A Randomized Phase 2 Study of Combination Atezolizumab and CDX-1127 (Varlilumab) With or Without Addition of Cobimetinib in Previously Treated Unresectable Biliary Tract Cancers
Phase: PHASE2
Conditions: Metastatic Distal Bile Duct Adenocarcinoma, Metastatic Gallbladder Carcinoma, Metastatic Intrahepatic Cholangiocarcinoma, Recurrent Distal Bile Duct Adenocarcinoma, Recurrent Gallbladder Carcinoma, Recurrent Intrahepatic Cholangiocarcinoma, Stage IV Distal Bile Duct Cancer AJCC v8, Stage IV Gallbladder Cancer AJCC v8, Stage IV Intrahepatic Cholangiocarcinoma AJCC v8, Unresectable Liver Carcinoma
Sponsor: National Cancer Institute (NCI)

NCI Protocol #: 10476 
Version Date: October 9, 2023 
i 
 
 
 
To: 
CTEP Protocol and Information Office 
From: 
Nilofer Azad, M.D. 
Date: 
October 9, 2023 
Re: 
Amendment in response to Dr. 
 request for rapid amendment dated 
9/29/23. 
 
SUMMARY OF CHANGES – Protocol 
 
I. 
Response to a RRA from Dr. 
, dated 09/29/2023: 
 
# 
Section 
Comments 
1. 
Header, 
Title Page 
Updated protocol version. 
2. 
7.1.2, 7.3 
Updated instructions for managing specific AEs for Atezolizumab. 
3. 
10.1.1.1 
Revised Atezolizumab CAEPR. 
 
SUMMARY OF CHANGES – Consent Form: 
 
# 
Section 
Comments 
1. 
Header 
Updated protocol version. 
2. 
What possible 
risks can I 
expect from 
taking part in 
this study? 
Added risks to Atezolizumab Rare, And Serious: 
x Damage to organs in the body when the body produces too many 
white cells 
x Abnormal movement of the facial muscles 
x Swelling of the spinal cord 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
1 
 
 
 
NCI Protocol #: 
10476 
 
Local Protocol #: 
ETCTN10476 
 
ClinicalTrials.gov Identifier: NCT04941287 
 
TITLE: A Randomized Phase 2 Study of Combination Atezolizumab and CDX-1127 
(Varlilumab) With or Without Addition of Cobimetinib in Previously Treated Unresectable 
Biliary Tract Cancers 
 
Corresponding Organization:  LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer 
Center LAO 
 
Principal Investigator: 
Nilofer Azad, M.D. 
Johns Hopkins University 
1650 Orleans Street 
Room 4M10 
Baltimore, MD 21287, USA 
410-614-9169 
410-614-8216 (fax) 
nazad2@jhmi.edu 
 
Co-Investigator: 
Thatcher Heumann, MD, MPH 
Vanderbilt University 
2220 Pierce Ave 
PRB Suite 798 
Nashville, TN 37232 
 
Thatcher.Heumann@vumc.org 
 
Translational PIs: 
, M.D. 
Johns Hopkins University 
1650 Orleans Street 
CRB1 4M 
Baltimore, MD 21287, USA 
410-614-8216 
410-614-8216 (fax) 
 
 
, Ph.D., MPH 
Emory University 
1365 Clifton Rd NE 
Building C, Room 
 
Atlanta, GA 30322, USA 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
2 
 
 
 
 
 
 
Participating Organizations 
 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
EDDOP / Early Drug Development Program 
CATCHUP / Creating Access to Targeted Cancer Therapy for Underserved Populations 
 
Statistician: 
 
John Hopkins University 
550 N. Broadway 
Suite 1103 
Baltimore, MD 21205 
 
 
 
Study Contact: 
, CCRC 
Johns Hopkins University 
201 N. Broadway Street, Viragh 9120-46 
Baltimore, MD 21287 
 
 
 
NCI-Supplied Agents: CDX-1127 (varlilumab) (NSC 778372), Atezolizumab (NSC 783608), 
and Cobimetinib (NSC 781257) 
 
 
IND Sponsor: DCTD, NCI 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
3 
 
 
 
 
Protocol Type / Version # / Version Date: 
Original / February 23, 2021 
Revision 1 / April 23, 2021 
Revision 2 / May 24, 2021 
Revision 3a / July 6, 2021 
Revision 3b / August 4, 2021 
Amendment 1 / October 30, 2021 
Amendment 2/ December 8, 2021 
Amendment 3/ January 28, 2022 
Amendment 4 / April 26, 2022 
Amendment 5 / July 18, 2022 
Amendment 6 / November 1, 2022 
Amendment 7 / October 9, 2023 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
4 
 
 
 
SCHEMA 
 
 
 
 
Stratification Factor: 
Site of Disease (Gallbladder cancer (GBC) vs. Intrahepatic cancer (IHC) vs. Extrahepatic 
cholangiocarcinoma (EHC)) 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
5 
 
 
 
TABLE OF CONTENTS 
SCHEMA ......................................................................................................................................... 4 
1. 
OBJECTIVES ..................................................................................................................... 8 
1.1 
Primary Objectives .................................................................................................. 8 
1.2 
Secondary Objectives .............................................................................................. 8 
 
 
2. 
BACKGROUND ................................................................................................................. 9 
2.1 
Study Disease(s) ...................................................................................................... 9 
2.2 
CTEP IND Agents ................................................................................................... 9 
2.3 
Rationale................................................................................................................ 24 
2.4 
Correlative Studies Background ............................................................................ 29 
3. 
PATIENT SELECTION ................................................................................................... 34 
3.1 
Eligibility Criteria ................................................................................................. 34 
3.2 
Exclusion Criteria .................................................................................................. 35 
3.3 
Inclusion of Women and Minorities ...................................................................... 39 
4. 
REGISTRATION PROCEDURES ................................................................................... 41 
4.1 
Investigator and Research Associate Registration with CTEP ............................. 41 
4.2 
Site Registration .................................................................................................... 42 
4.3 
Patient Registration ............................................................................................... 44 
4.4 
General Guidelines ................................................................................................ 46 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................ 47 
5.1 
Summary Table for Specimen Collection ............................................................. 47 
5.2 
Summary Table(s) for Interventional Radiologist for Research Biopsies ............. 48 
5.3 
Specimen Procurement Kits and Scheduling ........................................................ 50 
5.4 
Specimen Tracking System Instructions ............................................................... 52 
5.5 
Specimen Collection ............................................................................................. 56 
5.6 
Shipping Specimens from Clinical Site to the EET Biobank ................................ 59 
5.7 
Shipping of Specimens from Clinical Site to Other Laboratories ......................... 61 
5.8 
Biomarker Plan ...................................................................................................... 65 
5.9 
Integrated Correlative Studies ............................................................................... 71 
5.10 
Exploratory/Ancillary Correlative Studies ............................................................ 72 
6. 
TREATMENT PLAN ....................................................................................................... 75 
6.1 
Agent Administration ............................................................................................ 75 
6.2 
Continuation after Unconfirmed Progression ........................................................ 79 
6.3 
General Concomitant Medication and Supportive Care Guidelines ..................... 80 
6.4 
Duration of Therapy .............................................................................................. 82 
6.5 
Duration of Follow-Up .......................................................................................... 82 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 83 
7.1 
CDX-1127 (varlilumab) and Atezolizumab (all participants) ............................... 83 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
6 
 
 
7.2 
Cobimetinib plus Atezolizumab and CDX-1127 (varlilumab) (Treatment 
Arm A patients only) ............................................................................................. 89 
7.3 
AE Management and Dose Interruption/Modification Guidelines ....................... 92 
8. 
PHARMACEUTICAL INFORMATION ....................................................................... 141 
8.1 
CTEP IND Agents ............................................................................................... 141 
9. 
STATISTICAL CONSIDERATIONS ............................................................................ 148 
9.1 
Study Design/Endpoints ...................................................................................... 148 
9.2 
Sample Size/Accrual Rate ................................................................................... 148 
9.3 
Stratification Factors ........................................................................................... 150 
9.4 
Analysis of Secondary Endpoints ....................................................................... 150 
9.5 
Reporting and Exclusions .................................................................................... 152 
9.6 
3Data Safety Monitoring Board .......................................................................... 154 
10. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .......................... 155 
10.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ............... 155 
10.2 
Adverse Event Characteristics ............................................................................. 165 
10.3 
Expedited Adverse Event Reporting ................................................................... 166 
10.4 
Routine Adverse Event Reporting ....................................................................... 173 
10.5 
Pregnancy ............................................................................................................ 173 
10.6 
Secondary Malignancy ........................................................................................ 173 
10.7 
Second Malignancy ............................................................................................. 173 
11. 
STUDY CALENDAR ..................................................................................................... 174 
12. 
MEASUREMENT OF EFFECT ..................................................................................... 177 
12.1 
Antitumor Effect – Solid Tumors ........................................................................ 177 
12.2 
Other Response Parameters ................................................................................. 183 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .......................................................................................................... 184 
13.1 
Study Oversight ................................................................................................... 184 
13.2 
Data Reporting .................................................................................................... 184 
13.3 
Data Quality Portal .............................................................................................. 186 
13.4 
CTEP Multicenter Guidelines ............................................................................. 187 
13.5 
Collaborative Agreements Language .................................................................. 187 
13.6 
Genomic Data Sharing Plan ................................................................................ 188 
13.7 
Incidental/Secondary Findings Disclosure Procedure ......................................... 188 
14. 
REFERENCES ................................................................................................................ 189 
APPENDIX A .................................................................. PERFORMANCE STATUS CRITERIA 
. ........................................................................................................................................ 201 
APPENDIX B ..................... FORMULA TO ESTIMATE RENAL FUNCTION USING SERUM 
CREATININE ................................................................................................................. 202 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
7 
 
 
APPENDIX C ..................................................... PATIENT CLINICAL TRIAL WALLET CARD 
. ......................................................................................................................................... 203 
APPENDIX D .................................................................................. PRE-BIOPSY ASSESSMENT 
. ......................................................................................................................................... 204 
APPENDIX E ............................................................................................. MEDICATION DIARY 
. ......................................................................................................................................... 205 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
8 
 
 
1. OBJECTIVES 
1.1 
Primary Objectives 
To assess the response rate (ORR) of patients with unresectable, pre-treated biliary 
cancers treated with the combination of atezolizumab and CDX-1127 (varlilumab) with 
or without cobimetinib. 
To assess the progression free survival (PFS) of patients with unresectable, pre-treated 
biliary cancers treated with the combination of atezolizumab and CDX-1127 (varlilumab) 
with or without cobimetinib 
1.2 
Secondary Objectives 
To assess the safety and tolerability of combination of atezolizumab and CDX-1127 
(varlilumab) with or without cobimetinib in patients with unresectable, pre-treated biliary 
cancers. 
To assess overall survival (OS) of patients with unresectable, pre-treated biliary cancers 
treated with the combination of atezolizumab and CDX-1127 (varlilumab) with or 
without cobimetinib. 
To determine the effect of combination atezolizumab and CDX-1127 (varlilumab) +/- 
cobimetinib on T cell subpopulations systemically and intratumorally. 
 
 
 
 
 
 
 
 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
9 
 
 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
Biliary Tract Cancer (BTC) refers to a group of heterogenous malignancies arising from biliary 
epithelial cells along different sites of the biliary tree that include intrahepatic 
cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer 
(GBC). Overall survival for this disease, even when including resectable patients, is poor with 
less than 5% of patients living beyond 5 years (Shaib and El Serag, 2004). Unresectable CCA 
patients treated with standard frontline therapy, gemcitabine plus cisplatin, have a median overall 
survival (OS) of less than one year (Valle et al., 2010). The benefit of cytotoxic chemotherapy 
in the second line setting is small, underscoring the need for additional treatment options for 
these patients (Lamarca et al., 2014; Rogers et al., 2014; Lamarca et al., 2019). Inhibition of 
programmed cell death protein 1 (PD-1) or its ligand (PD-LD1) has shown limited clinical 
activity in BTC as monotherapy, with response rates of approximately 5-11% in the largest 
reported prospective clinical trials (Ueno et al., 2019; Ioka et al., 2019; Ueno et al., 2018; Kim et 
al., 2020). The development of novel therapeutic combinations that can extend the clinical 
benefit of ICIs to immunologically resistant tumors such as BTC remains a significant challenge. 
 
2.2 
CTEP IND Agents 
 
Atezolizumab 
 
Atezolizumab is a human immunoglobulin (Ig) G1 monoclonal antibody consisting of two heavy 
chains (448 amino acids) and two light chains (214 amino acids) and is produced in Chinese 
hamster ovary cells (Investigator’s Brochure, 2016). Atezolizumab was engineered to eliminate 
Fc-effector function via a single amino acid substitution (asparagine to alanine) at position 298 
on the heavy chain, which results in a non-glycosylated antibody that has minimal binding to 
Fc receptors, thus eliminating detectable Fc-effector function and associated antibody-mediated 
clearance of activated effector T cells. Atezolizumab targets human programmed death-ligand 1 
(PD-L1) and inhibits the interaction with its PD-L1 and its receptors, PD-1 and B7-1 (also 
known as CD80), both of which function as inhibitory receptors expressed on T cells. 
 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients and is 
being investigated as a potential therapy in a wide variety of malignancies. Atezolizumab is 
being studies as a single agent in the advanced cancer and adjuvant therapy settings, as well as in 
combination with chemotherapy, targeted therapy, and cancer immunotherapy. 
 
Atezolizumab is approved in the United States for the treatment of locally advanced or metastatic 
urothelial carcinoma and as well as metastatic non-small cell lung carcinoma. 
 
2.2.1.1 Mechanism of Action 
 
PD-L1 expression is prevalent in many human tumors (e.g., lung, bladder, ovarian, melanoma, 
colon carcinoma), and its overexpression has been associated with poor prognosis in patients 
with several cancers (Thompson et al., 2006; Hamanashi et al., 2007; Okazaki and Honjo 2007; 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
10 
 
 
 
Hino et al., 2010). PD-L1 binds to two known inhibitory receptors expressed on activated T 
cells (PD-1 and B7.1), and receptor expression is sustained in states of chronic stimulation such 
as chronic infection or cancer (Blank et al., 2005; Keir et al., 2008). Ligation of PD-L1 with 
PD-1 or B7.1 inhibits T-cell proliferation, cytokine production, and cytolytic activity, leading to 
the functional inactivation or inhibition of T cells. Aberrant expression of PD-L1 on tumor cells 
has been reported to impede anti-tumor immunity, resulting in immune evasion (Blank and 
Mackensen, 2007). Therefore, interruption of the PD-L1/PD-1 and PD-L1/B7.1 pathway 
represents an attractive strategy to reinvigorate tumor-specific T-cell immunity. 
 
Blockade of PD-L1 or PD-1 with monoclonal antibodies has been reported to result in strong and 
often rapid antitumor effects in several mouse tumor models (Iwai et al., 2002; Strome et al., 
2003). These data suggest that tumor-specific T cells may be present in the tumor 
microenvironment in an inactive or inhibited state, and blockade of the PD-L1/PD-1 pathway can 
reinvigorate tumor-specific T-cell responses. 
 
Collectively, these data establish the PD-L1/PD-1 pathway as a promising new therapeutic target 
in patients with advanced tumors. Immune-related adverse events (AEs) reported from the two 
recent studies were consistent with the role of the PD-L1/PD-1 pathway in regulating peripheral 
tolerance. 
 
2.2.1.2 Summary of Nonclinical Experience 
 
The safety, pharmacokinetics (PK), and toxicokinetics of atezolizumab were investigated in mice 
and cynomolgus monkeys to support intravenous (IV) administration and to aid in projecting the 
appropriate starting dose in humans. Given the similar binding of atezolizumab for cynomolgus 
monkey and human PD-L1, the cynomolgus monkey was selected as the primary and relevant 
nonclinical model for understanding the safety, PK, and toxicokinetics of atezolizumab. 
 
Overall, the nonclinical PK and toxicokinetics observed for atezolizumab supported entry into 
clinical studies, including providing adequate safety factors for the proposed phase 1 starting 
doses. The results of the toxicology program were consistent with the anticipated pharmacologic 
activity of down-modulating the PD-L1/PD-1 pathway and supported entry into clinical trials in 
patients. 
 
Refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical studies. 
 
2.2.1.3 Summary of Clinical Experience 
 
A summary of clinical data from company-sponsored atezolizumab trials is presented below. 
Details of all ongoing studies can be found in the Atezolizumab Investigator’s Brochure. 
 
2.2.1.3.1 Clinical PK and Immunogenicity 
 
On the basis of available preliminary PK data (0.0320 mg/kg), atezolizumab shows linear PK at 
doses 1 mg/kg (Investigator’s Brochure, 2016). Based on an analysis of exposure, safety, and 
efficacy data, the following factors had no clinically relevant effect: age (21í89 years), body 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
11 
 
 
 
weight, gender, positive ATA status, albumin levels, tumor burden, region or ethnicity, renal 
impairment, mild hepatic impairment, level of PD-L1 expression, or ECOG status. No formal 
PK drug-drug interaction studies have been conducted with atezolizumab, and the interaction 
potential is unknown. Further details can be found in the current Investigator’s Brochure. 
 
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in all dose 
cohorts and was associated with changes in PK for some patients in the lower dose cohorts (0.3, 
1, and 3 mg/kg) (Investigator’s Brochure, 2016). Patients dosed at 10 mg/kg maintained Cmin 
values well above the target serum concentration of 6 mcg/mL despite the detection of ATAs. 
Accordingly, the development of detectable ATAs does not appear to have a clinically 
significant impact on PK for doses above 10 mg/kg. To date, no relationship between the 
development of measurable ATAs and safety or efficacy has been observed. 
 
2.2.1.3.2 Clinical Safety Summary 
 
As of May 10, 2016, atezolizumab has been administered (alone or in combination with other 
agents) to approximately 6053 patients with solid tumors and hematologic malignancies 
(Investigator’s Brochure, 2016). The first-in-human monotherapy study PCD4989g (in patients 
with locally advanced or metastatic solid tumors or hematologic malignancies) provides the 
majority of monotherapy safety data, with 629 safety-evaluable patients as of the data extraction 
date. Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no 
clear dose-related trends in the incidence of AEs have been determined. 
 
Fatigue, decreased appetite, nausea, diarrhea, constipation, and cough were commonly reported 
AEs in single and combination therapy (Investigator’s Brochure, 2016). AE profiles are similar 
across tumor types studied, including non-small cell lung cancer (NSCLC), renal cell carcinoma 
(RCC), triple-negative breast cancer (TNBC), and urothelial carcinoma (UC), and are consistent 
with the mechanism of action of atezolizumab. The overall immune-mediated AEs reported 
were considered moderate in severity, and the majority of patients were able to continue on 
atezolizumab therapy. 
 
As of the data extraction date of December 15, 2015, there were 629 safety-evaluable patients 
from the first-in-human phase 1a study PCD4989g (Investigator’s Brochure, 2016). The median 
age was 61 years. Of the 629 patients, 619 patients (98.4%) reported at least one AE of any 
grade or attribution to atezolizumab, and 316 patients (50.2%) experienced at least one grade 3 
or 4 AE of any attribution. A total of 444 patients (70.6%) reported at least one treatment-related 
AE, and 86 patients (13.7%) experienced at least one treatment-related grade 3 or 4 AE. The 
most frequently observed AEs of any grade and attribution (occurring in t10% of treated 
patients) include fatigue, decreased appetite, nausea, pyrexia, constipation, cough, dyspnea, 
diarrhea, anemia, vomiting, asthenia, back pain, headache, arthralgia, pruritus, rash, abdominal 
pain, insomnia, peripheral edema, and dizziness. 
 
Serious AEs (SAEs) have been reported in 261 patients (41.5%) in study PCD4989g 
(Investigator’s Brochure, 2016). Reported SAEs were consistent with the underlying disease. 
Treatment-related SAEs (57 patients [9.1%]) included pyrexia, dyspnea, pneumonitis, malaise, 
fatigue, hypoxia, colitis, and bone pain. Pooled single-agent safety data from 1978 patients with 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
12 
 
 
 
UC, NSCLC, and other indications (including trial PCD4989g) indicate that the most frequent 
(>1% of patients) serious adverse drug reactions (regardless of grade) include dyspnea (3.0%), 
back pain (1.2%), and abdominal pain (1.1%). A list of AEs considered “expected” for 
atezolizumab is presented in Section 10.1.1.1. 
 
2.2.1.3.3 Immune-Related Adverse Events 
 
Given the mechanism of action of atezolizumab, events associated with inflammation and/or 
immune-mediated AEs have been closely monitored during the atezolizumab clinical program 
(Investigator’s Brochure, 2016). To date, immune-related adverse events associated with 
atezolizumab include hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré syndrome, myasthenic 
syndrome/myasthenia gravis, and meningoencephalitis. 
 
For further details, see the most recent Atezolizumab Investigator’s Brochure. 
 
2.2.1.3.4 Clinical Efficacy Summary 
 
Patients with multiple tumor types were included in study PCD4989g, with the largest cohorts 
consisting of patients with NSCLC, RCC, and UC (Investigator’s Brochure, 2016). Objective 
responses with atezolizumab monotherapy were observed in a broad range of malignancies, 
including NSCLC, RCC, melanoma, UC, colorectal cancer, head and neck cancer, gastric cancer, 
breast cancer, and sarcoma. Both the preliminary and more mature efficacy data available 
suggest that treatment with atezolizumab as a single agent or in combination with other 
therapeutic agents results in anti-tumor activity across a range of tumor types and hematologic 
malignancies (UC, NSCLC, RCC, TNBC, melanoma, CRC, and NHL) and across lines of 
therapy. Clinical benefit was observed in terms of objective responses, durability of responses, 
and overall survival (OS). Improved efficacy of atezolizumab was observed in the unselected 
patient population, as well as in patients with higher PD-L1 expression on TCs or ICs (e.g., 
NSCLC) or on ICs only (e.g., mUC, RCC). 
 
Cobimetinib 
 
Cobimetinib (GDC-0973, XL518) is a low-molecular weight, orally available, potent non-ATP- 
competitive inhibitor of MEK1 and MEK2 (Choo et al. 2012). Selectivity of cobimetinib has 
been demonstrated in biochemical, cell-based, and in vivo assays (Hatzivassiliou et al. 2013; 
Hoeflich et al. 2012; Wong et al. 2012; Musib et al. 2013). As rationale for its development, the 
inhibition of MEK has been shown to be a promising strategy to control the growth of tumors 
dependent on aberrant signaling in the Ras/RAF pathway (Hoeflich et al. 2012). 
 
2.2.2.1 Summary of Nonclinical Experience 
 
Nonclinical data show that cobimetinib is a potent and highly selective inhibitor of 
MEK1/2, resulting in inhibition of cellular phosphorylation of ERK1/2 and anti-proliferative 
activity in a variety of human tumor cell lines and tumor xenograft models. Cobimetinib 
accumulates in tumor xenografts and remains at high concentrations in the tumor after 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
13 
 
 
 
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. The findings of in vitro and in vivo nonclinical safety pharmacology 
studies indicated that there was a low potential for cardiovascular (CVS), neurobehavioral, or 
respiratory function in patients (Investigator’s Brochure, 2019). 
 
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 
(Investigator’s Brochure, 2019). 
 
The nonclinical toxicity of cobimetinib was characterized in single-dose and repeat-dose studies 
in rats and dogs, 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 assay 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. 
 
2.2.2.2 Summary of Clinical Experience 
 
The following are key clinical trials in the cobimetinib clinical development program for 
melanoma. 
 
2.2.2.2.1 Cobimetinib Monotherapy 
 
Study MEK4592g was a multicenter, Phase 1, single-agent dose escalation study. The primary 
objectives of this study were to evaluate the safety, tolerability, and maximum tolerated dose 
(MTD) of cobimetinib administered orally as repeated doses in patients with solid tumors. 
 
In Stage I, 36 patients with advanced solid malignancies were enrolled in successive cohorts and 
received cobimetinib on a 21-day on, 7-day off (21/7) dosing schedule at the following dose 
levels: 0.05 mg/kg, 0.10 mg/kg, and 0.20 mg/kg in liquid dosage formulation and 10 mg, 20 mg, 
40 mg, 60 mg, and 80 mg in capsule formulation (Cohorts 1-8, respectively). The MTD is 60 mg 
on a 21/7 dosing schedule. 
 
In Stage IA, 20 patients were treated with cobimetinib on a 14-day on, 14-day off (14/14) dosing 
schedule in successive cohorts at the following dose levels: 60 mg, 80 mg, 100 mg, and 125 mg 
in capsule formulation (Cohorts 1A-4A, respectively). The MTD is 100 mg on a 14/14 dosing 
schedule. 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
14 
 
 
 
 
Stages II and IIA are expansion stages that further evaluate the safety, potential efficacy, and 
pharmacodynamic effects of cobimetinib at the MTDs determined in Stage I and Stage IA in 
patients with Ras- or RAF-mutant tumors. In Stage II, 20 patients were enrolled and received 60 
mg cobimetinib on a 21/7 dosing schedule. In Stage IIA, 21 patients were enrolled and received 
100 mg cobimetinib on a 14/14 dosing schedule. In Stage II, the dedicated DDI study, 20 
patients with solid tumors received 60 mg daily (QD) 21/17. 
 
2.2.2.2.2 Combination of Cobimetinib with Vemurafenib in Melanoma 
 
The objective of the clinical investigation of the combination of vemurafenib with GDC-0973 
(MEK inhibitor) is to simultaneously inhibit both oncogenic BRAF kinase (vemurafenib) and 
MEK (GDC-0973) in patients with previously untreated, BRAFV600E mutation-positive, locally 
advanced and unresectable or metastatic melanoma, OR those previously treated with 
vemurafenib in Phase 1 (PLX06-02, clinical pharmacology), Phase 2, and Phase 3 clinical trials, 
with evidence of mixed progression. 
 
Phase 1b Open-Label Cobimetinib and Vemurafenib Study (NO25395; BRIM-7) 
Study NO25395 (BRIM-7) was a Phase 1b study designed to assess the safety, tolerability, and 
pharmacokinetics of combined MEK inhibition with cobimetinib and BRAF inhibition with 
vemurafenib. This multicenter study had two stages: a dose-escalation stage and a cohort- 
expansion stage. 
 
All patients in the dose-escalation stage received vemurafenib (720 mg or 960 mg) twice daily 
(BID) in combination with cobimetinib (60 mg, 80 mg, or 100 mg) administered daily according 
to one of the following 28-day schedules: 
- 
14 consecutive days of study drug followed by a 14-day drug holiday (14/14) 
- 
21 consecutive days of study drug followed by a 7-day drug holiday (21/7) 
- 
Continuous daily dose (28/0) 
Cohorts 1A and 1B were expansion cohorts because both cohorts were declared safe and 
tolerable after dose escalation; furthermore, they delivered the single-agent maximum tolerated 
dose and schedule of cobimetinib and, in the case of Cohort 1B, the approved dose and schedule 
of vemurafenib (Ribas et al. 2014a; Ribas et al. 2014b; Pavlick et al. 2015). 
 
Randomized Phase 3 Study of Vemurafenib and Cobimetinib (GO28141; CoBRIM) 
This randomized, open-label, multicenter, Phase 3 study assessed previously untreated patients 
with metastatic melanoma confirmed by histopathology (unresectable stage IIIC or stage IV) and 
with a BRAFV600 mutation by the Cobas® 4800 BRAFV600 Mutation Test (Larkin et al. 2014). 
In this study, 495 patients were randomly assigned to receive vemurafenib (960 mg BID orally 
[PO]) and cobimetinib (60 mg QD PO) for the first 21 days of each 28-day cycle (combination 
group) or vemurafenib and placebo (control group). The primary endpoint was investigator- 
assessed PFS according to RECIST version 1.1. The secondary endpoints included overall 
survival (OS), rate of confirmed objective response, DOR, IRC-assessed PFS, and safety. The 
final analysis was planned to occur after 206 events, which was reached in May 2014. The 
initial results were reported based on data analyses from July 2014 after the pre-specified number 
of progression events was reached in May 2014 (Larkin et al. 2014). Updated results were 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
15 
 
 
 
presented at American Society of Clinical Oncology (ASCO) 2015 (Larkin et al. 2015) based on 
a data cutoff date of January 16, 2015. 
 
Vemurafenib plus cobimetinib was significantly superior to vemurafenib alone: median PFS was 
12.3 months in the combination group and 7.2 months in the vemurafenib group (HR=0.58; 95% 
CI: 0.46, 0.72). The PFS benefit was observed across key subgroups including LDH levels and 
BRAF mutation type. ORR was 69.9% (95% CI: 63.5%, 75.3%) with 15.8% CRs in the 
combination arm and 50% (95% CI: 43.6%, 56.4%) with 10.5% CRs in the single-agent arm 
(Larkin et al. 2015). After 255 patient deaths, the median OS was 22.3 months (95% CI: 20.3- 
not estimable) for the combination group and 17.4 months (95% CI: 15.0-19.8) for the 
monotherapy group, with a hazard ratio (HR) of 0.70 (95% CI: 0.55-0.90; P=0.005) (Ascierto et 
al. 2016). 
 
2.2.2.2.3 Clinical Safety Summary 
Cobimetinib Monotherapy 
As of the data cutoff date of June 11, 2013, 115 patients were treated across all study stages in 
Study MEK4592g (single agent cobimetinib), including 74 patients treated with cobimetinib 60 
mg 21/7. 
 
All patients in Study MEK4592g experienced an adverse event (AE). The most frequent AEs 
were diarrhea (67.0%), fatigue (50.4%), rash (49.6%), nausea, vomiting (33.9% each), and 
edema peripheral (28.7%). Other events that occurred in 10% of patients included anemia, 
abdominal pain, constipation, hypokalemia, decreased appetite, headache, dizziness, back pain, 
increased AST, dermatitis acneiform, pruritus, and dry skin. 
 
Amongst the patients who received cobimetinib 60 mg 21/7, the most frequent treatment 
emergent AEs in the cobimetinib 60 mg QD 21/7 group were diarrhea (64.4%), rash (53.3%), 
fatigue (48.9%), nausea, edema peripheral (31.1% each), and vomiting (28.9%). 
 
Amongst all cobimetinib-treated patients, 5 patients (4.3%) experienced a Grade 4 AE, and 53 
patients (46.1%) experienced a Grade 3 AE. The most frequent Grade 3 and Grade 4 AEs were 
hyponatremia (9.6%), fatigue (8.7%), anemia (7.8%), diarrhea, and hypokalemia (6.1% each). 
Grade 5 AEs, which in Study MEK4592g included disease progression reported as an AE, are 
discussed separately below. 
 
A total of 49 patients (42.6%) experienced a serious adverse event (SAE). The most common 
types of SAE were gastrointestinal (GI) disorders (n=17), but there were no trends in specific 
preferred terms. The GI SAEs, such as intestinal obstructions and GI hemorrhages, occurred in 
patients with GI malignancies. SAEs reported for more than two patients among all patients in 
the study were anemia, bile duct obstruction, dehydration, syncope, and respiratory arrest (3 
patients each [2.6%]). 
 
As of the clinical-data cutoff date (20 September 2013), a total of 29 patients (25.2%) had died, 
including 11 patients in the cobimetinib 60 mg QD 21/7 group. A total of 14 deaths were 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
16 
 
 
 
reported for patients treated in Stage I of the study. With the exception of 1 patient who died of 
cardiopulmonary arrest secondary to progressive disease (PD), all Stage I deaths occurred 
because of PD and no death was considered by the investigator to be related to the study drug. 
 
During Stages IA, II, and IIA of the study, 12 deaths were reported, all of which occurred 30 
days after the last dose of study drug. Of these, 2 deaths were considered by the investigator to 
be possibly related to study drug. In both cases, the investigator considered the metastatic cancer 
to be a contributing etiologic factor to the patient’s death. 
 
Three deaths were reported in Stage III of this study. None was assessed by the investigator as 
treatment related. Other contributing etiologic factors to the deaths included the patients’ 
underlying diseases and malignant tumor progression 
 
Adverse events of special interest for cobimetinib monotherapy (without vemurafenib) include 
the following. Details of these events are described in the section for the combination of 
vemurafenib and cobimetinib. A comprehensive list of AEs related to cobimetinib is included in 
CAEPR. 
 
Adverse Events of Interest: 
Hemorrhage: Hemorrhage, including major hemorrhages defined (symptomatic bleeding in a 
critical area or organ), can occur with cobimetinib. Events observed included cerebral 
hemorrhage, GI hemorrhage, reproductive tract hemorrhage, and hematuria. 
 
In randomized phase 3 trial of cobimetinib + vemurafenib vs. vemurafenib-placebo, hemorrhagic 
events were 13.0% with cobimetinib + vemurafenib vs. 7.3% with vemurafenib. Grade 3 to 4 
hemorrhage occurred in 1.2% vs. 0.8% of patients. Increased hemorrhage was seen in several 
sites: cerebral hemorrhage (0.8% vs. 0), gastrointestinal tract hemorrhage (3.6% vs. 1.2%), 
reproductive system hemorrhage (2.0% vs. 0.4%), and hematuria (2.4% vs. 0.8%). 
 
Caution should be used in patients with additional risk factors for bleeding, such as brain 
metastases, and/or in patients that use concomitant medications that increase the risk of bleeding 
(including antiplatelet or anticoagulant therapy). 
 
Cardiomyopathy: Cardiomyopathy, defined as symptomatic and asymptomatic decline in left 
ventricular ejection fraction (LVEF), can occur with cobimetinib. The safety of cobimetinib has 
not been established in patients with a baseline LVEF that is either below institutional lower 
limit of normal (LLN) or below 50%. In randomized phase 3 trial of cobimetinib + vemurafenib 
vs. vemurafenib + placebo, patients were assessed for LVEF by echocardiograms or multiple- 
gated acquisition (MUGA) at baseline, Week 5, Week 17, Week 29, Week 43, and then every 4 
to 6 months thereafter while receiving treatment. 
 
Grade 2 or 3 decrease in LVEF occurred in 26% vs. 19% of patients receiving the combination 
vs. vemurafenib. The median time to first onset of LVEF decrease was 4 months (range: 23 days 
to 13 months). Two patients on the combination arm (0.8%) were symptomatic 
 
Of the patients with decreased LVEF, 22% had dose interruption and/or reduction and 14% 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
17 
 
 
 
required permanent discontinuation. Decreased LVEF resolved to above the LLN or within 10% 
of baseline in 62% of patients receiving cobimetinib with a median time to resolution of 3 
months (range: 4 days to 12 months). 
 
Serous Retinopathy and Retinal Vein Occlusion: Serous retinopathy (fluid accumulation 
within the layers of the retina) has been observed in patients treated with MEK inhibitors, 
including cobimetinib. In the randomized phase 3 trial of cobimetinib-vemurafenib vs. 
vemurafenib-placebo, ophthalmologic examinations including retinal evaluation were performed 
pretreatment and at regular intervals during treatment. 
 
Symptomatic and asymptomatic serous retinopathy was identified in 26% of patients receiving 
cobimetinib and vemurafenib. The majority of these events were reported as chorioretinopathy 
(13%) or retinal detachment (12%). The time to first onset of serous retinopathy events ranged 
between 2 days to 9 months. The reported duration of serous retinopathy ranged from 1 day to 
15 months. One patient in each arm developed retinal vein occlusion. Perform an 
ophthalmological evaluation at regular intervals and any time a patient reports new or worsening 
visual disturbances. 
 
CPK elevation and rhabdomyolysis: Elevations in creatine phosphokinase (CPK) have been 
observed in patients treated with cobimetinib monotherapy. The majority of CPK elevations 
reported were asymptomatic, non-serious, and resolved with or without study drug interruption. 
In Study GO28141 (cobimetinib-vemurafenib vs. vemurafenib), elevated CPK was more 
frequent in the combination arm, (32.4% vs. 8.1% all grades, 11.3% vs. 0 > G3). CPK increase 
of more than 10 times the baseline value with a concurrent increase in serum creatinine >1.5 
times of baseline occurred in 3.6% of patients receiving combination and in 0.4% of patients 
receiving vemurafenib. The median time to first occurrence of Grade 3 or 4 CPK elevations was 
16 days (range: 12 days to 11 months); the median time to complete resolution was 15 days 
(range: 9 days to 11 months). 
 
One event of rhabdomyolysis was reported in the Phase 3 study GO28141 (cobimetinib plus 
vemurafenib), and rhabdomyolysis has been reported in postmarketing experience. 
 
Rash and Skin reactions: Severe rash and other skin reactions can occur with cobimetinib. 
In the Phase 3 study GO28141 (phase 3 cobimetinib-vemurafenib vs. vemurafenib), combined 
rash events of all types and grades were more frequent (71.7% vs. 66.7%), although Grade 3 
events (approximately 16%) and types of rash were similar between arms. Grade 4 rash in 1.6% 
vs. 0.8%. Specific events included rash (39% all grades, 5.9% Grade 3, 1.6% SAE) and rash 
maculo-papular (14.6% all grades, 6.3% Grade 3, 1.2% SAE). 
 
The median time to onset of Grade 3 or 4 rash events was 11 days (range: 3 days to 2.8 months). 
Among patients with Grade 3 or 4 rash events, 95% experienced complete resolution with the 
median time to resolution of 21 days (range 4 days to 17 months). Generally, Grade 3 rash 
events were effectively managed with dose modification guidelines. Approximately 90% of 
Grade 3 rash events resolved in both arms. 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
18 
 
 
 
Hepatotoxicity: Hepatotoxicity can occur with cobimetinib. 
In the Phase 3 study GO28141 (cobimetinib-vemurafenib vs. vemurafenib), Grade 3 or 4 liver 
laboratory (LFT) abnormalities in the cobimetinib-vemurafenib arm compared to vemurafenib 
were 20.5% vs. 15.1%, including 11% vs. 5% for alanine aminotransferase, 8% vs. 2.1% for 
aspartate aminotransferase, 1.6% vs. 1.2% for total bilirubin, and 7% vs. 3.3% for alkaline 
phosphatase. In one (0.4%) vs. no patient receiving combination vs. vemurafenib alone, there 
was concurrent elevation in ALT >3 times the upper limit of normal (ULN) and bilirubin >2 X 
ULN in the absence of significant alkaline phosphatase >2 X ULN occurred. 
 
In the Phase 3 study GO28141, in cobimetinib + vemurafenib or vemurafenib arm, the majority 
of Grade 3 liver laboratory test abnormalities resolved. 
 
Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal 
reproduction studies, cobimetinib can cause fetal harm when administered to a pregnant woman. 
In animal reproduction studies, oral administration of cobimetinib in pregnant rats during the 
period of organogenesis was teratogenic and embryotoxic at doses resulting in exposures [area 
under the curves (AUCs)] that were 0.9 to 1.4-times those observed in humans at the 
recommended human dose of 60 mg. Advise pregnant women of the potential risk to a fetus. 
Advise females of reproductive potential to use effective contraception during treatment with 
cobimetinib, and for 3 months following the final dose of cobimetinib. 
 
2.2.2.2.4 Clinical Pharmacokinetics of Cobimetinib 
 
Cobimetinib pharmacokinetics has been characterized in cancer patients following oral 
administration after single and multiple dosing in the Phase 1a dose-escalation study 
(MEK4592g). Cobimetinib showed high variability in pharmacokinetic parameters. 
The pharmacokinetics of cobimetinib was studied in healthy subjects and cancer patients. 
Cobimetinib exhibits linear pharmacokinetics in the dose range of 3.5 to 100 mg (i.e., 0.06 to 1.7 
times the recommended dosage). Following oral administration of COTELLIC 60 mg once daily, 
steady-state was reached by 9 days with a mean accumulation ratio of 2.4-fold (44% CV). 
 
Absorption: Following oral dosing of 60 mg once daily in cancer patients, the median time to 
achieve peak plasma levels (Tmax) was 2.4 (range:1–24) hours, geometric mean steady-state 
AUC0-24h was 4340 ngāh/mL (61% CV) and the maximum plasma concentration (Cmax) was 273 
ng/mL (60% CV). The absolute bioavailability of COTELLIC was 46% (90% CI: 40%, 53%) in 
healthy subjects. A high-fat meal (comprised of approximately 150 calories from protein, 250 
calories from carbohydrate, and 500–600 calories from fat) had no effect on cobimetinib AUC 
and Cmax after a single 20 mg COTELLIC was administered to healthy subjects. 
 
Distribution: Cobimetinib is 95% bound to human plasma proteins in vitro, independent of drug 
concentration. No preferential binding to human red blood cells was observed (blood to plasma 
ratio of 0.93). The estimated apparent volume of distribution was 806 L in cancer patients based 
on a population PK analysis. 
 
Elimination: Following oral administration of COTELLIC 60 mg once daily in cancer patients, 
the mean elimination half-life (t1/2) was 44 (range: 23–70) hours and the mean apparent clearance 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
19 
 
 
 
(CL/F) was 13.8 L/h (61% CV). 
 
Metabolism: CYP3A oxidation and UGT2B7 glucuronidation were the major pathways of 
cobimetinib metabolism in vitro. Following oral administration of a single 20 mg radiolabeled 
cobimetinib dose, no oxidative metabolites >10% of total circulating radioactivity were 
observed. 
 
Excretion: Following oral administration of a single 20 mg radiolabeled cobimetinib dose, 76% 
of the dose was recovered in the feces (with 6.6% as unchanged drug) and 17.8% of the dose was 
recovered in the urine (with 1.6% as unchanged drug). 
 
2.2.2.2.5 Cobimetinib Drug Interactions 
 
In vitro studies showed that cobimetinib is a time-dependent inhibitor of CYP3A and a 
competitive inhibitor of CYP2D6. In vitro studies also show that cobimetinib is a substrate 
of CYP3A and UGT2B7. 
 
Effect of Strong or Moderate CYP3A Inhibitors on Cobimetinib 
Coadministration of cobimetinib with itraconazole (a strong CYP3A4 inhibitor) increased 
cobimetinib systemic exposure by 6.7-fold. Avoid concurrent use of cobimetinib and strong or 
moderate CYP3A inhibitors. 
 
