobimetinib 
and hydroxychloroquine. a 
Rhabdomyolysis 
or 
symptomatic 
CPK 
elevation 
 Withhold 
atezolizumab 
(if 
applicable), 
cobimetinib, 
and 
hydroxychloroquine. 
 If symptoms improve by at least one 
grade 
within 
28 
days, 
resume 
cobimetinib and hydroxychloroquine 
with dose level reduced by one. If not, 
permanently discontinue cobimetinib 
and hydroxychloroquine.a 
a Resuming atezolizumab (if applicable) 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 
 
 
 


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Table A1.11. Guidelines for managing hemorrhage and other toxicities in response to 
atezolizumab and/or cobimetinib. 
Event 
Action  
Hemorrhage 
Note: There are no clinical data on the effectiveness of cobimetinib dose modifications for 
hemorrhage events 
Grade 3 hemorrhage other than cerebral 
hemorrhage 
 Withhold cobimetinib. 
 Continue atezolizumab (if applicable). 
 If cobimetinib cannot be resumed 
within 
28 
days, 
permanently 
discontinue. 
Grade 4 hemorrhage or any grade cerebral 
hemorrhage 
 Permanently discontinue cobimetinib 
if event is attributed to the drug.  
Otherwise, withhold cobimetinib.  
 Continue atezolizumab (if applicable). 
Atezolizumab-related toxicities not described above (if applicable) 
Grade 1  
 Continue atezolizumab (if applicable) 
and cobimetinib. 
Grade 2 (intolerable) 
 Withhold atezolizumab. 
 Continue cobimetinib. 
 If event resolves to Grade 1 within 12 
weeks, resume atezolizumab at fixed 


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dose. If not, permanently discontinue 
atezolizumab. 
Grade 3 or 4 
 Withhold 
atezolizumab 
and 
cobimetinib. 
 If event resolves to Grade 1 within 12 
weeks, resume atezolizumab at fixed 
dose. If not, permanently discontinue 
atezolizumab. 
 If event resolves to Grade 1 within 28 
days, resume cobimetinib at fixed 
dose. If not, permanently discontinue 
cobimetinib. 
Other toxicities not described above 
Grade 3 or 4, or intolerable Grade 2 
treatment-related toxicities 
 Withhold 
atezolizumab 
and 
cobimetinib. 
 If event resolves to Grade 1 or better 
within 
12 
weeks, 
resume 
atezolizumab at fixed dose. If not, 
permanently 
discontinue 
atezolizumab. 
 If event resolves to Grade 1 or better 
within 28 days, resume cobimetinib 
with dose level reduced by 1. If not, 
permanently discontinue cobimetinib. 
a Resuming 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 
 
 


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Table A1.12. Guidelines for managing electrocardiogram QT corrected interval prolonged in 
response to atezolizumab, cobimetinib, and/or hydroxychloroquine. 
Event 
Action  
QTc > 500ms and change form pre-treatment value remains ≤𝟔0ms 
 
 
1st Occurrence 
Temporarily interrupt treatment until QTc 
decreases below 500 ms; reduce Cobimetinib 
by 1 dose level 
2nd Occurrence 
 
Temporarily interrupt treatment until QTc 
decreases 
below 
500 
ms; 
reduce 
Hydroxychlorquine by 1 dose level 
3rd Occurrence grade 3 
 
Temporarily interrupt treatment until QTc 
decreases below 500 ms; reduce Cobimetinib 
and Hydroxychloroquine by 1 more dose level 
Grade 4  
Torsade de pointes; polymorphic ventricular 
tachycardia; 
signs/symptoms 
of 
serious 
arrhythmia 
Permanently discontinue study drugs 
QTc increase meets values of both > 500 ms and >60 ms change from pre-treatment values 
1st Occurrence 
Discontinue drugs permanently  
 
Drugs should be interrupted for 3 ± 2 days and Electrocardiogram repeated until QTc below 500ms for four attempts. 
Subject should be referred to an electro cardiologist if QTc does not decrease below 500ms after study drug held for 
greater than 7 days (consecutively).  
 
 


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Table A1.13. Guidelines for managing rhabdomyolysis or CPK elevation in response to 
atezolizumab, cobimetinib, and/or hydroxychloroquine. 
Event 
Action  
Rhabdomyolysis or CPK elevation 
General guidance 
 Evaluate for cardiac cause (check ECG, 
serum cardiac troponin, and CPK-isoforms 
M and B fraction) and 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. 
Asymptomatic CPK elevation, Grade 1, 2, 
or 3 
• Continue study drugs.  
• Recheck CPK at least once a week. 
Asymptomatic CPK elevation, Grade 4 
• Withhold cobimetinib, hydroxychloroquine, 
and if applicable atezolizumab.  
• If event resolves to Grade ≤ 3 within 28 days, 
resume cobimetinib and hydroxychloroquine 
with dose reduced by one level 
for 
cobimetinib. If not, permanently discontinue 
cobimetinib.  
• Resumption of atezolizumab may be 
considered in patients who are deriving benefit 
after discussion with the Principal Investigator. 
Rhabdomyolysis or symptomatic CPK 
elevation 
• Withhold all study drugs.  
• If event improves by at least one grade and 
symptoms resolve within 28 days, resume 
cobimetinib and hydroxychloroquine with 
dose reduced by one level, if possible. If not, 
permanently discontinue cobimetinib.  
• Resumption of atezolizumab may be 
considered in patients who are deriving benefit 
after discussion with the Principal Investigator. 
 