If concurrent short term (14 days or less) use of moderate CYP3A inhibitors including certain 
antibiotics (e.g., erythromycin, ciprofloxacin) is unavoidable for patients who are taking 
cobimetinib 60 mg, reduce cobimetinib dose to 20 mg. After discontinuation of a moderate 
CYP3A inhibitor, resume cobimetinib at the previous dose. 
 
Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced 
dose of cobimetinib (40 or 20 mg daily) 
 
Effect of Strong or Moderate CYP3A Inducers on Cobimetinib: Coadministration of 
cobimetinib with a strong CYP3A inducer may decrease cobimetinib systemic exposure by more 
than 80% and reduce its efficacy. Avoid concurrent use of cobimetinib and strong or moderate 
CYP3A inducers including but not limited to carbamazepine, efavirenz, phenytoin, rifampin, and 
St. John’s Wort 
 
Effect of Cobimetinib on CYP Substrates: Coadministration of cobimetinib 60 mg once daily for 
15 days with a single 30 mg dose of dextromethorphan (sensitive CYP2D6 substrate) or a single 
2 mg dose of midazolam (sensitive CYP3A substrate) to 20 patients with solid tumors did not 
change dextromethorphan or midazolam systemic exposure. In vitro data indicated that 
cobimetinib may inhibit CYP3A and CYP2D6. Cobimetinib at clinically relevant concentrations 
is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9 and 2C19 or inducer of CYP1A2, 2B6 and 3A4. 
 
Effect of Transporters on Cobimetinib: Cobimetinib is a substrate of efflux transporter P- 
glycoprotein (P-gp), but is not a substrate of Breast Cancer Resistance Protein (BCRP), Organic 
Anion Transporting Polypeptide (OATP1B1 or OATP1B3) or Organic Cation Transporter 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
20 
 
 
 
(OCT1) in vitro. Drugs that inhibit P-gp may increase cobimetinib concentrations. 
 
Effect of Cobimetinib on Transporters: In vitro data suggest that cobimetinib at clinically 
relevant concentrations does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OAT1, 
OAT3, or OCT2. 
 
Effect of Gastric Acid Reducing Drugs on Cobimetinib:  Coadministration of a proton pump 
inhibitor, rabeprazole 20 mg once daily for 5 days, with a single dose of 20 mg COTELLIC 
under fed and fasted conditions did not result in a clinically important change in cobimetinib 
exposure. 
 
CDX-1127 (varlilumab) 
 
CDX-1127 (varlilumab) is a recombinant, fully human monoclonal antibody (mAb) of the IgG1ț 
isotype that specifically binds human CD27 (Investigator’s Brochure, 2020). The costimulatory 
molecule CD27 is a member of the tumor necrosis factor (TNF) receptor superfamily and is 
constitutively expressed on the majority of mature T cells, memory B cells, and a portion of 
natural killer (NK) cells. The interaction of CD27 with its ligand CD70 plays key roles in the 
following processes: 
 
• Costimulation through CD27 on T cells promotes activation, proliferation, survival, and 
maturation of effector capacity and memory 
• Costimulation through CD27 on human B cells has also been implicated to promote 
proliferation, the production of immunoglobulin, and generation of plasma cells 
• Costimulation through CD27 on NK cells induces cytolytic activity 
 
The importance of this pathway is highlighted by rare individuals that are characterized with 
CD27 deficiency that arise due to genetic alterations and are associated with uncontrolled 
Epstein Barr virus infections and other disorders (Alkhairy, et al. 2015, van Montfrans, et al. 
2012). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
24 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3 
Rationale 
 
Atezolizumab (anti-PDL1) plus Cobimetinib (MEK inhibitor) in BTC (NCI10139) 
 
MEK inhibitors have shown immunomodulatory effects and substantial efficacy when combined 
with PD-(L)1 inhibitors in multiple preclinical models (Peng et al., 2020; Dushyanthen et al., 
2020; Ebert et al., 2016). Targeting of the MAPK pathway through MEKi is hypothesized to 
modulate the tumor immune microenvironment (TME) through effects on both tumor cells and 
direct effects on immune cells, resulting in enhanced major histocompatibility complex class I 
(MHC-1) expression and CD8+ T cell infiltration (Dushyanthen et al., 2020; Hellmann et al., 
2019; Liu et al., 2015; Brea et al., 2016; Caunt et al., 2015; Mimura et al., 2013; Angell et al., 
2014). The combination of a MEK inhibitor (cobimetinib) plus a PD-L1 inhibitor (atezolizumab) 
failed to show compelling immune activity in a large phase 3 clinical study in colon cancer 
(Bendell et al., 2018), however a therapeutic signal was demonstrated in our CTEP-sponsored 
trial of this strategy trial in BTC patients, the largest randomized immunotherapy trial to date in 
BTC 20. Presented as a plenary at AACR 2020, our group reported the results of the ETCTN 
randomized phase 2 trial of atezolizumab as monotherapy or in combination with the MEK 
inhibitor cobimetinib in heavily pretreated advanced BTC patients (N=77) (Yarchoan, et al., 
2020a). The trial met its primary endpoint, with a median PFS of 3.65 months in the 
atezolizumab plus cobimetinib combination arm, versus 1.87 months in the atezolizumab 
monotherapy arm (p=0.027). However, only one patient in each had a RECIST criteria partial 
response, suggesting that optimization of the strategy of immunomodulation through MEK 
inhibition is still needed. Importantly, the combination was tolerable without significant 
differences in discontinuation compared to the single agent arm due to adverse events. 
Correlative studies utilizing a limited number of paired tumor biopsies demonstrated that 
treatment with cobimetinib resulted in an increase in CD8+ T cell to FoxP3+ regulatory T cell 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
25 
 
 
 
 
Figure 1: Clinical and immunologic response in BTC patients treated with atezolizumab (Atezo) with or without 
cobimetinib (Cobi). PFS Kaplan Meier curve of Atezo + Cobi compared to Atezo alone showing a significant prolongation 
in PFS (p=0.027); B) Waterfall plot of tumor response of respective trial arms Atezo alone [B1] and Atezo + Cobi [B2]; C) 
Fold changes in TIL composition of CD8+ [C1], CD4+ [C2], CD8+:FOXP3 ratio [C3]; D) HLA expression of sample at 
days 1 & 21 of first cycle Atezo + Cobi vs. Atezo alone (Yarchoan, et al., 2020b). 
ratio, supporting the hypothesis that MEK inhibition can prime a cancer to become a checkpoint 
sensitive tumor (see Figure 1) (Yarchoan, et al., 2020b). 
 
MEKi plus anti-PDL1 
 
Although our randomized study of cobimetinib plus atezolizumab demonstrated that the 
combination therapy is tolerable and can prolong PFS in BTC, additional therapies in 
combination may be necessary to induce more compelling response rates in patients. 
Unpublished ongoing work from our group and other groups have further interrogated the 
mechanisms of immunomodulation with MEK inhibitors, using both commercially available 
genetic tools and small molecular MEK inhibitors in tumor models. Using a MEK1 knock-out 
RAS-driven tumor model (CT26 MEK1 KO), we find that MEK1 inhibition reprograms the 
tumor immune microenvironment, enhancing JAK/STAT1 signaling and antigen presentation in 
tumor cells, enhanced CD8+ T cell activation and IFNJ and granzyme B expression, and 
markedly prolonging survival in immune competent mice (Figure 2). 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
26 
 
 
 
 
 
Figure 2: Genetic knockout of MEK1 in tumor cells augments immune responses in mice bearing RAS-driving 
malignancy. A) CT26 MEK1 KO impairs tumor growth in vivo in an immune-competent mouse, but has no effect on 
tumor growth in an immune-compromised RAG-KO mouse; B) Activation of the MAPK pathway through EGF leads to 
downregulation of MHCI [B1] and MHCII [B2], but cobimetinib reversed this by increasing MHC I/II presentation thus 
supporting MAPK signaling negatively regulating MHCI and MHCII; C) MEK1 KO tumors (CT26 background) 
upregulated antigen processing [C1] and the JAK STAT pathway [C2] D) MEK1 KO tumors (CT26 background) had 
increased numbers effector T cell infiltration and markers of effector proliferation, and function (Dennison & 
Yarchoan, Unpublished) 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
27 
 
 
 
 
 
 
 
Figure 3: Impaired T cell response after MEKi treatment can be rescued by addition of 4-1BBL. A) Percentage of 
CD8+ cells expression INFy+ and GZMB+ in WT, WT + MEKi, MEK1 KO B) Combination MEKi+Anti-PD1+ 41BBL 
improves survival. C) Pictorial summary of exploratory findings (Dennison & Yarchoan, Unpublished) 
 
While MEK1 inhibition in tumor cells has uniformly positive anti-tumor immune effects in our 
model, the effects of systemic MEK inhibition (thereby inhibiting MEK on both tumor cells and 
lymphocytes) is complex. MEK is downstream of TCR signaling, and systemic MEK inhibitors 
may impair T cell priming and activation (Figure 3). This data may provide a potential 
mechanism for why dual blockade of MEK and PD-L1 has failed to induce compelling response 
rates in human clinical trials, and suggests the possibility that the activity of MEKi plus PD-L1 
may be improved with the addition of a co-stimulatory agent that can function independently of 
the MAPK pathway. Our findings are consistent with the results of other groups, which 
consistently show that while pharmacologic MEKi relieves TME immunosuppression and 
facilitates accumulation of antigen-specific CD8+ TILs, it simultaneously impairs T cell priming, 
and effector proliferation/function systemically (Ebert et al., 2016; Vella et al., 2014). Several 
reports have shown that agonist therapy (OX-40, 41BBL, etc.,) restores T cell function and 
increases antitumor immunity mediated by MEK inhibitors with PD-L1 blockade.(Dushyanthen 
et al., 2017; Baumann et al., 2020; Allegrezza et al., 2016). Consistent with this hypothesis, the 
addition of a costimulatory agonist, 41BB (anti-CD137), significantly prolonged survival in our 
preclinical model as compared all other treatment doublets/monotherapies in the CT26 tumor 
model. MEKi may also protect T cells against activation induced cell death, which has hampered 
the development of multiple agonist antibodies, further supporting the rationale for combining 
MEK with a stimulatory agent. 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
28 
 
 
 
CD27 Agonism 
 
Relative to the robust translational and clinical experience with ICIs, immune agonists that 
activate costimulatory receptors on T cells have proven to be challenging to develop despite 
great promise. Part of this is due to the challenges in inducing immune stimulation safely as seen 
with cases of cytokine release syndrome documented with CD28 agonism, and dose-limiting 
immunotoxicities with OX-40 and 41BBL therapies (Suntharalingam et al., 2006; Yonezawa et 
al., 2015; Vonderheide and Glennie, 2013; Ramakrishna et al., 2015). Another target for 
immune agonists is CD27, a member of the tumor necrosis factor receptor superfamily and a 
costimulatory molecule on T cells (Ansell et al., 2020). With engagement of its ligand CD70, 
CD27 promotes T-cell activation, proliferation, survival, and maturation of effector capacity as 
well as T-cell memory, B-cell proliferation, B-cell memory, and induces of the cytolytic activity 
of natural killer (NK) cells (Burris et al., 2017). Notably, CD27’s costimulatory effects on T 
cell activation/proliferation and augmentation of immune response remains cannot occur without 
concomitant TCR signaling. The first-in-class anti-CD27 agonist mAb, CDX-1127 (varlilumab) 
(CellDex), has not only demonstrated T cell activation and anti-tumor activity in preclinical 
models, but has shown to be safe and well-tolerated in early clinical trials of patients with 
advanced solid and hematologic malignancies (Ramakrishna et al., 2015; Ansell et al., 2020; 
Burris et al., 2017). Pre-clinical models demonstrate that agonist antibodies targeting CD27 act 
synergistically with anti–PD-1/L1 to increase CD8+ T-cell proliferation, effector function, and 
tumor clearance through distinct but complementary gene expression mechanisms (Buchan et al., 
2018). Clinical trials with these therapy combinations have proven safe and well-tolerated 
(Ansell et al., 2020; Burris et al., 2017; Shapira-Frommer et al., 2020). Correlative analyses of 
these clinical trials have showed that CDX-1127 (varlilumab) treatment activates memory CD4+ 
and CD8+ T cells, with a bias toward CD8+ T lymphocyte proliferation while also decreasing 
circulating Tregs (Ramakrishna et al., 2015). 
 
Rationale for MEK inhibition, PD-L1 inhibition, and CD27 agonism in BTC 
 
Immune checkpoint inhibitors have demonstrated limited activity in BTC as monotherapy, and 
while the combination of MEKi plus PD-L1 improved PFS in our prior randomized phase 2 
study, response rates remain low. Our unpublished preclinical work indicates that immune 
agonists that activate costimulatory receptors on T cells can rescue T cell activation in the setting 
of MEKi plus PD-L1i, resulting in improved survival. Although 41BB was used to show proof 
of principle in our experiments because the wide availability of murine 41BB agonists, the 
clinical development of 41BB agonists has been hampered by off-target toxicity. CD27 is a 
more compelling agonist because of the established safety and promising clinical activity of 
CD27 agonists in combination with PD-(L)1 inhibitors. Furthermore, we and others have found 
that CD27 is one of the most positively differentially expressed genes in tumors treated with 
MEKi plus PD-L1 (Ebert et al., 2016). This suggests a CD27-targeted therapy may be 
particularly effective at rescuing T cell activation in the setting of MEKi. The combination of 
MEK, PD-L1, and CD27 is also supported by preclinical work from other groups showing that 
MEK inhibition can protect T cells from death from activation-induced cell death (AICD) (Ebert 
et al., 2016). Chronic overstimulation from constitutive activation of CD27 in mice may result in 
depletion of the naïve T cells through AICD and may limit the clinical activity of CD27. Thus, 
MEK inhibition may synergize with CD27 agonism and PD-L1 inhibition by preventing T cell 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
29 
 
 
 
exhaustion and preventing AICD, while simultaneously reprograming the tumor immune 
microenvironment through direct effects on tumor antigen presentation and stromal cells. 
Collectively, the strong translational data when combined the favorable safety profiles and 
therapeutic signal in BTC supports a study of this triple combination therapy. This trial will be 
the first in human study to assess the combination of atezolizumab, CDX-1127 (varlilumab) and 
cobimetinib. 
 
2.4 
Correlative Studies Background 
 
CD8+ effector cells 
 
Integrated biomarker assessed with IHC using Cell Marque, CD8 (C8/144B) mouse monoclonal 
antibody (Ref#108M-98, status IVD, Validated for CTEP by study collaborator Dr. Robert 
Anders. 
 
Our primary correlative objective will be to compare infiltration of CD8+ T cells into the tumor 
microenvironment between patients receiving atezolizumab and variliumab and those receiving 
this same combination with concurrent cobimetinib. This validated metric will be considered an 
integrated biomarker for the clinical study. 
 
It has been demonstrated in various malignancies that the presence of CD8+ effector T cells 
within tumors increases the likelihood of responding to PD-1/PD-L1 antibody blockade (ICB) 
(Chen et al., 2020; Maibach et al., 2020). 
 
This correlative objective has two distinct hypotheses. First, we hypothesize the combination of 
atezolizumab and variliumab will increase the total number of CD8+ T effector cells and lead to 
an increased intratumoral ratio of CD8+ T effector cells CD4+FoxP3+ T regulatory cells. We 
postulate this effect will be further augmented in patients receiving concurrent cobimetinib. 
Second, we hypothesize that greater treatment-related changes in CD8+ T cell infiltration will 
occur in biliary tract tumors and that increased CD8+ T cell infiltration will correlate with a 
favorable clinical response to therapy. 
 
PD-L1 expression 
 
Exploratory biomarker assessed with IHC using SP142 [Spring, Biosciences] in collaboration 
with Dr. Robert Anders. 
 
Across tumors of multiple histologic type, PD-L1 expression measured by 
immunohistochemistry (IHC) is a well-characterized biomarker for predicting patient response 
with PD-1/PD-L1 blockade (Patel & Kurzrock, 2015). However, the utility of this biomarker in 
biliary tract cancers in the context of combination immunotherapy, and the effect of MEK 
inhibition on PD-L1 expression, are unknown. In theory, upregulation of PD-L1 may reflect a 
tumor with potential for immune reactivity, as various T cell derived cytokines (i.e. interferon- 
gamma) are well-characterized positive regulators of PD-L1 expression. We will use a 
previously validated technique and assay to assess this exploratory biomarker (Mody et al., 
2016; Rimm et al., 2017) 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
30 
 
 
 
 
We hypothesize that patients with increased expression of PD-L1 at baseline will be more likely 
to respond to therapy regardless of treatment arm. 
 
We hypothesize that treatment with atezolizumab and CDX-1127 (varlilumab) will increase PD- 
L1 expression and TILs as compared to each patient’s baseline, and that addition of cobimetinib 
to this combination will induce further increase in both PD-L1 and TIL in patient tumors. 
 
Tumor Microenvironment (TME) Assessment 
 
Panel of exploratory biomarkers assessed multiplex IHC and RNA seq [Johns Hopkins Core Lab 
Platforms] to characterize TME and immune subsets 
 
Both novel therapeutic combinations being tested in this clinical trial have the potential increase 
the potency of on-site anti-tumor immune response through direct action on TILs and/or indirect 
modulation of the TME. This trial provides a unique opportunity to conduct exploratory analysis 
to assess quantitative and qualitative changes in the TME and specifically the effects on immune 
cell subsets. This will be assessed with a broad panel of exploratory biomarkers through 
multiplex IHC for purposes of hypothesis-generating studies. 
 
We hypothesize the combination of cobimetinib, CDX-1127 (varlilumab), and atezolizumab will 
result in increased activated effector T cell, decreased regulatory T-cells, increased MHC-I 
expressions, as well decreased expression of inhibitor receptors and exhaustion markers as 
compared to baseline or doublet therapy. 
 
Paired tumor biopsies will be used to assess the effect of treatment arm on changes in the TME. 
This analysis will be performed on paired samples from patients enrolled in the trial. Baseline 
pretreatment biopsies, when available, will be collected. In addition, specimens from the on- 
treatment biopsy (obtained cycle 1 day 21 [+/- 5days]) will be collected under the guidance of 
the collaborating pathologist and tissue procurement staff at the time of biopsy. 
 
Our study design will enable us to isolate the effect of each treatment arm treatment 
combinations on immune cells, and other biomarkers in the TME in the context of atezolizumab 
and varilulumab +/- cobimetinib. 
 
A series of exploratory biomarkers will be assessed on tissue from this study. A sample of 
immune and other markers in Table 1 will be the stains of high priority for these exploratory 
investigations, in order of priority based on amount and quality of tissue obtained. At time of 
tissue analysis, the final components of this exploratory TME panel may be updated based on 
scientific and biomarker advances that have taken place since writing of original study protocol. 
 
We will explore changes in the TME using a multispectral IHC platform co-developed by 
investigators at Johns Hopkins University that incorporates a computational image processing 
workflow. This approach enables simultaneous evaluation of 12 biomarkers on one FFPE section 
and co-localization of multiple markers for highly specific immune cell phenotyping and has 
previously been used to characterize the tumor microenvironment (Romero et al., 2018). This 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
31 
 
 
 
work will be conducted in collaboration with a liver pathologist and immunologist, Dr. Robert 
Anders. 
 
Table 1 - Example Immunohistochemical (IHC) and Immunofluorescence (IF) analysis 
 
IHC Stains** 
IF Stains** 
 
CD8* 
CD8+Ki67+ 
Priority 1 
PD-L1 
CD4+FoxP3+ 
 
CD4 
 
 
MHC-I 
 
 
CD11c 
CD33+S100+ 
Priority 2 
CD19 
CD4+IL-17+ 
 
CD38 
 
 
CD68 
 
 
CD69 
 
 
CD163 
 
 
PD1 
 
 
IDO1 
 
 
LAG3 
 
 
*Denotes integrated biomarker 
**At time of tissue analysis, the final components of the exploratory IHC/IF panel may 
be updated based on scientific and biomarker advances that have taken place since 
writing of original study protocol 
 
Atezolizumab and CDX-1127 (varlilumab) clearance as an early marker of response and 
survival 
 
Antibody drug clearance has demonstrated potential as an early biomarker for outcomes from 
immune checkpoint inhibitor therapy (Desnoyer et al., 2020; Mir et al., 2020). In particular, 
baseline clearance (CL0, the clearance of the first dose of antibody drug) and/or changes in 
clearance over time have been demonstrated to associate with progression-free and/or overall 
survival for CTLA-4-targeted (Sanghavi et al., 2019), PD1-targeted (Baverel et al., 2018; Coss et 
al., 2018; Food and Drug Administration, 2016b; Turner et al., 2018; Zheng et al., 2018), and 
PD-L1-targeted agents (Baverel et al., 2018; Wilkins et al., 2019), including atezolizumab (Food 
and Drug Administration, 2016a) (low baseline clearance and decreasing clearance over time 
correlates with better outcomes). 
 
Elevated baseline clearance is also observed in patients with cancer-associated cachexia, and 
decreasing clearance over time trends with weight gain in patients who are responding to therapy 
(Turner et al., 2018; Patel et al., 2016;, Roch et al., 2020; Shek et al., 2020; Li et al., 2017). 
 
We hypothesize baseline clearance of atezolizumab will correlate with progression-free survival 
(lower baseline clearance will be associated with longer PFS). Atezolizumab and CDX-1127 
(varlilumab) blood levels will be measured by two separate ELISAs (one for each drug) in blood 
serum pre-dose and within 30 minutes after the end-of-infusion. The drug clearance for 
atezolizumab and CDX-1127 (varlilumab) will be assessed. We will also assess the correlations 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
32 
 
 
 
between atezolizumab and CDX-1127 (varlilumab) clearance at baseline and over time, as well 
as associations between cachexia and antibody drug clearance. Finally, we will assess 
immunogenicity by testing for the presence of anti-drug antibodies (ADAs) to both atezolizumab 
and CDX-1127 (varlilumab) using screening ELISAs followed by bridging ELISAs for positive 
samples. 
 
Circulating immune markers in peripheral blood (Th/Tc, phenotype, naïve/memory and 
exhaustion markers [PD-1, CTLA4, ICOS, BTLA, LAG3, TIM-3]) and plasma cytokines 
(Th1/Th2/Th17). 
 
Administration of the immunomodulatory agents included in this clinical trial has potential to 
elicit potent systemic shifts in cytokines that occur downstream of T cell activation. Each 
therapeutic antibody included in the regimen has potential to induce immune cell activation. 
Similarly, MEKi may be particularly adept at modulating cytokine secretion from tumor or 
stromal cells that lead to local or systemic shifts in Th1, Th2 and Th17 profiles. 
 
Since, in many cases of BTC, it is difficult to obtain enough biopsy tissue to reflect all tumor 
heterogeneity and to properly study TIL phenotype and location in situ. Thus, increasing studies 
have focused on studying the profile of blood circulating immune cells to predict the 
immunotherapy response. 
 
This trial provides a unique opportunity to conduct exploratory analysis to assess quantitative 
and qualitative changes in peripheral T-cell response and evaluate T-cell quality by 
characterizing cellular markers associated with poly–functionality, exhaustion, memory, and 
activation. The interactions between CD27 agonism and PD-L1 and/or MEK inhibition on 
systemic immune biomarkers have not been carefully examined and will provide a 
comprehensive dataset that can be integrated with clinical outcome measures including survival, 
response, or toxicity (Sanjabi & Lear, 2021) 
 
We hypothesize a greater frequency of circulating T cells with memory phenotype will be 
evident in patients receiving cobimetinib in combination with atezolizumab and CDX-1127 
(varlilumab) as compared to patients treated with atezolizumab and CDX-1127 (varlilumab) 
alone. In addition, we predict that patients who respond to treatment will have fewer inhibitory 
checkpoint receptors concurrently expressed on their circulating CD4+ or CD8+ T cells and a 
lower frequency of circulating cytokines or cells that are associated with an IL-17-driven 
immune responses. 
 
ctDNA 
 
Molecular profiling of advanced cancer is increasingly clinically relevant in terms of tailor 
targeted therapies and identifying prognostic marker. The clinical utility of circulating tumor 
DNA (ctDNA)for patients diagnosed with advanced BTC (especially iCCA) is widely accepted 
(Lamarca et al., 2020). BTCs have the greatest number of actionable molecular abnormalities 
among GI cancers (Marin et al., 2020), including ~15% with FGFR2 rearrangements/fusions 
(FDA-approved FGFRi (Bekaii-Saab et al., 2020) ), 20-25% with IDH1 mutations (ivosidenib 
with a survival benefit (Abou-Alfa et al., 2020)) and 3-5 % with Her2 amplifications (response 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
33 
 
 
 
rate >30% with Her2 directed therapy (Javle et al., 2017)). 
 
FoundationOne Liquid CDx is a qualitative next generation sequencing based in vitro diagnostic 
test that uses targeted high throughput hybridization-based capture technology to detect and 
report substitutions, insertions and deletions (indels) in 311 genes, rearrangements in four (4) 
genes and copy number alterations in three (3) genes (Foundations Medicine, 2021). It is already 
approved for use as a companion diagnostic tool in advanced NSCLC, Prostate, Ovarian, and 
Breast Cancers (Foundations Medicine, 2021; Food and Drug Administration, 2020) 
 
The emergence of ctDNA analysis represents a vital tool in the diagnosis and management of 
BTC patients given the standard tissue biopsy samples are often inadequate for molecular 
profiling. From a treatment perspective, in addition to identifying actionable mutations with a 
growing list of targeted therapies in this tumor space, ctDNA can be used for monitoring 
response to therapy. Accordingly, plasma sampling for ctDNA to assess for the status of these 
mutations has become standard of care (SOC) for BTC patients at baseline, and is reimbursed by 
insurance in normal practice. 
 
Several studies have demonstrated high concordance between tissue and commercial ctDNA 
assays in BTC patients (Aguado et al., 2020; Ettrich et al., 2019; Lamarca et al., 2020; Mody et 
al., 2019). Gatekeeper mutations have been identified that result in resistance to molecularly 
targeted therapies, discovered by serial and post-progression liquid biopsies (Goyal et al., 2017; 
Parikh et al., 2019; Parikh et al., 2020). Beyond diagnostics and precision medicine guidance, 
the use of high tumor mutation burden (hTMB, 10 mut/mb) as a biomarker in BTC, specifically 
as predictor of response to immunotherapies, is any area of particular clinical relevance to this 
study of novel immunotherapy combination regimens. A recently published study by Zhang and 
colleagues reported three BTC cases (one iCCA and two dCCAs) with TMB-H, which were 
treated with ICIs with two achieving partial responses (PRs) and one patient achieving a 
complete response (CR) (Zhang et al., 2020) 
 
In this study, we will use ctDNA to explore circulating tumor genomic characteristics (e.g. 
TMB) as biomarkers for response and resistance to therapy. 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
34 
 
 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
Pathologically confirmed biliary tract cancer, having received at least 1 prior line of 
systemic therapy, and received no more than 2 prior lines of therapy in the metastatic 
setting (disease recurrence < 6 months from the last dose of perioperative therapy/day of 
surgery [whichever is more recent] in resected patients will be considered the first line of 
therapy) 
x Includes intrahepatic cholangiocarcinoma (IHC), extrahepatic 
cholangiocarcinoma (EHC), and gallbladder carcinoma (GBC), but not Ampulla 
of Vater cancers.
 
Patients must have measurable disease by RECIST v1.1 
 
Age 18 years. Because no dosing or adverse event data are currently available on the 
use of atezolizumab, cobimetinib, and CDX-1127 (varlilumab) in patients <18 years of 
age, children are excluded from this study. 
 
ECOG performance status 1 (Karnofsky 80%, see Appendix A). 
 
Patients must have adequate organ and marrow function as defined below: 
 
 
absolute neutrophil count 
1,500/mcL 
 
hemoglobin 
 9.0 g/dl 
 
platelets 
100,000/mcL 
 
total bilirubin 
 1.5 x institutional upper limit of normal 
(ULN) (Patients with known Gilbert disease 
who have serum bilirubin level d3 u ULN may 
be enrolled) 
 
AST(SGOT)/ALT(SGPT) 
 3 × institutional ULN 
 
Serum creatinine 
 1.5 x institutional ULN 
OR 
 
creatinine clearance 
>30 mL/min/1.73 m2 (calculated by Cockcroft- 
Gault method) for patients with creatinine levels 
above institutional normal 
 
albumin 
 3.0 g/dL 
 
PT/aPTT 
d 1.5 u ULN 
(This applies only to patients who do not 
receive therapeutic anticoagulation; patients 
receiving therapeutic anticoagulation, such as 
low-molecular-weight heparin or warfarin, 
should be on a stable dose) 
- 
CK/CPK 
< 5 x ULN 
 
Oxygen saturation 
 92% on room air 
 
Left Ventricular Ejection Fraction 
> 50% 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
35 
 
 
 
 
HIV-infected patients on effective anti-retroviral therapy with undetectable viral load 
within 6 months are eligible for this trial. 
 
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated. 
 
Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured. For patients with HCV infection who are currently on treatment, they are eligible 
if they have an undetectable HCV viral load. 
 
Patients must be willing to undergo 2 sets of core needle biopsies. If possible, biopsied 
sites should be different than those used for measurable disease/RECIST measurements, 
but this is not mandatory. 
 
Patients must have an estimated life expectancy of greater than 3 months. 
 
Patients must be able to swallow pills 
 
Patients should not have evidence of retinal pathology on ophthalmologic examination; 
or neurosensory retinal detachment, RVO, or neovascular macular degeneration. 
 
The effects of atezolizumab, cobimetinib, and CDX-1127 (varlilumab) on the developing 
human fetus are unknown. For this reason, women of child-bearing potential and men 
must agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, and 5 months after 
the last dose of Atezolizumab. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately. Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, 
and 5 months (150 days) after completion of atezolizumab, cobimetinib, and CDX-1127 
(varlilumab) administration. 
 
Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
Patients with prior allogeneic bone marrow transplantation within the past 5 years or 
prior solid organ transplantation at any point. 
 
Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events (other than alopecia or neuropathy) due to agents administered more 
than 4 weeks earlier. However, the following therapies are allowed: 
x 
Hormone-replacement therapy or oral contraceptives
x 
Herbal therapy !1 week prior to Randomization (herbal therapy intended as

NCI Protocol #: 10476 
Version Date: October 9, 2023 
36 
 
 
 
anticancer therapy must be discontinued at least 1 week prior to Randomization) 
x 
Palliative radiotherapy for bone metastases !2 weeks prior to Randomization
 
Prior treatment with anti-CTLA-4, anti-PD-1, or anti-PD-L1 or other immune checkpoint 
inhibitor therapeutic antibodies or pathway-targeting agents with the following 
exceptions: 
x 
Patients who have only received previous durvalumab (anti-PD-L1) as part of first 
line in combination with gemcitabine and cisplatin (TOPAZ-1 regimen 
[NCT03875235]) are eligible.
x 
Patients who have only received previous pembrolizumab (anti-PD-1) as part of 
first line in combination with gemcitabine and cisplatin (KEYNOTE-966 regimen 
[NCT04003636]) are eligible.
 
Prior treatment with MEK or ERK inhibitors 
 
Treatment with any other investigational agent within 4 weeks prior to Randomization. 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon [IFN]-D or interleukin [IL]-2) within 6 weeks prior to Randomization. 
 
Treatment with systemic immunosuppressive medications (including, but not limited to, 
prednisone (>10mg), cyclophosphamide, tacrolimus, sirolimus, azathioprine, 
methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 
weeks prior to Randomization. 
o Patients who have received acute, low dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. 
o The use of physiologic doses of systemic corticosteroids and mineralocorticoids 
(e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical 
insufficiency is allowed. 
o The use of topical and inhaled corticosteroids are allowed due to low systemic 
absorption. 
 
Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use of 
bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is 
allowed. 
 
Presence of therapeutically actionable mutation with approved targeted therapy (e.g. 
FGFR fusion patients are eligible for study therapy in the 3rd line setting). Patient must 
have received somatic mutation testing (tissue or liquid) prior to enrollment. 
 
Clinically significant ascites (palpable on exam, paracentesis in last 3 months, and/or 
symptomatic). 
 
Patients with known primary central nervous system (CNS) malignancy or symptomatic 
CNS metastases are excluded, with the following exceptions: 
x Patients with asymptomatic treated CNS metastases may be enrolled, provided all

NCI Protocol #: 10476 
Version Date: October 9, 2023 
37 
 
 
 
the criteria listed above are met as well as the following: 
o Radiographic demonstration of improvement upon the completion of 
CNS-directed therapy and no evidence of interim progression between the 
completion of CNS-directed therapy and the screening radiographic study 
o No stereotactic radiation or whole-brain radiation within 28 days prior to 
Randomization 
o Screening CNS radiographic study t4 weeks from completion of 
radiotherapy and t2 weeks from discontinuation of corticosteroids 
o Follow-up brain imaging 3 months after central nervous system (CNS)- 
directed therapy shows no evidence of progression 
 
History of malignant bowel obstruction. 
 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to Chinese 
hamster ovary cell products, chimeric, humanized, or other recombinant human 
antibodies or fusion proteins 
 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to atezolizumab, cobimetinib, or CDX-1127 (varlilumab). 
 
Patients receiving any medications or substances that are considered moderate to strong 
inhibitors or inducers of CYP3A and are not able to switch to an alternative that 
minimizes interaction potential will ineligible. Coadministration of cobimetinib with a 
strong CYP3A4 inhibitor can increase cobimetinib systemic exposure significantly (e.g. 
itraconazole increased serum systemic cobimetinib exposure by 6.7 fold). On the other 
end, coadministration of cobimetinib with a strong CYP3A inducer may decrease 
cobimetinib systemic exposure by more than 80% thus reducing its efficacy. Because the 
lists of these agents are constantly changing, it is important to regularly consult a 
frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; medical 
reference texts such as the Physicians’ Desk Reference may also provide this 
information. As part of the enrollment/informed consent procedures, the patient will be 
counseled on the risk of interactions with other agents, and what to do if new medications 
need to be prescribed or if the patient is considering a new over-the-counter medicine or 
herbal product. Appendix C should be presented to patient. 
x Patients on mild inhibitors or inducers of CYP3A are allowed.
 
Patients with a known clinically significant liver disease, including active viral, alcoholic, 
or other hepatitis; cirrhosis; fatty liver; and inherited liver disease. 
x Patients with past or resolved hepatitis B infection (defined as having a negative 
hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to 
hepatitis B core antigen] antibody test) are eligible.
x Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction (PCR) is negative for HCV RNA.
 
Patients who have received immunosuppressive treatment for systemic autoimmune 
disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
38 
 
 
 
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis within the last 2 years. 
x Patients with a history autoimmune endocrine disorders on stable doses of 
physiologic hormone replacement may be eligible.
x Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may 
be eligible.
x Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions:
o Patients with psoriasis must have a baseline ophthalmologic exam to rule 
out ocular manifestations 
o Rash must cover less than 10% of body surface area (BSA) 
o Disease is well controlled at baseline and only requiring low potency topical 
steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, 
flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%) 
o No acute exacerbations of underlying condition within the last 12 months 
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral 
steroids) 
o Patients with history Guillain-Barré syndrome or myasthenia gravis at any 
point will not be eligible. 
 
History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, 
etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) 
scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Patients with active tuberculosis (TB) are excluded. 
 
Severe infections within 4 weeks prior to Randomization, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia. 
 
Signs or symptoms of infection within 2 weeks prior to Randomization. 
 
Received oral or intravenous (IV) antibiotics within 2 weeks prior to Randomization. 
 
Patients receiving prophylactic/suppressive antibiotics will not be eligible. 
 
Major surgical procedure within 28 days prior to Randomization or anticipation of need 
for a major surgical procedure during the course of the study. 
 
Administration of a live, attenuated vaccine within 4 weeks before Randomization or 
anticipation that such a live, attenuated vaccine will be required during the study and up 
to 5 months after the last dose of atezolizumab. 
x Influenza vaccination should be given during influenza season only

NCI Protocol #: 10476 
Version Date: October 9, 2023 
39 
 
 
 
(approximately October to March). Patients must not receive live, attenuated 
influenza vaccine within 4 weeks prior to Randomization or at any time during 
the study. 
x COVID-19 vaccination is not exclusionary but should be administered at least 7 
days before study start.
 
Patients with psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
Pregnant women are excluded from this study because one or more study agents have the 
potential for teratogenic or abortifacient effects. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with atezolizumab, cobimetinib, and CDX-1127 (varlilumab), breastfeeding should be 
discontinued if the mother is treated with atezolizumab, cobimetinib, and CDX-1127 
(varlilumab). 
 
Patients who are using ethinyl estradiol containing oral contraceptives when administered 
concomitantly with cobimetinib, are excluded due to increased risk of venous 
thromboembolism. 
 
Patients with a history of clinically significant cardiac dysfunction, including the 
following: 
 
Left ventricular ejection fraction (LVEF) below institutional LLN or 
below 50%, whichever is lower 
 
Current unstable angina 
 
Current symptomatic congestive heart failure (CHF) of New York Heart 
Association class 2 or higher 
 
Uncontrolled hypertension Grade 2 (patients with a history hypertension 
controlled with anti-hypertensives to Grade 1 are eligible). 
 
Uncontrolled arrhythmias 
 
Myocardial infarction, severe/unstable angina, symptomatic CHF, 
cerebrovascular accident or transient ischemic attack within the previous 6 
months 
 
History of treatment with cardiotoxic agents 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH- 
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research. Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification. Cost is not an acceptable reason for 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
40 
 
 
 
exclusion except when the study would duplicate data from other sources. Women of 
childbearing potential should not be routinely excluded from participation in clinical research. 
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
41 
 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr. 
 
RCR utilizes five person registration types. 
x IVR: MD, DO, or international equivalent,
x NPIVR: advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD),
x AP: clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System (RUMS), OPEN, Rave, acting as a 
primary site contact, or with consenting privileges,
x Associate (A): other clinical site staff involved in the conduct of NCI-sponsored trials, 
and
x Associate Basic (AB): individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems.
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
ط 
ط 
 
 
 
Financial Disclosure Form 
ط 
ط 
ط  
 
NCI Biosketch (education, training, employment, license, 
and certification) 
ط 
ط 
ط  
 
GCP training 
ط 
ط 
ط  
 
Agent Shipment Form (if applicable) 
ط  
 
 
 
CV (optional) 
ط 
ط 
ط  
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
x Addition to a site roster,
x Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN,

NCI Protocol #: 10476 
Version Date: October 9, 2023 
42 
 
 
 
x Act as the site-protocol Principal Investigator (PI) on the IRB approval, and
x Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).
 
In addition, all investigators acting as the Site-Protocol PI (Investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the Clinical 
Investigator (CI) on the DTL must be rostered at the enrolling site with a participating 
organization. 
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval 
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate 
their intent to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network. Site preferences can be set at the network 
or protocol level. Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
x Holds an active CTEP status,
x Active status at the site(s) on the IRB/REB approval (applies to US and Canadian sites 
only) on at least one participating organization’s roster,
x If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s) record,
x Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile,
x Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile, and
x Holds the appropriate CTEP registration type for the protocol.
 
Additional Requirements 
 
Additional site requirements to obtain an approved site registration status include: 
x An active Federalwide Assurance (FWA) number,

NCI Protocol #: 10476 
Version Date: October 9, 2023 
43 
 
 
 
x An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO),
x An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only), and
x Compliance with all protocol-specific requirements (PSRs).
 
Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents 
is restricted to institutions and its associated investigators and staff or on a participating roster.To 
view/download site registration forms: 
 
x Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password,
x Click on Protocols in the upper left of the screen
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-MD017, 
and protocol number 10476 
x Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration, and download to complete the forms provided. (Note: For sites 
under the CIRB, IRB data will load automatically to the CTSU.)
 
Protocol Specific Requirements For 10476 Site Registration 
 
x A Site Initiation Visit (SIV) is required for each participating site prior to activation. 
The local site PI must participate on the call as well as their research nurse, study 
coordinator, and pharmacist. To schedule a SIV, please email the Study Contact and 
reference the protocol in the subject line of the email.
x Specimen Tracking System Training Requirement:
o All data entry users (Clinical Research Associate role) at each participating site will 
need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual. If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU. However, new versions of the Specimen Tracking System 
may require new training. 
o This training will need to be completed before the first patient enrollment at a given 
site. 
o Please contact STS Support at Theradex for the training 
(STS.Support@theradex.com, Theradex phone: 609-799-7580). 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
44 
 
 
 
Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website. 
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website, go to the 
Regulatory section, and select Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878) or 
CTSURegHelp@coccg.org in order to receive further instruction and support. 
 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific DTL using the DTL application in the Delegation 
Log section on the CTSU members’ website. The Clinical Investigator (CI) is required to review 
and electronically sign the DTL prior to the site receiving an approved site registration status and 
enrolling patients to the study. To maintain an approved site registration status the CI must re- 
sign the DTL at least annually and when a new version of the DTL is released; and activate new 
task assignments requiring CI sign-off. Any individual at the enrolling site on a participating 
roster may initiate the site DTL. Once the DTL is submitted for CI approval, only the designated 
DTL Administrators or the CI may update the DTL. Instructions on completing the DTL are 
available in the Help Topics button in the DTL application and include a Master Task List, 
which describes DTL task assignments, CI signature, and CTEP registration requirements. 
 
Checking Site Registration Status 
 
Site’s registration status may be verified on the CTSU website. 
 
x Click on Regulatory at the top of the screen,
x Click on Site Registration, and
x Enter the site’s 5-character CTEP Institution Code and click on Go.
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
4.3 
Patient Registration 
 
OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
45 
 
 
 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN or IWRS will populate the 
patient enrollment data in NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access: 
 
x A valid CTEP-IAM account.
x To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an Associate Plus (AP) registration type.
x If a DTL is required for the study, the registrar must hold the OPEN Registrar task on the 
DTL for the site.
x Have an approved site registration for the protocol prior to patient enrollment.
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
x Patient has met all eligibility criteria within the protocol stated timeframes, and
x All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable).
 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. IWRS system also sends an email confirmation of the registration. You 
may print this confirmation for your records. 
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Special Instructions for Patient Enrollment 
 
Pre-registration Step 0 and Registration Step 1 are to performed at the same time and after 
patient has completed all elements of the screening and eligibility requirements and is ready to 
enroll/be randomized. 
 
The Baseline Biopsy is to be conducted after Registration Step 1 is completed and prior to 
starting the assigned treatment regimen. 
 
This Study will use the ETCTN Specimen Tracking System (STS). 
x All biospecimens collected for this trial must be submitted using the ETCTN Specimen

NCI Protocol #: 10476 
Version Date: October 9, 2023 
46 
 
 
 
Tracking System (STS) unless otherwise noted. 
x The system is accessed through Rave user roles: “Rave CRA” and “Rave CRA 
(Labadmin)” for data entry at the treating institutions and “Biorepository” for users 
receiving the specimens for processing and storage at reference labs and the NCI Early- 
Phase and Experimental Clinical Trials Biospecimen Bank (EET Biobank, formerly 
known as the ETCTN Biorepository).
x Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website in the Data Management section under the Rave Home tab and then 
under Rave Resource Materials.
x Important: Failure to complete required fields in STS may result in a delay in 
sample processing. Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS.
 
Detailed instructions on use of the STS can be found in Section 5.4. 
 
OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN link of the CTSU website 
at https://www.ctsu.org or at https://open.ctsu.org. For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website: http://www.theradex.com/clinicalTechnologies/?National- 
Cancer-Institute-NCI-11. This link to the Theradex website is also on the CTSU website OPEN 
tab. For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at 
609-619-7862 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 days. Issues that would 
cause treatment delays should be discussed with the Principal Investigator. If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled. The Study Coordinator should be notified of cancellations as soon as possible. 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
47 
 
 
 
5. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
5.1 
Summary Table for Specimen Collection 
 
Time Point 
Specimen 
Send Specimens To: 
Archival 
 
x Formalin-fixed paraffin-embedded 
(FFPE) tumor tissue block 
(preferred) (mandatory) 
 
If a block is not available, then submit: 
x 1 H&E stained slide (4 μm) 
x 15 unstained, 4 micron, positively 
charged slides, no cover 
Yarchoan Laboratory 
Baseline 
 
x 3 FFPE tumor tissue blocks 
(mandatory)1 
x 2 snap frozen tumor cores (mandatory)1 
Yarchoan Laboratory 
 
x 8.5 mL peripheral blood in 
FoundationOne Liquid CDx cfDNA 
tubes (optional) (see Section 11 
[Footnote L]) 
Foundation Medicine 
 
x 30 mL peripheral blood in EDTA tubes 
(mandatory) 
Lesinski Laboratory 
 
x 20 mL in Streck cfDNA tube 
(mandatory) 
EET Biobank 
Day 1 of Cycles 1-6, 9 and 12 
x Pre infusion 
x 30 minutes 
after the end of 
infusion of 
CDX-1127 
(varlilumab), 
which will be 
administered 
after 
atezolizumab 
x 6 mL Peripheral blood in red-top tube 
processed for serum and frozen 
(mandatory) 
OSU Comprehensive 
Cancer Center (OSUCCC) 
Pharmacoanalytical Shared 
Resource (PhASR) 
Laboratory 
Day 15 of Cycles 1 and 2 
x Pre infusion 
x 30 minutes 
after the end of 
infusion of 
CDX-1127 
(varlilumab), 
which will be 
x 6 mL Peripheral blood in red-top tube 
processed for serum and frozen 
(mandatory) 
OSU Comprehensive 
Cancer Center (OSUCCC) 
Pharmacoanalytical Shared 
Resource (PhASR) 
Laboratory 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
48 
 
 
 
administered 
after 
atezolizumab) 
 
 
Cycle 1 Day 21 
 
x 3 FFPE tumor tissue blocks 
(mandatory)1 
x 2 snap frozen tumor cores (mandatory)1 
Yarchoan Laboratory 
 
x 30 mL peripheral blood in EDTA tubes 
(mandatory) 
Lesinski Laboratory 
 
x 20 mL in Streck cfDNA tube 
(mandatory) 
EET Biobank 
Week 12 (End of Cycle 3) 
 
x 30 mL peripheral blood in EDTA tubes 
(mandatory) 
Lesinski Laboratory 
End of Treatment (EOT) 
 
x 30 mL peripheral blood in EDTA tubes 
(mandatory) 
Lesinski Laboratory 
 
x 20 mL in Streck cfDNA tube 
(mandatory) 
EET Biobank 
1See Sections 5.2 and 5.5.2 for priority of cores. 
 
5.2 
Summary Table(s) for Interventional Radiologist for Research Biopsies 
 
Biopsy #: 1 
Trial Time Point: Baseline 
IR Biopsy Definition: Research – No Clinical Impact (All cores from a single biopsy 
procedure impact research goals, but do not directly impact patient care or benefit the patient. 
Core 
Priority 
Use in the 
Trial 
Biomarker 
Name(s) 
Tumor 
Content 
Required 
Post-Biopsy Processing 
1 
Integrated 
CD8+T effector 
cells 
10% 
FFPE 
2 
Exploratory 
PD-L1 expression 
on tumor and 
tumor infiltrating 
lymphocytes 
(TILs) 
10% 
FFPE 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
49 
 
 
 
3 
Exploratory 
Analysis of tumor 
microenvironment 
examining 
changes to 
focused tumor 
immune 
infiltrating 
lymphocyte 
populations by 
multiplex IHC 
10% 
FFPE 
4-5 
Exploratory 
Analysis of 
expression of 
immune-related 
pathways in the 
tumor 
microenvironment 
by RNA seq 
10% 
Snap Frozen 
 
Biopsy #: 2 
Trial Time Point: Cycle 1, Day 21 
IR Biopsy Definition: Research – No Clinical Impact (All cores from a single biopsy 
procedure impact research goals, but do not directly impact patient care or benefit the patient. 
Core 
Priority 
Use in the 
Trial 
Biomarker 
Name(s) 
Tumor 
Content 
Required 
Post-Biopsy Processing 
1 
Integrated 
CD8+T effector 
cells 
10% 
FFPE 
2 
Exploratory 
PD-L1 expression 
on tumor and 
tumor infiltrating 
lymphocytes 
(TILs) 
10% 
FFPE 
3 
Exploratory 
Analysis of tumor 
microenvironment 
examining 
changes to 
focused tumor 
immune 
infiltrating 
lymphocyte 
populations by 
multiplex IHC 
10% 
FFPE 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
50 
 
 
 
4-5 
Exploratory 
Analysis of 
expression of 
immune-related 
pathways in the 
tumor 
microenvironment 
by RNA seq 
10% 
Snap Frozen 
 
Note: Pre-biopsy assessments will be reported and tracked through a trial-specific Case Report 
Form (CRF) within the CTEP Medidata Rave system (see Appendix D). 
 
5.3 
Specimen Procurement Kits and Scheduling 
 
5.3.1 Specimen Procurement Kits 
 
Kits for the collection of blood in FoundationOne Liquid CDX cfDNA tubes can be ordered 
from Foundation Medicine for the ctDNA assay if needed. 
 
Kits for the collection and shipment of blood in Streck cfDNA tubes to the EET Biobank can be 
ordered online via the Kit Management system: https://kits.bpc-apps.nchri.org. 
 
Users at the clinical sites will need to set up an account in the Kit Management system and select 
a specific clinical trial protocol to request a kit. Please note that protocol may include more than 
one type of kit. Each user may order two kits per kit type per day (daily max = 6 kits). Kits are 
shipped ground, so please allow 5-7 days for receipt. A complete list of kit contents for each kit 
type is located on the Kit Management system website. 
 
Note: Institutional supplies must be used for all other specimen collection and processing. 
 
5.3.2 Scheduling of Specimen Collections 
 
5.3.2.1 Scheduling of Specimen Collection to the Yarchoan Laboratory 
 
All tissue samples should be sent to the Yarchoan Lab (archival and fresh tumor biopies) on a 
rolling bases post-processing. Snap frozen cores should be stored in vapor phase liquid nitrogen. 
If the collecting site does not have liquid nitrogen storage capabilities, fresh frozen tissue should 
be kept at -80ၨC and sent to the Yarchoan laboratory within 5 days of tissue procurement (ship 
on Monday-Wednesday only). An email notification must be sent to the Yarchoan Laboratory on 
the date of shipping to the following email addresses: (jleathe3@jhmi.edu, smitch55@jhmi.edu, 
and ctep10476@lists.johnshopkins.edu) to alert us of shipment with tracking number if 
available. To ensure the integrity of tissue specimens, shipment should occur on Monday- 
Wednesday to avoid unanticipated delivery delay due to weekends or holidays. 
 
5.3.2.2 Scheduling of Specimen Collection to the Lesinski Laboratory 
 
Whole blood samples (three 10mL EDTA tubes total) should be shipped the same day as 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
51 
 
 
 
collection and can be stored at ambient temperature until shipped. It is imperative that samples 
be drawn only Monday – Thursday only and shipped same day to ensure quality of the cells and 
plasma and avoid problems with weekend/holiday delivery. 
 
On the day that the specimens are to be shipped, notify 
 at 
 
 of the pending specimen shipments. 
Include the Fed-Ex tracking number in the email. 
 
5.3.2.3 Scheduling of Specimen Collection to the OSUCCC PhASR Laboratory 
 
Specimens should be stored through the end of Cycle 12 and shipped as a batch by participant 
(more than one participant/shipment is acceptable). A participant's samples should be shipped to 
the OSUCCC PhASR lab within 2 weeks of the last sample's collection date. (i.e., if C12D1 
sample is collected on 9/1/2021, all of that participant's samples should be at the OSUCCC 
PhASR lab by 9/15/2021). The OSUCCC PhASR lab may contact the study team to request 
shipment off-schedule. 
 
Please ship only 1 aliquot to the OSUCCC PhASR laboratory within each shipment. Once 
receipt is confirmed, the back-up aliquot(s) may also be shipped. The back-up aliquots can be 
shipped at a later date with subsequent batches of samples for other participants. 
 
All samples should be shipped via overnight express courier in insulated containers with enough 
dry ice to maintain the samples in a frozen state. Overnight shipments should occur on Monday 
through Wednesday except when the following day is a holiday. 
 
Please notify the OSUCCC PhASR lab by email (PhASR@osumc.edu) within 24 hours prior to 
shipment. 
 
The OSUCCC PhASR laboratory is equipped with -80°C freezers that are continuously 
monitored and recorded to ensure freezer integrity and that temperatures stay within specified 
ranges. If freezers deviate outside of specified ranges, PhASR staff is immediately notified, and 
any necessary corrective action is initiated. All samples acquired from patients enrolled on this 
study and that are sent to the OSUCCC PhASR will be stored within these monitored freezer 
systems prior to and after sample processing and analysis is completed. 
 
5.3.2.4 Scheduling of Specimen Collection to Foundation Medicine 
 
Whole blood samples should be shipped the same day as collection and should be stored at 
ambient temperature until shipped. Do not freeze or refrigerate the samples. Samples should 
only be collected monday-thursday. 
 
5.3.2.5 Scheduling of Specimen Collection to the EET Biobank 
 
Fresh blood specimens may be collected and shipped Monday through Friday. 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
52 
 
 
 
5.4 
Specimen Tracking System Instructions 
 
Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
x Protocol Number 
x Investigator Identification 
o Institution and affiliate name 
o Investigator’s name 
x Eligibility Verification: Patients must meet all the eligibility requirements listed in 
Section 3. 
x Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID. The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this or any other protocol that uses the ETCTN Specimen Tracking 
System. The UPID contains no information or link to the treatment protocol. IWRS will 
maintain an association between the UPID for ETCTN biobanking and molecular 
characterization and any treatment protocols the patient participates in, thereby allowing analysis 
of the molecular characterization results with the clinical data. 
 
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave. The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial. For newly acquired biopsies without a corresponding 
pathology report, the radiology and operative report(s) must also be uploaded into Rave, when 
available. Important: Remove any personally identifying information, including, but not 
limited to, the patient’s name, date of birth, initials, medical record number, and patient 
contact information from the institutional pathology report prior to submission. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software. 
 
For questions regarding the Specimen Tracking System, please contact STS Support at 
STS.Support@theradex.com. 
 
The Shipping List report must be included with all sample submissions. 
 
5.4.2 Specimen Labeling 
 
5.4.2.1 Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum): 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
53 
 
 
 
x Patient Study ID 
x Universal Patient ID (UPID) 
x Specimen ID (automatically generated by Rave) 
x Time point 
x Specimen type (e.g., blood, serum) 
x Collection date (to be added by hand) 
 
5.4.2.2 Tissue Specimen Labels 
 
Include the following on all tissue specimens (e.g., FFPE block, or frozen tissue): 
x Patient Study ID 
x Universal Patient ID (UPID) 
x Specimen ID (automatically generated by Rave) 
x Time point 
x Specimen type (e.g., formalin-fixed paraffin-embedded [FFPE] Block, Formalin 
Fixed Tissue, Fresh Tissue in Media, etc.) 
x Tissue type (P for primary, M for metastatic or N for normal) 
x Surgical pathology ID (SPID) number (when applicable) 
x Block number from the corresponding pathology report (FFPE tissue) 
x Collection date (to be added by hand) 
x Slide section number (only if archival tissue is submitted as slides) (to be added by 
hand) 
 
5.4.2.3 Example of Specimen Label Generated by STS 
 
STS includes a label printing facility, accessed via the Print Label CRF in the All Specimens 
folder. A generated PDF is emailed to the user as a result of saving that form. 
 
The following image is an example of a tissue specimen label printed on a label that is 0.5” high 
and 1.28” wide. 
 
 
 
 
The QR code in the above example is for the Specimen ID shown on the second line. 
 
Labels may be printed on a special purpose label printer, one label at a time, or on a standard 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
54 
 
 
 
laser printer, multiple labels per page. Theradex recommends the use of these low temperature 
waterproof labels for standard laser printers: https://www.labtag.com/shop/product/cryo-laser- 
labels-1-28-x-0-5-cl-23-colors-available/ 
 
The last line item on the label includes the following data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. An optional alpha-numeric code that is protocol specific and is only included if the 
protocol requires an additional special code classification 
 
Space is provided at the bottom of the label for the handwritten date and optional time. 
The last line on the example label is for the handwritten date and optional time. 
 
5.4.3 Overview of Process at Treating Site 
 
5.4.3.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system. OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization, and any prescribed slot 
assignments. If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration without eligibility specimen analysis: 
 
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal Patient 
ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.4.3.2 Rave Specimen Tracking Process Steps 
 
Step 0: Log into Rave via your CTEP-IAM account, then navigate to the appropriate participant. 
 
Step 1: Complete the Histology and Disease form (but do not upload reports until a specimen 
label can be applied to them) and the Baseline forms regarding Prior Therapies. Enter the 
initial clinical specimen data: 
x Specimen Tracking Enrollment CRF: Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, and number of labels 
needed (include extra labels to apply to reports to be uploaded). CRF generates unique 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
55 
 
 
 
Specimen ID. 
 
Step 2: Print labels using the Print Labels CRF located in the All Specimens folder, then 
collect specimen. 
x Label specimen containers and write collection date on each label. After collection, 
store labeled specimens as described in Section 5.4.2. 
x Apply an extra specimen label to each report before scanning. Return to the Histology 
and Disease form to upload any initial Pathology, Radiology, Bone Marrow [if bone 
marrow is submitted], Molecular Reports (up to 4), and Surgical (or Operative) reports. 
Return to Specimen Tracking Enrollment CRF to upload any molecular report (one per 
specimen) and/or specimen specific pathology or related report (one per specimen) and/or 
the Tissue Biopsy Verification form (when applicable). Uploaded reports should have 
protected health information (PHI) data, like name, date of birth, mailing address, 
medical record number or social security number (SSN), redacted. Do not redact SPID, 
block number, diagnosis or relevant dates (such as collection date), and include the 
UPID and patient study ID on each document (either by adding a label or hand 
writing). 
 
Step 3: Complete specimen data entry. 
x Specimen Transmittal Form: Enter collection date and time and other required 
specimen details. 
 
Step 4: When ready to ship, enter shipment information. 
x Shipping Status CRF: Enter tracking number, your contact information, recipient, 
number of sample containers and ship date once for the first specimen in a shipment. 
x Copy Shipping CRF: In the specimen folders for additional specimens (if any) that will 
be shipped with the initial specimen, please use the Copy Shipping form to derive 
common data into additional Shipping Status forms. A few unique fields will still need 
to be entered in Shipping Status. 
Step 5: Print shipping list report and prepare to ship. 
x Shipping List report is available at the site level. 
x Print two copies of the shipping list, one to provide in the box, the other for your own 
records. 
x Print pathology or other required reports to include in the box. Be sure the printed copy 
includes the specimen label. 
 
Step 6: Send email notification. 
x For only one of the specimens in the shipment, click “Send Email Alert” checkbox on the 
Shipping Status CRF to email recipient. 
 
Step 7: Ship the specimen(s). 
 
Step 8: Monitor the Receiving Status form located in each specimen folder for acknowledgment 
of receipt and adequacy. 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
56 
 
 
 
5.5 
Specimen Collection 
 
Archival Tumor Tissues 
a. Attempts to obtain biopsy or surgical archival tumor samples will be made for 
every subject. The tissue sample should have proper size to enable analysis. 
Request for tissue samples should begin during Screening Visit and continue to be 
requested until tissue sample is obtained or documentation that the sample cannot 
be obtained. Samples should be from the most recent biopsy or surgical resection 
of the original tumor (or metastatic site, if original tumor is not available). 
b. One formalin-fixed paraffin-embedded tissue block, or cut unstained slides will 
be requested. If sufficient tissue is available, we request 1 H&E cut at 4 
micrometers, 15 unstained sections, cut at 4 micrometers and mounted in poly-l- 
lysine-coated or plus (+) slides. 
c. The sectioning of FFPE tissue for the immunohistochemical studies, and 
molecular study should be done at the same time as the standard clinical H&E 
section and the immunohistochemical sections to minimize tissue loss. Remaining 
tissue will be archived by the Pathology Department at each respective institution. 
FNA samples do not contain adequate material for analysis and will not be 
requested. 
d. The following guidelines should be used for preparation of slides: 
i. Slides #1: to be regular 4 microns, positively charged slide, H&E, with 
cover 
ii. Slides #2 and above: 4 microns, positively charged slides, unstained, NO 
COVER 
iii. Blades need to be changed between blocks, if more than one block is 
being cut. 
iv. If possible, slides and process need to be DNAase free and tissue should 
be mounted on the bottom third of the slide. 
 
Fresh Tumor Specimens 
a. Supplies 
i. 10% Neutral Buffered Formalin (ambient/room temperature) (VWR 
#16004-115) 
ii. Cryovial tubes – 1.8 ml cryotubes/vials (e.g., Nunc Code #377267 or 
equivalent) 
iii. Conical tubes – 15 mL (e.g., Sarstedt Code #62.554.001 PP or equivalent) 
b. For patients with tumor that is amenable to biopsy, core biopsies will be collected 
at study baseline and at cycle 1 day 21 (+/-5 days). 
c. A maximum of 5 core biopsies (or fine needle aspirates, if cores are considered 
unsafe) will be obtained from each subject whose tumor is amenable to undergo a 
biopsy. 
d. The biopsies will be used to prepare paraffin embedded and frozen samples. A 
total of 5 biopsies is preferred, when possible. 
e. The first pass will generally be used for on-site examination of the material, to 
determine presence and quality of lesional tissue. 
f. The remaining biopsy tissue will be paraffin embedded and frozen at each 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
57 
 
 
 
respective institution. 
g. If a limited amount of tumor tissue is obtained, paraffin embedded tissue should 
be prioritized over frozen tissue. 
h. Archived or freshly obtained paraffin embedded formalin fixed (FFPE) or frozen 
tissues of biopsied specimens are needed for the purposes of: 
i. 
Pathological examination (for conventional pathology examination, such 
as H&E stain) 
ii. 
Examination of immune and inflammatory fibroblast biomarkers via 
IHC or IF analysis, as appropriate. 
iii. 
Future analysis of genomic and transcriptome features within the tumor 
microenvironment. 
i. Samples will be collected in this order: 
i. 
Core 1 – Formalin-fixed paraffin-embedded (FFPE) 
ii. 
Core 2 – FFPE 
iii. 
Core 3 – Snap Frozen 
iv. 
Core 4 – FFPE 
v. 
Core 5+ – Snap Frozen 
vi. 
For example, if only 2 cores are obtained, one core should be FFPE and 
one core should be snap frozen. 
j. Formalin-Fixed Paraffin-Embedded (FFPE) Tumor Specimens guide 
i. 
FFPE tumor tissue block(s) must be submitted. The optimal block is at 
least 70% tumor. 
ii. 
Specimen size requirement is as follows: 
1. Surface area: 25 mm2 is optimal. Minimum is 5 mm2. 
2. Volume: 1 mm3 optimal. Minimum volume is 0.2 mm3, however 
the success of DNA extraction decreases at suboptimal tissue 
volume. 
k. Snap Frozen Specimens guide 
i. 
The biopsy specimen should be placed in a 1.8 ml cryotubes/vials (e.g., 
Nunc Code #377267 or equivalent) 
ii. 
Label the cryovial with the timepoint (eg pretreatment or C1D21), and 
subject’s study ID. 
iii. 
Rapidly cool - the cryovial should be cooled to -70°C (or lower) very 
rapidly using dry ice, a -80°C freezer, or liquid nitrogen. 
iv. 
The snap frozen samples should never be thawed. 
 
Blood Collection 
 
5.5.3.1 Collection of Blood in Red Top Tube for Serum Processing 
 
a. Venous whole blood (6 mL) will be collected into pre-labeled serum (red-top; e.g. 
BD 367815 or 368660) tubes at the time points specified. Collect each PK sample 
as close as possible to the planned (nominal) time relative to dosing. 
b. If a cannula is used, the cannula will be inserted into an arm vein within sufficient 
time prior to dosing, kept patent with normal saline or heparin solution, and will 
be removed as instructed by physician or earlier if the subject requests. To avoid 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
58 
 
 
 
artificial dilution of the PK samples by saline, 1 mL of whole blood will be 
collected and discarded before each whole blood PK sample is collected. 
c. Processing at the collection site: 
i. Allow blood to clot upright at room temperature for at least 30 minutes 
(maximum 60 minutes) prior to processing. 
ii. If the blood is not immediately processed after the clotting period, then 
tubes should be stored (after the 30-60 minutes of clotting time) at 4°C for 
no longer than 4 hours. 
iii. Centrifuging for 10 minutes at 1,200 × g at room temperature. 
iv. Using a clean transfer pipette, aliquot serum into the labeled cryovials 
(~2-3) at an aliquot volume of 1 mL per tube. Labeling should be printed 
from the ETCTN Specimen Tracking System (label should include at a 
minimum the Study ID, Patient ID, sample type, sample collection date, 
exact sample collection time). 
v. Avoid picking up red blood cells when aliquoting by keeping the pipet 
above the red blood cell layer and leaving a small amount of serum in the 
tube. 
vi. Tightly secure the cap of the vials before storage. 
vii. Aliquoting and freezing of serum specimens should be completed within 1 
hour of centrifugation. 
viii. Store serum cryovials upright in a specimen box or rack in a -70°C to - 
90°C or colder freezer. Do not allow specimens to thaw after freezing. 
5.5.3.2 Collection of Blood in EDTA Tubes for Shipping Whole Blood 
 
1. Label EDTA tubes according to the instructions in Section 5.4.2. 
2. Collect blood in EDTA tube(s) and gently invert tube to mix. 
3. Samples must be collected Monday-Thursday and shipped the same day as collection. 
Samples can be stored at ambient temperature until shipped as indicated in section 
5.6.2.1 below 
4. If blood cannot be shipped on the day of collection (e.g., a late scheduled collection), 
then refrigerate until shipment. 
5. Upon arrival at the site of processing (Lesinski Laboratory) biospecimen processing 
for plasma and PBMCs and subsequent storage methods will follow standard 
guidelines (Fisher et al., 2018). 
 
5.5.3.3 Collection of Blood in FoundationOne Liquid CDx cfDNA tubes 
 
1. Label tubes with the labels supplied in the FoundationOne Liquid CDx kit. 
2. Check the blood collection tubes are clear without cloudiness or crystals. 
3. Collect 8.5 mL whole blood in the tube. Fill tube completely but prevent backflow to 
the patient. Collect sample Monday through Thursday only. Collect sample Monday 
through Thursday only. 
4. Immediately mix by gentle inversions 8 to 10 times. One inversion is a complete turn 
of the wrist 180 degrees and back. 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
59 
 
 
 
5. Store at room temperature until shipment. Ship same day as collection. Do NOT 
freeze or refrigerate samples. 
 
5.5.3.4 Collection of Blood in Streck cfDNA tube for shipment to the EET Biobank 
 
1. Label two 10 mL Streck cfDNA tubes according to the instructions in Section 5.4.2. 
2. Collect 10 mL of blood into each pre-labeled tube and gently invert to mix. Note: blood 
must be thoroughly mixed to ensure preservation of specimen. If patients may have an 
indwelling catheter: heparin should be avoided in pre-collection flush procedures. If 
therapeutic heparin dosing contamination is a possibility, then venipuncture is 
recommended as the first-choice collection method. If a Streck cfDNA tube immediately 
follows a heparin tube in the draw order, then collecting an EDTA tube as a waste tube 
prior to collection in the Streck Cell-Free DNA BCT is recommended. 
3. After collection, blood in Streck cfDNA tubes should never be refrigerated, as this 
will compromise the specimen. Blood collected in Streck cfDNA tubes is stable at room 
temperature until shipment to the EET Biobank. 
 
5.6 
Shipping Specimens from Clinical Site to the EET Biobank 
 
5.6.1 General Shipping Information 
 
When kits are provided, the shipping container sent with kit contents should be used to ship 
specimens to the EET Biobank. In winter months, please include extra insulation, such as bubble 
wrap, inside the shipping container. 
 
5.6.1.1 
Required Forms for Specimen Submissions: 
 
Each document submitted with the specimen must be labeled with a label printed from the 
STS, or the Universal ID and Patient Study ID. 
 
Tissue 
Required Forms 
Blood in Streck cfDNA tubes 
Shipping List 
 
5.6.2 Specimen Shipping Instructions 
 
Fresh blood may be shipped on Monday through Friday. Please select “Saturday Delivery” 
when shipping fresh blood on a Friday. 
 
5.6.2.1 
Shipping Blood in an Ambient Shipper 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions in 5.4.2.1 and that the lids of all primary receptacles containing liquid are 
tightly sealed. 
2. Prepare the SAF-T-TEMP Gel Pak for shipment. Note: If contents of the Pak are 
crunchy, place Pak in a warm water bath until gel is smooth. Do not refrigerate, freeze, 
or microwave. 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
60 
 
 
 
3. Place the SAF-T-TEMP Pak in bottom of insulated chest. Note: The insulated chest 
must be shipped inside the provided cardboard box(es). 
4. Place the blood collection tubes in zip-lock bags. 
5. Next, place blood into a biohazard envelope with absorbent material. Expel as much air 
as possible and seal the envelope securely. 
6. Place the biohazard envelope into a Tyvek envelope. Expel as much air as possible and 
seal securely. 
7. Place packaged blood collection tube(s) and a copy of the shipping manifest from the 
Sample Tracking System on top of SAF-T-TEMP Pak. 
8. Place the lid on the insulated chest. 
9. Close the outer flaps of the shipping box and tape shut. 
10. Attach a shipping label to the top of the shipping container. 
11. Attach an Exempt Human Specimen sticker to the side of the box. 
12. Ship specimens via overnight courier to the address below. FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt. 
 
5.6.2 Shipping Address 
 
Ship to the address below. Ship fresh blood specimens the same day of specimen collection. Do 
not ship specimens the day before a holiday. 
 
EET Biobank 
The Research Institute at Nationwide Children's Hospital 
700 Children's Drive, WA1340 
Columbus, Ohio 43205 
PH: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred. 
 
NOTE: The EET Biobank FedEx Account will not be provided to submitting institutions. There 
is no central Courier account for this study. Sites are responsible for the cost of shipments to the 
EET Biobank. 
 
5.6.3 Contact Information for Assistance 
 
For all queries, please use the contact information below: 
 
EET Biobank 
Toll-free Phone: (800) 347-2486 
E-mail: BPCBank@nationwidechildrens.org 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
61 
 
 
 
5.7 
Shipping of Specimens from Clinical Site to Other Laboratories 
 
Shipping of Specimens to Yarchoan Laboratory 
 
5.7.1.1 Specimen Shipping Instructions 
 
Frozen tissue samples (snap frozen cores) must be shipped frozen in cryovials and maintained in 
the frozen state. All shipments should be made in freezer boxes containing DRY ICE, and 
labeled as HUMAN SAMPLES: NONINFECTIOUS. 
 
FFPE specimens may be shipped at room temperature along with corresponding frozen cores, or 
as a batch shipment. 
 
Each tumor sample must be clearly labelled with the study number (10476) the subject’s ID, the 
date and time of collection, tissue biopsy site (i.e. liver), the study time point (i.e. BL, C1D21), 
and the tissue type. 
5.7.1.2 Shipping address for TISSUE BIOPSIES (NOT RESEARCH BLOODS) follows: 
Yarchoan Laboratory 
Attn: 
, NCI 10476 
1550 Orleans Street 
CRBI Room 
 
Baltimore, MD 21287 
Tel:
 
5.7.1.3 Contact Information for Assistance 
 
 
 
ctep10476@lists.johnshopkins.edu 
 
Shipping of Specimens to Lesinski Laboratory 
 
5.7.2.1 Specimen Shipping Instructions 
 
Three 10 mL purple top tubes of blood containing EDTA as an anti-coagulant will be obtained 
for correlative studies at each of the pre-specified time points. 
 
Adherent labels will be placed on each tube and using an ethanol-resistant permanent marker 
label EDTA tubes according to the instruction in Section 5.4.2. 
Samples should be shipped the same day as collection and can be stored at ambient temperature 
until shipped. 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
62 
 
 
 
To ensure quality of the cells and plasma, it is imperative that samples be shipped on Monday – 
Thursday only to avoid problems with weekend/holiday delivery. 
 
For shipment of blood samples, specimens will remain in the purple top tubes, which are to be 
placed into a cardboard box containing stryofoam holders that stabilize the glass tubes. An ice 
pack should be added to each shipment to reduce temperature for shipment. 
 
The box containing blood and cold pack should be contained within a Fed-Ex UN3373 Clinical 
Pak. 
 
All blood specimens should be shipped via Fed-Ex priority overnight the same day of collection 
for next day processing and analysis to the address below. 
5.7.2.2 Shipping Address for RESEARCH BLOODS (NOT TISSUE BIOPSIES) follows: 
Lesinski Laboratory 
Suite C3054, Bay 17 
1365-C Clifton Rd. NE 
Winship Cancer Institute of Emory University 
Atlanta, GA 30322 
 
5.7.2.3 Contact Information for Assistance 
 
On the day that the specimens are to be shipped, email 
EMORYCTEP10476@listserv.cc.emory.edu and cc 
 
 and Dr. 
 
 of the pending specimen shipments. Include the Fed-Ex 
tracking number in the email. 
 
Research blood contact information: 
 
, Ph.D., MPH 
 
 
 
Shipping of Specimens to OSUCCC PhASR Laboratory (Blood Samples for Drug 
Clearance and Immunogenicity Studies only) 
 
5.7.3.1 Specimen Shipping Instructions 
 
Specimens should be stored through the end of Cycle 12 or End of Treatment (whichever comes 
first) and shipped as a batch by participant (more than one participant/shipment is acceptable). 
 
A participant's samples should be shipped to the OSUCCC PhASR lab within 2 weeks of the last 
sample's collection date. (i.e., if C12D1 sample is collected on 9/1/2021, all of that participant's 
samples should be at the OSUCCC PhASR lab by 9/15/2021). 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
63 
 
 
 
The OSUCCC PhASR lab may contact the study team to request shipment off-schedule. 
 
Please ship only 1 aliquot to the OSUCCC PhASR laboratory within each shipment. Once 
receipt is confirmed, the back-up aliquot(s) may also be shipped. The back-up aliquots can be 
shipped at a later date with subsequent batches of samples for other participants. 
 
Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, LxWxH) with dividers. (e.g., 
VWR Box item number is 82021-114; divider item number is 82007-154.) 
 
Please organize the samples by Patient and Time point in the box. 
 
Do not store in plastic bags (they break on dry-ice and labels will detach). 
 
A copy of each of the pharmacokinetic sample collection forms for the respective patients or a 
sample list should be included with each shipment. To prevent problems with illegible writing on 
tubes, consider numbering them (in addition to sample label) and numbering samples on the 
sample sheet. 
 
Note the study number, PI, and the drugs used/to be measured (i.e. atezolizumab and CDX-1127 
(varlilumab). 
 
A name, phone number and email address should be included with samples so that receipt can be 
acknowledged. 
 
All samples should be shipped via overnight express courier in insulated containers with enough 
dry ice to maintain the samples in a frozen state. 
 
Overnight shipments should occur on Monday through Wednesday except when the following 
day is a holiday. 
 
Please notify the OSUCCC PhASR lab by email (PhASR@osumc.edu) within 24 hours prior to 
shipment. 
 
5.7.3.2 Shipping Address 
 
The OSUCCC Pharmacoanalytical Shared Resource 
Attn: 
, Ph.D. 
441 Biomedical Research Tower 
460 West 12th Avenue 
Columbus, OH 43210 
Phone: 
 
 
5.7.3.3 Contact Information for Assistance 
OSUCCC PhASR lab 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
64 
 
 
 
PhASR@osumc.edu 
, PhD or 
, PhD can be reached at: (
 
, PhD can be reached at: (
 
 
Shipping of Specimens to Foundation Medicine (Blood Samples for ctDNA Studies only) 
 
5.7.4.1 Specimen Shipping Instructions 
 
Package and mail the specimen(s) to the Foundation Medicine laboratory. Each kit should be 
utilized for one patient. Do not include different patient samples in the same box. 
 
Shipping Instructions 
 
1. Remove the kit tracking information and keep for your records. 
2. Place the specimen kit (including samples and paperwork) into the provided FedEx 
shipping pack, first ensuring that primary specimen containers (e.g. tubes) are labeled 
with two patient-specific identifiers. Seal the shipping pack. 
3. If using shipping pack provided in this kit (recommended), recording the Kit ID # will 
allow you to properly track specimen. If you use a different shipping pack, consider 
recording that pack’s tracking number. 
4. Call 800.463.3339 to request a pick-up or drop the package at your site’s designated 
FedEx pick-up location and ship sealed shipping pack. 
 
5.7.4.2 Shipping Address 
Foundation Medicine, Inc. 
150 Second Street 
Cambridge, MA 02141 
 
5.7.4.3 Contact Information for Assistance 
Phone: 888.988.3639 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
65 
 
 
 
 
5.8 
Biomarker Plan 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
66 
 
 
List of Biomarker Assays in Order of Priority 
Note for participating sites: Please see Section 5.1 for details on specimens to collect. The specimens tested are not always the 
same specimens that are submitted by the site, as processing of blood and tissue will occur at the laboratory prior to testing. 
Priority 
Biomarker 
Name 
Assay 
(CLIA: Y/N) 
Use in the Trial 
and Purpose 
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or Optional 
Assay Laboratory and 
Lab PI 
Tissue-based Biomarkers 
1 
CD8+T 
effector cells 
IHC 
CLIA: N 
Integrated 
To determine the 
effect of 
combination 
atezolizumab and 
CDX-1127 
(varlilumab) +/- 
cobimetinib on 
CD8+ effector 
tumor infiltrating 
lymphocytes 
population 
FFPE 
Tumor 
tissue 
Archival, 
Baseline and 
C1D21 
M 
Assay (Validated by 
) 
Yarchoan Laboratory, 
Johns Hopkins School of 
Medicine 
 
 
 
 
Johns Hopkins University 
School of Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
Tumor PD-L1 
expression 
IHC 
CLIA: N 
Exploratory 
To explore changes 
in the tumor 
microenvironment 
that may impact 
response to therapy 
FFPE 
Tumor 
Tissue 
Archival, 
Baseline and 
C1D21 
M 
Assay (Validated by 
 
Yarchoan Laboratory, 
Johns Hopkins School of 
Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Johns Hopkins University 
School of Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
67 
 
 
 
Priority 
Biomarker 
Name 
Assay 
(CLIA: Y/N) 
Use in the Trial 
and Purpose 
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or Optional 
Assay Laboratory and 
Lab PI 
3 
Analysis of 
tumor 
microenviron 
ment (TME) 
Multiplex IHC 
CLIA: N 
Exploratory 
To explore the effect 
of combination 
CDX-1127 
(varlilumab), and 
atezolizumab +/- 
cobimetinib on the 
tumor 
microenvironment 
examining changes 
to tumor immune 
infiltrating 
lymphocyte 
populations (TILs) 
and correlate these 
trends with 
therapeutic response 
FFPE 
Tumor 
tissue 
Archival, 
Baseline and 
C1D21 
M 
Yarchoan Laboratory, 
Johns Hopkins School of 
Medicine 
 
 
4 
Analysis of 
expression of 
immune- 
related 
pathways in 
the tumor 
microenviron 
ment (TME) 
RNA Seq 
CLIA: N 
Exploratory 
To explore the effect 
of combination 
CDX-1127 
(varlilumab), and 
atezolizumab +/- 
cobimetinib on the 
tumor 
microenvironment 
examining changes 
to expression of 
immune-related 
pathways and 
correlate these 
trends with 
therapeutic response 
Snap 
Frozen 
Archival, 
Baseline and 
C1D21 
M 
Yarchoan Laboratory, 
Johns Hopkins School of 
Medicine 
 
 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
68 
 
 
 
Priority 
Biomarker 
Name 
Assay 
(CLIA: Y/N) 
Use in the Trial 
and Purpose 
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or Optional 
Assay Laboratory and 
Lab PI 
Blood-based Biomarkers 
1 
Atezolizumab 
and CDX- 
1127 
(varlilumab) 
clearance 
 
 
Immunogenici 
ty, anti-drug 
antibodies 
(ADAs) for 
atezolizumab 
and CDX- 
1127 
(varlilumab) 
ELISA for 
CDX-1127 
(varlilumab) 
PK 
CLIA: N but 
GLP 
and 
ELISA for 
atezolizumab 
PK 
CLIA: N but 
GLP 
Integrated 
PK samples are to 
explore baseline and 
time-varying 
clearance of 
atezolizumab and 
CDX-1127 
(varlilumab) as 
potential biomarkers 
for response 
therapy. 
 
The same samples 
will also be used to 
identify 
immunogenicity and 
presence of ADA 
for both 
atezolizumab and 
CDX-1127 
(varlilumab) 
Serum from 
peripheral 
blood in red 
top tubes 
Day 1 of 
Cycles 1-6, 9 
and 12 
Pretreatment 
and 30 
minutes after 
the end of 
infusion of 
CDX-1127 
(varlilumab), 
which will be 
administered 
after 
atezolizumab 
Day 15 of 
Cycles 1-2: 
Pretreatment 
and 30 
minutes after 
the end of 
infusion of 
CDX-1127 
(varlilumab), 
which will be 
administered 
after 
atezolizumab 
M 
Pharmacoanalytic at 
Shared Resource 
(PhASR), Ohio State 
University (OSU) 
Comprehensive Cancer 
Center 
 
 
2 
ctDNA 
NGS 
CLIA: Y 
Integrated 
To explore how 
circulating tumor 
genomic 
characteristics (e.g. 
tumor mutation 
burden) may serve 
DNA from 
Peripheral 
blood in 
Foundation 
One Liquid 
CDx cfDNA 
tubes 
Baseline 
O 
Foundation Medicine 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
69 
 
 
 
Priority 
Biomarker 
Name 
Assay 
(CLIA: Y/N) 
Use in the Trial 
and Purpose 
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or Optional 
Assay Laboratory and 
Lab PI 
 
 
 
as biomarkers for 
response and/or 
resistance to study 
therapies. 
 
 
 
 
3 
Circulating T 
cell 
phenotypic 
and functional 
markers in 
peripheral 
blood (Th/Tc, 
phenotype, 
naïve/memory 
and exhaustion 
markers 
Mass 
Cytometry 
CLIA: N 
Exploratory 
To explore the effect 
of dual anti- 
combination CDX- 
1127 (varlilumab), 
and atezolizumab 
+/- cobimetinib on T 
cell immune 
regulatory markers, 
and their impact on 
response to therapy. 
PBMCs 
from 
Peripheral 
blood in 
EDTA tubes 
Baseline, 
C1D21, and 
Week 12 (end 
of Cycle 3), 
EOT 
M 
Lesinski Laboratory, 
Winship Cancer Institute 
of Emory University 
 
 
Paulos Laboratory, 
Winship Cancer Institute 
of Emory University 
 
 
4 
Circulating 
Plasma 
Cytokines 
(Th1/Th2/Th1 
7 cytokine 
profiles) 
Luminex, 
ELISA 
CLIA: N 
Exploratory 
To explore the effect 
of CDX-1127 
(varlilumab), and 
atezolizumab +/- 
cobimetinib on 
systemic cytokine 
biomarkers, their 
relationship to Th- 
profile and impact 
on response therapy. 
Plasma from 
Peripheral 
blood in 
EDTA tubes 
Baseline, 
C1D21, and 
Week 12 (end 
of Cycle 3), 
EOT 
M 
Lesinski Laboratory, 
Winship Cancer Institute 
of Emory University 
 
 
Paulos Laboratory, 
Winship Cancer Institute 
of Emory University 
 
 

NCI Protocol #: 10476 
Version Date: October 9, 2023 
70 
 
 
 
Priority 
Biomarker 
Name 
Assay 
(CLIA: Y/N) 
Use in the Trial 
and Purpose 
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or Optional 
Assay Laboratory and 
Lab PI 
5 
Circulating 
Tumor DNA 
(ctDNA) 
TSO500 
CLIA: N 
Exploratory 
To assess 
concordance 
between the tissue 
and liquid biopsies; 
to capture a 
comprehensive 
mutational profile; 
and to explore how 
circulating tumore 
genomic 
characteristic may 
serve as biomarkers 
for response and/or 
resistance to study 
therapies. 
Plasma from 
blood in 
Streck 
cfDNA tube 
Baseline, 
C1D21, and 
EOT 
M 
NCLN Genomics or 
MoCha, Frederick 
National Laboratory for 
Cancer Research 
(FNLCR) 
 
 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
71 
 
 
5.9 
Integrated Correlative Studies 
 
CD8+T effector cells 
 
5.9.1.1 Specimen Receipt and Processing Yarchoan Laboratory, Johns Hopkins School of 
Medicine 
 
FFPE blocks will be received and stored as appropriate until analysis. 
 