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Table A1.14. Guidelines for managing Immune-related Myocarditis in response to 
atezolizumab, cobimetinib, and/or hydroxychloroquine. 
Event 
Action  
Myocarditis Events 
Grade 1 
• Refer patient to cardiologist.  
• Initiate treatment as per institutional 
guidelines. 
Grade 2 
• Withhold atezolizumab for up to 12 weeks 
after event onset and contact Principal 
Investigator  
• Refer patient to cardiologist.  
• Initiate treatment as per institutional 
guidelines and consider antiarrhythmic drugs, 
temporary pacemaker, ECMO, or VAD as 
appropriate.  
• Consider 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, in consultation 
with Principal Investigator. 
• If event resolves to Grade 1 or better, resume 
atezolizumab. 
• If event does not resolve to Grade 1 or better 
while withholding atezolizumab, permanently 
discontinue 
atezolizumab 
Principal 
Investigator.  
 
Immune-related myocarditis, Grade 3-4 
• Permanently discontinue atezolizumab and 
contact Principal Investigator.  
• Refer patient to cardiologist.  
• Initiate treatment as per institutional 
guidelines and consider antiarrhythmic drugs, 
temporary pacemaker, ECMO, or VAD as 
appropriate.  
• Initiate treatment with 1−2 mg/kg/day IV 
methylprednisolone or equivalent and convert 
to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement, in consultation 
with Principal Investigator. 
• If event does not improve within 48 hours 
after initiating corticosteroids, consider adding 


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an immunosuppressive agent in consultation 
with Principal Investigator. 
 • If event resolves to Grade 1 or better, taper 
corticosteroids over ≥ 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
 
 
Table A1.15. Guidelines for managing Immune-related nephrotoxicity in response to 
atezolizumab, cobimetinib, and/or hydroxychloroquine. 
Event 
Action  
Myocarditis Events 
Grade 1 
• Continue atezolizumab, cobimetinib, and 
hydroxychloroquine 
 Continue atezolizumab, cobimetinib, and 
hydroxychloroquine 
Grade 2 
• Withhold atezolizumab for up to 12 weeks 
after event onset and contact Principal 
Investigator when considering reinitiation 
• Refer patient to nephrologist 
• Initiate treatment with corticosteroids 
equivalent to 1-2mg/kg/day oral prednisone in 
consultation with Principal Investigator. 
• If event resolves to Grade 1 or better, resume 
atezolizumab. 
• If event does not resolve to Grade 1 or better 
while withholding atezolizumab, permanently 
discontinue 
atezolizumab 
Principal 
Investigator.  
 
Grade 3-4 
• Permanently discontinue atezolizumab and 
contact Principal Investigator.  
• Refer patient to nephrologist and consider 
renal 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, in consultation 
with Principal Investigator. 
• If event does not improve within 48 hours 
after initiating corticosteroids, consider adding 
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with Principal Investigator. 
 • If event resolves to Grade 1 or better, taper 
corticosteroids over ≥ 1 month. 
 
21.2 
Appendix 2: Strong CYP3A4 Inducers and Inhibitors 
 
Table A2.1. Strong CYP3A4 Inducers and Inhibitors. 
Strong Inhibitors 
Strong Inducers 
Protease inhibitors 
     -Ritonavir 
     -Indinavir 
     -Nelfinavir 
Anticonvulsants, mood stabilizers 
     -Phenytoin 
     -Carbamazepine 
     -Oxcarbazepine 
Macrolide antibiotics 
     -Erythromycin 
     -Telithromycin 
     -Clarithromycin 
Non-nucleoside reverse transcriptase 
inhibitors 
     -Efavirenz 
     -Nevirapine 
     -Etravirine 
Azole antifungals 
     -Fluconazole 
     -Ketoconazole 
     -Itraconazole 
Phenobarbitol (barbiturate) 
Chloramphenicol (antibiotic) 
Rifampicin (bactericidal) 
Nefazodone (antidepressant) 
Modafinil (stimulant) 
Bergamottin (constituent of grapefruit juice) 
Hyperforin (constituent of St. Johns Wort) 
Aprepitant (antiemetic) 
Cyproterone (antiandrogen, progestin) 
Verapamil (calcium channel blocker)