5.9.1.2 Site(s) Performing Correlative Study 
 
Yarchoan Laboratory, Johns Hopkins School of Medicine 
 
5.9.1.3 Contact information for notification of specimen shipment 
See Section 5.6.1 
Atezolizumab and CDX-1127 (varlilumab) clearance and ADA 
 
5.9.2.1 Specimen Receipt and Processing at PhASR, Ohio State University 
 
Aliquots of serum will be received and stored until the time of analysis. Sample analysis for PK 
will be completed using two validated ELISA assays, one each for CDX-1127 (varlilumab) and 
atezolizumab. Using drug concentration vs. time data through Cycle 6 and nonlinear mixed 
effects modeling, we will estimate the baseline and time-varying clearance for each of the two 
drugs. For immunogenicity assessment, two separate ADA screening ELISAs will be used, one 
each for CDX-1127 (varlilumab) and atezolizumab. Samples yielding positive results will be 
subsequently tested in bridging ELISAs, one each for CDX-1127 (varlilumab) and atezolizumab, 
for confirmation of ADA. 
 
5.9.2.2 
Site(s) Performing Correlative Study 
PhASR, Ohio State University 
5.9.2.3 Contact information for notification of specimen shipment 
See Section 5.6.3. 
ctDNA 
 
5.9.3.1 Specimen Receipt and Processing Foundation Medicine 
 
Whole blood will be received and processed to plasma. The DNA will then be isolated from the 
plasma and analyzed (https://www.accessdata.fda.gov/cdrh_docs/pdf19/P190032B.pdf). 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
72 
 
 
5.9.3.2 Site(s) Performing Correlative Study 
Foundation Medicine per standard of care. 
5.9.3.3 Contact information for notification of specimen shipment 
See Section 5.6.4. 
5.10 Exploratory/Ancillary Correlative Studies 
 
Tumor PD-L1 expression 
 
5.10.1.1 Specimen Receipt and Processing Yarchoan Laboratory, Johns Hopkins School of 
Medicine 
 
FFPE blocks will be received and stored as appropriate until analysis. 
 
5.10.1.2 Site(s) Performing Correlative Study 
 
Yarchoan Laboratory, Johns Hopkins School of Medicine 
 
5.10.1.3 Contact information for notification of specimen shipment 
See Section 5.6.1 
Tumor Microenvironment (TME) Assessment - Tumor infiltrating lymphocyte and 
immune pathway analysis 
 
5.10.2.1 Specimen Receipt and Processing Yarchoan Laboratory, Johns Hopkins School of 
Medicine 
 
FFPE blocks and frozen tumor cores will be received and stored as appropriate until analysis. 
 
5.10.2.2 
Site(s) Performing Correlative Study 
Yarchoan Laboratory, Johns Hopkins School of Medicine. 
5.10.2.3 
Contact information for notification of specimen shipment 
See Section 5.6.1 
Circulating T cell phenotypic and functional markers in peripheral blood (Th/Tc, 
phenotype, naïve/memory and exhaustion markers [e.g. PD-1, CTLA4, ICOS, BTLA, 
LAG3, TIM, etc.,.]) 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
73 
 
 
5.10.3.1 Specimen Receipt and Processing Lesinski Laboratory, Winship Cancer Institute of 
Emory University 
 
Blood in EDTA tubes will be received, processed for PBMCs, and stored frozen until analysis. 
 
5.10.3.2 
Site(s) Performing Correlative Study 
 
Lesinski Laboratory, Winship Cancer Institute of Emory University and Paulos Laboratory, 
Winship Cancer Institute of Emory University 
 
5.10.3.3 
Contact information for notification of specimen shipment 
See Section 5.6.2. 
Circulating Plasma Cytokines (Th1/Th2/TH17 cytokine profiles) 
 
5.10.4.1 Specimen Receipt and Processing Lesinski Laboratory, Winship Cancer Institute of 
Emory University 
 
Blood in EDTA tubes will be received, processed to plasma, and stored frozen until analysis. 
 
5.10.4.2 
Site(s) Performing Correlative Study 
 
Lesinski Laboratory, Winship Cancer Institute of Emory University and Paulos Laboratory, 
Winship Cancer Institute of Emory University 
 
5.10.4.3 
Contact information for notification of specimen shipment 
See Section 5.6.2. 
ctDNA Sequencing 
 
5.10.5.1 
Specimen(s) Receipt and Processing at the EET Biobank 
 
Whole blood collected in Streck cfDNA tubes will be processed for plasma and buffy coat. 
Plasma and buffy coat aliquots will be stored in a -80°C freezer. 
 
5.10.5.2 Site(s) Performing Correlative Study 
 
ctDNA sequencing will be performed at the NCLN Genomics Laboratory or the MoCha, 
Frederick National Laboratory for Cancer Research (FNLCR) under the supervision of Dr. 
 
 
5.10.5.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
Specimens will be shipped from the EET Biobank to one of the laboratories designated in 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
74 
 
 
Section 5.10.5.2. 
 
5.10.5.4 
Contact Information for Notification of Specimen Shipment 
 (NCLNGenomicsReceiving@nih.gov) 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
75 
 
 
6. TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. For all patients, atezolizumab is 
administered first, followed by CDX-1127 (varlilumab). For patients on Arm A and on infusion 
days, cobimetinib is to be taken prior to starting atezolizumab. Reported adverse events and 
potential risks are described in Section 10. Appropriate dose modifications are described in 
Section 7. No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy. 
 
Regimen Description -Arm A 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule** 
Cycle 
Length 
Atezolizumab 
Premeds are not 
permitted for the 
first infusion. If 
patient 
experiences an 
Infusion-Related 
Reaction (IRR), 
pre-medication 
with 
antihistamines 
may be 
administered for 
subsequent 
infusions at the 
discretion of the 
treating 
physician. 
840 mg 
IV (Initial dose 
delivered over 
approximately 
60 minutes. 
Subsequent 
infusions may 
be delivered 
over 
approximately 
30 minutes if 
initial infusion 
is tolerated 
without 
infusion- 
associated AEs. 
Days 1 and 
15 
 
 
 
 
 
 
 
 
 
 
 
 
28 days 
(4 weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
76 
 
 
 
 
 
 
 
 
 
 
Cobimetinib 
Cobimetinib 
should be taken 
at the same time 
every morning. It 
can be taken with 
or without food*. 
60 mg 
PO 
Daily, Days 
1-21 
* The patient will be requested to maintain a medication diary of each dose of medication. The 
medication diary will be returned to clinic staff at the end of each course (Appendix E). If 
patient misses a day, they should resume their normal dose/time the next day and not “make up” 
the missed dose. If patient is unable to take their dose within 4 hours of regularly scheduled 
time on the same day, that day’s dose should be considered missed and not taken. Resume 
dosing at the next scheduled dose/time. 
 
 
**On Days 1 and 15, Cobimetinib should be taken before arrival for infusion of Atezolizumab 
& CDX-1127 (varlilumab). Atezolizumab infusion should be administered first followed by 
CDX-1127 (varlilumab). Required wait time of 30 minutes between completion of atezolizumab 
and subsequent start of CDX-1127 (varlilumab). If unable to take dose prior to infusion, patient 
may still take that day’s dose as long as it is within 4 hours of regularly scheduled morning time, 
otherwise it should be considered missed and not taken. Resume dosing at the next scheduled 
dose/time. 
 
Regimen Description -Arm B 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule** 
Cycle 
Length 
Atezolizumab 
Premeds are not 
permitted for the 
first infusion. If 
patient 
experiences an 
Infusion-Related 
Reaction (IRR), 
pre-medication 
with 
antihistamines 
may be 
administered for 
subsequent 
infusions at the 
840 mg 
IV (initial dose 
over 
approximately 
60 minutes. 
Subsequent 
infusions may 
be delivered 
over 
approximately 
30 minutes if 
initial infusion 
is tolerated 
without 
infusion- 
Days 1 and 
15 
 
 
 
 
28 days 
(4 weeks) 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
77 
 
 
Subsequent Infusions 
First Infusion 
 
 
discretion of the 
treating 
physician. 
 
associated AEs.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
**Atezolizumab should be administered first followed by CDX-1127 (varlilumab). Required 
wait time of 30 minutes between completion of atezolizumab and subsequent start of CDX-1127 
(varlilumab). 
 
CTEP IND Agents 
 
6.1.1.1 Atezolizumab 
 
For anaphylaxis precautions, see the management guidelines. Atezolizumab infusions will be 
administered per the instructions outlined in table below: 
 
Administration of First and Subsequent Atezolizumab Infusions 
 
 
x No premedication is permitted prior to the 
atezolizumab infusion. 
x Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) will be 
measured within 60 minutes prior to the 
infusion. 
x Atezolizumab should be infused over 
60 (r15) minutes. 
x Vital signs will be measured every 
15 (r5) minutes during the infusion and at 
30 (r10) minutes after the infusion. 
x Patients will be observed for at least 4 
x 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. 
x Vital signs will be measured within 
60 minutes prior to the infusion, within 30 
minutes after the infusion, and as clinically 
indicated during the infusion. 
x Atezolizumab should be infused over 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
78 
 
 
hours after the completion of all infusions. 
x Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
30 (r10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (r15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion. 
x If the patient experienced an 
infusionrelated reaction with the previous 
infusion or if clinically indicated, vital 
signs should be measured during the 
infusion and at 30 (r 10) minutes after the 
infusion. 
x Patients should be observed for at least 1 
hour after the last study drug infusion. 
 
For anaphylaxis precautions, use the following procedure: 
 
Equipment Needed 
 
Ɣ Monitoring devices: ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
Ɣ Oxygen 
Ɣ Epinephrine for subcutaneous, intravenous, intramuscular, and/or endotracheal 
use in accordance with standard practice 
Ɣ Antihistamines 
Ɣ Corticosteroids 
Ɣ IV infusion solutions, tubing, catheters, and tape 
 
Procedures 
 
In the event of a suspected anaphylactic reaction during atezolizumab infusion, the 
following procedures should be performed: 
 
1. Stop the study drug infusion. 
2. Call for additional medical assistance. 
3. Maintain an adequate airway. 
4. Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring, if possible. 
5. Administer antihistamines, epinephrine, or other medications as required by 
patient status and directed by the physician in charge. 
6. Continue to observe the patient and document observations. 
 
6.1.1.2 CDX-1127 (varlilumab) 
 
CDX-1127 (varlilumab) will be given on Day 1 and Day 15 of each 28 day cycle at a dose of 3 
mg/kg. Baseline weight may be used for calculating the dose each cycle. The dose will be 
recalculated when weight changes by ± 10%. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
79 
 
 
 
Required wait time of 30 minutes between completion of atezolizumab and subsequent start of 
CDX-1127. 
 
All patients will be monitored for at least 4 hours following the completion of all infusions on 
the first dose (i.e. Day 1 of Cycle 1) and at least 1 hour following all subsequent doses. Vital 
sign measurements should be done similar as is stated for atezolizumab (section 6.1.1.1). 
 
CDX-1127 (varlilumab) cannot be mixed with any other drug in the infusion bag or the 
administration set. 
 
6.1.1.3 Cobimetinib 
 
Patients will receive cobimetinib at a dose of 60 mg (three tablets of 20 mg each) orally once 
daily for Days 1í21 of a 28-day cycle. This 4-week period is considered a treatment cycle. 
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
Section 7. 
 
Cobimetinib should be taken in the morning at the same time every day. It can be taken with or 
without food. If a dose of cobimetinib is not taken within 4 hours of the scheduled dose, it should 
be considered missed and not taken. Resume dosing at the next scheduled dose. If vomiting 
occurs when the dose is taken, resume dosing with the next scheduled dose. 
 
Patients receiving cobimetinib will be requested to maintain a medication diary (see Appendix E) 
of each dose of medication. The medication diary will be returned to clinic staff at the end of 
each course. The study team should review the diary for completeness and any inconsistencies 
and discuss them with the participant at the visit. 
 
6.1.1.4 Pregnancy 
 
All women of child bearing potential should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (e.g., missed or late menstrual period) at any time during 
study participation and 5 months after the last dose of Atezolizumab or 3 months after the last 
dose of cobimetinib. 
 
6.2 
Continuation after Unconfirmed Progression 
 
The study regimens in this trial trigger immune-mediated responses, which require activation of 
the immune system prior to the observation of clinical responses. Patients may continue 
receiving their assigned treatment if their disease progresses based on RECIST 1.1 criteria if 1) 
the patient is clinically stable; 2) No symptoms or signs indicating disease progression, including 
clinically significant laboratory values; 3) the patient is informed of their scan results and agrees 
to continue therapy, and 4) the patient provider agrees that remaining on study would be 
appropriate for the patient. If the following scan after first noted progression confirms 
progressive disease by RECIST 1.1, the scan where progression was first note will be used to 
calculate PFS. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
80 
 
 
 
6.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of atezolizumab, cobimetinib, and CDX-1127 
(varlilumab) with other concomitantly administered drugs, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies. The 
Principal Investigator should be alerted if the patient is taking any agent known to affect or with 
the potential for drug interactions. The study team should check a frequently-updated medical 
reference for a list of drugs to avoid or minimize use of. Appendix C (Patient Clinical Trial 
Wallet Card) should be provided to patients if available. 
 
Atezolizumab General Concomitant Medication Guidelines 
 
Concomitant therapy includes any prescription medications or over the counter preparations used 
by a patient between the 7 days preceding the screening evaluation and the treatment 
discontinuation visit. 
 
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or cimetidine or another H2 receptor 
antagonist, as per standard practice (for sites outside the United States, equivalent medications 
may be substituted per local 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 E2-adrenergic agonists). 
 
Systemic corticosteroids and TNFD inhibitors may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab but may be administered at the discretion of the treating 
physician. If feasible, alternatives to corticosteroids should be considered. Premedication may 
be administered for Cycles 2 at the discretion of the treating physician. The use of inhaled 
corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension or adrenocortical insufficiency is allowed. Megestrol administered as appetite 
stimulant is acceptable while the patient is enrolled in the study. 
 
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or therapeutic 
anticoagulation therapy (such as low-molecular-weight heparin or warfarin at a stable dose 
level), or other allowed maintenance therapy should continue their use. Males and females of 
reproductive potential should use highly effective means of contraception. 
 
Atezolizumab Excluded Therapies 
 
Any concomitant therapy intended for the treatment of cancer, whether health 
authority-approved or experimental, is prohibited unless it is specifically included in the 
treatment regimen described in this protocol. This includes but is not limited to the following: 
x Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational 
agents, or herbal therapy (except for maintenance therapies outlined in Section 6.2.1). 
o After Cycle 1, certain forms of radiotherapy may be considered for pain palliation 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
81 
 
 
if patients are deriving benefit (e.g., treatment of known bony metastases); 
atezolizumab administration may be suspended during radiotherapy. 
 
It is strongly recommended that: 
x Traditional herbal medicines not be administered because the ingredients of many 
herbal medicines are not fully studied and their use may result in unanticipated 
drug-drug interactions that may cause, or confound assessment of, toxicity. 
 
Initiation or increased dose of granulocyte colony-stimulating factors (e.g., granulocyte 
colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, and/or 
pegfilgrastim) is prohibited for patients with solid malignancies. 
 
Patients are not allowed to receive immunostimulatory agents, including, but not limited to, IFN- 
D, IFN-J, or IL-2, during the entire study. These agents, in combination with atezolizumab, 
could potentially increase the risk for autoimmune conditions. 
 
Patients should also not be receiving immunosuppressive medications, including, but not limited 
to, cyclophosphamide, azathioprine, methotrexate, and thalidomide. These agents could 
potentially alter the activity and the safety of atezolizumab. Systemic corticosteroids and anti- 
TNFD agents may attenuate potential beneficial immunologic effects of treatment with 
atezolizumab but may be administered at the discretion of the treating physician. If feasible, 
alternatives to these agents should be considered. 
 
 
 
 
 
 
 
 
 
Cobimetinib 
 
Coadministration of cobimetinib with a strong CYP3A inducer may decrease cobimetinib 
systemic exposure by more than 80% and reduce its efficacy. Avoid concurrent use of 
cobimetinib and strong or moderate CYP3A inducers. Use an alternative to a strong or moderate 
CYP3A inhibitor in patients who are taking a reduced dose of cobimetinib (40 or 20 mg daily). 
If concurrent short term (14 days or less) use of moderate CYP3A inhibitors is unavoidable for 
patients who are taking cobimetinib 60 mg, the dose of cobimetinib may be reduced to 20 mg 
and the previous dose of cobimetinib 60 mg can be resumed following moderate CYP3A 
inhibitor discontinuation. See Section 8 for further information. Concomitant administration of 
cobimetinib with oral contraceptives containing ethinyl estradiol is prohibited due to increased 
risk of venous thromboembolism. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
82 
 
 
6.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
x 
Disease progression 
 
x 
Intercurrent illness that prevents further administration of treatment 
 
x 
Unacceptable toxicity [adverse event(s)] 
 
x 
Patient decides to withdraw from the study 
 
x 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
x 
Clinical progression 
 
x 
Patient non-compliance 
 
x 
Pregnancy 
 
o All women of child bearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period) at any time during study participation and 5 months after the last dose of 
Atezolizumab. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
x 
Termination of the study by sponsor 
 
x 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
6.5 
Duration of Follow-Up 
 
Patients will be monitored for disease status at least every three months until death, withdrawal 
of consent, or study closure. Patients removed from study for unacceptable adverse event(s) will 
be followed until resolution or stabilization of the adverse event. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
83 
 
 
7. DOSING DELAYS/DOSE MODIFICATIONS 
 
7.1 
CDX-1127 (varlilumab) and Atezolizumab (all participants) 
 
General AE Management and Dose Modification Guidelines 
 
Dosing of both CDX-1127 (varlilumab) and atezolizumab is fixed with no dose-modification 
permitted. Both CDX-1127 (varlilumab) and atezolizumab should always be administered on the 
same day. Monotherapy with atezolizumab or CDX-1127 (varlilumab) alone is not permitted. 
 
On cycle 1 day 1 (first dose), patients will be observed for at least 4 hours after the last study 
drug administration to monitor for infusion reaction/cytokine release syndrome/hypersensitivity 
reaction. For all subsequent doses/cycles, patients should be monitored for at least 1 hour 
following the last administration of study drug. Infusions should be given in a monitored setting 
that has ready access to an intensive care unit in case of a severe infusion reaction. 
Acetaminophen may be used to manage drug-related adverse events such as fever, myalgias or 
arthralgias and anti-histamines may be used to manage drug-related adverse events such pruritus. 
 
Patients may temporarily suspend study treatment for up to 84 days (12 weeks) beyond the 
scheduled date of delayed infusion if study drug-related toxicity requiring dose suspension is 
experienced. If atezolizumab and CDX-1127 (varlilumab) are held because of AEs for !84 days 
beyond the scheduled date of infusion, the patient will be discontinued from atezolizumab-CDX- 
1127 (varlilumab) and will be followed for safety and efficacy as specified in this protocol. If 
the AE resolves within 84 days and the patient is receiving corticosteroid therapy for the event, 
atezolizumab-CDX-1127 (varlilumab) may be held for longer than 84 days (up to 4 weeks) in 
order to allow tapering of the steroid dose to 10 mg oral prednisone or equivalent. 
 
Dose interruptions for reasons other than toxicity, such as surgical procedures, may be allowed. 
The acceptable length of interruption will be at the discretion of the study PI in consultation with 
CTEP. 
 
 
 
 
 
 
Because of this, the algorithm used for the management of adverse events associated with 
atezolizumab monotherapy will be applied to the management of adverse events associated with 
atezolizumab-CDX-1127 (varlilumab) combination therapy. Guidelines for management of 
atezolizumab-associated adverse events described in depth below (Section 7.1.2 have been 
amended from “atezolizumab” alone to apply both “atezolizumab and CDX-1127 (varlilumab)” 
as a single treatment unit. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
84 
 
 
 
Generally speaking, patients receiving CDX-1127 (varlilumab) and atezolizumab should be 
monitored for signs and symptoms of enterocolitis, dermatitis, hepatotoxicity, neuropathy, 
pulmonary toxicity and endocrinopathy. Patients should be advised to immediately report 
symptoms such as unexplained abdominal pain, diarrhea, nausea or vomiting, severe rash or 
vision changes. Patients with unexplained symptoms such as fatigue, myalgias, impotence, 
mental status changes, or constipation should be investigated for the presence of thyroid, 
pituitary or adrenal endocrinopathies. Laboratory tests must be performed as outlined in study 
calendar. Visual complaints should be investigated by an ophthalmologist. 
 
The primary approach to grade 1 to 2 irAEs is supportive and symptomatic care with continued 
treatment with atezolizumab and CDX-1127 (varlilumab); for higher-grade irAEs, atezolizumab 
and CDX-1127 (varlilumab) should both be withheld and oral and/or parenteral steroids 
administered. Recurrent grade 2 irAEs may also mandate withholding of both atezolizumab & 
CDX-1127 (varlilumab) and/or the use of steroids. Assessment of the benefit-risk balance 
should be made by the investigator, with consideration of the totality of information as it pertains 
to the nature of the toxicity and the degree of clinical benefit a given patient may be experiencing 
prior to further administration of atezolizumab and CDX-1127 (varlilumab). Atezolizumab and 
CDX-1127 (varlilumab) should both be permanently discontinued in patients with 
life-threatening irAEs. 
 
Systemic Immune Activation 
 
Systemic immune activation is a rare condition characterized by an excessive immune response. 
Given the respective mechanisms of action of atezolizumab and CDX-1127 (varlilumab), 
systemic immune activation is considered a potential risk when given in combination. Systemic 
immune activation should be included in the differential diagnosis for patients who, in the 
absence of an alternative etiology, develop a sepsis-like syndrome after administration of 
atezolizumab and CDX-1127 (varlilumab), and the initial evaluation should include the 
following: 
x CBC with peripheral smear 
x PT, PTT, fibrinogen, and D-dimer 
x Ferritin 
x Triglycerides 
x AST, ALT, and total bilirubin 
x LDH 
x Complete neurologic and abdominal examination (assess for 
hepatosplenomegaly) 
 
If systemic immune activation is still suspected after the initial evaluation, contact the Principal 
Investigator for additional recommendations. 
 
Management of Specific AEs 
 
Management of certain AEs of concern, including immune-related pneumonitis, hepatitis, colitis, 
endocrinopathies, pancreatitis, neuropathies, meningoencephalitis, and potential ocular toxicities 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
85 
 
 
are presented in the Atezolizumab Investigator’s Brochure and CDX-1127 (varlilumab) 
Investigator’s Brochure. See Section 6.1.1 for guidelines for the management of Infusion 
Related Reactions and Anaphylaxis or otherwise follow institutional protocol. 
 
Atezolizumab has been associated with risks such as the following: IRRs and immune-mediated 
hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, 
adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, facial paresis, myelitis, meningoencephalitis, myocarditis, pericardial 
disorders, nephritis, myositis, and severe cutaneous adverse reactions. In addition, immune- 
mediated reactions may involve any organ system and lead to hemophagocytic 
lymphohistiocytosis (HLH). Neutropenia and lymphopenia associated with chemotherapy may 
increase the risk for developing an infection in patients receiving atezolizumab in combination 
with chemotherapy. 
 
Immune-mediated Cardiac Events 
 
Immune-mediated myocarditis and pericarditis have been associated with the administration of 
atezolizumab. Management guidelines for cardiac events are provided in the table below. 
 
Immune-mediated Myocarditis 
 
Immune-mediated myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-type 
natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, 
decreased exercise tolerance, or syncope. Myocarditis may also be a clinical manifestation of 
myositis or associated with pericarditis (see section on pericardial disorders below) and should 
be managed accordingly. Immune-mediated myocarditis needs to be distinguished from 
myocarditis resulting from infection (commonly viral, e.g., in a patient who reports a recent 
history of gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy. 
 
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines. A cardiologist should be consulted. An endomyocardial 
biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if clinically 
indicated. 
 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in the table below. 
 
Immune-mediated Pericardial Disorders 
 
Immune-mediated pericarditis should be suspected in any patient presenting with chest pain and 
may be associated with immune-mediated myocarditis (see section on myocarditis above). 
 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in any patient 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
86 
 
 
presenting with chest pain associated with dyspnea or hemodynamic instability. 
 
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac injury related 
(post myocardial infarction or iatrogenic), and autoimmune disorders, and should be managed 
accordingly. 
 
All patients with suspected pericardial disorders should be urgently evaluated by performing an 
ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as appropriate per 
institutional guidelines. A cardiologist should be consulted. Pericardiocentesis should be 
considered for diagnostic or therapeutic purposes, if clinically indicated. 
 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac tamponade, in 
the absence of an identified alternate etiology, should be treated according to the guidelines in 
the table below. Withhold treatment with atezolizumab for Grade 1 pericarditis and conduct a 
detailed cardiac evaluation to determine the etiology and manage accordingly. 
 
Event 
Management 
Immune-mediated 
myocarditis, Grade 
24 
 
Immune-mediated 
pericardial disorders, 
Grade 24 
x Permanently discontinue atezolizumab. 
x Refer patient to cardiologist. 
x Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, VAD, or 
pericardiocentesis as appropriate. 
x Initiate treatment with corticosteroids equivalent to 12 
mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
x If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
x If event resolves to Grade 1 or better, taper corticosteroids 
over t1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
 
Pulmonary events 
 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab. Patients will be assessed for pulmonary signs and 
symptoms throughout the study. 
 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease, or pulmonary hypertension. Management 
guidelines for pulmonary events are provided in the table below. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
87 
 
 
Endocrine disorders 
 
Patients experiencing one or more unexplained AEs possibly indicative of endocrine dysfunction 
(including fatigue, myalgias, impotence, mental status changes, and constipation) should be 
investigated for the presence of thyroid, pituitary, or adrenal endocrinopathies. The patient 
should be referred to an endocrinologist if an endocrinopathy is suspected. Thyroid-stimulating 
hormone (TSH) and free T3 and T4 levels should be measured to determine whether thyroid 
abnormalities are present. TSH, prolactin, and a morning cortisol level will help to differentiate 
primary adrenal insufficiency from primary pituitary insufficiency. The table below describes 
dose management guidelines for hyperthyroidism, hypothyroidism, symptomatic adrenal 
insufficiency, and hyperglycemia. 
 
Meningoencephalitis 
 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab. Immune-related meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness. Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process. 
 
All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If deemed 
safe by the treating physician, a lumbar puncture should be performed and a neurologist should 
be consulted. 
 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines. 
 
Neurologic disorders 
 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab. Patients may present with signs and symptoms of sensory and/or motor 
neuropathy. Diagnostic work-up is essential for an accurate characterization to differentiate 
between alternative etiologies. . Management guidelines for neurologic disorders, and specific 
guidelines for myelitis, are provided in the tables below. 
 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
x Continue atezolizumab. 
x Investigate etiology. 
x Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
88 
 
 
 
Event 
Management 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 2 
x Withhold atezolizumab for up to 12 weeks after event onset. a 
x Investigate etiology and refer patient to neurologist. 
x Initiate treatment as per institutional guidelines. 
x For general immune-mediated neuropathy: 
o If event resolves to Grade 1 or better, resume 
atezolizumab. b 
o If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab. c 
x For facial paresis: 
o If event resolves fully, resume atezolizumab. b 
o If event does not resolve fully while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 3 or 4 
x Permanently discontinue atezolizumab. c 
x Refer patient to neurologist. 
x Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
x Permanently discontinue atezolizumab. c 
x Refer patient to neurologist. 
x Initiate treatment as per institutional guidelines. 
x Consider initiation of corticosteroids equivalent to 12 
mg/kg/day oral or IV prednisone. 
a Atezolizumab may be withheld for a longer period of time (i.e., !12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of d10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over t1 month to the equivalent of 
d10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event. The decision to rechallenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate). 
 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
x 
Continue atezolizumab unless symptoms worsen or do 
not improve. 
x 
Investigate etiology and refer patient to a neurologist. 
Immune-mediated myelitis, 
Grade 2 
x 
Permanently discontinue atezolizumab. 
x 
Investigate etiology and refer patient to a neurologist. 
x 
Rule out infection. 
x 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
89 
 
 
 
Event 
Management 
Immune-mediated myelitis, 
Grade 3 or 4 
x 
Permanently discontinue atezolizumab. 
x 
Refer patient to a neurologist. 
x 
Initiate treatment as per institutional guidelines. 
 
 
For recommendations to hold atezolizumab and CDX-1127 (varlilumab) and begin corticosteroid 
treatment, use the following guidance for tapering the corticosteroid and resuming atezolizumab 
and CDX-1127 (varlilumab) therapy after resolution of the event: 
 
x Corticosteroids must be tapered over t1 month to d10 mg/day oral prednisone or 
equivalent before atezolizumab and CDX-1127 (varlilumab) can be resumed. 
x Atezolizumab and CDX-1127 (varlilumab) may be held for a period of time 
beyond 12 weeks to allow for corticosteroids to be reduced to d10 mg/day oral 
prednisone or equivalent. 
 
7.2 
Cobimetinib plus Atezolizumab and CDX-1127 (varlilumab) (Treatment Arm A 
patients only) 
 
Recommended Cobimetinib Dose Modifications 
 
In order to standardize the management of AEs, suggested treatment management algorithms for 
adverse events of particular concern for cobimetinib plus atezolizumab &CDX-1127 
(varlilumab) are included in Section 7.3. The following general dose modifications table for 
cobimetinib is for AEs not specified in the subsequent tables. 
 
Grade (CTCAE)a 
Recommended Cobimetinib Dose 
Grade 1 or Grade 2 
(tolerable) 
No dose reduction. Maintain cobimetinib at a dose of 60 mg 
QD (3 tablets) 
Grade 2 (intolerable) or 
Grade 3b or 4 (any) 
First appearance 
Interrupt treatment until 
Grade  1, restart treatment at 
40 mg QD (2 tablets) 
 
Second appearance 
Interrupt treatment until 
Grade  1, restart treatment at 
20 mg QD (1 tablet) 
Third appearance Consider permanent discontinuation 
CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer 
Institute; QD = once daily. 
a The intensity of clinical adverse events graded by NCI CTCAE v5.0. 
b An exception to this is for Grade 3 anemia, without presence of hemorrhage and/or 
hemolytic process. In this case, participants can be treated with transfusions as needed in 
order to improve to grade 2 or better and do not require treatment interruption or dose 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
90 
 
 
reduction. If recurrent transfusions are needed, treating provider can consider dose 
reduction. 
 
Toxicities will be evaluated using NCI CTCAE v5.0. If toxicity occurs, the toxicity will be 
graded and appropriate supportive care treatment will be administered to decrease symptoms. 
Generally, in the case of Grade 4 hematologic or Grade 3 to 4 non-hematologic toxicity (except 
for Grade 3 skin cancer, squamous or basal cell type), treatment with cobimetinib should be 
interrupted until recovery to baseline or Grade 1 and then resumed at one dose level reduction. 
Below is a table for cobimetinib dosing upon dose modification: 
 
Dose level 
Dose 
0 
60 mg QD 21 days out of 28 days 
(-1) 
40 mg QD, 21 days out of 28 days 
(-2) 
20 mg QD, 21 days out of 28 days 
 
Up to two dose reductions of cobimetinib will be allowed as follows: 40 mg PO daily and then 
20 mg PO daily for 21 days of a 28-day cycle. In the case of recurrent toxicity after two dose 
reductions, cobimetinib should be discontinued 
Management of Cobimetinib plus Atezolizumab and CDX-1127 (varlilumab)íAssociated 
Adverse Events of particular concern (Treatment Arm A) 
 
Due to the triplet combination acting through a range of mechanisms with potential overlapping 
and also distinct adverse events (AE), patients who experience intolerance or adverse events 
should be carefully evaluated to examine whether the AE can attributable to one of the two 
classes of therapies: 1) targeted therapy (cobmitinib); 2) immunotherapy [Atezolizumab and 
CDX-1127 (varlilumab)]. For example, a patient removed from cobimetinib therapy after 
developing retinal vein occlusion may continue on with their Atezolizumab and CDX-1127 
(varlilumab) combination. If there is ambiguity regarding the responsible drug/class of drug, all 
three agents should be held/discontinued with special consideration for full/partial regimen 
resumption as indicated by management guidelines detailed in section 7.3. 
 
Below are recommended management of specific adverse events of particular concern with the 
triplet combination therapy are provided here. 
 
GASTROINTESTINAL TOXICITY 
Diarrhea and colitis have been associated with the administration of Cobimetinib plus 
Atezolizumab. Diarrhea can frequently be managed with anti-diarrheal agents but can also 
progress to clinically significant dehydration and/or electrolyte imbalances with effects on other 
organs, possibly resulting in renal, hepatic, and/or cardiac failure. Patients should be instructed to 
promptly contact the investigators if they develop diarrhea. Investigators should treat diarrhea 
and intervene promptly for patients who appear to be at increased risk of developing significant 
dehydration, electrolyte imbalances, and/or multi-organ failure. Patients should receive 
maximum supportive care per institutional guidelines. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
91 
 
 
HEPATOTOXICITY 
Hepatoxicity has been associated with the administration of atezolizumab and cobimetinib. 
Eligible patients must have adequate liver function, as manifested by measurements of total 
bilirubin and hepatic transaminase, and liver function will be monitored throughout study 
treatment. 
 
While in this study, patients presenting with right upper-quadrant abdominal pain and/or 
unexplained nausea or vomiting should have liver function tests (LFTs) performed immediately 
and reviewed before administration of the next dose of study drug. 
 
If LFTs increase, neoplastic, concurrent medications, viral hepatitis, and toxic etiologies should 
be considered and addressed, as appropriate. Imaging of the liver, gall bladder, and biliary tree 
should be performed to rule out neoplastic or other causes for the increased LFTs. Anti-nuclear 
antibody, perinuclear anti-neutrophil cytoplasmic antibody, anti-liver kidney microsomal 
antibodies, and anti-smooth muscle antibody tests should considered. 
 
DERMATOLOGIC TOXICITY 
Treatment-emergent rash has been associated with atezolizumab and cobimetinib. The majority 
of the cases of rash were mild in severity and self-limited, with or without pruritus. Although 
uncommon, cases of severe cutaneous adverse reactions such as Stevens-Johnson syndrome and 
toxic epidermal necrolysis have been reported with atezolizumab. 
 
PULMONARY TOXICITY 
Mild-to-moderate events of pneumonitis have been reported with atezolizumab and cobimetinib. 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia/infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, 
chronic obstructive pulmonary disease, or pulmonary hypertension: 
x Measurement of oxygen saturation (i.e., arterial blood gas) 
x High-resolution computed tomography (CT) scan of the chest 
x Bronchoscopy with bronchoalveolar lavage and biopsy (if clinically feasible) 
x Pulmonary function tests (diffusion capacity of the lung for carbon monoxide) 
x Pulmonary function testing with a pulmonary embolism protocol 
 
Patients will be assessed for pulmonary signs and symptoms throughout the study. Patients will 
also have CT scans of the chest at every tumor assessment. Chest CT should be reviewed for 
pulmonary toxicities as well as for disease status. 
 
OCULAR TOXICITY 
An ophthalmologist should evaluate visual complaints. 
 
Uveitis or episcleritis and other immuneímediated ocular disease may be associated with 
atezolizumab and may be treated with topical corticosteroid eye drops. Atezolizumab should be 
permanently discontinued for immune-mediated ocular disease that is unresponsive to local 
immunosuppressive therapy. 
 
Serous retinopathy have been associated with cobimetinib. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
92 
 
 
 
DECREASED LEFT VENTRICULAR EJECTION FRACTION (LVEF) 
Decreased LVEF has been seen with cobimetinib. Permanent discontinuation of cobimetinib 
treatment should be considered if cardiac symptoms are attributed to cobimetinib and do not 
improve after temporary interruption. 
 
Decreased LVEF may also result from immune related cardiomyopathy, a potential risk of 
atezolizumab therapy. For this reason, atezolizumab & CDX-1127 (varlilumab) should also be 
held in the setting of decreased LVEF, pending the results of a cardiac workup. This work up 
should generally include troponin, CPK, cardiac MRI, EKG, and cardiology consultation. 
Atezolizumab & CDX-1127 (varlilumab) may be restarted on a case-by-case basis as long as 
LVEF is > 40% (or  10% absolute decrease from BL) and myocarditis has been excluded. For 
patients with more severe reductions in the LVEF, atezolizumab & CDX-1127 (varlilumab) may 
be restarted only if the patient is clinically stable, and after consultation with the trial PI. 
 
ELEVATED CPK 
Elevated CPK has been reported with cobimetinib. Recommended Dose Modifications for 
Cobimetinib in Patients with CPK Elevations are presented below in section 7.3. 
 
HEMORRHAGE 
Bleeding complications have been associated with cobimetinib treatment. There is no data on the 
effectiveness of cobimetinib dose modification for hemmorhagic events. 
 
7.3 
AE Management and Dose Interruption/Modification Guidelines 
 
AE Management and Dose Interruption Guidelines for Specific Toxicities 
Toxicity 
Severity/ 
Duration 
Management 
 
CDX-1127 (varlilumab) 
& Atezolizumab 
Cobimetinib plus 
CDX-1127 (varlilumab) 
& Atezolizumab 
Abdominal pain 
Acute 
abdominal pain 
Symptoms of abdominal 
pain associated with 
elevations of amylase 
and lipase, suggestive of 
pancreatitis, have been 
associated with 
administration of other 
immunomodulatory 
agents. The differential 
diagnosis of acute 
abdominal pain should 
include pancreatitis. 
Appropriate workup 
should include an 
evaluation for 
Symptoms of abdominal 
pain associated with 
elevations of amylase 
and lipase, suggestive of 
pancreatitis, have been 
associated with 
administration of other 
immunomodulatory 
agents. The differential 
diagnosis of acute 
abdominal pain should 
include pancreatitis. 
Appropriate workup 
should include an 
evaluation for 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
93 
 
 
 
 
 
obstruction, as well as 
serum amylase and 
lipase tests. See the 
guidelines for “Amylase 
and/or lipase increase” 
and “Immune-related 
pancreatitis” elsewhere 
in this table, as needed. 
obstruction, as well as 
serum amylase and 
lipase tests. See the 
guidelines for “Amylase 
and/or lipase increase” 
and “Immune-related 
pancreatitis” elsewhere 
in this table, as needed. 
Right upper-quadrant 
abdominal pain and/or 
unexplained nausea or 
vomiting should be 
evaluated for potential 
hepatotoxicity (see the 
“Hepatotoxicity” 
guideline elsewhere in 
this table). 
Right upper-quadrant 
abdominal pain and/or 
unexplained nausea or 
vomiting should be 
evaluated for potential 
hepatotoxicity (see the 
“Hepatotoxicity” 
guideline elsewhere in 
this table). 
Adrenal 
insufficiency * 
Hypohysitis (pan- 
hypopituarism) 
Grade 2+ 
(symptomatic) 
Hold Atezolizumab & 
CDX-1127 (varlilumab) 
 
Refer patient to 
endocrinologist. 
Hold Atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib 
 
Refer patient to 
endocrinologist. 
 
 
Perform appropriate 
imaging. 
 
Perform appropriate 
imaging. 
 
 
Initiate treatment with 
12 mg/kg/day 
intravenous 
methylprednisolone or 
equivalent and convert to 
12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
Initiate treatment with 
12 mg/kg/day 
intravenous 
methylprednisolone or 
equivalent and convert 
to 12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
 
If event resolves to grade 
1 or better and patient is 
stable on replacement 
therapy (if required) 
within 12 weeks, taper 
corticosteroids and 
resume atezolizumab & 
CDX-1127 (varlilumab) 
according to the 
guidelines above. 
 
If event resolves to 
grade 1 or better and 
patient is stable on 
replacement therapy (if 
required) within 12 
weeks, taper 
corticosteroids and 
resume Atezolizumab & 
CDX-1127 (varlilumab) 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
94 
 
 
 
 
 
 
For recurrent 
hypophysitis, treat as a 
Grade 4 event. 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) if 
event does not resolve to 
grade 1 or better or 
patient is not stable on 
replacement therapy 
within 12 weeks. 
and cobimetinib at same 
doses 
 
For recurrent 
hypophysitis, treat as a 
Grade 4 event. 
 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib if event 
does not resolve to grade 
1 or better or patient is 
not stable on 
replacement therapy 
within 12 weeks. 
Amylase and/or 
lipase increased 
Grade 1 
Continue atezolizumab 
& CDX-1127 
(varlilumab). 
Continue atezolizumab 
& CDX-1127 
(varlilumab) and 
cobimetinib. 
 
 
Monitor amylase and 
lipase prior to dosing. 
 
Monitor amylase and 
lipase prior to dosing. 
 
Grade 2 
Continue atezolizumab 
& CDX-1127 
(varlilumab). 
Continue atezolizumab 
& CDX-1127 
(varlilumab) and 
cobimetinib. 
 
 
Monitor amylase and 
lipase weekly. 
 
Monitor amylase and 
lipase weekly. 
 
 
For prolonged elevation 
(e.g., !3 weeks), 
consider treatment with 
10 mg/day oral 
prednisone or equivalent. 
 
Asymptomatic with 
amylase and/or lipase 
! 2.05.0 u ULN: 
Treat as a Grade 3 event. 
 
For prolonged elevation 
(e.g., !3 weeks), 
consider treatment with 
10 mg/day oral 
prednisone or 
equivalent. 
 
Asymptomatic with 
amylase and/or lipase 
! 2.05.0 u ULN: 
Treat as a Grade 3 event. 
 
Grade 3 or 4 
Hold atezolizumab & 
CDX-1127 (varlilumab). 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
95 
 
 
 
 
 
Refer patient to 
gastrointestinal (GI) 
specialist. 
 
Monitor amylase and 
lipase every other day. 
 
If no improvement, 
consider treatment with 
12 mg/kg/day oral 
prednisone or equivalent. 
 
If event resolves to grade 
1 or better within 12 
weeks, taper 
corticosteroids and 
resume atezolizumab & 
CDX-1127 (varlilumab) 
according to the 
guidelines above. 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) if 
event does not resolve to 
grade 1 or better within 
12 weeks. 
 
For recurrent events, 
permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab). 
 
Refer patient to 
gastrointestinal (GI) 
specialist. 
 
Monitor amylase and 
lipase every other day. 
 
If no improvement, 
consider treatment with 
12 mg/kg/day oral 
prednisone or 
equivalent. 
 
If event resolves to 
grade 1 or better within 
12 weeks, taper 
corticosteroids and 
resume atezolizumab & 
CDX-1127 (varlilumab) 
at previous fixed and 
cobimetinib with 1 dose- 
level reduction. 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib if event 
does not resolve to grade 
1 or better within 12 
weeks. 
 
For recurrent events, 
permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. 
Anemia 
Grade 3 
 
Without 
presence of 
active 
hemorrhage or 
immune- 
mediated 
hemolysis 
Continue atezolizumab 
& CDX-1127 
(varlilumab). 
 
Transfuse prn to Grade 
2 or resolution of 
symptomatic anemia 
 
Monitor CBC weekly 
Continue atezolizumab 
& CDX-1127 
(varlilumab) and 
cobimetinib 
 
Transfuse prn to Grade 
2 or resolution of 
symptomatic anemia 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
96 
 
 
 
 
 
 
Workup for etiologies of 
anemia 
Monitor CBC weekly 
 
Workup for etiologies of 
anemia 
 
For recurrent grade 3 
anemia, can consider 1 
dose level reduction for 
cobimetinib 
Cardiac Event – 
Decreased Left 
Ventricular Ejection 
Fraction (LVEF) 
Asymptomatic, 
absolute 
decrease in 
LVEF from 
baseline of 
greater than 
10% and LVEF 
less than 50% 
Hold atezolizumab & 
varlilumab. Assess for 
symptoms and complete 
work up. Repeat ECHO 
in 2 weeks. 
 
Work up should 
generally include 
troponin, CPK, EKG, 
echocardiogram and/or 
cardiac MRI, and 
cardiology consultation 
 
Resume atezolizumab & 
CDX-1127 (varlilumab) 
at fixed dose if all of the 
following are present 
x LVEF is 50% or 
greater, OR 
x Absolute 
decrease from 
baseline LVEF is 
more than 10% 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab)* if 
any of the following are 
present 
x LVEF is 50% or 
greater, AND 
x Absolute 
decrease from 
baseline LVEF is 
more than 10% 
 
* If etiology of 
Hold atezolizumab, 
CDX-1127 (varlilumab), 
and cobimetinib. Assess 
for symptoms and 
complete work up. 
Repeat ECHO in 2 
weeks. 
 
Work up should 
generally include 
troponin, CPK, EKG, 
echocardiogram and/or 
cardiac MRI, and 
cardiology consultation 
 
Resume atezolizumab & 
CDX-1127 (varlilumab) 
at fixed dose and 
cobimetinib at next 
lower dose if all of the 
following are present 
x LVEF is 50% or 
greater, OR 
x Absolute 
decrease from 
baseline LVEF is 
more than 10% 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab)* and 
cobimetinib any of the 
following are present 
x LVEF is 50% or 
greater, AND 
x Absolute 
decrease from 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
97 
 
 
 
 
 
decreased LVEF can be 
confidently attributed to 
a non-immune-mediated 
etiology, LVEF is > 40% 
(or  10% absolute 
decrease from BL) and 
myocarditis has been 
excluded, resumption of 
atezolizumab & CDX- 
1127 (varlilumab) at 
fixed dose can be 
considered on case by 
case basis with 
discussion & approval 
by trial PI. For patients 
with more severe 
reductions in the LVEF, 
atezolizumab & CDX- 
1127 (varlilumab) may 
be restarted only if the 
patient is clinically 
stable, and after 
consultation with the 
trial PI. 
baseline LVEF is 
more than 10% 
 
*If etiology of decreased 
LVEF can be 
confidently attributed to 
cobimetinib alone or a 
non-immune-mediated 
etiology , LVEF is > 
40% (or  10% absolute 
decrease from BL) and 
myocarditis has been 
excluded, resumption of 
atezolizumab & CDX- 
1127 (varlilumab) at 
fixed dose can be 
considered on case by 
case basis with 
discussion & approval 
by trial PI. For patients 
with more severe 
reductions in the LVEF, 
atezolizumab & CDX- 
1127 (varlilumab) may 
be restarted only if the 
patient is clinically 
stable, and after 
consultation with the 
trial PI. 
 
Symptomatic 
LVEF decrease 
from baseline 
Withhold atezolizumab 
& CDX-1127 
(varlilumab) for up to 4 
weeks; repeat LVEF 
Withhold atezolizumab 
& CDX-1127 
(varlilumab) and 
cobimetinib for up to 4 
weeks; repeat LVEF 
 
Work up should 
generally include 
troponin, CPK, EKG, 
echocardiogram and/or 
cardiac MRI, and 
cardiology consultation 
 
Work up should 
generally include 
troponin, CPK, EKG, 
echocardiogram and/or 
cardiac MRI, and 
cardiology consultation 
 
Resume atezolizumab & 
CDX-1127 (varlilumab) 
at fixed dose if all of the 
following are present 
x Symptoms 
 
Resume atezolizumab & 
CDX-1127 (varlilumab) 
at fixed dose and 
cobimetinib at next 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
98 
 
 
 
 
 
resolved, and 
x LVEF is 50% or 
greater, OR 
x Absolute 
decrease from 
baseline LVEF is 
10% or less 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab)* if 
any of the following are 
present 
x Symptoms 
persist, or 
x Symptoms 
resolved, but 
LVEF is less than 
50% andAbsolute 
decrease from 
baseline LVEF is 
more than 10% 
 
* If etiology of 
decreased LVEF can be 
confidently attributed to 
a non-immune-mediated 
etiology, LVEF is > 
40% (or  10% absolute 
decrease from BL) and 
myocarditis has been 
excluded, resumption of 
atezolizumab & CDX- 
1127 (varlilumab) at 
fixed dose can be 
considered on case by 
case basis with 
discussion & approval 
by trial PI. For patients 
with more severe 
reductions in the LVEF, 
atezolizumab & CDX- 
1127 (varlilumab) may 
be restarted only if the 
patient is clinically 
stable, and after 
lower dose if all of the 
following are present 
x Symptoms 
resolved, and 
x LVEF is 50% or 
greater, OR 
x Absolute 
decrease from 
baseline LVEF is 
10% or less 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab)* and 
cobimetinib any of the 
following are present 
x Symptoms 
persist, or 
x Symptoms 
resolved, but 
LVEF is less 
than50% and 
Absolute 
decrease from 
baseline LVEF is 
more than 10% 
 
*If etiology of decreased 
LVEF can be 
confidently attributed to 
cobimetinib alone or a 
non-immune-mediated 
etiology , LVEF is > 
40% (or  10% absolute 
decrease from BL) and 
myocarditis has been 
excluded, resumption of 
atezolizumab & CDX- 
1127 (varlilumab) at 
fixed dose can be 
considered on case by 
case basis with 
discussion & approval 
by trial PI. For patients 
with more severe 
reductions in the LVEF, 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
99 
 
 
 
 
 
consultation with and 
approval from the trial 
PI. 
atezolizumab & CDX- 
1127 (varlilumab) may 
be restarted only if the 
patient is clinically 
stable, and after 
consultation with and 
approval from the trial 
PI. 
Creatine Kinase 
(CPK) Elevation 
General 
Guidance 
Rule out cardiac cause 
(check ECG, serum 
cardiac troponin, and 
CPK-isoforms M and B 
fraction) and rule out 
rhabdomyolysis (clinical 
examination; serum 
creatinine, potassium, 
calcium, phosphorus, 
uric acid, and albumin; 
and urine myoglobin). 
Rule out cardiac cause 
(check ECG, serum 
cardiac troponin, and 
CPK-isoforms M and B 
fraction) and rule out 
rhabdomyolysis (clinical 
examination; serum 
creatinine, potassium, 
calcium, phosphorus, 
uric acid, and albumin; 
and urine myoglobin). 
 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) if 
there is evidence of 
clinically significant 
cardiac injury or 
rhabdomyolysis.. Assess 
patient for any history of 
strenuous physical 
activity, blunt trauma, or 
recent IM injections. 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib if there is 
evidence of clinically 
significant cardiac injury 
or rhabdomyolysis. 
Assess patient for any 
history of strenuous 
physical activity, blunt 
trauma, or recent IM 
injections. 
 
Grade 3 that are 
asymptomatic 
and deemed not 
clinically 
significant 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
pending workup to rule 
out immune related 
cardiomyopathy, 
myocarditis or other 
cardiac conditions. 
Workup should 
generally include ECG, 
serum cardiac troponin, 
and CPK-isoforms M 
and B fraction. 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib pending 
workup to rule out 
immune related 
cardiomyopathy, 
myocarditis or other 
cardiac conditions. 
Workup should 
generally include ECG, 
serum cardiac troponin, 
and CPK-isoforms M 
and B fraction. 
 
Atezolizumab & CDX- 
 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
100 
 
 
 
 
 
1127 (varlilumab) at 
fixed dosage only if 
cardiac etiology is ruled 
out. 
 
Recheck CPK at least 
once a week. If CPK 
remains Grade 3 or 
decreases, continue 
Atezolizumab & CDX- 
1127 (varlilumab) at 
fixed dosage. 
Atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib may be 
restarted at previous 
dose and schedule only 
if cardiac etiology is 
ruled out. 
 
Recheck CPK at least 
once a week. If CPK 
remains Grade 3 or 
decreases, continue 
Atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib at fixed 
dosage and cobimetinib 
at current dose and 
schedule. 
 
Grade 4 CPK 
elevations or 
any grade CPK 
with clinically 
significant 
effect (signs of 
cardiac injury 
and/or renal 
injury) 
Hold atezolizumab & 
CDX-1127 (varlilumab). 
Work up and treat per 
institutional guidelines. 
Rule out immune-related 
cardiomyopathy, 
myocarditis, other 
cardiac conditions, and 
myoglobin-induced 
kidney injury. 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib. Work 
up and treat per 
institutional guidelines. 
Rule out immune-related 
cardiomyopathy, 
myocarditis, other 
cardiac conditions, and 
myoglobin-induced 
kidney injury. 
 
Recheck CPK within 3 
days. When CPK is 
Grade  3 and cardiac 
immune-related 
cardiomyopathy has 
been ruled out, 
atezolizumab & CDX- 
1127 (varlilumab) may 
be resumed 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) if 
Grade 4 CPK elevation 
recurs or if there is 
evidence of cardiac/renal 
 
Recheck CPK within 3 
days. When CPK is 
Grade  3 and cardiac 
immune-related 
cardiomyopathy has 
been ruled out, 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib may be 
resumed with a dose 
reduction of cobimetinib 
by 1 dose level on the 
same schedule (e.g., 60 
to 40 mg). 
 
If Grade 4 CPK 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
101 
 
 
 
 
 
injury with any instance 
of CPK elevation*. 
 
*If non-immune related 
etiology is most likely, 
resumption of 
atezolizumab & CDX- 
1127 (varlilumab) at 
fixed dose will require 
consultation with and 
approval by study PI 
elevation recurs after 1 
dose reduction, 
cobimetinib may be 
reduced by another dose 
level (e.g., 40 to 20 mg). 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib if Grade 4 
CPK elevation recurs 
after 2 dose reductions 
of cobimetinib OR if 
there is evidence of 
cardiac/renal injury 
associated with any 
instance CPK elevation. 
 
*If non-immune related 
etiology is most likely, 
resumption of 
atezolizumab & CDX- 
1127 (varlilumab) at 
fixed dose without 
cobimetinib will require 
consultation with and 
approval by study PI 
Dermatologic 
toxicity/rash (e.g., 
maculopapular or 
purpura) 
Grade 1 
Continue atezolizumab 
& CDX-1127 
(varlilumab). 
Continue atezolizumab 
& CDX-1127 
(varlilumab) and 
cobimetinib 
 
 
Initiate symptomatic 
therapy with 
antihistamine PRN. 
 
Initiate symptomatic 
therapy with 
antihistamine PRN. 
 
 
Consider topical steroids 
and/or other 
symptomatic therapy 
(e.g., antihistamines). 
 
Consider topical steroids 
and/or other 
symptomatic therapy 
(e.g., antihistamines). 
 
 
 
For acneiform rash, 
consider topical 
corticosteroids 
(hydrocortisone 2.5%, 
alclometasone) and oral 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
102 
 
 
 
 
 
 
antibiotics (minocycline, 
doxycycline, or 
antibiotics covering skin 
flora) BID for at least 4 
weeks. 
Grade 2 
Continue atezolizumab 
& CDX-1127 
(varlilumab). 
Continue atezolizumab 
& CDX-1127 
(varlilumab) and 
cobimetinib. 
 
Consider consultation 
with a dermatologist for 
evaluation and if 
indicated, biopsy. 
 
Consider consultation 
with a dermatologist. 
 
 
Administer topical 
steroids. 
Administer topical 
steroids. 
 
 
Consider higher potency 
topical steroids if rash 
does not improve. 
Consider higher potency 
topical steroids if rash 
does not improve. 
 
 
For acneiform rash, 
topical corticosteroids 
(hydrocortisone 2.5%, 
alclometasone) and oral 
antibiotics (minocycline, 
doxycycline, or 
antibiotics covering skin 
flora) BID for at least the 
first 6 weeks 
For acneiform rash, 
administer topical 
corticosteroids 
(hydrocortisone 2.5%, 
alclometasone) and oral 
antibiotics (minocycline, 
doxycycline, or 
antibiotics covering skin 
flora) for at least the 6 
weeks. 
 
 
For an initial grade 2 
rash that is considered 
attributable to 
Cobimetinib and 
remains grade 2 at the 
start of the next cycle, 
despite appropriate 
topical treatments and 
oral antibiotics, continue 
atezolizumab & CDX- 
1127 (varlilumab) at 
fixed dose, but can 
consider holding 
cobimetinib until 
resolution to grade 1 or 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
103 
 
 
 
 
 
 
lower. Cobimetinib 
should be reduced one 
dose level. 
Grade 3 
Hold atezolizumab & 
CDX-1127 (varlilumab). 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib. 
 
Refer patient to 
dermatologist for 
evaluation and if 
indicated, biopsy. 
 
Refer patient to 
dermatologist. 
 
 
Administer oral 
prednisone 10 mg or 
equivalent. If the event 
does not improve within 
4872 hours, increase 
dose to1–2 mg/kg/day or 
equivalent. 
 
Restart atezolizumab & 
CDX-1127 (varlilumab) 
if event resolves to grade 
2 (tolerable) or better 
within 12 weeks. 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) if 
event does not resolve to 
tolerable grade 2 or 
better within 12 weeks. 
Administer oral 
prednisone 10 mg or 
equivalent if the rash is 
at least possibly 
attributable to the 
atezolizumab therapy. If 
the event does not 
improve within 48-72 
hours, increase dose to 
1–2 mg/kg/day or 
equivalent. 
 
For acneiform rash, 
consider continuation of 
topical corticosteroids 
2.5%, alclometasone) 
and oral antibiotics 
(minocycline, 
doxycycline or 
antibiotics covering skin 
flora) for at least 6 
weeks 
 
 
Restart atezolizumab & 
CDX-1127 (varlilumab) 
at fixed dose and 
cobimetinib at 1 dose 
reduction if rash resolves 
to  tolerable grade 2, 
and systemic dose is less 
than or equal to 10 mg 
oral prednisone 
equivalent per day. 
Grade 4 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab). 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
104 
 
 
 
 
 
Patient may not resume 
treatment, regardless of 
benefit.  Otherwise, 
manage as above. 
cobimetinib. Patient may 
not resume treatment, 
regardless of benefit. 
Manage as above. 
Persistent and/or 
severe rash or 
pruritus, any 
grade 
A dermatologist should 
evaluate the event. A 
biopsy should be 
performed unless 
contraindicated. 
A dermatologist should 
evaluate the event. A 
biopsy should be 
performed unless 
contraindicated. 
 
Stevens-Johnson 
syndrome or 
toxic epidermal 
necrolysis (any 
grade) 
Withhold atezolizumab 
& CDX-1127 
(varlilumab) for 
suspected 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis. 
Withhold atezolizumab 
& CDX-1127 
(varlilumab) and 
cobimetinib for 
suspected 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis. 
 
Confirm diagnosis by 
referring patient to a 
specialist (dermatologist, 
ophthalmologist, or 
urologist as relevant) for 
evaluation and, if 
indicated, biopsy. 
 
Confirm diagnosis by 
referring patient to a 
specialist (dermatologist, 
ophthalmologist, or 
urologist as relevant) for 
evaluation and, if 
indicated, biopsy. 
 
Follow the applicable 
treatment and 
management guidelines 
above. 
 
Follow the applicable 
treatment and 
management guidelines 
above. 
 
If Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis is 
confirmed, permanently 
discontinue 
atezolizumab& CDX- 
1127 (varlilumab) 
 
If Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis is 
confirmed, permanently 
discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. 
Diarrhea or colitis 
Any grade 
Patients should be 
advised to inform the 
investigator if any 
diarrhea occurs, even if 
it is mild. 
Patients should be 
advised to inform the 
investigator if any 
diarrhea occurs, even if 
it is mild. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
105 
 
 
 
 
 
All events of diarrhea or 
colitis should be 
thoroughly evaluated for 
other more common 
etiologies. 
All events of diarrhea or 
colitis should be 
thoroughly evaluated for 
other more common 
etiologies. 
For events of significant 
duration or magnitude or 
associated with signs of 
systemic inflammation 
or acute-phase reactants 
(e.g., increased CRP, 
platelet count, or 
bandemia): Perform 
sigmoidoscopy (or 
colonoscopy, if 
appropriate) with colonic 
biopsy, with three to five 
specimens for standard 
paraffin block to check 
for inflammation and 
lymphocytic infiltrates to 
confirm colitis diagnosis. 
For events of significant 
duration or magnitude or 
associated with signs of 
systemic inflammation 
or acute-phase reactants 
(e.g., increased CRP, 
platelet count, or 
bandemia): Perform 
sigmoidoscopy (or 
colonoscopy, if 
appropriate) with 
colonic biopsy, with 
three to five specimens 
for standard paraffin 
block to check for 
inflammation and 
lymphocytic infiltrates 
to confirm colitis 
diagnosis. 
Grade 1 
Continue atezolizumab 
& CDX-1127 
(varlilumab). 
Continue atezolizumab, 
CDX-1127 (varlilumab) 
and cobimetinib. 
 
Initiate symptomatic 
treatment. 
Initiate symptomatic 
treatment. 
 
Suggested regimen: 
Loperamide: Initiate 
dose with 4 mg, then 4 
mg/6 hr around the 
clock, alternating with 
Lomotil. 
Lomotil (diphenoxylate 
and atropine): 2 tablets 
(diphenoxylate 5 mg) 
every 6 hr around the 
clock 
Continue Lomotil and 
loperamide until no 
loose stools for 24 hours 
Suggested regimen: 
Loperamide: Initiate 
dose with 4 mg, then 4 
mg/6 hr around the 
clock, alternating with 
Lomotil. 
Lomotil (diphenoxylate 
and atropine): 2 tablets 
(diphenoxylate 5 mg) 
every 6 hr around the 
clock 
Continue Lomotil and 
loperamide until no 
loose stools for 24 hours 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
106 
 
 
 
 
 
 
Endoscopy is 
recommended if 
symptoms persist for 
! 7 days. 
 
Endoscopy is 
recommended if 
symptoms persist for 
! 7 days. 
Monitor closely. 
Monitor closely. 
Grade 2 
Hold atezolizumab & 
CDX-1127 (varlilumab). 
Hold atezolizumab, 
CDX-1127 (varlilumab), 
and cobimetinib. 
 
Initiate symptomatic 
treatment. 
 
Initiate symptomatic 
treatment. 
 
Suggested regimen: 
Loperamide: Initiate 
dose with 4 mg, then 4 
mg/6 hr around the 
clock, alternating with 
Lomotil. 
Lomotil (diphenoxylate 
and atropine): 2 tablets 
(diphenoxylate 5 mg) 
every 6 hr around the 
clock 
Continue Lomotil and 
loperamide until no 
loose stools for 24 hours. 
 
Suggested regimen: 
Loperamide: Initiate 
dose with 4 mg, then 4 
mg/6 hr around the 
clock, alternating with 
Lomotil. 
Lomotil (diphenoxylate 
and atropine): 2 tablets 
(diphenoxylate 5 mg) 
every 6 hr around the 
clock 
Continue Lomotil and 
loperamide until no 
loose stools for 24 hours. 
 
If Grade  2 diarrhea 
persists after 48 hr total 
treatment with Lomotil 
and loperamide, consider 
second-line agents (e.g., 
octreotide, budesonide, 
tincture of opium). 
 
If Grade  2 diarrhea 
persists after 48 hr total 
treatment with Lomotil 
and loperamide, consider 
second-line agents (e.g., 
octreotide, budesonide, 
tincture of opium). 
 
Patient referral to GI 
specialist for endoscopy 
is recommended. 
 
Patient referral to GI 
specialist for endoscopy 
is recommended. 
 
For initial event that 
persist for 5 days, and 
do not require steroids, 
restart atezolizumab & 
CDX-1127 (varlilumab) 
at fixed dose once event 
 
For initial event that 
persist for 5 days, and 
do not require steroids, 
restart atezolizumab & 
CDX-1127 (varlilumab) 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
107 
 
 
 
 
 
grade  1 
 
For recurrent and/or 
events lasting >5 days: 
 
For recurrent events or 
events that persist >5 
days, initiate treatment 
with 12 mg/kg/day oral 
prednisone or equivalent. 
 
If recurrent event and/or 
event persist >5 days, 
requires steroids, and 
resolves to grade 1 or 
better within 12 weeks, 
taper corticosteroids and 
resume atezolizumab & 
CDX-1127 (varlilumab) 
once event grade  1. 
 
For recurrent events or 
events that persist >5 
days, require steroids, 
but event DOES NOT 
resolves to grade 1 or 
better within 12 weeks, 
permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab)* 
 
*Resumption of 
atezolizumab & CDX- 
1127 (varlilumab) may 
be considered, after 
consultation with the 
trial PI, in patients who 
are deriving benefit and 
have fully recovered 
from the immune-related 
event. 
at fixed dosea and 
cobimetinib at 1 dose 
reduction once grade  
1 
 
For recurrent and/or 
events lasting >5 days: 
 
For recurrent events or 
events that persist >5 
days, initiate treatment 
with 12 mg/kg/day oral 
prednisone or 
equivalent. 
 
For recurrent events or 
events that persist >5 
days, requiring steroids, 
and event resolves to 
grade 1 or better within 
12 weeks, restart 
atezolizumab & CDX- 
1127 (varlilumab) at 
fixed dose and 
cobimetinib at 1 dose 
reduction once event 
grade  1. 
 
For recurrent events or 
events that persist >5 
days, require steroids, 
but event DOES NOT 
resolves to grade 1 or 
better within 12 weeks, 
permanently discontinue 
combimetinib plus 
atezolizumab & CDX- 
1127 (varlilumab)* 
 
*Resumption of 
atezolizumab & CDX- 
1127 (varlilumab) at 
fixed dose and 
cobimetinib at 1 level 
dose reduction after 
consultation with the 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
108 
 
 
 
 
 
 
trial PI, in patients who 
are deriving benefit 
treatment benefit and 
have fully recovered. 
Grade 3 
Hold atezolizumab & 
CDX-1127 (varlilumab). 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib. 
 
Refer patient to GI 
specialist for evaluation 
and confirmatory biopsy. 
 
Refer patient to GI 
specialist for evaluation 
and confirmatory biopsy. 
 
Initiate treatment with 
12 mg/kg/day 
intravenous 
methylprednisolone or 
equivalent and convert to 
12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
Initiate treatment with 
12 mg/kg/day 
intravenous 
methylprednisolone or 
equivalent and convert 
to 12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
 
If event resolves to grade 
1 or better within 12 
weeks, taper 
corticosteroids and 
resume atezolizumab 
according to the 
guidelines above. 
 
For events that require 
steroids, but event 
DOES NOT resolves to 
grade 1 or better within 
12 weeks, permanently 
discontinue 
atezolizumab & CDX- 
1127 (varlilumab)* 
 
For events that require 
 
If event resolves to 
grade 1 or better within 
12 weeks, taper 
corticosteroids and 
restart atezolizumab & 
CDX-1127 (varlilumab) 
at fixed doses and 
cobimetinib at 1 dose 
reduction once at 
baseline stool frequency. 
 
For events that require 
steroids, but event 
DOES NOT resolves to 
grade 1 or better within 
12 weeks, permanently 
discontinue 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
109 
 
 
 
 
 
steroids AND biologic 
immunosuppressive 
therapy (e.g. infliximab, 
mycophenolate mofetil, 
etc.,.) but event DOES 
resolves to grade 1 or 
better within 12 weeks, 
permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab)* 
 
*Resumption of 
atezolizumab & CDX- 
1127 (varlilumab) may 
be considered after 
consultation with and 
approval from the trial 
PI, in patients who are 
deriving benefit and 
have fully recovered 
from the immune-related 
event 
 
For events that require 
steroids AND biologic 
immunosuppressive 
therapy (e.g. infliximab, 
mycophenolate mofetil, 
etc.,.) but event DOES 
NOT resolves to grade 1 
or better within 12 
weeks, permanently 
discontinue 
atezolizumab & CDX- 
1127 (varlilumab). 
Patient may not resume 
treatment, regardless of 
benefit 
combimetinib plus 
atezolizumab & CDX- 
1127 (varlilumab)* 
 
For events that require 
steroids AND biologic 
immunosuppressive 
therapy (e.g. infliximab, 
mycophenolate mofetil, 
etc.,.) but event DOES 
resolves to grade 1 or 
better within 12 weeks, 
permanently discontinue 
combimetinib plus 
atezolizumab & CDX- 
1127 (varlilumab)* 
 
*Resumption of 
atezolizumab & CDX- 
1127 (varlilumab) at 
fixed dose and 
cobimetinib at 1 level 
dose reduction can be 
considered after 
consultation with and 
approval from trial PI, in 
patients who are 
deriving benefit 
treatment benefit and 
have fully recovered. 
 
For events that require 
steroids AND biologic 
immunosuppressive 
therapy (e.g. infliximab, 
mycophenolate mofetil, 
etc.,.) but event DOES 
NOT resolves to grade 1 
or better within 12 
weeks, permanently 
discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. Patient may 
not resume treatment, 
regardless of benefit. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
110 
 
 
 
 
Grade 4 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab). 
Patient may not resume 
treatment, regardless of 
benefit. 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. Patient may 
not resume treatment, 
regardless of benefit. 
 
Refer patient to GI 
specialist for evaluation 
and confirmation biopsy. 
Refer patient to GI 
specialist for evaluation 
and confirmation biopsy. 
 
Initiate treatment with 
12 mg/kg/day 
intravenous 
methylprednisolone or 
equivalent and convert to 
12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
Initiate treatment with 
12 mg/kg/day 
intravenous 
methylprednisolone or 
equivalent and convert 
to 12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
 
If event resolves to grade 
1 or better, taper 
corticosteroids over t1 
month. 
If event resolves to 
grade 1 or better, taper 
corticosteroids over t1 
month. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
111 
 
 
 
Hemophagocytic 
Lymphohistiocytosis 
and Macrophage 
Activation 
Syndrome 
Suspected HLH 
or MAS 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab). 
 
Consider patient referral 
to hematologist. 
 
Initiate supportive care, 
including intensive care 
monitoring if indicated 
per institutional 
guidelines. 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. 
 
Consider patient referral 
to hematologist. 
Initiate supportive care, 
including intensive care 
monitoring if indicated 
per institutional 
guidelines. 
 
 
Consider initiation of IV 
corticosteroids, an 
immunosuppressive 
agent, and/or anti- 
cytokine therapy. 
If event does not respond 
to treatment within 24 
hours, initiate treatment 
as appropriate according 
to published guidelines 
(La Rosée 2015; Schram 
and Berliner 2015; 
La Rosée et al., 2019). 
 
If event resolves to 
Grade 1 or better, taper 
corticosteroids over 
t1 month. 
Consider initiation of IV 
corticosteroids, an 
immunosuppressive 
agent, and/or anti- 
cytokine therapy. 
 
If event does not 
respond to treatment 
within 24 hours, initiate 
treatment as appropriate 
according to published 
guidelines (La Rosée 
2015; Schram and 
Berliner 2015; La Rosée 
et al., 2019). 
 
If event resolves to 
Grade 1 or better, taper 
corticosteroids over 
t1 month. 
Hemorrhage 
Grade 3 events: 
Continue atezolizumab 
& CDX-1127 
(varlilumab) 
Continue atezolizumab 
& CDX-1127 
(varlilumab) 
 
 
 
Hold cobimetinib 
 
 
 
If improved to Grade 0 
 
 
 
or 1, resume at the next 
 
 
 
lower dose level. 
 
 
 
If not improved within 4 
weeks, permanently 
discontinue 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
112 
 
 
 
 
Grade 4 events 
or 
Cerebral 
hemorrhage (all 
grades): 
Consultation with study 
PI prior to continue 
atezolizumab & CDX- 
1127 (varlilumab) 
Continue atezolizumab 
& CDX-1127 
(varlilumab) 
 
Permanently discontinue 
cobimetinib. 
Hepatotoxicity 
Right upper- 
quadrant 
abdominal pain 
and/or 
unexplained 
nausea or 
vomiting 
Risk of immune- 
mediated hepatitis. 
LFTs should be 
performed immediately, 
and LFTs should be 
reviewed before 
administration of the 
next dose of study drug. 
For patients with 
elevated LFTs, 
concurrent medication, 
viral hepatitis, and toxic 
or neoplastic etiologies 
should be considered and 
addressed, 
as appropriate. 
Risk of immune- 
mediated hepatitis. LFTs 
should be performed 
immediately, and LFTs 
should be reviewed 
before administration of 
the next dose of study 
drug. For patients with 
elevated LFTs, 
concurrent medication, 
viral hepatitis, and toxic 
or neoplastic etiologies 
should be considered 
and addressed, 
as appropriate. 
 
 
 
Symptoms of abdominal 
pain associated with 
elevations of amylase 
and lipase, suggestive of 
pancreatitis, have been 
associated with the 
administration of 
atezolizumab & CDX- 
1127 (varlilumab). The 
differential diagnosis of 
acute abdominal pain 
should also include 
pancreatitis, as described 
below. 
Symptoms of abdominal 
pain associated with 
elevations of amylase 
and lipase, suggestive of 
pancreatitis, have been 
associated with the 
administration of 
atezolizumab & CDX- 
1127 (varlilumab). The 
differential diagnosis of 
acute abdominal pain 
should also include 
pancreatitis, as described 
below. 
 
Hepatic event, 
general 
guidance 
Consider possible tumor- 
related etiology, and 
consider earlier restaging 
imaging to inform 
clinical decision making 
(e.g. steroid initiation) 
Consider possible 
tumor-related etiology, 
and consider earlier 
restaging imaging to 
inform clinical 
management (e.g. 
steroid initiation) 
 
Grade 1 hepatic 
event 
Continue atezolizumab 
& CDX-1127 
Continue atezolizumab 
& CDX-1127 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
113 
 
 
 
 
 
(varlilumab). 
(varlilumab) and 
cobimetinib. 
Monitor LFTs weekly 
until values resolve to 
within baseline values. 
 
Monitor LFTs weekly 
until values resolve to 
within normal limits. 
Grade 2 hepatic 
event, 5 days 
 
*includes: 
AST/ALT is 
! ULN to 
d3uULN 
at baseline and 
increases to 
! 5uULN to 
d10uULN 
Continue atezolizumab 
& CDX-1127 
(varlilumab). 
 
Monitor LFTs biweekly 
until values resolve to 
baseline values. 
Continue atezolizumab 
& CDX-1127 
(varlilumab) and 
cobimetinib. 
 
Monitor LFTs biweekly 
until values resolve to 
baseline values. 
Grade 2 hepatic 
event, >5 days 
Hold atezolizumab & 
CDX-1127 (varlilumab). 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib. 
*includes: 
AST/ALT is 
! ULN to 
d3uULN 
at baseline and 
increases to 
! 5uULN to 
d10uULN 
Work to evaluate 
etiology of hepatic 
event. Consider patient 
referral to GI specialist 
for evaluation and liver 
biopsy to establish 
etiology of hepatic injury 
 
If suspicion for immune- 
mediated process is high, 
initiate treatment with 
12 mg/kg/day oral 
prednisone or equivalent. 
 
If event resolves to grade 
1 or better within 12 
weeks, taper 
corticosteroids and 
resume atezolizumab 
according to the 
guidelines above. 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) if 
event does not resolve to 
 
Work up to evaluate 
etiology of hepatic 
event. Consider patient 
referral to GI specialist 
for evaluation and liver 
biopsy to establish 
etiology of hepatic 
injury 
 
If suspicion for immune- 
mediated process is 
high, initiate treatment 
with 12 mg/kg/day oral 
prednisone or 
equivalent. 
 
If event resolves to 
grade 1 or better within 
12 weeks, taper 
corticosteroids and 
resume atezolizumab & 
CDX-1127 (varlilumab) 
at fixed doses and 
cobimetinib at 1 dose 
reduction. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
114 
 
 
 
 
 
Grade 1 or better within 
12 weeks. 
 
Resumption of 
atezolizumab 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib at 1 level 
dose reduction may be 
considered in patients 
who are deriving benefit 
and have fully recovered 
from the immune- 
mediated event. The 
decision to rechallenge 
patients with 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib should be 
based on investigator's 
assessment of 
benefitrisk, discussion 
with PI, and documented 
by the investigator (or an 
appropriate delegate) 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib if event 
does not resolve to 
Grade 1 or better within 
12 weeks. 
 
Resumption of 
atezolizumab 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib at 1 level 
dose reduction may be 
considered in patients 
who are deriving benefit 
and have fully recovered 
from the immune- 
mediated event. The 
decision to rechallenge 
patients with 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib should be 
based on investigator's 
assessment of 
benefitrisk, discussion 
with PI, and documented 
by the investigator (or an 
appropriate delegate) 
Grade 3 or 4 
hepatic event 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
hold cobimetinib. 
 
Consider patient referral 
to GI specialist for 
evaluation and liver 
biopsy to establish 
etiology of hepatic 
injury. 
 
Consider patient referral 
to GI specialist for 
evaluation and liver 
biopsy to establish 
etiology of hepatic 
injury. 
 
If suspicion for immune- 
mediated process is high, 
initiate treatment with 
12 mg/kg/day oral 
 
If suspicion for immune- 
mediated process is 
high, initiate treatment 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
115 
 
 
 
 
 
prednisone or equivalent. 
 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
 
If event resolves to grade 
1 or better, taper 
corticosteroids over t1 
month. 
 
Resumption of 
atezolizumab 
atezolizumab & CDX- 
1127 (varlilumab) may 
be considered in patients 
who are deriving benefit 
and have fully recovered 
from the immune- 
mediated event. The 
decision to rechallenge 
patients with 
atezolizumab should be 
based on investigator's 
assessment of 
benefitrisk and 
documented by the 
investigator (or an 
appropriate delegate). 
For grade 3 AEs, patient 
may only resume after 
consultation with the 
trial PI; for grade 4, 
patient cannot resume 
treatment, regardless of 
benefit. 
with 12 mg/kg/day oral 
prednisone or 
equivalent. 
 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
 
If event resolves to 
grade 1 or better, taper 
corticosteroids over t1 
month. 
 
Resumption of 
atezolizumab 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib at 1 level 
dose reduction may be 
considered in patients 
who are deriving benefit 
and have fully recovered 
from the immune- 
mediated event. The 
decision to rechallenge 
patients with 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib should be 
based on investigator's 
assessment of 
benefitrisk and 
documented by the 
investigator (or an 
appropriate delegate). 
For grade 3 AEs, patient 
may only resume after 
consultation with the 
trial PI; for grade 4, 
patient cannot resume 
treatment, regardless of 
benefit. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
116 
 
 
 
Hyperglycemia 
Grade 1 or 2 
Continue atezolizumab 
& CDX-1127 
(varlilumab) 
Continue atezolizumab 
& CDX-1127 
(varlilumab) and 
cobimetinib 
 
 
Initiate treatment with 
insulin if needed. 
 
Initiate treatment with 
insulin if needed. 
 
 
Monitor for glucose 
control. 
 
Monitor for glucose 
control. 
 
 
Investigate for diabetes. 
In the absence of 
corticosteroids or 
diabetes medication non- 
adherence may be an 
indication of beta-cell 
destruction and 
atezolizumab-induced 
diabetes. If patient has 
Type 1 diabetes (e.g. 
new-onset diabetes in the 
absence of 
corticosteroids or 
another inciting 
medication), treat as a 
Grade 3 event. 
 
Investigate for diabetes. 
In the absence of 
corticosteroids or 
diabetes medication non- 
adherence may be an 
indication of beta-cell 
destruction and 
atezolizumab-induced 
diabetes. If patient has 
Type 1 diabetes (e.g. 
new-onset diabetes in 
the absence of 
corticosteroids or 
another inciting 
medication), treat as a 
Grade 3 event. 
 
 
Exercise caution in 
utilizing non-insulin 
hypoglycemic agents in 
this setting, as new-onset 
hyperglycemia in the 
absence of 
corticosteroids may be 
an indication of beta-cell 
destruction and 
atezolizumab-induced 
diabetes. After a 
thorough investigation of 
other potential causes 
which may involve a 
referral to an 
endocrinologist, follow 
institutional guidelines. 
 
Exercise caution in 
utilizing non-insulin 
hypoglycemic agents in 
this setting, as new-onset 
hyperglycemia in the 
absence of 
corticosteroids may be 
an indication of beta-cell 
destruction and 
atezolizumab-induced 
diabetes. After a 
thorough investigation 
of other potential causes 
which may involve a 
referral to an 
endocrinologist, follow 
institutional guidelines. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
117 
 
 
 
 
Grade 3 or 4 
Hold atezolizumab & 
CDX-1127 (varlilumab). 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib 
 
Initiate treatment with 
insulin. 
 
Initiate treatment with 
insulin. 
 
Monitor for glucose 
control. 
 
Monitor for glucose 
control. 
 
Strongly consider 
referral to 
endocrinologist, consider 
obtaining C-peptide 
level paired with 
glucose, autoantibody 
levels (e.g. GAD65, islet 
cell autoantibodies), and 
hemoglobin A1C level. 
 
Strongly consider 
referral to 
endocrinologist, 
consider obtaining C- 
peptide level paired with 
glucose, autoantibody 
levels (e.g. GAD65, islet 
cell autoantibodies), and 
hemoglobin A1C level. 
 
If patient is found to 
have diabetic 
ketoacidosis or 
hyperglycemic 
hyperosmolar syndrome, 
treat as per institutional 
guidelines with 
appropriate management 
and laboratory values 
(e.g. anion gap, ketones, 
blood pH, etc.) reported. 
 
If patient is found to 
have diabetic 
ketoacidosis or 
hyperglycemic 
hyperosmolar syndrome, 
treat as per institutional 
guidelines with 
appropriate management 
and laboratory values 
(e.g. anion gap, ketones, 
blood pH, etc.) reported. 
 
Resume atezolizumab & 
CDX-1127 (varlilumab) 
when symptoms resolve 
and glucose levels are 
stable. 
 
Resume atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib when 
symptoms resolve and 
glucose levels are stable. 
Hyperthyroidism 
Grade 1 
(asymptomatic) 
TSH t 0.1 mU/L and 
 0.5 mU/L: 
TSH t 0.1 mU/L and 
 0.5 mU/L: 
 
 
Continue atezolizumab 
& CDX-1127 
(varlilumab) 
Continue atezolizumab 
& CDX-1127 
(varlilumab) 
 
 
Monitor TSH every 4 
weeks. 
Monitor TSH every 4 
weeks. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
118 
 
 
 
 
 
 
TSH  0.1 mU/L: 
 
Follow guidelines for 
symptomatic 
hyperthyroidism. 
 
TSH  0.1 mU/L: 
 
Follow guidelines for 
symptomatic 
hyperthyroidism 
Grade 2+ 
(symptomatic) 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
 
Initiate treatment with 
anti-thyroid drug such as 
methimazole or 
carbimazole as needed. 
 
Consider patient referral 
to endocrinologist. 
 
Resume atezolizumab & 
CDX-1127 (varlilumab) 
when symptoms are 
controlled and thyroid 
function is improving. 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) for 
life-threatening immune- 
related hyperthyroidism. 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
and combimetinib 
 
Initiate treatment with 
anti-thyroid drug such as 
methimazole or 
carbimazole as needed. 
 
Consider patient referral 
to endocrinologist. 
 
Resume atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib when 
symptoms are controlled 
and thyroid function is 
improving. 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobmetinib* for 
life-threatening immune- 
related hyperthyroidism. 
Hypothyroidism 
Grade 1-2 
Continue atezolizumab 
& CDX-1127 
(varlilumab) 
 
Start thyroid- 
replacement hormone. 
 
Monitor TSH weekly. 
Continue atezolizumab 
& CDX-1127 
(varlilumab) and 
cobimetinib 
 
Start thyroid- 
replacement hormone. 
 
Monitor TSH weekly. 
Grades 3-4 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
 
Start thyroid- 
replacement hormone. 
Consider referral to an 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib 
 
Start thyroid- 
replacement hormone. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
119 
 
 
 
 
 
endocrinologist. 
 
Monitor TSH weekly. 
 
Restart atezolizumab & 
CDX-1127 (varlilumab) 
when symptoms are 
controlled and thyroid 
function is improving. 
Consider referral to an 
endocrinologist. 
 
Monitor TSH weekly. 
 
Restart atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib when 
symptoms are controlled 
and thyroid function is 
improving. 
Infusion Reactions 
Grade 1 a 
Fever b with or 
without 
constitutional 
symptoms 
Immediately interrupt 
infusion. 
 
Upon symptom 
resolution, wait for 30 
minutes and then restart 
infusion at half the rate 
being given at the time 
of event onset. 
Immediately interrupt 
infusion. 
 
Upon symptom 
resolution, wait for 30 
minutes and then restart 
infusion at half the rate 
being given at the time 
of event onset. 
 
 
If the infusion is 
tolerated at the reduced 
rate for 30 minutes, the 
infusion rate may be 
increased to the original 
rate. 
If symptoms recur, 
discontinue infusion of 
this dose. 
If the infusion is 
tolerated at the reduced 
rate for 30 minutes, the 
infusion rate may be 
increased to the original 
rate. 
If symptoms recur, 
discontinue infusion of 
this dose. 
 
 
Administer symptomatic 
treatment, c including 
maintenance of IV fluids 
for hydration. 
Administer symptomatic 
treatment, c including 
maintenance of IV fluids 
for hydration. 
 
 
In case of rapid decline 
or prolonged CRS (!2 
days) or in patients with 
significant symptoms 
and/or comorbidities, 
consider managing as 
per Grade 2. 
In case of rapid decline 
or prolonged CRS (!2 
days) or in patients with 
significant symptoms 
and/or comorbidities, 
consider managing as 
per Grade 2. 
 
 
For subsequent 
infusions, consider 
For subsequent 
infusions, consider 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
120 
 
 
 
 
 
administration of oral 
premedication with 
antihistamines, anti- 
pyretics, and/or 
analgesics, and monitor 
closely for IRRs and/or 
CRS. 
administration of oral 
premedication with 
antihistamines, anti- 
pyretics, and/or 
analgesics, and monitor 
closely for IRRs and/or 
CRS. 
 
Grade 2 a 
Fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia 
requiring low- 
flow oxygen d 
by nasal cannula 
or blow-by 
Immediately interrupt 
infusion. 
 
Upon symptom 
resolution, wait for 30 
minutes and then restart 
infusion at half the rate 
being given at the time 
of event onset. 
 
If symptoms recur, 
discontinue infusion of 
this dose. 
Immediately interrupt 
infusion. 
 
Upon symptom 
resolution, wait for 30 
minutes and then restart 
infusion at half the rate 
being given at the time 
of event onset. 
 
If symptoms recur, 
discontinue infusion of 
this dose. 
 
Administer symptomatic 
treatment. c 
Administer symptomatic 
treatment. c 
 
For hypotension, 
administer IV fluid bolus 
as needed. 
For hypotension, 
administer IV fluid bolus 
as needed. 
 
Monitor 
cardiopulmonary and 
other organ function 
closely (in the ICU, if 
appropriate). Administer 
IV fluids as clinically 
indicated, and manage 
constitutional symptoms 
and organ toxicities as 
per institutional practice. 
Monitor 
cardiopulmonary and 
other organ function 
closely (in the ICU, if 
appropriate). 
Administer IV fluids as 
clinically indicated, and 
manage constitutional 
symptoms and organ 
toxicities as per 
institutional practice. 
 
Rule out other 
inflammatory conditions 
that can mimic CRS 
(e.g., sepsis). If no 
improvement within 24 
hours, initiate workup 
and assess for signs and 
 
Rule out other 
inflammatory conditions 
that can mimic CRS 
(e.g., sepsis). If no 
improvement within 24 
hours, initiate workup 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
121 
 
 
 
 
 
symptoms of HLH or 
MAS as described in this 
appendix. 
and assess for signs and 
symptoms of HLH or 
MAS as described in this 
appendix. 
Consider IV 
corticosteroids (e.g., 
methylprednisolone 
2 mg/kg/day or 
dexamethasone 10 mg 
every 6 hours). 
 
Consider IV 
corticosteroids (e.g., 
methylprednisolone 
2 mg/kg/day or 
dexamethasone 10 mg 
every 6 hours). 
Consider anti-cytokine 
therapy. 
 
Consider anti-cytokine 
therapy. 
Consider hospitalization 
until complete resolution 
of symptoms. If no 
improvement within 24 
hours, manage as per 
Grade 3, that 
is, hospitalize patient 
(monitoring in the ICU 
is recommended), 
permanently discontinue 
atezolizumab. e 
If symptoms resolve to 
Grade 1 or better for 3 
consecutive days, the 
next infusion may be 
administered. 
 
Consider hospitalization 
until complete resolution 
of symptoms. If no 
improvement within 24 
hours, manage as per 
Grade 3, that 
is, hospitalize patient 
(monitoring in the ICU 
is recommended), 
permanently discontinue 
atezolizumab. e 
If symptoms resolve to 
Grade 1 or better for 3 
consecutive days, the 
next infusion may be 
administered. 
For subsequent 
infusions, consider 
administration of oral 
premedication with 
antihistamines, 
anti-pyretics, and/or 
analgesics and monitor 
closely for IRRs and/or 
CRS. 
 
For subsequent 
infusions, consider 
administration of oral 
premedication with 
antihistamines, 
anti-pyretics, and/or 
analgesics and monitor 
closely for IRRs and/or 
CRS. 
If symptoms do not 
resolve to Grade 1 or 
better for 3 consecutive 
days, contact the 
investigator. 
 
If symptoms do not 
resolve to Grade 1 or 
better for 3 consecutive 
days, contact the 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
122 
 
 
 
 
 
 
investigator. 
 
Grade 3 a 
Fever b with 
hypotension 
requiring a 
vasopressor 
(with or without 
vasopressin) 
and/or 
Hypoxia 
requiring high- 
flow oxygen d 
by nasal 
cannula, face 
mask, 
non-rebreather 
mask, or 
Venturi mask 
Permanently discontinue 
atezolizumab. e 
Administer symptomatic 
treatment. c 
For hypotension, 
administer IV fluid bolus 
and vasopressor as 
needed. 
Monitor 
cardiopulmonary and 
other organ function 
closely; monitoring in 
the ICU is 
recommended. 
Administer IV fluids as 
clinically indicated, and 
manage constitutional 
symptoms and organ 
toxicities as per 
institutional practice. 
Rule out other 
inflammatory conditions 
that can mimic CRS 
(e.g., sepsis). If no 
improvement within 24 
hours, initiate workup 
and assess for signs and 
symptoms of HLH or 
MAS as described in this 
appendix. 
Administer IV 
corticosteroids (e.g., 
methylprednisolone 
2 mg/kg/day or 
dexamethasone 10 mg 
every 6 hours). 
Consider anti-cytokine 
therapy. 
Hospitalize patient until 
complete resolution of 
symptoms. If no 
improvement within 24 
hours, manage as per 
Grade 4, that is, admit 
patient to ICU and 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. e 
 
Administer symptomatic 
treatment. c 
 
For hypotension, 
administer IV fluid bolus 
and vasopressor as 
needed. 
 
Monitor 
cardiopulmonary and 
other organ function 
closely; monitoring in 
the ICU is 
recommended. 
Administer IV fluids as 
clinically indicated, and 
manage constitutional 
symptoms and organ 
toxicities as per 
institutional practice. 
 
Rule out other 
inflammatory conditions 
that can mimic CRS 
(e.g., sepsis). If no 
improvement within 24 
hours, initiate workup 
and assess for signs and 
symptoms of HLH or 
MAS as described in this 
appendix. 
 
Administer IV 
corticosteroids (e.g., 
methylprednisolone 
2 mg/kg/day or 
dexamethasone 10 mg 
every 6 hours). 
Consider anti-cytokine 
therapy. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
123 
 
 
 
 
 
initiate hemodynamic 
monitoring, mechanical 
ventilation, and/or IV 
fluids and vasopressors 
as needed; for patients 
who are refractory to 
anti-cytokine therapy, 
experimental treatments 
may be considered at the 
discretion of the 
investigator. 
 
Atezolizumab & CDX- 
1127 (varlilumab) may, 
under limited and 
compelling 
circumstances, be 
resumed in patients who 
have recovered from the 
following events, but 
only after consultation 
with the trial Principal 
Investigator 
 
Hospitalize patient until 
complete resolution of 
symptoms. If no 
improvement within 24 
hours, manage as per 
Grade 4, that is, admit 
patient to ICU and 
initiate hemodynamic 
monitoring, mechanical 
ventilation, and/or IV 
fluids and vasopressors 
as needed; for patients 
who are refractory to 
anti-cytokine therapy, 
experimental treatments 
may be considered at the 
discretion of the 
investigator. 
 
Atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib may, under 
limited and compelling 
circumstances, be 
resumed in patients who 
have recovered from the 
following events, but 
only after consultation 
with the trial Principal 
Investigator 
 
Grade 4 a 
Fever b with 
hypotension 
requiring 
multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia 
requiring 
oxygen by 
positive 
pressure (e.g., 
CPAP, BiPAP, 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab). e 
 
Administer symptomatic 
treatment. c 
 
Admit patient to ICU 
and initiate 
hemodynamic 
monitoring, mechanical 
ventilation, and/or IV 
fluids and vasopressors 
as needed. Monitor 
other organ function 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. e 
 
Administer symptomatic 
treatment. c 
 
Admit patient to ICU 
and initiate 
hemodynamic 
monitoring, mechanical 
ventilation, and/or IV 
fluids and vasopressors 
as needed. Monitor 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
124 
 
 
 
 
intubation and 
mechanical 
ventilation) 
closely. Manage 
constitutional symptoms 
and organ toxicities as 
per institutional practice. 
other organ function 
closely. Manage 
constitutional symptoms 
and organ toxicities as 
per institutional practice. 
 
Rule out other 
inflammatory conditions 
that can mimic CRS 
(e.g., sepsis). If no 
improvement within 24 
hours, initiate workup 
and assess for signs and 
symptoms of HLH or 
MAS as described in this 
appendix. 
 
Rule out other 
inflammatory conditions 
that can mimic CRS 
(e.g., sepsis). If no 
improvement within 24 
hours, initiate workup 
and assess for signs and 
symptoms of HLH or 
MAS as described in this 
appendix. 
 
Administer IV 
corticosteroids (e.g., 
methylprednisolone 
2 mg/kg/day or 
dexamethasone 10 mg 
every 6 hours). 
 
Administer IV 
corticosteroids (e.g., 
methylprednisolone 
2 mg/kg/day or 
dexamethasone 10 mg 
every 6 hours). 
 
Consider anti-cytokine 
therapy. For patients 
who are refractory to 
anti-cytokine therapy, 
experimental treatments f 
may be considered at the 
discretion of the 
investigator. 
 
Consider anti-cytokine 
therapy. For patients 
who are refractory to 
anti-cytokine therapy, 
experimental treatments f 
may be considered at the 
discretion of the 
investigator. 
 
Hospitalize patient until 
complete resolution of 
symptoms. 
 
Hospitalize patient until 
complete resolution of 
symptoms. 
ASTCT   American Society for Transplantation and Cellular Therapy; BiPAP   bi-level 
positive airway pressure; CAR   chimeric antigen receptor; CPAP   continuous positive 
airway pressure; CRS   cytokine-release syndrome; CTCAE   Common Terminology Criteria 
for Adverse Events; eCRF   electronic Case Report Form; HLH   hemophagocytic 
lymphohistiocytosis; ICU   intensive care unit; IRR   infusion-related reaction; 
MAS   macrophage activation syndrome; NCCN   National Cancer Comprehensive Network; 
NCI   National Cancer Institute. 
Note: These management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cellrelated toxicities (Version 2.2019). 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
125 
 
 
 
a Grading system for these management guidelines is based on ASTCT consensus grading for 
CRS. NCI CTCAE v5.0 should be used when reporting severity of IRRs, CRS, or organ 
toxicities associated with CRS on the Adverse Event eCRF. Organ toxicities associated with 
CRS should not influence overall CRS grading. 
b Fever is defined as temperature t38qC not attributable to any other cause. In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no 
longer required when subsequently determining event severity (grade). In this case, the grade 
is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen. For bronchospasm, urticaria, or dyspnea, additional treatment 
may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at d6 L/min, and high flow is defined as oxygen 
delivered at !6 L/min. 
e Resumption of study therapy may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event. The decision to rechallenge patients 
with study therapy should be based on investigator's assessment of benefitrisk, discussion 
and approval of PI, and documented by the investigator (or an appropriate delegate). For 
subsequent infusions, administer oral premedication with antihistamines, anti-pyretics, and/or 
analgesics, and monitor closely for IRRs and/or CRS. Premedication with corticosteroids and 
extending the infusion time may also be considered after assessing the benefitrisk ratio. 
f Refer to Riegler et al. (2019). 
Meningo- 
encepahlitis, 
immune-related 
 
(signs and 
symptoms in 
absence of an 
identified alternate 
etiology) 
All grades 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab). 
Patient may not resume 
treatment, regardless of 
benefit. 
 
Refer patient to 
neurologist 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. Patient may 
not resume treatment 
with atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib, 
regardless of benefit. 
 
 
Initiate treatment with 
12 mg/kg/day IV 
methylprednisolone or 
equivalent and convert to 
12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
If event resolves to grade 
1 or better, taper 
corticosteroids over t1 
month. 
 
If event does not 
Refer patient to 
neurologist 
 
Initiate treatment with 
12 mg/kg/day IV 
methylprednisolone or 
equivalent and convert 
to 12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
If event resolves to 
grade 1 or better, taper 
corticosteroids over t1 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
126 
 
 
 
 
 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
month. 
 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
Myasthenia gravis 
and Guillain-Barré 
syndrome 
All grades 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab). 
Patient may not resume 
treatment, regardless of 
benefit. 
 
See Section 7.1.2 for 
further instructions. 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. Patient may 
not resume treatment 
with atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib, 
regardless of benefit. 
 
 
 
See Section 7.1.2 for 
further instructions. 
Myocarditis 
(immune-related) 
Grades 2-4 
Permanently discontinue 
atezolizumab and CDX- 
1127 (varlilumab) and 
contact the study PI. See 
Section 7.1.2 for further 
instructions. 
Permanently discontinue 
atezolizumab and CDX- 
1127 (varlilumab) and 
cobimetinib contact the 
study PI. See Section 
7.1.2 for further 
instructions. 
 
Myositis 
Grade 1 
Continue atezolizumab 
& CDX-1127 
Continue atezolizumab 
& CDX-1127 and 
cobimetinib 
 
 
Refer patient to 
rheumatologist or 
neurologist. 
 
Refer patient to 
rheumatologist or 
neurologist. 
 
 
Initiate treatment as per 
institutional guidelines. 
 
Initiate treatment as per 
institutional guidelines. 
 
Grade 2 
Withhold atezolizumab 
& CDX-1127 
(varlilumab). 
Withhold atezolizumab 
& CDX-1127 
(varlilumab) and 
cobimetinib. a 
 
 
Refer patient to 
rheumatologist or 
 
Refer patient to 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
127 
 
 
 
 
 
neurologist. 
rheumatologist or 
neurologist. 
 
Initiate treatment as per 
institutional guidelines. 
Consider treatment with 
corticosteroids 
equivalent to 
12 mg/kg/day IV 
methylprednisolone and 
convert to 
12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
If corticosteroids are 
initiated and event does 
not improve within 
48 hours after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
 
If event resolves to 
Grade 1 or better, 
resume infusions at 
some dose and 
cobimetinib at 1 dose 
reduction. 
 
If event does not resolve 
to Grade 1 or better 
while withholding study 
therapy, permanently 
discontinue therapy. c 
Initiate treatment as per 
institutional guidelines. 
Consider treatment with 
corticosteroids 
equivalent to 
12 mg/kg/day IV 
methylprednisolone and 
convert to 
12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
If corticosteroids are 
initiated and event does 
not improve within 
48 hours after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
If event resolves to 
Grade 1 or better, 
resume. 
If event does not resolve 
to Grade 1 or better 
while withholding 
infusions, permanently 
discontinue infusions. c 
Grade 3 
Withhold atezolizumab 
& CDX-1127 
(varlilumab). 
Withhold atezolizumab 
& CDX-1127 
(varlilumab). 
 
Refer patient to 
rheumatologist or 
neurologist. 
Refer patient to 
rheumatologist or 
neurologist. 
 
Initiate treatment as per 
institutional guidelines. 
Initiate treatment as per 
institutional guidelines. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
128 
 
 
 
 
 
 
Respiratory support may 
be required in more 
severe cases. 
 
Respiratory support may 
be required in more 
severe cases. 
Initiate treatment with 
corticosteroids 
equivalent to 
12 mg/kg/day IV 
methylprednisolone, or 
higher-dose bolus if 
patient is severely 
compromised (e.g., 
cardiac or respiratory 
symptoms, dysphagia, or 
weakness that severely 
limits mobility); convert 
to 12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
Initiate treatment with 
corticosteroids 
equivalent to 
12 mg/kg/day IV 
methylprednisolone, or 
higher-dose bolus if 
patient is severely 
compromised (e.g., 
cardiac or respiratory 
symptoms, dysphagia, or 
weakness that severely 
limits mobility); convert 
to 12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
If event resolves to 
Grade 1 or better, 
resume study therapy. 
 
If event does not resolve 
to Grade 1 or better 
while withholding study 
therapy, permanently 
discontinue. 
 
For recurrent events, 
treat as a Grade 4 event. 
If event resolves to 
Grade 1 or better, 
resume infusions at 
some dose and 
cobimetinib at 1 dose 
reduction. 
 
If event does not resolve 
to Grade 1 or better 
while withholding study 
treatment, permanently 
discontinue study 
treatment. 
 
For recurrent events, 
treat as a Grade 4 event. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
129 
 
 
 
 
Grade 4 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab). c 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. c 
 
Refer patient to 
rheumatologist or 
neurologist. 
 
Refer patient to 
rheumatologist or 
neurologist. 
 
Initiate treatment as per 
institutional guidelines. 
 
Initiate treatment as per 
institutional guidelines. 
 
Respiratory support may 
be required in more 
severe cases. 
 
Respiratory support may 
be required in more 
severe cases. 
 
Initiate treatment with 
corticosteroids 
equivalent to 
12 mg/kg/day 
IV methylprednisolone, 
or higher-dose bolus if 
patient is severely 
compromised (e.g., 
cardiac or respiratory 
symptoms, dysphagia, or 
weakness that severely 
limits mobility); convert 
to 12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
Initiate treatment with 
corticosteroids 
equivalent to 
12 mg/kg/day 
IV methylprednisolone, 
or higher-dose bolus if 
patient is severely 
compromised (e.g., 
cardiac or respiratory 
symptoms, dysphagia, or 
weakness that severely 
limits mobility); convert 
to 12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
 
If event resolves to 
Grade 1 or better, taper 
corticosteroids over 
t1 month. 
 
If event resolves to 
Grade 1 or better, taper 
corticosteroids over 
t1 month. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
130 
 
 
 
Neuropathy, 
immune-related 
 
(sensory and/or 
motor) 
All Grades 
Grade 1 
See Section 7.1.2 for 
further instructions. 
See Section 7.1.2 for 
further instructions. 
 
 
 
 
 
 
Ocular events – 
inflammation (e.g. 
uveitis, iritis or 
episcleritis) 
Grade 1 
Continue atezolizumab 
& CDX-1127 
(varlilumab) 
Continue atezolizumab 
& CDX-1127 
(varlilumab) and 
cobimetinib. 
 
 
Patient referral to 
ophthalmologist is 
strongly recommended. 
 
Patient referral to 
ophthalmologist is 
strongly recommended. 
 
 
Initiate treatment with 
topical corticosteroid eye 
drops and topical 
immunosuppressive 
therapy. 
 
Initiate treatment with 
topical corticosteroid 
eye drops and topical 
immunosuppressive 
therapy. 
 
Grade 2 
(Symptomatic) 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
 
Patient referral to 
ophthalmologist is 
strongly recommended. 
 
Initiate treatment with 
topical corticosteroid eye 
drops and topical 
immunosuppressive 
therapy. 
 
If event resolves to grade 
1 or better within 12 
weeks, taper 
corticosteroids and 
resume atezolizumab & 
CDX-1127 (varlilumab) 
according to the 
guidelines above. 
 
Permanently discontinue 
atezolizumab & CDX- 
Hold atezolizumab & 
CDX-1127 
(varlilumab) and 
cobimetinib. 
 
Patient referral to 
ophthalmologist is 
strongly recommended. 
 
Initiate treatment with 
topical corticosteroid 
eye drops and topical 
immunosuppressive 
therapy. 
 
If event resolves to 
grade 1 or better within 
12 weeks, taper 
corticosteroids and 
resume atezolizumab & 
CDX-1127 (varlilumab) 
according to the 
guidelines above. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
131 
 
 
 
 
 
1127 (varlilumab) if 
event does not resolve to 
grade 1 or better within 
12 weeks. 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
combimetinib for 
immuneímediated 
ocular disease that is 
unresponsive to 
immunosuppressive 
therapy. 
Grade 3 or 4 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab). 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
combimetinib. 
 
Refer patient to 
ophthalmologist. 
 
Refer patient to 
ophthalmologist. 
 
Initiate treatment with 
12 mg/kg/day oral 
prednisone or equivalent. 
 
If event resolves to grade 
1 or better, taper 
corticosteroids over t1 
month. For grade 3 AEs, 
patient may only resume 
treatment after 
consultation with the 
trial PI; for grade 4, 
patient cannot resume 
treatment, regardless of 
benefit. 
 
Initiate treatment with 
12 mg/kg/day oral 
prednisone or 
equivalent. 
 
If event resolves to 
grade 1 or better, taper 
corticosteroids over t1 
month. For grade 3 AEs, 
patient may only resume 
treatment after 
consultation with the 
trial PI; for grade 4, 
patient cannot resume 
treatment, regardless of 
benefit. 
Ocular Events - 
Serous retinopathy 
(Severity grade 
assessment based 
on 
NCI CTCAE v 5.0 
“Eye Disorders – 
Other” scale) 
Grade 1: 
Asymptomatic 
or mild 
symptoms; 
clinical or 
diagnostic 
observations 
only; 
intervention 
not indicated 
Continue atezolizumab 
& CDX-1127 
(varlilumab) 
 
Continue ophthalmology 
follow-up as clinically 
indicated. 
Continue atezolizumab 
& CDX-1127 
(varlilumab) and 
cobimetinib without 
dose change. 
 
Continue ophthalmology 
follow-up as clinically 
indicated. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
132 
 
 
 
 
Grade 2: 
Moderate; 
minimal, local 
or noninvasive 
intervention 
indicated; 
limiting age 
appropriate 
instrumental 
ADL. 
 
Grade 3: 
Severe or 
medically 
significant but 
not 
immediately 
sight 
threatening; 
hospitalization 
or prolongation 
of existing 
hospitalization 
indicated; 
disabling; 
limiting self- 
care ADL. 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
 
Consult ophthalmology 
and undergo complete 
ophthalmologic 
examination, which 
includes visual acuity 
testing, intra-ocular 
pressure measurements, 
slit lamp 
ophthalmoscopy, 
indirect 
ophthalmoscopy, visual 
field, and OCT. 
Consider a fluorescein 
angiogram and/or 
indocyanine green 
angiogram, if clinically 
indicated. 
 
If Grade 2 or 3 serous 
retinopathy, 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib dosing 
should be held until 
symptoms improve to 
Grade 1. Restart 
atezolizumab & CDX- 
1127 (varlilumab) at 
fixed doses. 
 
If no recovery within 4 
weeks or if Grade 2 or 3 
serous retinopathy 
recurs, discuss 
permanent 
discontinuation of 
atezolizumab & CDX- 
1127 (varlilumab) with 
study PI. 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib. 
 
Consult ophthalmology 
and undergo complete 
ophthalmologic 
examination, which 
includes visual acuity 
testing, intra-ocular 
pressure measurements, 
slit lamp 
ophthalmoscopy, 
indirect 
ophthalmoscopy, visual 
field, and OCT. 
Consider a fluorescein 
angiogram and/or 
indocyanine green 
angiogram, if clinically 
indicated. 
 
If Grade 2 or 3 serous 
retinopathy, 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib dosing 
should be held until 
symptoms improve to 
Grade 1. Restart 
atezolizumab & CDX- 
1127 (varlilumab) at 
fixed doses and 
cobimetinib at 1 dose 
reduction. If no 
recovery within 4 
weeks, cobimetinib 
should be permanently 
discontinued. 
 
If Grade 2 or 3 serous 
retinopathy recurs 
despite 2 dose level 
reductions, 
atezolizumab & CDX- 
1127 (varlilumab)* and 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
133 
 
 
 
 
 
 
cobimetinib should be 
permanently 
discontinued. 
*Resumption of 
atezolizumab & CDX- 
1127 (varlilumab) at 
fixed dose without 
cobimetinib can be 
considered only after 
consultation with and 
approval by the trial PI, 
in patients who are 
deriving benefit 
treatment benefit and 
have fully recovered. 
Grade 4: Sight- 
threatening 
consequences; 
urgent 
intervention 
indicated; 
blindness 
(20/200 or 
worse) in the 
affected eye 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab). 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. 
Ocular Events – 
Rentinal Vein 
Occlusion (RVO) 
RVO 
Any grade 
RVO work up and 
treatment per 
institutional guidelines. 
 
Atezolizumab & CDX- 
1127 (varlilumab) 
therapy may be 
continued. 
If RVO (any grade) is 
diagnosed, cobimetinib 
dosing should be 
permanently 
discontinued and RVO 
treated per institutional 
guidelines. 
 
 
Atezolizumab & CDX- 
1127 (varlilumab) 
therapy may be 
continued. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
134 
 
 
 
Pancreatitis, 
immune related 
Grade 2 or 3 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib 
 
 
Refer patient to GI 
specialist. 
 
Refer patient to GI 
specialist. 
 
 
Initiate treatment with 
12 mg/kg/day 
intravenous 
methylprednisolone or 
equivalent and convert to 
12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
Initiate treatment with 
12 mg/kg/day 
intravenous 
methylprednisolone or 
equivalent and convert 
to 12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
 
If event resolves to grade 
1 or better within 12 
weeks, taper 
corticosteroids and 
resume atezolizumab & 
CDX-1127 (varlilumab) 
according to the 
guidelines above. 
 
If event resolves to 
grade 1 or better within 
12 weeks, taper 
corticosteroids and 
resume atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib at same 
doses. 
 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) if 
event does not resolve to 
grade 1 or better within 
12 weeks. Patient may 
only resume treatment 
after consultation with 
the trial PI. 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib if event 
does not resolve to grade 
1 or better within 
12 weeks. 
 
 
 
For recurrent events, 
permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab). 
Patient may not resume 
treatment, regardless of 
benefit. 
Patient may only resume 
treatment after 
consultation with the 
trial PI. 
 
For recurrent events, 
permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. Patient 
may not resume 
treatment, regardless of 
benefit. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
135 
 
 
 
 
Grade 4 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab). 
Patient may not resume 
treatment, regardless of 
benefit. 
Permanently 
discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. Patient may 
not resume treatment, 
regardless of benefit. 
 
Refer patient to GI 
specialist. 
 
Refer patient to GI 
specialist. 
 
Initiate treatment with 
12 mg/kg/day 
intravenous 
methylprednisolone or 
equivalent and convert to 
12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
Initiate treatment with 
12 mg/kg/day 
intravenous 
methylprednisolone or 
equivalent and convert 
to 12 mg/kg/day oral 
prednisone or equivalent 
upon improvement. 
 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
 
If event resolves to grade 
1 or better, taper 
corticosteroids over t1 
month. 
 
If event resolves to 
grade 1 or better, taper 
corticosteroids over t1 
month. 
Pulmonary toxicity 
All pulmonary 
events 
Evaluate thoroughly for 
other commonly 
reported etiologies such 
as pneumonia/infection, 
lymphangitic 
carcinomatosis, 
pulmonary embolism, 
heart failure, chronic 
obstructive pulmonary 
disease (COPD), or 
pulmonary hypertension. 
Evaluate thoroughly for 
other commonly 
reported etiologies such 
as pneumonia/infection, 
lymphangitic 
carcinomatosis, 
pulmonary embolism, 
heart failure, chronic 
obstructive pulmonary 
disease (COPD), or 
pulmonary hypertension. 
Grade 1 
Continue atezolizumab 
& CDX-1127 
(varlilumab) and monitor 
Continue atezolizumab 
& CDX-1127 
(varlilumab) and 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
136 
 
 
 
 
 
closely. 
cobimetinib and monitor 
closely. 
Re-evaluate on serial 
imaging. 
 
Consider patient referral 
to a pulmonary 
specialist. 
 
For recurrent 
pneumonitis, treat as a 
grade 3 or 4 event. 
 
Consider serial imaging 
(repeat imaging scan or 
x-ray 1-2 weeks later). 
 
Consider patient referral 
to a pulmonary 
specialist. 
 
For recurrent 
pneumonitis, treat as a 
grade 3 or 4 event. 
Grade 2 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
Hold atezolizumab & 
CDX-1127 (varlilumab) 
and cobimetinib. 
 
Refer patient to 
pulmonary and 
infectious disease 
specialists and consider 
bronchoscopy or 
bronchoscopic alveolar 
lavage (BAL). 
 
Refer patient to 
pulmonary and 
infectious disease 
specialists and consider 
bronchoscopy or 
bronchoscopic alveolar 
lavage (BAL). 
 
Initiate treatment with 
12 mg/kg/day oral 
prednisone or equivalent. 
 
If event resolves to grade 
1 or better within 12 
weeks, taper 
corticosteroids and 
resume atezolizumab & 
CDX-1127 (varlilumab) 
according to the 
guidelines above. 
 
If corticosteroids have 
been initiated, they must 
be tapered over t 1 
month to the equivalent 
of d10 mg/day oral 
prednisone before 
atezolizumab & CDX- 
1127 (varlilumab) can be 
 
Initiate treatment with 
12 mg/kg/day oral 
prednisone or 
equivalent. 
 
If event resolves to 
grade 1 or better within 
12 weeks, taper 
corticosteroids and 
resume atezolizumab & 
CDX-1127 (varlilumab) 
at fixed doses and 
cobimetinib at 1 dose 
reduction if 
GGO/infiltrates 
improving. 
 
If corticosteroids have 
been initiated, they must 
be tapered over t 1 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
137 
 
 
 
 
 
resumed. 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) if 
event does not resolve to 
grade 1 or better within 
12 weeks. 
month to the equivalent 
of d10 mg/day oral 
prednisone before 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib can be 
resumed. 
 
For recurrent events, or 
events with no 
improvement after 48– 
72 hours of 
corticosteroids, treat as a 
Grade 3 or 4 event. 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib if event 
does not resolve to grade 
1 or better within 
12 weeks. 
 
For recurrent events, or 
events with no 
improvement after 48– 
72 hours of 
corticosteroids, treat as a 
Grade 3 or 4 event. 
Grade 3 or 4 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib. 
 
Bronchoscopy or BAL is 
recommended. 
 
Bronchoscopy or BAL is 
recommended. 
 
Initiate treatment with 
12 mg/kg/day IV 
methylprednisolone or 
equivalent. 
 
Initiate treatment with 
12 mg/kg/day IV 
methylprednisolone or 
equivalent. 
 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
 
If event does not 
improve within 48 hours 
after initiating 
corticosteroids, consider 
adding an 
immunosuppressive 
agent. 
 
If corticosteroids have 
been initiated, they must 
be tapered over t 1 
month to the equivalent 
 
If corticosteroids have 
been initiated, they must 
be tapered over t 1 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
138 
 
 
 
 
 
of d10 mg/day oral 
prednisone before 
atezolizumab & CDX- 
1127 (varlilumab) can be 
resumed. 
 
For grade 3 AEs, patient 
may only resume 
treatment with fixed 
dose atezolizumab & 
CDX-1127 (varlilumab) 
after consultation with 
the trial PI; for grade 4, 
patient cannot resume 
treatment, regardless of 
benefit. 
month to the equivalent 
of d10 mg/day oral 
prednisone before 
atezolizumab & CDX- 
1127 (varlilumab) and 
cobimetinib can be 
resumed. 
 
For grade 3 AEs, patient 
may only resume 
treatment with fixed 
dose atezolizumab & 
CDX-1127 (varlilumab) 
and 1 – level dose 
reduced cobimetinib 
after consultation with 
the trial PI. 
 
For grade 4, patient 
cannot resume treatment, 
regardless of benefit. 
Renal Dysfunction 
Renal event, 
general 
guidance 
Consider possible tumor- 
related etiology, and 
consider earlier restaging 
imaging to inform 
clinical decision making 
(e.g. steroid initiation) 
Consider possible 
tumor-related etiology, 
and consider earlier 
restaging imaging to 
inform clinical 
management (e.g. 
steroid initiation) 
 
Grade 2 
increased serum 
creatinine/CrCl 
Withhold atezolizumab 
& CDX-1127 
(varlilumab) 
Withhold atezolizumab 
& CDX-1127 
(varlilumab) & 
cobimetinib 
 
 
Refer to renal specialist 
for evaluation, work up 
and consideration of 
kidney biopsy to 
establish etiology of 
kidney event 
 
Refer to renal specialist 
for evaluation, work up 
and consideration of 
kidney biopsy to 
establish etiology of 
kidney event 
 
 
If immune-related 
etiology highly 
suspected following 
work up, initiate 
treatment with 
corticosteroids 
equivalent to 
 
If immune-related 
etiology highly 
suspected following 
work up, initiate 
treatment with 
corticosteroids 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
139 
 
 
 
 
 
12 mg/kg/day oral 
prednisone. 
equivalent to 
12 mg/kg/day oral 
prednisone. 
Resume in patients with 
complete or partial 
resolution (Grade 0 to 1) 
after appropriate 
intervention 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) 
if no complete or partial 
resolution within 12 
weeks of initiating 
steroids or inability to 
reduce prednisone to 10 
mg per day or less (or 
equivalent) within 12 
weeks of initiating 
steroids 
 
Resume in patients with 
complete or partial 
resolution (Grade 0 to 1) 
after appropriate 
intervention. Consider 
cobimetinib dose 
reduction if contributing 
to event 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) & 
cobimetinib if no 
complete or partial 
resolution within 12 
weeks of initiating 
steroids or inability to 
reduce prednisone to 10 
mg per day or less (or 
equivalent) within 12 
weeks of initiating 
steroids 
Grade 3 or 4 
increased serum 
creatinine/CrCl 
Discontinue 
atezolizumab & CDX- 
1127 (varlilumab) 
Discontinue 
atezolizumab & CDX- 
1127 (varlilumab) & 
cobimetinib 
 
Work to evaluate 
etiology of renal event. 
 
Refer to renal specialist 
for evaluation, work up 
and consideration kidney 
biopsy to establish 
etiology of kidney event 
 
If immune-related 
etiology highly 
suspected following 
work up, initiate 
treatment with 
corticosteroids 
equivalent to 
 
Refer to renal specialist 
for evaluation, work up 
and consideration kidney 
biopsy to establish 
etiology of kidney event 
 
If immune-related 
etiology highly 
suspected following 
work up, initiate 
treatment with 
corticosteroids 
equivalent to 
12 mg/kg/day oral 
prednisone. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
140 
 
 
 
 
 
12 mg/kg/day oral 
prednisone. 
 
Resume in patients with 
complete or partial 
resolution (Grade 0 to 1) 
after corticosteroid taper 
at same doses. 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) 
if no complete or partial 
resolution within 12 
weeks of initiating 
steroids or inability to 
reduce prednisone to 10 
mg per day or less (or 
equivalent) within 12 
weeks of initiating 
steroids 
 
Resume in patients with 
complete or partial 
resolution (Grade 0 to 1) 
after corticosteroid taper 
at same doses. 
 
Permanently discontinue 
atezolizumab & CDX- 
1127 (varlilumab) & 
cobimetinib if no 
complete or partial 
resolution within 12 
weeks of initiating 
steroids or inability to 
reduce prednisone to 10 
mg per day or less (or 
equivalent) within 12 
weeks of initiating 
steroids 
 
If event resolves to grade 
1 or better, taper 
corticosteroids over t1 
month. For grade 3 AEs, 
patient may only resume 
treatment after 
consultation with the 
trial PI; for grade 4, 
patient cannot resume 
treatment, regardless of 
benefit. 
If event resolves to 
grade 1 or better, taper 
corticosteroids over t1 
month. For grade 3 AEs, 
patient may only resume 
treatment (infusions at 
same dose, and 
cobimetinib at one dose 
reduction) after 
consultation with the 
trial PI; for grade 4, 
patient cannot resume 
treatment, regardless of 
benefit. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
141 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agents 
 
Atezolizumab (NSC 783608) 
Other Names: TecentriqTM, MPDL3280A 
Classification: monoclonal antibody 
M.W.: 150 KD 
Mode of Action: anti-PD-L1 
 
Description: 
Atezolizumab is a humanized IgG1 monoclonal antibody consisting of two heavy chains (448 
amino acids) and two light chains (214 amino acids). Atezolizumab targets human PD-L1 and 
inhibits its interaction with its receptor PD-1. Atezolizumab also blocks the binding of PD-L1 to 
B7.1, an interaction that is reported to provide additional inhibitory signals to T cells (Butte et al. 
2007). 
 
How Supplied: 
Atezolizumab is provided by Genentech/F.Hoffmann-La Roche LTD and distributed by the 
Pharmaceutical Management Branch, CTEP, NCI. The agent is supplied in a single-use, 20-mL 
glass vial as a colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution intended 
for IV administration. Each 20 mL vial contains 1200 mg of atezolizumab and is formulated 
glacial acetic acid (16.5 mg), L-histidine (62 mg), polysorbate 20 (8 mg), and sucrose (821.6 
mg), with a pH of 5.8. 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. 
 
Preparation: 
The prescribed dose of atezolizumab should be diluted in 0.9% NaCl to a concentration between 3.2 
mg/mL and 16.8 mg/mL and infused with or without a low-protein binding 0.2 or 0.22 micrometer 
in-line filter. The IV bag may be constructed of polyvinyl chloride (PVC), polyolefin (PO), or 
polyethylene (PE). The prepared solution may be stored at 2°C-8°C for up to 24 hours or at 
ambient < 25°C (77°F) for 6 hours from the time of preparation. If the dose solution is stored at 
2°C–8°C (36°F–46°F), it should be removed from refrigeration and allowed to reach room 
temperature prior to administration. These times include the storage and administration times for 
the infusion. Do not shake or freeze infusion bags containing the dose solution. 
Storage: 2°C–8°C (36°F–46°F). Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. 
 
If a storage temperature excursion is identified, promptly return atezolizumab to 2°C-8°C (36°F- 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
142 
 
 
46°F) and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Stability studies are ongoing. 
 
CAUTION: No preservative is used in atezolizumab; therefore, the vial is intended for single 
use only. Discard any unused portion of drug remaining in a vial. 
 
Route of Administration: IV infusion 
 
Method of Administration: 
Atezolizumab is administered as an intravenous infusion over 60 minutes. If the first infusion is 
tolerated, all subsequent infusions may be delivered over 30 minutes. Do not administer 
atezolizumab as an intravenous push or bolus. No premedication is indicated for administration 
of Cycle 1 of atezolizumab. Patients who experience an infusion related reaction with Cycle 1 of 
atezolizumab may receive premedication with subsequent infusions. 
 
Potential Drug Interactions: 
Cytochrome P450 enzymes as well as conjugation/glucuronidation reactions are not involved in 
the metabolism of atezolizumab. No drug interaction studies for atezolizumab have been 
conducted or are planned. There are no known interactions with other medicinal products or 
other form of interactions. 
 
Patient Care Implications: 
Male patients and female patients of childbearing potential should utilize contraception and take 
active measures to avoid pregnancy while undergoing atezolizumab treatment and for at least 
150 days after the last dose of atezolizumab or 3 months after the last dose of cobimetinib. 
 
Availability 
 
Atezolizumab is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
143 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
144 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Availability 
 
CDX-1127 (varlilumab) is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Cobimetinib (NSC 781257) 
 
Chemical Name: (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] 
[3 hydroxy-3-(piperidin-2-yl)azetidin-1-yl]methanone hemifumarate 
 
Other Names: COTELLIC®, RO5514041, GDC0973 
 
Classification: MEK inhibitor 
 
Molecular Formula: C46H46F6I2N6O8 
M.W.: 1178.69 g/mol as hemifumarate 
salt 
531.31 g/mol as free base 
 
Approximate Solubility: At 37°C, the solubility of cobimetinib is 0.744 mg/mL in water 
 
Mode of Action: Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase 
(MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. 
 
Description: Cobimetinib API is a hemifumarate salt, appearing as a white to off-white solid. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
145 
 
 
How Supplied: Genentech supplies and CTEP, DCTD, NCI distributes Cobimetinib as a 
20-mg film coated, immediate-release tablets debossed on one side with “COB”. Drug 
concentrations and strengths of tablet drug products are expressed as the free-base equivalents. 
The tablet formulation consists of the cobimetinib drug product and the following inactive 
ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium 
stearate (non-bovine), and Opadry White film coat. All excipients used in the tablet formulation 
are compendial (USP/NF and/or EP) grade with the exception of the film coating. The tablet 
coating consists of polyvinyl alcohol-part hydrolyzed, titanium dioxide, macrogol 3350, and talc. 
The ingredients in the film coating are compendial. Each bottle contains 63 tablets. 
 
Storage: Store at room temperature below 30°C (86°F). 
 
If a storage temperature excursion is identified, promptly return cobimetinib to below 30°C and 
quarantine the supplies. Provide a detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for 
determination of suitability. 
 
Stability: Refer to the package label for expiration. 
 
Route(s) of Administration: oral 
 
Method of Administration: cobimetinib can be administered with or without food 
 
Potential Drug Interactions: 
Avoid concurrent use of cobimetinib and strong or moderate CYP3A inhibitors. If concurrent 
short term (14 days or less) use of moderate CYP3A inhibitors including certain antibiotics (e.g., 
erythromycin, ciprofloxacin) is unavoidable, consider reducing the dose of cobimetinib while on 
CYP3A inhibitor. Coadministration of cobimetinib with a strong CYP3A inducer may decrease 
cobimetinib systemic exposure by more than 80% and reduce its efficacy. Avoid concurrent use 
of cobimetinib and strong or moderate CYP3A inducers including but not limited to 
carbamazepine, efavirenz, phenytoin, rifampin, and St. John’s Wort. 
 
Cobimetinib is a substrate of efflux transporter P-glycoprotein (P-gp), but is not a substrate of 
Breast Cancer Resistance Protein (BCRP), Organic Anion Transporting Polypeptide (OATP1B1 
or OATP1B3) or Organic Cation Transporter (OCT1) in vitro. Drugs that inhibit P-gp may 
increase cobimetinib concentrations. In vitro data suggest that cobimetinib at clinically relevant 
concentrations does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or 
OCT2. 
 
Coadministration of a proton pump inhibitor, rabeprazole 20 mg once daily for 5 days, with a 
single dose of 20 mg COTELLIC under fed and fasted conditions did not result in a clinically 
important change in cobimetinib exposure. 
 
Reproductive Risks: 
Based on its mechanism of action and findings from animal reproduction studies, cobimetinib 
can cause fetal harm when administered to a pregnant woman. For this reason, women of child- 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
146 
 
 
bearing potential and men must agree to use adequate contraception (hormonal or barrier method 
of birth control; abstinence) prior to study entry and, for the duration of study participation, and 5 
months after the last dose of Atezolizumab and 3 months after the last dose of cobimetinib. 
 
Availability 
 
Cobimetinib is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
Agent Ordering and Agent Accountability 
 
8.1.4.1 NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF). If there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
participating investigator at that institution. 
 
Sites may order atezolizumab, varlilumab and cobimetinib once a patient has been 
enrolled to the study . 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status. For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time. 
Refer to the PMB’s website for specific policies and guidelines related to agent 
management. 
 
8.1.4.2 Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page. Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
 
 
Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application. Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, a “current” password and 
active person registration status. Questions about IB access may be directed to the PMB IB 
Coordinator via email. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
147 
 
 
 
Useful Links and Contacts 
x CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/
x NCI CTEP Registration: RCRHelpDesk@nih.gov
x PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm
x 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP
x CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/
x CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov
x IB Coordinator: IBCoordinator@mail.nih.gov
x PMB email: PMBAfterHours@mail.nih.gov
x PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET)

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
148 
 
 
9. STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
The proposed study is an open-label, randomized phase 2 trial evaluating atezolizumab in 
combination with CDX-1127 (varlilumab) with or without the addition of cobimetinib in 
unresectable, pre-treated cholangiocarcinoma. Patients will be randomized in a 1:1 ratio to the 
two arms. The primary objective of the trial is to determine whether these the combination of 
checkpoint blockade with an immune co-stimulatory yields a clinically compelling antitumor 
activity (measured as overall response rates [ORR, assessed by RECIST 1.1] and progression 
free survival [PFS, assessed by RECIST 1.1]) and if this effect can be further amplified with the 
addition of MEK inhibition. Secondary endpoints include safety, overall survival (OS), 
immunologic correlates, and pharmacokinetics of atezolizumab and varlilumab. Objective 
response (OR) and PFS are co-primary endpoints. 
 
Analysis of Co-Primary Efficacy Endpoints 
 
Overall Response Rate (ORR): 
The objective response rate defined as the proportion of response evaluable subjects who have a 
complete response (CR) or partial response (PR) using RECIST 1.1 criteria at any time during 
the study. The evaluable population includes all subjects who initiated therapy. Patient who have 
not received a follow-up scan, and thus are not evaluable for response, will be counted as non- 
responders. 
 
Progression Free Survival (PFS): 
PFS is defined as the duration of time from date of randomization to time of progression or 
death. This analysis is intent-to-treat including all randomized patients. Patients who come off of 
study treatment for clinical progression without radiographic progression (i.e. clinical 
progression) will be coded as progression for the analysis, and the date of progression is the date 
of clinical progression. Due to the rapid progression of the disease in the majority of patients, 
little loss to follow up is expected, but subjects who are lost to follow-up as of the data analysis 
cutoff date will be right-censored. The censoring date will be determined from the date the 
subject was last evaluated for progression. PFS within each treatment arm will be summarized 
descriptively using Kaplan-Meier plots, and compared between arms using log-rank tests. 
 
9.2 
Sample Size/Accrual Rate 
 
The study is planned for 64 evaluable subjects (32 subjects per treatment arm). The objective 
response rate (ORR) of BTCs treated with FOLFOX, anti-PD-1 monotherapy or anti- 
PDL1+MEKi is around 5%. A clinically meaningful improvement that warrants further study 
would be a 20% ORR. A Simon two-stage minimax design is planned for each arm. Arm specific 
type I error is set at 0.1 (one-sided) when evaluating the co-primary endpoints of ORR and PFS. 
For each arm, 18 patients will be enrolled in the first stage. If none have OR, the accrual to that 
arm will be terminated. If 1 or more respond, then additional 14 patients will be enrolled (for a 
total of 32 patients in that arm). If 4 or more patients achieve OR (12.5%) in stage 1 and stage 2 
combined, the endpoint is met in that arm. The design yields at least 90% power to detect a true 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
149 
 
 
response rate of at least 20%, with at least .90 probability of a negative result (no more than 3 
responses if the true response rate is no more than 5%, for each of the two arms. The chance of 
early stopping after stage 1 in each arm is 0.4 when the true response rate is 5%. 
 
If both arms meet the response endpoint criteria, the comparison of PFS will be performed. The 
median progression free survival of BTCs treated with FOLFOX, anti-PD-1 monotherapy, & 
anti-PDL1+MEKi is 4.0, 2.0, and 3.5 months, respectively. Randomization of 64 patients, with 
observation of 55 PFS events would yield 90% power to detect an HR = 0.5 (corresponding to 
3.5 vs. 7 months median PFS in the doublet and triplet arm, respectively), at the one-sided 0.10 
significance level. An observed 40% increase in median PFS for the triplet arm (approximately 
1.4 months, assuming an approximately 3.5-month median PFS in the doublet arm; observed 
HR=0.714) would be sufficient to achieve statistical significance. 
 
Taking into account dropout/study attrition, we anticipate screening between 70-80 patients in 
order to achieve 32 evaluable patients per treatment arm (N=64) with an anticipated accrual rate 
of 4 patients/month. 
 
PLANNED ENROLLMENT REPORT 
 
DOMESTIC PLANNED ENROLLMENT REPORT (SCREENING) 
 
Racial Categories 
Ethnic Categories 
 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
1 
1 
0 
0 
2 
Asian 
2 
2 
0 
0 
4 
Native Hawaiian or 
Other Pacific 
Islander 
 
1 
 
1 
 
0 
 
0 
 
2 
Black or African 
American 
4 
4 
0 
0 
8 
White 
23 
23 
3 
3 
52 
More Than One 
Race 
2 
2 
1 
1 
6 
Total 
33 
33 
4 
4 
74 
 
 
DOMESTIC PLANNED ENROLLMENT REPORT (TREATMENT) 
 
Racial Categories 
Ethnic Categories 
 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
1 
1 
0 
0 
2 
Asian 
2 
2 
0 
0 
4 
Native Hawaiian or 
Other Pacific 
Islander 
 
1 
 
1 
 
0 
 
0 
 
2 
Black or African 
American 
4 
4 
0 
0 
8 
White 
20 
20 
1 
1 
42 
More Than One 
Race 
2 
2 
1 
1 
6 
Total 
30 
30 
2 
2 
64 
 
PHS 398 / PHS 2590 (Rev. 03/20 Approved Through 2/28/2023) 
OMB No. 0925-0001/0002 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
150 
 
 
 
9.3 
Stratification Factors 
 
Site of disease (1 level of stratification with 3 categories): 
After the screening phase, eligible subjects will undergo stratified randomization according to 
the site of disease: 1) gallbladder cancer (GBC); 2) intrahepatic (IHC); and 3) extrahepatic 
cholangiocarcinoma (EHC) to ensure similar distribution of BTCs subtypes across treatment 
arms. There will be no further stratification based on other patient or tumor characteristics (such 
as age, sex) in this trial. Sample size calculations were performed without stratification, as the 
sample size is small. 
 
9.4 
Analysis of Secondary Endpoints 
Clinical Secondary Endpoints: 
Overall survival (OS) 
OS is defined as the duration of time from start of study treatment to time of death. For subjects 
lost to follow-up or whose vital status is unknown, every effort will be made to determine the 
date such subjects were last known to be alive. Such efforts may include phone calls, certified 
mail, and the checking of public records. Subjects who are alive or lost to follow-up as of the 
data analysis cutoff date will be right-censored. The censoring date will be determined from the 
date the subject was last known to be alive. OS will be summarized descriptively using the 
Kaplan-Meier method. The analysis of OS will be performed on all randomized patients, as well 
as all the individuals who complete at least one dose of therapy. Median OS will be reported and 
the associated 95% confidence interval will be estimated. 
 
Correlative Secondary Endpoints: 
 
Change in T-Cell populations (TILs): 
The density of CD8+ T cells in each treatment group, at baseline and after treatment, will be 
visualized using boxplots, and described using summary statistics including means and standard 
deviation presented with 95% confidence intervals. A student t-test or nonparametric Wilcoxon 
rank-sum test will be used to determine whether the increase in CD8+ T cells is greater in 
treatment arm B (combination atezolizumab and CDX-1127 (varlilumab) plus cobimetinib) than 
in treatment arm A (atezolizumab and CDX-1127 (varlilumab)). 
 
Pharmacokinetics and Immunogenicity: 
x Atezolizumab and CDX-1127 (varlilumab) serum concentrations will be measured using 
validated ELISAs. Commercially available ELISA assays for atezolizumab will be used 
to quantify atezolizumab in patient serum samples. For varlilumab, we will develop and 
validate, per FDA guidance criteria, an ELISA assay using immobilized CD27 and a 
labeled secondary anti-human IgG1 for detection. Similarly, for immunogenicity, we will 
establish screening assays for both atezolizumab and CDX-1127 (varlilumab) and 
perform immunodepletion in bridging assays for samples testing positive for ADAs. This 
will be completed within the OSUCCC PhASR lab, which is experienced with 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
151 
 
 
bioanalytical assay development and validation per FDA guidance criteria, using ELISA, 
LC-MS and other platforms. 
x Atezolizumab and CDX-1127 (varlilumab) clearance, including a time-varying rate of 
change, will be determined for each patient using mixed effects pharmacokinetic 
modeling. The methods for this will include adopting published PK models for 
atezolizumab as a starting point (e.g. Netterberg, et al. 2019; Stroh, et al. 2017) and using 
Bayesian estimation with the published model parameter values as priors in NONMEM 
(Icon, Dublin, Ireland). As no published mixed effects model for varlilumab is currently 
available, we will evaluate a basic 2-compartment model as a starting point and add 
additional structural parameters (e.g. time-varying clearance), as statistically justified. 
We will use the likelihood ratio test for decision-making when adding each new 
parameter, using the objective function value (OFV), which is chi-square distributed, and 
a cut-off of -3.84 change in OFV, which corresponds to a p-value of 0.05 with one degree 
of freedom. Once a base model is established, we will also evaluate covariates (e.g. 
albumin, CLcr, ADA, etc.) using forward addition/backward deletion with p = 0.01 as a 
cut-off for covariate retention. 
x The primary assessment will be individual baseline atezolizumab clearance as a 
continuous variable in uni-variate and multi-variate Cox proportional hazards models for 
PFS. We hypothesize baseline atezolizumab clearance will be a predictor of PFS (higher 
baseline atezolizumab clearance will associate with shorter PFS). 
x Several secondary assessments will be completed to determine associations of baseline or 
time-varying atezolizumab clearance with CDX-1127 (varlilumab) baseline clearance, 
CDX-1127 (varlilumab) time-varying clearance, and presence of cachexia. The 
secondary assessments will evaluate associations with PFS and OS. We hypothesize 
patients with high baseline atezolizumab clearance will also have high baseline CDX- 
1127 (varlilumab) clearance, and that the baseline clearance for both antibodies will be 
higher in patients with cachexia compared to patients without cachexia. 
 
Analysis of Exploratory Endpoints: 
 
Tumor Microenvironment Modulation and Immunologic Response 
The overarching aim of these studies is to establish baseline levels for, and measure changes in 
immunological pathways after treatment. Little is known about baseline levels for these variables 
in biliary tract cancer, let alone changes after treatment, and if the primary and secondary aims 
are successful, these investigations will establish a biological foundation on which to build in 
follow up studies that will include the following comparisons with the aim of correlating these 
observed changes with treatment response, and toxicity: 
 
x Baseline versus on-treatment expression of PD-L1 
x Baseline versus on-treatment of immune markers quantifying ratio of CD8+ T effector 
cells and CD4+FoxP3+ T regulatory cells, and major histocompatibility complex (MHC) 
class I expression. 
x Baseline versus on-treatment immune markers of T cell function and quality (see 
correlative studies sections above) 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
152 
 
 
x Baseline versus on-treatment circulating immune cells (Tc, TH1, TH2, TH17) and 
cytokine profiles in peripheral blood by flow cytometry 
 
Immunological variables will be examined in plots and summary statistics, to characterize 
distributions, identify outliers and other potential problems in the data. Joint exploratory analysis 
will identify associations and potential interactions. Variables may be transformed on the basis of 
these investigations, to reduce skewness, minimize the influence of outliers and/or to regularize 
relationships between predictors and response for better model fit. Exploratory analysis of the 
molecular markers, including visualizations and statistical summaries such as hierarchical cluster 
analysis, heat maps, multidimensional scaling, and principle component analysis will offer 
important views of the structural characteristics of the expression data. 
 
Response will be described categorically, and associations between response and immunological 
variables will be characterized, in each arm, using multivariate logistic regression models, with 
adjustment for clinical and pathological co-variates that may be associated with response. 
Estimated effects will be reported with standard errors and confidence intervals. 
 
9.5 
Reporting and Exclusions 
 
Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with cobimetinib, 
atezolizumab, and CDX-1127 (varlilumab). A baseline measurement and at least 1 laboratory or 
other safety-related measurement obtained after at least 1 dose of study treatment may be 
required for inclusion in the analysis of a specific safety parameter (e.g., lab shifts from 
baseline). A complete list of all AE data will be provided along with an assessment of NCI 
CTCAE grade and relationship to study drug. The incidence of AEs will be tabulated by 
subgroups of interest (e.g. grade 3 or higher, organ class, relationship to study drug). For 
analyses at the individual level, the highest grade and relationship to study drug will be assumed 
if multiple events have occurred. Toxicity will be tabulated by type and grade and will be 
summarized with descriptive statistics. Other safety data will be assessed in terms of physical 
examination, clinical chemistry, hematology, vital signs, and ECGs. Negative binomial 
regression and Cox proportional hazards models will be used to assess the rate of AE and time to 
first toxicity, respectively. 
 
While the combination of our proposed three study medications (or similar in-class alternatives) 
have not been studied in human trials, CDX-1127 (varlilumab) has been shown to be well 
tolerated in combination with anti-PD1, Nivolumab in patients with advanced solid tumors 
(NCT02335918). Additionally, the combination of cobimetinib and atezolizumab demonstrated a 
favorable safety profile at full doses in BTC patients (CTEP 10476). The present study will be 
continuously monitored for adverse events. 
 
We will incorporate the following safety run-in and stopping rule that will be applied within each 
treatment group, A and B, respectively: if 2 or more “unacceptable toxicities,” at least possibly 
attributable to study therapy, are observed among the first 6 patients enrolled in the same 
treatment arm during their initial treatment cycle, we will pause the accrual in that arm and re- 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
153 
 
 
evaluate safety. Accrual will be limited until the safety has been achieved in the first 6 patients 
in each arm, respectively. 
 
“Unacceptable toxicities” are defined as the following treatment-related events: 
x Any grade 2 uveitis, retinitis, eye pain, or blurred vision that does not respond to 
topical therapy and does not improve to grade 1 severity within 2 weeks of starting 
therapy OR requires systemic treatment 
x Recurrent grade 2 pneumonitis 
x Symptomatic heart failure associated 10% reduction in LVEF 
x Grade 3 uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, 
hypersensitivity reaction, or infusion reaction 
x Any grade 3 non-skin, drug-related AE lasting >7 days, with the following exceptions: 
 Grade 3 endocrinopathies adequately controlled with only physiologic hormone 
replacement do not require discontinuation 
 Grade 3 laboratory abnormalities do not require treatment discontinuation except: 
o Grade 3 thrombocytopenia >7 days OR that is associated with bleeding requires 
discontinuation 
o Any liver function test (LFT) abnormality that meets the following criteria 
require discontinuation: 
 
Total bilirubin >3 × ULN 
 
Concurrent AST or ALT >3 × ULN and total bilirubin >2 × ULN 
 
In participants with liver metastasis with baseline grade 2 elevation of AST 
or ALT, hepatitis with AST or ALT increases 50% and lasts 1 week 
x Any grade 4 AE or laboratory abnormality, except for the following events which do 
not require discontinuation: 
 Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations, or radiographic signs of pancreatitis. It is recommended to 
consult with the IND Sponsor for grade 4 amylase or lipase abnormalities. 
 Isolated grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset. 
 Grade 4 lymphopenia and leukopenia. 
 Grade 4 treatment-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose intolerance, 
which resolve or are adequately controlled with physiologic hormone replacement 
(corticosteroids, thyroid hormones) or glucose-controlling agents, respectively, 
may not require discontinuation after discussion with and approval from the IND 
Sponsor. 
x Any grade 5 adverse event 
x Any dosing interruption lasting >6 weeks with the following exceptions: 
 Dosing interruptions to allow for prolonged steroid tapers to manage drug- 
related adverse events are allowed. 
 Dosing interruptions >6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Principal Investigator. 
 Prior to re-initiating treatment in a subject with a dosing interruption lasting >6 
weeks, the Principal Investigator must be consulted. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
154 
 
 
 
Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations. Each patient will be assigned one of the following 
categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) 
early death from malignant disease, 6) early death from toxicity, 7) early death because of other 
cause, or 9) unknown (not assessable, insufficient data). [Note: By arbitrary convention, 
category 9 usually designates the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria and completed at least one dose of therapy of 
one the three study medications. should be included in the main analysis of the response rate. 
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression). Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be 
protocol specific. 
 
All conclusions should be based on all eligible patients. Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported. 
 
9.6 
Data Safety Monitoring Board 
 
The conduct of this study will be overseen by the ETCTN DSMB. The DSMB will be 
responsible for recommendations to the Principal Investigator and NCI regarding possible trial 
closure and/or early reporting of the study. The study team (with the exception of the study 
statistician) will not have access to the summary outcome data until released by the DSMB. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
155 
 
 
10. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of AEs (Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 
10.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
10.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
CAEPRs for CTEP IND Agents 
 
10.1.1.1 CAEPR for Atezolizumab 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Atezolizumab (MPDL3280A, NSC 783608) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3097 patients. Below is the CAEPR for 
Atezolizumab (MPDL3280A). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE 
in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and 
has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
Version 2.4, September 14, 20231 
Adverse Events with Possible 
Relationship to Atezolizumab (MPDL3280A) 
(CTCAE 5.0 Term) 
[n= 3097] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
 
CARDIAC DISORDERS 
 
 
 
Heart failure2 
 
 
 
Myocarditis2 
 
 
 
Pericardial effusion2 
 
 
 
Pericardial tamponade2 
 
 
 
Pericarditis2 
 
ENDOCRINE DISORDERS 
 
 
 
Adrenal insufficiency2 
 
 
 
Endocrine disorders - Other 
(diabetes)2 
 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
156 
 
 
 
Adverse Events with Possible 
Relationship to Atezolizumab (MPDL3280A) 
(CTCAE 5.0 Term) 
[n= 3097] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Hyperthyroidism2 
 
 
 
 
Hypophysitis2 
 
 
Hypothyroidism2 
 
 
EYE DISORDERS 
 
 
 
Eye disorders - Other (ocular 
inflammatory toxicity)2 
 
 
 
Uveitis2 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
Abdominal pain (Gr 2) 
 
 
Colitis2 
 
 
Diarrhea 
 
Diarrhea (Gr 2) 
 
Dysphagia 
 
 
 
Nausea 
 
Nausea (Gr 2) 
 
 
Pancreatitis2 
 
 
Vomiting 
 
Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Fatigue 
 
 
Fatigue (Gr 2) 
 
Fever3 
 
 
 
Flu like symptoms3 
 
 
HEPATOBILIARY DISORDERS 
 
 
 
Hepatic failure2 
 
 
 
Hepatobiliary disorders - Other 
(hepatitis [immune related 
hepatitis])2 
 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction3 
 
 
 
 
Anaphylaxis3 
 
 
 
Cytokine release syndrome3 
 
 
 
Immune system disorders - 
Other (hemophagocytic 
lymphohistiocytosis 
(HLH)/macrophage activation 
syndrome (MAS))2 
 
 
 
Immune system disorders - 
Other (systemic immune 
activation)2 
 
INFECTIONS AND INFESTATIONS 
 
Infection4 
 
 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
Infusion related reaction3 
 
 
INVESTIGATIONS 
 
 
Alanine aminotransferase 
increased2 
 
 
 
Alkaline phosphatase 
increased2 
 
 
 
Aspartate aminotransferase 
increased2 
 
 
 
Blood bilirubin increased2 
 
 
 
 
Creatinine increased 
 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
157 
 
 
 
Adverse Events with Possible 
Relationship to Atezolizumab (MPDL3280A) 
(CTCAE 5.0 Term) 
[n= 3097] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
GGT increased 
 
 
 
Lipase increased* 
 
 
 
 
Platelet count decreased 
 
 
Serum amylase increased* 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
Anorexia (Gr 2) 
 
 
Hyperglycemia2 
 
 
Hypokalemia 
 
 
 
Hyponatremia 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Arthralgia2 
 
 
 
Back pain 
 
 
 
 
Generalized muscle weakness 
 
 
Myalgia 
 
 
 
 
Myositis2 
 
NERVOUS SYSTEM DISORDERS 
 
 
 
Ataxia2 
 
 
 
Encephalopathy2 
 
 
 
Guillain-Barre syndrome2 
 
 
 
Myasthenia gravis2 
 
 
 
Nervous system disorders - 
Other (meningitis non-infective)2 
 
 
 
Nervous system disorders - 
Other (facial paresis)2 
 
 
 
Nervous system disorders - 
Other (encephalitis non- 
infective)2 
 
 
 
Nervous system disorders - 
Other (immune-mediated 
myelitis)2 
 
 
 
Paresthesia2 
 
 
 
Peripheral motor neuropathy2 
 
 
 
Peripheral sensory neuropathy2 
 
RENAL AND URINARY DISORDERS 
 
 
 
Acute kidney injury 
 
 
 
Renal and urinary disorders - 
Other (nephritis)2 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Cough 
 
Cough (Gr 2) 
 
Dyspnea 
 
 
 
Hypoxia 
 
 
 
Nasal congestion 
 
Nasal congestion (Gr 2) 
 
 
Pleural effusion2 
 
 
 
Pneumonitis2 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
 
Bullous dermatitis2 
 
 
 
Erythema multiforme2 
 
 
Pruritus 
 
 
 
Rash acneiform 
 
 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
158 
 
 
 
Adverse Events with Possible 
Relationship to Atezolizumab (MPDL3280A) 
(CTCAE 5.0 Term) 
[n= 3097] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Rash maculo-papular 
 
 
 
 
Skin and subcutaneous tissue 
disorders - Other (Drug reaction 
with eosinophilia with systemic 
symptoms [DRESS])2 
 
 
 
Skin and subcutaneous tissue 
disorders - Other 
(Exanthematous pustulosis)2 
 
 
 
 
 
 
Skin and subcutaneous tissue 
disorders - Other (lichen 
planus)2 
 
 
 
 
Stevens-Johnson syndrome2 
 
 
 
Toxic epidermal necrolysis2 
 
 
*Denotes adverse events that are <3%. 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Atezolizumab, being a member of a class of agents involved in the inhibition of “immune checkpoints,” 
may result in severe and possibly fatal immune-mediated adverse events probably due to T-cell activation 
and proliferation. Immune-mediated adverse reactions have been reported in patients receiving 
atezolizumab. Adverse events potentially related to atezolizumab may be manifestations of immune- 
mediated adverse events. In clinical trials, most immune-mediated adverse reactions were reversible and 
managed with interruptions of atezolizumab, administration of corticosteroids and supportive care. 
 
3Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, and cytokine release 
syndrome, which have been observed following administration of atezolizumab, may manifest as fever, 
chills, shakes, itching, rash, hypertension or hypotension, or difficulty breathing during and immediately 
after administration of atezolizumab. 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on atezolizumab (MPDL3280A) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that atezolizumab (MPDL3280A) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Febrile neutropenia 
CARDIAC DISORDERS - Cardiac arrest; Ventricular tachycardia 
GASTROINTESTINAL DISORDERS - Constipation; Dry mouth; Ileus 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Malaise; 
Multi-organ failure 
HEPATOBILIARY DISORDERS - Portal vein thrombosis 
INVESTIGATIONS - Lymphocyte count decreased; Neutrophil count decreased; Weight loss; White blood 
cell decreased 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
159 
 
 
METABOLISM AND NUTRITION DISORDERS - Hypophosphatemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Muscle cramp: Pain in 
extremity 
NERVOUS SYSTEM DISORDERS - Headache 
PSYCHIATRIC DISORDERS - Confusion; Insomnia; Suicide attempt 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Pulmonary hypertension; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin2; Hyperhidrosis 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event 
 
Note: Atezolizumab (MPDL3280A) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ye 
 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
161 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
162 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.1.1.3 CAEPR for Cobimetinib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Cobimetinib (RO5514041, GDC0973, NSC 781257) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 274 patients. Below is the CAEPR for 
Cobimetinib (RO5514041, GDC0973). 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
163 
 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
Version 2.2, March 25, 20201 
 
Adverse Events with Possible 
Relationship to Cobimetinib (RO5514041, GDC0973) 
(CTCAE 5.0 Term) 
[n= 274] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
Anemia (Gr 2) 
CARDIAC DISORDERS 
 
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
 
 
 
Cardiac disorders - Other (left 
ventricular dysfunction) 
 
 
 
Heart failure 
 
EYE DISORDERS 
 
 
Eye disorders - Other 
(chorioretinopathy) 2 
 
 
 
Eye disorders - Other (eye 
disorders)3 
 
Eye disorders - Other (eye 
disorders)3 (Gr 2) 
 
 
Eye disorders - Other (retinal 
vein occlusion)2 
 
 
Retinal detachment 
 
 
GASTROINTESTINAL DISORDERS 
 
Diarrhea 
 
 
Diarrhea (Gr 2) 
 
Mucositis oral 
 
Mucositis oral (Gr 2) 
Nausea 
 
 
Nausea (Gr 2) 
Vomiting 
 
 
Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
 
Chills 
 
Chills (Gr 2) 
Fatigue 
 
 
Fatigue (Gr 2) 
 
Fever2 
 
Fever2 (Gr 2) 
Generalized edema4 
 
 
Generalized edema4 (Gr 2) 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction 
 
 
INVESTIGATIONS 
 
 
Alanine aminotransferase 
increased2 
 
Alanine aminotransferase 
increased2 (Gr 2) 
 
Alkaline phosphatase 
increased2 
 
Alkaline phosphatase 
increased2 (Gr 2) 
 
Aspartate aminotransferase 
increased2 
 
Aspartate aminotransferase 
increased2 (Gr 2) 
CPK increased 
 
 
CPK increased (Gr 2) 
 
Ejection fraction decreased 
 
 
 
GGT increased2 
 
GGT increased2 (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
Anorexia (Gr 2) 
 
Dehydration 
 
Dehydration (Gr 2) 
 
Hyperglycemia 
 
Hyperglycemia (Gr 2) 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
164 
 
 
 
 
Adverse Events with Possible 
Relationship to Cobimetinib (RO5514041, GDC0973) 
(CTCAE 5.0 Term) 
[n= 274] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Hypokalemia 
 
 
 
Hyponatremia 
 
Hyponatremia (Gr 2) 
 
Hypophosphatemia 
 
Hypophosphatemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
 
Rhabdomyolysis 
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) 
 
 
 
Neoplasms benign, malignant 
and unspecified (incl cysts and 
polyps) - Other (new primary 
malignancies, cutaneous and 
non-cutaneous)2 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
 
 
Headache 
 
Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
 
Pneumonitis 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Dry skin 
 
Dry skin (Gr 2) 
 
Photosensitivity2 
 
Photosensitivity2 (Gr 2) 
 
Pruritus 
 
Pruritus (Gr 2) 
 
Rash acneiform 
 
Rash acneiform (Gr 2) 
Rash maculo-papular5 
 
 
Rash maculo-papular5 (Gr 2) 
VASCULAR DISORDERS 
 
 
Vascular disorders - Other 
(hemorrhage)6 
 
 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Observed in combination with Vemurafenib. 
 
3Includes photopsia, blurred vision, vitreous floaters. 
 
4Includes peripheral edema, periorbital edema, edema, and facial edema. 
 
5Includes rash, dermatitis acneiform, rash pruritic, rash generalized dermatitis, exfoliative rash, rash 
erythermatous, and rash maculo-papular. 
 
6Hemorrhage includes cerebral hemorrhage, contusion, ecchymosis, epistaxis, gastrointestinal 
hemorrhage, hematuria, rectal hemorrhage, retinal hemorrhage, and vaginal hemorrhage. 
 
Adverse events reported on cobimetinib (RO5514041, GDC0973) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that cobimetinib 
(RO5514041, GDC0973) caused the adverse event: 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
165 
 
 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Cardiac disorders - Other (cardiac ventricular 
thrombosis); Pericardial effusion 
EAR AND LABYRINTH DISORDERS - Ear pain 
EYE DISORDERS - Eye disorders - Other (retinal disorder); Vision decreased 
GASTROINTESTINAL DISORDERS - Abdominal pain; Colitis; Constipation; Dysphagia; Ileus; Lower 
gastrointestinal hemorrhage; Small intestinal perforation 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Non-cardiac chest 
pain 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (autoimmune hepatitis); Hepatobiliary 
disorders - Other (bile duct obstruction); Hepatobiliary disorders - Other (cholangitis) 
INFECTIONS AND INFESTATIONS - Catheter related infection; Gallbladder infection; Infections and 
infestations - Other (diverticulitis); Lung infection; Paronychia; Sepsis; Skin infection; Thrush; Urinary tract 
infection 
INVESTIGATIONS - Blood bilirubin increased; Blood lactate dehydrogenase increased; 
Electrocardiogram QT corrected interval prolonged; Lymphocyte count decreased; Neutrophil count 
decreased; Platelet count decreased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Neck pain; 
Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (malignant neoplasm progression); 
Tumor hemorrhage 
NERVOUS SYSTEM DISORDERS - Encephalopathy; Facial muscle weakness; Nervous system 
disorders - Other (immune-mediated encephalitis); Nervous system disorders - Other (intracranial 
pressure increased); Nervous system disorders - Other (7th nerve palsy); Somnolence; Syncope 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Epistaxis; Nasal 
congestion; Oropharyngeal pain; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Eczema; Hyperkeratosis 
SURGICAL AND MEDICAL PROCEDURES - Surgical and medical procedures - Other (medical device 
change) 
VASCULAR DISORDERS - Hypertension; Thromboembolic event 
 
Note: Cobimetinib (RO5514041, GDC0973) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the combination 
may result in events never previously associated with either agent. 
 
10.2 Adverse Event Characteristics 
 
x CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
x For expedited reporting purposes only: 
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
 
x Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
166 
 
 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 Expedited Adverse Event Reporting 
 
10.3.1 Rave-CTEP-AERS Integration 
 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP- 
AERS) integration enables evaluation of post-baseline AEs entered in Rave to determine 
whether they require expedited reporting and facilitates entry in CTEP-AERS for those 
AEs requiring expedited reporting. Sites must initiate all AEs for this study in Medidata 
Rave. 
 
Treatment-emergent AEs: All AEs that occur after baseline are collected in Medidata 
Rave using the Adverse Event form, which is available for entry at each treatment or 
reporting period and is used to collect AEs that start during the period or persist from the 
previous reporting period. CRA will enter AEs that occur prior to the start of treatment 
on a baseline form that is not included in the Rave-CTEP-AERS integration. AEs that 
occur prior to enrollment must begin and end on the baseline Adverse Event form and 
should not be included on the standard Adverse Events form that is available at treatment 
unless there has been an increase in grade. AEs that occur 30 Days after the Last 
Administration of the Investigational Agent/Intervention are collected using the Late 
Adverse Event form. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
 
x The reporting period (course/cycle) is correct, and 
x AEs are recorded and complete (no missing fields) and the form is query-free. 
 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting. A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements. The CRA completes the report by accessing CTEP- 
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
Contact the CTSU Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com 
if you have any issues submitting an expedited report in CTEP-AERS. 
 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497. Once internet connectivity is restored, the 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
167 
 
 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the direct link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 
 
x Study specific documents: Protocols > Documents > Protocol Related 
Documents > Adverse Event Reporting, and
x Additional resources: Resources > CTSU Operations Information> User Guides 
& Help Topics.
 
NCI requirements for SAE reporting are available on the CTEP website: 
 
x NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid 
elines.pdf.
 
Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals: Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter. CTEP-AERS provides a copy feature for other e-mail recipients. 
 
Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note: A death on study requires both routine and expedited reporting, regardless of 
causality as long as the death occurred within 30 days after the last administration of the 
investigational agent. Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted. 
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
168 
 
 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening adverse event 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for  24 
hours 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
 24 hrs 
 
10 Calendar Days 
 
 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization 
 24 hrs 
 
Not required 
 
10 Calendar Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
x 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
 
Adverse Events of Special Interest 
 
Adverse Event Special Interest (AESIs) are a subset of events of scientific and/or medical 
concern specific to this protocol, for which ongoing monitoring and communication by the 
Investigator to the Sponsor is required. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
169 
 
 
General AESI: 
x Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law 
and based on the following observations: - Treatment-emergent ALT or AST > 3 x 
baseline value in combination with total bilirubin > 2 x ULN (of which > 35% is direct 
bilirubin) - Treatment-emergent ALT or AST > 3 x baseline value in combination with 
clinical jaundice
Suspected transmission of an infectious agent by the study treatment, as defined below - Any 
organism, virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. A 
transmission of an infectious agent may be suspected from clinical symptoms or laboratory 
findings that indicate an infection in a patient exposed to a medicinal product. This term applies 
only when a contamination of study treatment is suspected. 
 
Atezolizumab: 
AESI for Atezolizumab are: 
x Systemic lupus erythematosus
x Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, macrophage activating syndrome, hemophagocytic lymphohistiocytosis
x Nephritis
x Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)
x Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)
x Vasculitis
x Autoimmune hemolytic anemia
x Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis)
 
Cobimetinib: 
x AESI for Cobimetinib are:
x Any grade Serous retinopathy, including events of retinal detachment, retinal pigment 
epithelium detachment, neurosensory retinal detachment or central serous 
chorioretinopathy
x Significant liver toxicity: AST and/or ALT > 10 X upper limit of normal
x Symptomatic heart failure / Grade  2 left ventricular dysfunction
x Grade  3 CPK elevation or Rhabdomyolysis
x Grade  3 Diarrhea
x Grade  3 rash
 
Biopsy: 
Adverse Events of Special Interest (AESIs) for this study are related to the biopsy component of 
the study. These events should be captured in Rave as they occur and should be reported 
expeditiously according to the table above. Four of these AESIs are not currently part of the 
CTCAE and must be reported in Rave/CTEP-AERS using the term: Injury, poisoning and 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
170 
 
 
procedural complications - Other, specify. The AESI Terms and Grading Table below (Section 
10.3.4.1) lists the AESI terms and their grading. The AESI Reporting Table (Section 10.3.4.2) 
provides instruction on how to record these events in Rave/CTEP-AERS. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
171 
 
 
10.3.4.1 Adverse Event Special Interest (AESI) Terms and Grading 
Adverse Event Special Interest (AESI) Terms and Grading 
AESI 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Definition 
Biopsy-related 
hemorrhage 
Symptomatic 
hematoma requiring 
medications 
Any hematoma 
(symptomatic or 
asymptomatic) requiring 
unplanned observation with 
less than 24 hours of 
hospitalization 
Hemorrhage requiring 
transfusion, radiologic, 
endoscopic or surgical 
intervention or greater than 24 
hours of hospitalization 
Hemorrhage with life- 
threatening consequences; 
urgent intervention indicated 
Death 
A disorder characterized by 
bleeding related to a biopsy 
procedure. 
Biopsy-related 
nerve injury 
Symptomatic nerve 
pain or injury 
requiring medications 
Any nerve injury requiring 
unplanned observation with 
less than 24 hours of 
hospitalization 
Any nerve injury requiring 
surgical intervention or 
greater than 24 hours of 
hospitalization 
Nerve injury with life- 
threatening consequences; 
urgent intervention indicated 
Death 
A finding of damage to a nerve 
related to a biopsy procedure. 
Biopsy-related 
organ injury 
Symptomatic organ 
pain or injury 
requiring medications 
Any organ injury requiring 
unplanned observation with 
less than 24 hours of 
hospitalization 
Any organ injury that requires 
radiologic, endoscopic or 
surgical intervention or 
greater than 24 hours of 
hospitalization 
Organ injury with life- 
threatening consequences; 
urgent intervention indicated 
Death 
A finding of damage to an organ 
related to a biopsy procedure. 
Biopsy-related 
anesthesia (local 
or moderate 
sedation) effects 
Symptomatic 
anesthesia effects 
requiring medications 
Any biopsy-related 
anesthesia effects requiring 
medical intervention for 
reversal of symptomatic 
effects and/or requiring 
unplanned observation with 
less than 24 hours of 
hospitalization 
Any anesthesia effects 
requiring intervention for 
reversal or treatment of 
symptomatic effects and/or 
requiring greater than 24 
hours of hospitalization 
Anesthesia effects with life- 
threatening consequences; 
urgent intervention indicated 
Death 
A disorder characterized by 
reactions related to the 
administration of local or 
moderate sedation given for a 
biopsy procedure. 
Pneumothorax 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; intervention 
indicated 
Sclerosis and/or operative 
intervention indicated; 
hospitalization indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
A disorder characterized by 
abnormal presence of air in the 
pleural cavity resulting in the 
collapse of the lung. 
Pain 
Mild pain 
Moderate pain; limiting 
instrumental ADL 
Severe pain; limiting self care 
ADL 
- 
- 
A disorder characterized by the 
sensation of marked discomfort, 
distress or agony. 
Wound infection 
Localized, local 
intervention indicated 
Oral intervention indicated 
(e.g., antibiotic, antifungal, 
or antiviral) 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; invasive 
intervention indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
A disorder characterized by an 
infectious process involving the 
wound. 
Allergic reaction 
Systemic intervention 
not indicated 
Oral intervention indicated 
Bronchospasm; 
hospitalization indicated for 
clinical sequelae; intravenous 
intervention indicated 
Life-threatening consequences; 
urgent intervention indicated 
Death 
A disorder characterized by an 
adverse local or general response 
from exposure to an allergen. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
172 
 
 
 
 
 
10.3.4.2 Adverse Event Special Interest (AESI) Reporting 
 
Adverse Event Special Interest (AESI) Reporting 
AESI Term 
CTCAE term to Select 
Other, specify language to record: 
Pneumothorax* 
Pneumothorax 
N/A 
Pain* 
Pain 
N/A 
Wound infection* 
Wound infection 
N/A 
Allergic reaction* 
Allergic reaction 
N/A 
Biopsy-related hemorrhage** 
Injury, poisoning and procedural 
complications - Other, specify 
Biopsy-related hemorrhage 
Biopsy-related nerve injury** 
Injury, poisoning and procedural 
complications - Other, specify 
Biopsy-related nerve injury 
Biopsy-related organ injury** 
Injury, poisoning and procedural 
complications - Other, specify 
Biopsy-related organ injury 
Biopsy-related anesthesia (local or moderate 
sedation) effects** 
Injury, poisoning and procedural 
complications - Other, specify 
Biopsy-related anesthesia (local or moderate 
sedation) effects 
 
*Select the indicated current CTCAE Term. 
 
**Select CTCAE term, “Injury, poisoning and procedural complications - Other, specify” and fill in the ‘Specify’ with the AESI 
term when prompted in Rave. 
 
For example, if the subject experienced a biopsy-related hemorrhage, select Injury, poisoning and procedural complications - Other, 
specify and write in ‘Biopsy-related hemorrhage’ when prompted in Rave and/or CTEP-AERS. 

 
NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
 
10.4 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions. AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave. For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
10.5 Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS. In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP. Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome. Newborn infants should be followed until 30 days old. Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP. 
 
10.6 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS. Three options are available to 
describe the event: 
 
x Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 
x Myelodysplastic syndrome (MDS) 
x Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
 
10.7 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
173 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
174 
 
 
11. STUDY CALENDAR 
 
Informed consent is to be obtained any time prior to conducting research procedures and may be greater than 14 days before 
Randomization. Baseline timepoint scans, Echocardiogram (or MUGA), Eye Exam, and Pre-Treatment Biopsy are highly 
recommended to be done within 14 days of randomization but can be done up to a maximum of 28 days prior to randomization, if 
needed to accommodate scheduling limitations. Screening labs must be done within 14 days of randomization. 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. All participants receiving atezolizumab will be assessed for pulmonary signs and symptoms on physical examination as well 
as imaging throughout the study. 
 
 
1 cycle = 28 days 
 
Baseline 
Cycle 1 
Cycle 2 
Cycle 3 and beyond 
Progression/ 
End of 
TreatmentS 
Day 1 
Day 15 
Day 21 
Day 28 
Day 1 
Day 15 
Day 21 
Day 28 
Day 1 
Day 15 
Day 21 
Day 28 
Visit windowA 
-Day 14 
to 
Randomi 
zation 
Day 0AA  
+/-2 
 
+/-2 
 
+/-5 
 
 
+/-2 
 
+/-2 
 
+/-5 
 
 
+/-2 
 
+/-2 
 
+/-5 
 
 
+14 
AtezolizumabB 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
CDX-1127 (varlilumab)C 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
CobimetinibD 
 
 
X -------------------------- X 
 
X -------------------------- X 
 
X -------------------------- X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Physical examF 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Vital signsG 
X 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Performance status 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CBC w/diffH 
X 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Serum chemistryI 
X 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Amylase, Lipase 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Coagulation (INR and 
aPTT) 
X 
 
 
 
XY 
 
 
 
 
 
 
 
 
 
 
Thyroid function testJ 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
EKGZ 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
B-HCGK 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK 
X 
 
 
 
 
 
XT 
 
 
 
XT 
 
 
 
 
cfDNAL 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGAU 
X 
 
 
 
1 month after first dose, then every 3 mo on cobimetinib (see U) 
 
Ophthalmologic examM,V 
X 
 
 
 
Every 2 months for 1 year, then every 6 months while on cobimetinib (see V) 
 
Adverse event evaluation 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
XW 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
175 
 
 
 
 
1 cycle = 28 days 
 
Baseline 
Cycle 1 
Cycle 2 
Cycle 3 and beyond 
Progression/ 
End of 
TreatmentS 
Day 1 
Day 15 
Day 21 
Day 28 
Day 1 
Day 15 
Day 21 
Day 28 
Day 1 
Day 15 
Day 21 
Day 28 
Visit windowA 
-Day 14 
to 
Randomi 
zation 
Day 0AA  
+/-2 
 
+/-2 
 
+/-5 
 
 
+/-2 
 
+/-2 
 
+/-5 
 
 
+/-2 
 
+/-2 
 
+/-5 
 
 
+14 
Tumor measurementsN 
X 
 
 
 
Tumor measurements are repeated every 8 weeks. Documentation (radiologic) must be provided for 
patients removed from study for progressive disease if possible. 
X 
CA 19-9O 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Archival tumor sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyP 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Peripheral blood in EDTA 
tubesQ 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
XX 
X 
Peripheral blood (Streck 
tube)Q 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Peripheral blood (red top 
tubes for serum)R. 
 
 
X 
X 
 
 
X 
X 
 
 
X 
 
 
 
 
Medication Diary 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
A: Longer durations to be approved by the Study Principal Investigator. Baseline timepoint scans, Echocardiogram (or MUGA), Eye Exam, and Pre-Treatment Biopsy are highly 
recommended to be done within 14 days of randomization but can be done up to a maximum of 28 days prior to randomization, if needed to accommodate scheduling limitations. 
Screening labs must be done within 14 days of randomization. 
B: To be administered to both Arm A and Arm B treatment arms. Dosing as follows: atezolizumab 840 mg IV q2wks. Atezolizumab will be administered before CDX-1127 
(varlilumab). 
C: To be administered to both Arm A and Arm B treatment arms. Dosing as follows: CDX-1127 (varlilumab) 3mg/kg IV q2wks. Wait 30 minutes between completion of 
atezolizumab and subsequent start of CDX-1127. 
D: For patients randomized to atezolizumab and CDX-1127 (varlilumab) plus cobimetinib (study arm A only). Dosing as follows: cobimetinib 60 mg daily (21 days on/7 days off). On 
Days 1 and 15 of each cycle, cobimetinib should be taken before receiving atezolizumab and CDX-1127 (varlilumab). Cobimetinib should be taken in the morning at the same 
time every day. It can be taken with or without food. If a dose of cobimetinib is not taken within 4 hours of the scheduled dose, it should be considered missed and not taken. 
Resume dosing at the next scheduled dose/time. If unable to take dose prior to infusion, patient may still take that day’s dose as long as it is within 4 hours of regularly 
scheduled time, otherwise it should be considered missed and not taken with dosing resumed at the next scheduled day/time. 
E: Includes history of lung disease, HIV, hepatitis B or C infection, and complete cancer history, including primary site of cancer, gross location of primary tumor, secondary sites of 
cancer, histology, histologic grade, date of initial diagnosis, date of metastatic diagnosis, and prior cancer therapy regimens. 
F: Complete physical exam will be completed at baseline; focused physical examinations will be conducted thereafter. Physical examinations should be performed within a window 
of up to 7 days prior to dosing on Days 1 and 15 of Cycle 1 and Day 1 for all subsequent cycles. 
G: 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. 
H: Clinical hematology: CBC with differential ANC, ALC, AEC, and platelet count. Labs may be collected within a window of up to 7 days prior to Cycle 1 Day 1 dosing and up to 
3 days prior to all other dosing days. Initial screening bloodwork does not need to be repeated if performed within 7 days of C1D1. 
I: Serum Chemistry should include Glucose, Calcium, Sodium, Potassium, CO2, Chloride, BUN, Creatinine, Alkaline phosphatase, Alanine amino transferase (ALT), Aspartate 
amino transferase (AST), Bilirubin, Albumin, GGT, Total Protein, and LDH. For patients on Arm A (i.e. receiving cobimetinib), also include Phosphorus and Magnesium. Labs 
may be collected within a window of up to 7 days prior to Cycle1 Day 1 dosing and up to 3 days prior to all other dosing days. Initial screening bloodwork does not need to be 
repeated if performed within 7 days of C1D1. 
J: Baseline thyroid testing should be done only in patients with a known history of thyroid dysfunction and/or if there is a clinical concern for thyroid dysfunction at the time of study 
screening. Free T3/T4 should be checked reflexively if TSH is abnormal. Subsequent labs during treatment may be collected within a window of up to 3 days prior to dosing 
days. 
K: Serum or urine pregnancy (women of childbearing potential only) is required at baseline. For women with a mildly elevated B-HCG who in the opinion of the investigator are not 
pregnant, a vaginal ultrasound must be obtained to confirm that the participant is not pregnant in order to enroll on this study. Pregnancy tests during treatment as clinically 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
176 
 
 
 
 
1 cycle = 28 days 
 
Baseline 
Cycle 1 
Cycle 2 
Cycle 3 and beyond 
Progression/ 
End of 
TreatmentS 
Day 1 
Day 15 
Day 21 
Day 28 
Day 1 
Day 15 
Day 21 
Day 28 
Day 1 
Day 15 
Day 21 
Day 28 
Visit windowA 
-Day 14 
to 
Randomi 
zation 
Day 0AA  
+/-2 
 
+/-2 
 
+/-5 
 
 
+/-2 
 
+/-2 
 
+/-5 
 
 
+/-2 
 
+/-2 
 
+/-5 
 
 
+14 
 
indicated. 
L: cfDNA is optional and should be collected per institional standards. Liquid biopsy recommended, if tissue-based molecular profiling was not previously performed or was 
performed but was inadequate for assessment of TMB and MSI/MMRd. If collected, a one time blood collection (8.5 mL) will be done at pre-treatment and sent for cfDNA 
analysis (NGS, blood tumor mutation burden, microsatellite instability status) on same day as collection with preference for Foundation Medicine 
(https://www.accessdata.fda.gov/cdrh_docs/pdf19/P190032B.pdf). Sites will be provided with cfDNA collection kits if needed (industry collection tubes). This is a standard of 
care test. 
M: Patients with ocular symptoms occurring during study treatment should be examined by an ophthalmologist. 
N: Baseline scans must be done <4 weeks prior to randomization. Tumor measurement will be performed with contrast CT chest/abdomen/pelvis. Non-contrast CT 
chest/abdomen/pelvis or CT Chest and MRI Abdomen/pelvis will be performed in subjects with contraindications or intolerance to contrast dye. For the first on-treatment scan, 
this should be done approximately 8 weeks from the start of treatment (not from the date of the pre-treatment baseline scan). Imaging will be repeated every 8 weeks, irrespective 
of dosing schedule or treatment delays. For the End of Treatment visit, scans do not need to be repeated if a scan has been performed within 8 weeks. For patients removed from 
study treatment for reasons other than progression, scans are to continue every 8 weeks until progression. 
O: CA19-9 does not need to be repeated in the event that the screening lab draw show that the patient’s tumor does not secrete CA19-9. 
P: Only for subjects with tumor that in the opinion of the study treatment team is safely accessible for biopsy. See Section 5.5.2 for the order of the tumor cores to be collected. The 
baseline biopsy is to be done after randomization but before C1D1. 
Q: Blood collection will be collected at baseline, C1D21, and Week 12 (end of Cycle 3). Pre-treatment baseline EDTA and Streck tube draws should only be drawn on enrolled 
patients and can be drawn anytime between time of enrollment and prior to start of treatment. These samples must be collected only Monday-Thursday and shipped overnight 
same day. See Section 5.1 for more details. 
R: D1 of Cycles 1-6, 9, 12; pharmacokinetic and immunogenicity: pharmacokinetic blood draws will be performed pre-infusion and 30 minutes after the end of infusion of CDX- 
1127 (varlilumab), which will be administered after atezolizumab and D15 of Cycle 1 and 2. See Section 5.1 for more details. 
S: End of Treatment evaluations will be completed no more than 30 days after the last dose of all study drugs and prior to start of next line systemic therpay. 
T: Patients receiving cobimetinib (study arm A only). Labs during treatment may be collected within a window of up to 3 days prior to dosing days. 
U: Evaluation of LV function by either echocardiogram (ECHO) or multiple-gated acquisition (MUGA) at baseline (all patients), 1 month after first dose (study arm A only), then 
every 3 months while on cobimetinib (visit window +/-7 days); (study arm A only). 
V: Ophthalmologic examination at baseline (all patients, within 4 weeks prior to randomization), then every 2 months for 1 year (study arm A only), then every 6 months while on 
cobimetinib (visit window +/- 14 days); (study arm A only). Eye exam should include retinal exam, slit lamp exam, and visual fields (preferably Goldmann Visual Field if 
available) for evidence of retinal pathology and other abnormalities. Alternatives to Goldmann Visual field tests such as Humphrey and Octupus visual field tests/machines are 
acceptable. Alternatives to checking visual acuity with Landolt chart such as ETDRS and documentation of Snellen equivalent are acceptable. 
W: Adverse events will be assessed at least 30 days after the last dose of either study agent. For patients removed due to unacceptable toxicity, they will be followed until resolution 
of the adverse event. 
X: End of Cycle 3 only (including up to prior to starting treatment on C4D1). 
Y: Before the on-study biopsy. 
Z: Patients receiving cobimetinib (study arm A only). EKG will be performed after randomization but before C1D1, at C1D15, monthly during the first 3 months, and then every 3 
months thereafter or more often as clinically indicated. 
AA: Day 0 = time period after randomization up until C1D1 of treatment. Baseline research blood draws (EDTA and Streck tubes) and baseline study tissue biopsies should take 
place during this period (after patient has completed enrollement and prior to start of therapy). 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
177 
 
 
 
12. MEASUREMENT OF EFFECT 
 
12.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained 4 weeks following initial 
documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
Definitions 
 
Evaluable for Toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with atezolizumab, cobimetinib, and CDX-1127 (varlilumab). 
 
Evaluable for Objective Response. Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
 
Disease Parameters 
 
Measurable Disease. Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as 20 mm (2 cm) by chest x-ray or as 
10 mm (1 cm) with CT scan, MRI, or 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 might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
 
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm (1.5 cm) in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and in follow-up, 
only the short axis will be measured and followed. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
178 
 
 
 
 
Non-Measurable Disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm] or pathological lymph nodes with 10 to <15 mm [1 to <1.5 cm] 
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 as 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, but in addition should 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 which 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. 
 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm (1 cm) diameter as assessed using 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
179 
 
 
 
calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
 
Chest X-Ray. Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans have slice 
thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of 
MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
180 
 
 
 
Tumor Markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 
2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008]. In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 
Cytology, Histology. These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
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 progression (particularly possible 'new' disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. 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, this is PD. 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. 
c. FDG-PET may be used to upgrade a response to a 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 which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
Response Criteria 
 
12.1.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
181 
 
 
 
(whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum 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 (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm (0.5 cm). (Note: the appearance of one or more new lesions is 
also considered progressions). 
 
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. 
 
12.1.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm [<1 cm] 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 review panel (or Principal Investigator). 
 
12.1.4.3 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. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
182 
 
 
 
For Patients with Measurable Disease (i.e., Target 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: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target 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 
 
Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started) or until death. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
183 
 
 
 
 
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. 
 
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. 
 
Progression-Free Survival – Co-Primary Endpoint 
 
PFS is defined as the duration of time from date of randomization to time of progression or death 
(whichever occurs first). This analysis is intent-to-treat including all randomized patients. 
Patients who come off of study treatment for clinical progression without radiographic 
progression (i.e. clinical progression) will be coded as progression for the analysis and the date 
of clinical progression is the time of progression. Due to the rapid progression of the disease in 
the majority of patients, little loss to follow up is expected, but subjects who are lost to follow-up 
as of the data analysis cutoff date will be right-censored. The censoring date will be determined 
from the date the subject was last evaluated for progression. PFS within each treatment arm will 
be summarized descriptively using Kaplan-Meier plots, and compared between arms using log- 
rank tests. 
 
Note: For participants who receive treatment beyond disease progression PFS will be dated as 
follows: 
- 
For patients who have progressive disease on two sequential scans, the date of 
progression will be backdated to the time of first progression. 
- 
For patients who do not have progressive disease on the scan after progressive disease 
was first documented, the date of progression will be dated to the time that a second 
scan shows progression. 
 
Overall Response Rate – Co-Primary Endpoint 
 
The objective response rate defined as the proportion of response evaluable subjects who have a 
complete response (CR) or partial response (PR) using RECIST 1.1 criteria at any time during 
the study. The evaluable population includes all subjects who initiated therapy. Patient who 
have not received a follow-up scan, and thus are not evaluable for response, will be counted as 
non-responders. 
 
12.2 Other Response Parameters 
 
Overall Survival (OS) 
 
OS is defined as the duration of time from date of randomization to time of death 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
184 
 
 
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 Study Oversight 
 
This protocol is monitored at several levels, as described in this section. The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s). The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study. This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments. 
Requirements to access Rave via iMedidata: 
 
x 
A valid account, and
x 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.
Rave role requirements: 
 
o Rave CRA or Rave CRA (Lab Admin) role, must have a minimum of an 
Associate Plus (AP) registration type, 
o Rave Investigator role, must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR), and 
o Rave Read Only role, site staff must have at a minimum an Associates (A) 
registration type. 
x 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required.
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
185 
 
 
 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation email 
from iMedidata. To accept the invitation, site staff must either click on the link in the email or 
log in to iMedidata via the CTSU members’ website under Data Management > Rave Home and 
click to accept the invitation in the Tasks pane located in the upper right-corner of the iMedidata 
screen. Site staff will not be able to access the study in Rave until all required Medidata and 
study specific trainings are completed. Trainings will be in the form of electronic learnings 
(eLearnings) and can be accessed by clicking on the eLearning link in the Tasks pane located in 
the upper right corner of the iMedidata screen. If an eLearning is required for a study and has 
not yet been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful completion of the eLearning 
has been recorded, access to the study in Rave will be granted, and a Rave EDC link will replace 
the eLearning link under the study name. 
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS). Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP). Information on CTMS reporting is available at: 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. On-site 
audits will be conducted on an 18-36 month basis as part of routine cancer center site visits. 
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission. For CTMS monitored studies, after users have activated their 
accounts, please contact the Theradex Help Desk at (609) 619-7862 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave. 
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks. The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS. Metrics for timeliness will be followed and assessed on a quarterly basis. 
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
186 
 
 
 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received. Queries will be issued by CTMS directly within Rave. The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve. Monthly web- 
based reports are posted for review by the Drug Monitors in the IDB, CTEP. Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) and 
CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics- 
resources/interoperability-and-semantics/metadata-and-models). Customized eCRFs will be 
included when appropriate to meet unique study requirements. The PI is encouraged to review 
the eCRFs, working closely with CTMS to ensure prospectively that all required items are 
appropriately captured in the eCRFs prior to study activation. CTMS will prepare the eCRFs 
with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex. CDUS submissions are performed by Theradex on a monthly 
basis. The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
13.3 Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics. 
 
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries. DQP Queries, DQP Delinquent Forms, DPQ Form Status and the DQP 
Reports modules are available to access details and reports of unanswered queries, 
delinquent forms, forms with current status and timeliness reports. Review the DQP 
modules on a regular basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
187 
 
 
 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP Reports 
modules. 
 
13.4 CTEP Multicenter Guidelines 
 
N/A 
 
13.5 Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
188 
 
 
 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non- 
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication. Collaborator(s) will have 30 days from the 
date of receipt for review. Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected. 
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings. Press 
releases and other media presentations must also be forwarded to CTEP prior to release. 
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
13.6 Genomic Data Sharing Plan 
 
N/A 
 
13.7 Incidental/Secondary Findings Disclosure Procedure 
 
N/A 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
189 
 
 
 
14. REFERENCES 
 
Abou-Alfa, G. K., Macarulla, T., Javle, M. M., et al. (2020). Ivosidenib in IDH1-mutant, 
chemotherapy-refractory cholangiocarcinoma (ClarIDHy): A multicentre, randomised, double- 
blind, placebo-controlled, phase 3 study. The Lancet Oncology. 21(6):796-807. 
 
Aguado, E., Abou-Alfa, G. K., Zhu, A. X., et al. (2020). IDH1 mutation detection in plasma 
circulating tumor DNA (ctDNA) and association with clinical response in patients with advanced 
intrahepatic cholangiocarcinoma (IHC) from the phase III ClarIDHy study. Journal of Clinical 
Oncology. 38(15_suppl):4576. 
 
Aithal, G., Watkins, P., Andrade, R., et al. (2011). Case definition and phenotype 
standardization in drug-induced liver injury. Clin Pharmacol Ther. 89:806-15. 
 
Alberts, B., Johnson, A., Lewis, J., et al. (2008). Mechanisms of Cell Communication. 
Molecular Biology of the Cell. 5th ed. New York: Garland Science. 
 
Alkhairy, O.K., Perez-Becker, R., Driessen, G.J., et al. (2015). Novel mutations in 
TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 
deficiency. J Allergy Clin Immunol. 136(3):703-712. 
 
Allegrezza, M.J., M.R. Rutkowski, T.L. Stephen, et al. (2016). Il-15 agonists overcome the 
immunosuppressive effects of mek inhibitors. Cancer Res. 76:2561-2572. 
 
Allen, L. F., Sebolt-Leopold, J., and Meyer, M.B. (2003). CI-1040 (PD184352), a targeted 
signal transduction inhibitor of MEK (MAPKK). Semin Oncol. 30:105-16. 
 
Angell, T.E., M.G. Lechner, J.K. Jang, et al. (2014). MHC class I loss is a frequent mechanism 
of immune escape in papillary thyroid cancer that is reversed by interferon and selumetinib 
treatment in vitro. Clin Cancer Res. 20:6034-6044. 
 
Ansell, S.M., I. Flinn, M.H. Taylor, et al. (2020). Safety and activity of varlilumab, a novel and 
first-in-class agonist anti-CD27 antibody, for hematologic malignancies. Blood advances. 
4:1917-1926. 
 
Ascierto, P.A., McArthur, G. A., Dréno, B., et al. (2016). Cobimetinib combined with 
vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results 
from a randomised, double-blind, phase 3 trial. Lancet Oncol. 17:1248-1260. 
 
Bamford, S., Dawson, E., Forbes, S., et al. (2004). The COSMIC (Catalogue of Somatic 
Mutations in Cancer) database and website. Br J Cancer. 91:355-8. 
 
Baudy, A.R., Dogan, T., Flores-Mercado, J. E., Hoeflich, K. P., Su, F., van Bruggen, N., 
Williams, S. P. (2012). FDG-PET is a good biomarker of both early response and acquired 
resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor 
GDC-0973. EJNMMI Res. 2:22. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
190 
 
 
 
Baumann, D., T. Hägele, J. Mochayedi, et al. (2020). Proimmunogenic impact of MEK 
inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy. 
Nature Commun. 11:2176. 
 
Baverel, P. G., Dubois, V. F. S., Jin, C. Y., et al. (2018a). Population pharmacokinetics of 
durvalumab in cancer patients and association with longitudinal biomarkers of disease status. 
Clinical Pharmacology and Therapeutics. 103(4), 631-642. 
 
Baverel, P. G., Dubois, V. F. S., Jin, C. Y., et al. (2018b). Population pharmacokinetics of 
durvalumab in cancer patients and association with longitudinal biomarkers of disease status. 
Clinical Pharmacology and Therapeutics. 103(4), 631-642. 
 
Bendell, J., F. Ciardiello, J. Tabernero, et al. (2018). Efficacy and safety results from 
IMblaze370, a randomised phase III study comparing atezolizumab+cobimetinib and 
atezolizumab monotherapy vs regorafenib in chemotherapy-refractory metastatic colorectal 
cancer. Annal Oncol. 29:123. 
 
Bekaii-Saab, T. S., Valle, J. W., Cutsem, E. V., et al. (2020). FIGHT-302: First-line 
pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 
rearrangements. Future Oncology. 16(30):2385–2399. 
 
Blank, C., T.F. Gajewski, A. Mackensen. (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. 54:307-314. 
 
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. 
 
Brea, E.J., C.Y. Oh, E. Manchado, et al. (2016). Kinase regulation of human MHC class I 
molecule expression on cancer cells. Cancer Immunol Res. 4:936-947. 
 
Buchan, S., M. Fallatah, S. Thirdborough, et al. (2018). PD-1 blockade and CD27 stimulation 
activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor 
immunity. Clin Cancer Res. 24:2383-2394. 
 
Burris, H.A., J.R. Infante, S.M. Ansell, et al. (2017). Safety and activity of varlilumab, a novel 
and first-in-class agonist anti-CD27 antibody, in patients with advanced solid tumors. J Clin 
Oncol. 35:2028-2036. 
 
Callahan, M.K., Rampal, R., Harding, J.J., et al. (2012). Progression of Ras-mutant leukemia 
during RAF inhibitor treatment. N Engl J Med. 367:2316-21. 
 
Caunt, C.J., M.J. Sale, P.D. Smith, et al. (2015). MEK1 and MEK2 inhibitors and cancer 
therapy: The long and winding road. Nat Rev Cancer. 15:577-592. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
191 
 
 
 
Chapman, P.B., Hauschild, A., Robert, C., et al. (2011). Improved survival with vemurafenib in 
melanoma with BRAFV600E mutation. N Engl J Med. 364:2507-16. 
 
Chen, B., Li, H., Liu, C., et al.. (2020). Prognostic value of the common tumour-infiltrating 
lymphocyte subtypes for patients with non-small cell lung cancer: A meta-analysis. PloS One. 
15(11), e0242173. 
 
Choo, E.F., Belvin, M., Boggs, J., et al. (2012). Preclinical disposition of GDC-0973 and 
prospective and retrospective analysis of human dose and efficacy predictions. Drug Metab 
Dispos. 40:919-27. 
 
Coss, C.C., S.K. Clinton, and M.A. Phelps. (2018). Cachectic cancer patients: Immune to 
check-point inhibitor therapy? Clin Cancer Res. 24:5787-5789. 
 
Davies, H., Bignell, G.R., Cox, C., et al. (2002). Mutations of the BRAF gene in human cancer. 
Nature. 417:949-54. 
 
Dennison, L., & Yarchoan, M. (Unpublished). Context-dependent immunomodulatory effects of 
MEK inhibition are enhanced with T cell agonist therapy. Unpublished manuscript. 
 
Desnoyer, A., S. Broutin, J. Delahousse, et al. (2020). Pharmacokinetic/pharmacodynamic 
relationship of therapeutic monoclonal antibodies used in oncology: Part 2, immune checkpoint 
inhibitor antibodies. Eur J Cancer. 128:119-128. 
 
Di Giacomo, A.M., M. Biagioli, M. Maio. (2010). The emerging toxicity profiles of 
antiCTLA-4 antibodies across clinical indications. Semin Oncol. 37:499-507. 
 
Dong, H.Y., Shahsafaei, A., Dorfman, D.M. (2002). CD148 and CD27 are expressed in B cell 
lymphomas derived from both memory and naive B cells. Leukemia & lymphoma. 43(9):1855- 
1858. 
 
Downward, J. (2003). Targeting Ras signalling pathways in cancer therapy. Nat Rev Cancer. 
3:11-22. 
 
Dummer, R., Goldinger, S.M., Turtsch,i C.P., et al. (2014). Vemurafenib in patients with 
BRAFV600 mutation-positive melanoma with symptomatic brain metastases: final results of an 
open-label pilot study. Eur J Cancer. 50:611-21. 
 
Dushyanthen, S., Z.L. Teo, F. Caramia, et al. (2017). Agonist immunotherapy restores T cell 
function following MEK inhibition improving efficacy in breast cancer. Nature Commun. 
8:606-18. 
 
Ebert, P.J.R., J. Cheung, Y. Yang, et al. (2016). MAP kinase inhibition promotes T cell and 
anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity. 44:609-621. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
192 
 
 
 
Eisenhauer, E.A., P. Therasse, J. Bogaerts, et al. (2009). New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 45:228-247. 
 
Ettrich, T. J., Schwerdel, D., Dolnik, A., et al. (2019). Genotyping of circulating tumor DNA in 
cholangiocarcinoma reveals diagnostic and prognostic information. Scientific Reports. 9(1): 
13261-11. 
 
FDA. (2016a). U.S. food and drug administration center for drug evaluation research, 
NDA/BLA multi-disciplinary review and evaluation {BLA 761097} {libtayo™/cemiplimab}. 
Food and Drug Administration. 
 
FDA. (2016b). U.S. food and drug administration center for drug evaluation research, BLA 
761041 clinical pharmacology review - atezolizumab. Food and Drug Administration. 
 
FDA. (2020). PMA P190032: FDA summary of safety and effectiveness data. Food and Drug 
Administration. https://www.accessdata.fda.gov/cdrh_docs/pdf19/P190032B.pdf 
 
Foundations Medicine. (2021). FoundationOne® liquid CDx 
technical information. Foundations Medicine. 
https://assets.ctfassets.net/w98cd481qyp0/3a8jFw3KUjIU3RWPdcT9Ax/cdb6d621b1d2e3baf81 
03af93059bce5/FoundationOne_Liquid_CDx_Label_Technical_Info.pdf 
 
Flaherty, L., Hamid, O., Linette, G., et al. (2014). A single-arm, open-label, expanded access 
study of vemurafenib in patients with metastatic melanoma in the United States. Cancer J. 
20:18-24. 
 
Flaherty, K.T., Hodi, F.S., and Bastian, B.C. (2010a). Mutation-driven drug development in 
melanoma. Curr Opin Oncol. 22:178-83. 
 
Flaherty, K.T., Puzanov, I., Kim, K.B., et al. (2010b). Inhibition of mutated, activated BRAF in 
metastatic melanoma. N Engl J Med. 363:809-19. 
 
Flaherty, K.T., Infante, J.R., Daud, A., et al. (2012). Combined BRAF and MEK inhibition in 
melanoma with BRAFV600 mutations. N Engl J Med. 367:1694-1703. 
 
Forbes, S.A., Bhamra, G., Bamford, S., et al. (2008). The Catalogue of Somatic Mutations in 
Cancer (COSMIC). Curr Protoc Hum Gene. Chapter 10:Unit 10.11. 
 
Forbes, S.A., Bindal, N., Bamford, S., et al. (2011). COSMIC: mining complete cancer 
genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 39:D945-50. 
 
Garnett, M.J. and Marais, R. Guilty as charged: B-RAF is a human oncogene. (2004). Cancer 
Cell. 6:313-19. 
 
Goyal, L., Saha, S. K., Liu, L. Y., et al. (2017). Polyclonal secondary FGFR2 mutations drive 
acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
193 
 
 
 
cholangiocarcinoma. Cancer Discovery. 7(3): 252-263. 
 
Hallmeyer, S., Hamid, O., Sorof, T.A., et al. (2014). Phase 2 study of vemurafenib in patients 
with advanced melanoma and activating Exon 15 BRAF mutations other than V600E. J Clin 
Oncol. 32:9075. Abstract. 
 
Hamanishi, J., M. Mandai, M. Iwasaki, et al. (2007). Programmed cell death 1 ligand 1 and 
tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc 
Natl Acad Sci USA. 104:3360-3365. 
 
Harding, J.J., Lacouture, M.E., Pulitzer, M., et al. (2012). Hypersensitivity skin reactions in 
melanoma patients treated with vemurafenib after ipilimumab therapy. J Clin Oncol. 30:8515. 
Abstract. 
 
Hatzivassiliou, G., Haling, J.R., Chen, H., et al. (2013). Mechanism of MEK inhibition 
determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature. 501:232-6. 
 
Hauschild, A., Grob, J.J., Demidov, L.V., et al. (2012). Dabrafenib in BRAF-mutated 
metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 
9839:358-65. 
 
Helfrich, I., Edler, L., Sucker, A., et al. (2009). Angiopoietin-2 levels are associated with 
disease progression in metastatic malignant melanoma. Clin Cancer Res. 15:1384-92 
 
Hellmann, M.D., T. Kim, C.B. Lee, et al. (2019). Phase Ib study of atezolizumab combined 
with cobimetinib in patients with solid tumors. Annal Oncol. 30:1134-1142. 
 
Herbst, R.S., J-C. Soria, M. Kowanetz, et al. (2014). Predictive correlates of response to the 
anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 515:563-567. 
 
Hino, R., K. Kabashima, Y. Kato, et al. (2010). Tumor cell expression of programmed cell 
death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 116:1757-1766. 
 
Hodi, F.S., O’Day, S.J., McDermott, D.F., et al. (2010). Improved survival with ipilimumab in 
patients with metastatic melanoma. N Engl J Med. 363:711-23. 
 
Hoeflich, K.P., Merchant, M., Orr, C., et al. (2012). Intermittent administration of MEK 
inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth 
inhibition. Cancer Res. 72:210-9. 
 
Investigator’s Brochure, Atezolizumab (MPDL3280A). Version 9, August 2016. 
Investigator’s Brochure, Cotellic (cobimetinib). Version 12, September 2019. 
Investigator’s Brochure, Varlilumab (CDX-1127). Version 8, January 2020. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
194 
 
 
 
Ioka, T., M. Ueno, D. Oh, et al. (2019). Evaluation of safety and tolerability of durvalumab (D) 
with or without tremelimumab (T) in patients (pts) with biliary tract cancer (BTC). J Clin Oncol. 
37:387. 
 
Javle, M. M., Hainsworth, J. D., Swanton, C et al. (2017). Pertuzumab + trastuzumab for 
HER2-positive metastatic biliary cancer: Preliminary data from MyPathway. Journal of Clinical 
Oncology. 35(4_suppl): 402. 
 
Jilaveanu, L.B., Sznol, J., Aziz, S.A., Duchen D, Kluger HM, Camp RL. (2012). CD70 
expression patterns in renal cell carcinoma. Hum Pathol. 43(9):1394-1399. 
 
Junker, K., Hindermann, W., von Eggeling, F., et al. (2005). CD70: anew tumor specific 
biomarker for renal cell carcinoma. J Urol. 173(6):2150-2153. 
 
Kefford, R., Maio, M., Arance, A., et al. Vemurafenib in metastatic melanoma patients with 
brain metastases: an open-label, single-arm, phase 2, multicenter study. Poster presented at: 10th 
International Meeting of the Society for Melanoma Research (SMR); November 17-20, 2013; 
Philadelphia, PA. 
 
Keir, M.E., M.J. Butte, G.J. Freeman, et al. (2008). PD-1 and its ligands in tolerance and 
immunity. Annual Rev Immunol. 26:677-704. 
 
Kim, R.D., V. Chung, O.B. Alese, et al. (2020). A phase 2 multi-institutional study of 
nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol. 6:888-894. 
 
Lamarca, A., R.A. Hubner, W. David Ryder, et al. (2014). Second-line chemotherapy in 
advanced biliary cancer: A systematic review. Annal Oncol. 25:2328-2338. 
 
Lamarca, A., Kapacee, Z., Breeze, M et al. (2020). Molecular profiling in daily clinical 
practice: Practicalities in advanced cholangiocarcinoma and other biliary tract cancers. Journal 
of Clinical Medicine. 9(9):2854. 
 
Lamarca, A., D.H. Palmer, H.S. Wasan, et al. (2019). ABC-06 | A randomised phase III, multi- 
centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU 
chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary 
tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy. J 
Clin Oncol. 37:4003. 
 
Larkin, J., Ascierto, P.A., Dréno, B., et al. (2014). Combined vemurafenib and cobimetinib in 
BRAF-mutated melanoma. N Engl J Med. 371:1867-76. 
 
Larkin, J., Yan, Y., McArthur, G., et al. (2015). Update of progressive-free survival (PFS) and 
correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus 
vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol. 33:9006. Abstract. 
 
Lens, S.M., Drillenburg, P., den Drijver, B.F., et al. (1999). Aberrant expression and reverse 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
195 
 
 
 
signallingof CD70 on malignant B cells. Br J Haematol. 106(2):491-503. 
 
Li, H., J. Yu, C. Liu, et al. (2017). Time dependent pharmacokinetics of pembrolizumab in 
patients with solid tumor and its correlation with best overall response. J Pharmacokinet 
Pharmacodyn. 44:403-414. 
 
Liu, L., P.A. Mayes, S. Eastman, et al. (2015). The BRAF and MEK inhibitors dabrafenib and 
trametinib: Effects on immune function and in combination with immunomodulatory antibodies 
targeting PD-1, PD-L1, and CTLA-4. Clin Cancer Res. 21:1639-1651. 
 
Maibach, F., Sadozai, H., Seyed Jafari, S. M., Hunger, R. E., & Schenk, M. (2020). Tumor- 
infiltrating lymphocytes and their prognostic value in cutaneous melanoma. Frontiers in 
Immunology. 11, 2105. 
 
Malumbres, M., Barbacid, M. (2003). RAS oncogenes: the first 30 years. Nat Rev Cancer. 
3:459í65. Erratum in: Nat Rev Cancer. 3:708. 
 
Marin, J. J. G., Prete, M. G., Lamarca, A., et al. (2020). Current and novel therapeutic 
opportunities for systemic therapy in biliary cancer. British Journal of Cancer. 123:1047-1059. 
 
McArthur, G.A., Chapman, P.B., Robert, C., et al. (2014). Safety and efficacy of vemurafenib 
in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): extended follow-up 
of a phase 3, randomised, open-label study. Lancet Oncol. 15:323-32. 
 
Middleton, M.R., Grob, J.J., Aaronson, N., et al. (2000). Randomized Phase III study of 
temozolomide versus dacarbazine in the treatment of patients with advanced metastatic 
malignant melanoma. J Clin Oncol. 18:158. 
 
Mimura, K., K. Shiraishi, A. Mueller, et al. (2013). The MAPK pathway is a predominant 
regulator of HLA-A expression in esophageal and gastric cancer. J Immunol. 191:6261-6272. 
 
Mir, O., S. Broutin, A. Desnoyer, et al. (2020). Pharmacokinetics/pharmacodynamic (PK/PD) 
relationship of therapeutic monoclonal antibodies used in oncology: What's new? Eur J Cancer. 
128:103-106. 
 
Mody, K., Feldman, R., Reddy, S. K., et al. (2016). PD-1/PD-L1 expression and molecular 
associations in HPB malignancies. Journal of Clinical Oncology. 34:4_suppl, 289-289. 
 
Mody, K., Kasi, P. M., Yang, J., et al. (2019). Circulating tumor DNA profiling of advanced 
biliary tract cancers. JCO Precision Oncology. 3:1-9. 
 
Molica, S., Vitelli, G., Levato, D., et al. (1998). CD27 in B-cell chronic lymphocytic leukemia. 
Cellular expression, serum release and correlation with other soluble molecules belonging to 
nerve growth factor receptors (NGFr) superfamily. Haematologica. 83(5):398-402. 
 
Murase, S., Saio, M., Takenaka, K., et al. (1998). Increased levels of CSF soluble CD27 in 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
196 
 
 
 
patients with primary central nervous system lymphoma. Cancer letters. 132(1-2):181-186. 
 
Musib, L., Choo, E., Deng, Y., et al. (2013). Absolute bioavailability and effect of formulation 
change, food, or elevated pH with rabeprazole on cobimetinib absorption in healthy subjects. 
Mol Pharm. 10:4046-54. 
 
Nazarian, R., Shi, H., Wang, Q., et al. (2010). Melanomas acquire resistance to BRAFV600E 
inhibition by RTK or N-RAS upregulation. Nature. 468:973-7. 
 
Netterberg I., C.C. Li, L. Molinero, et al. (2019). A PK/PD Analysis of Circulating Biomarkers 
and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung 
Cancer Patients. Clin Pharmacol Ther. 105(2):486-495. 
 
Okazaki, T., T. Honjo. (2007). PD-1 and PD-1 ligands: from discovery to clinical application. 
Int Immunol. 9:813-824. 
 
Parikh, A. R., Leshchiner, I., Elagina, L., et al. (2019). Liquid versus tissue biopsy for detecting 
acquired resistance and tumor heterogeneity in gastrointestinal cancers. Nature Medicine. 
25(9):1415-1421. 
 
Parikh, A. R., Mojtahed, A., Schneider, J. L., et al. (2020). Serial ctDNA monitoring to predict 
response to systemic therapy in metastatic gastrointestinal cancers. Clinical Cancer Research. 
26(8):1877-1885. 
 
Patel, S. P., & Kurzrock, R. (2015). PD-L1 expression as a predictive biomarker in cancer 
immunotherapy. Molecular Cancer Therapeutics. 14(4), 847-856. 
 
Patel, J.D., J.R. Pereira, J. Chen, et al. (2016). Relationship between efficacy outcomes and 
weight gain during treatment of advanced, non-squamous, non-small-cell lung cancer patients. 
Ann Oncol. 27:1612-1619. 
 
Pavlick, A.C., Ribas, A., Gonzalez, R., et al. (2015). Extended follow-up results of phase 1b 
study (BRIM7) of vemurafenib (VEM) with cobimetinib (COBI) in BRAF-mutant melanoma. J 
Clin Oncol. 33:9020. Abstract. 
 
Peng, D.H., B.L. Rodriguez, L. Diao, et al. (2020). Th17 cells contribute to combination MEK 
inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers. BioRxiv. 
2020.06.07.136366. 
 
Poulikakos, P.I., Zhang, C., Bollag, G., et al. (2010). Raf inhibitors transactivate RAF dimers 
and ERK signaling in cells with wild-type BRAF. Nature. 464:427-30. 
 
Powles, T., J.P. Eder, G.D. Fine, et al. (2014). MPDL3280A (anti-PD-L1) treatment leads to 
clinical activity in metastatic bladder cancer. Nature. 515:558-562. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
197 
 
 
 
Queirolo, P., Larkin, J., Blank, C., et al. (2014). Characteristics of patients with BRAFV600 
mutation positive metastatic melanoma benefiting long-term from vemurafenib in an open-label 
safety study. Presented at: 11th International Meeting of the Society for Melanoma Research 
(SMR); November 13-16, Zurich, Switzerland. 
 
Ramakrishna, V., K. Sundarapandiyan, B. Zhao, et al. (2015). Characterization of the human T 
cell response to in vitro CD27 costimulation with varlilumab. J Immunother Cancer. 3:37. 
 
Ranheim, E.A., Cantwell, M.J., Kipps, T.J. (1995). Expression of CD27 and its ligand, CD70, 
on chronic lymphocytic leukemia B cells. Blood. 85(12):3556-3565. 
 
Ribas, A., Hodi, F.S., Callahan, M., et al. (2012). Correspondence: hepatotoxicity with 
combination of vemurafenib and ipilimumab. N Engl J Med. 368:1365-6. 
 
Ribas, A., Gonzalez, R., Pavlick, A., et al. (2014a). Combination of vemurafenib and 
cobimetinib in patients with advanced BRAFV600-mutated melanoma: a phase 1b study. Lancet 
Oncol. 15:954-65. 
 
Ribas, A., Gonzalez, R., Pavlick, A., et al. (2014b). Combination of vemurafenib and 
cobimetinib in patients with advanced BRAFV600-mutated melanoma: a phase 1b study. Lancet 
Oncol. 15:1470-2045. 
 
Rimm, D. L., Han, G., Taube, J. M., et al. (2017). A prospective, multi-institutional, 
pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in Non– 
Small cell lung cancer. JAMA Oncology. 3(8), 1051-1058. 
 
Robert, C., Karaszewska, B., Schachter, J., et al. (2015). Improved overall survival in 
melanoma with combined dabrafenib and trametinib. N Engl J Med. 372:30-9. 
 
Roberts, P.J. and Der, C.J. (2007). Targeting the RAF-MEK-ERK mitogen-activated protein 
kinase cascade for the treatment of cancer. Oncogene. 26:3291-310. 
 
Roch, B., A. Coffy, S. Jean-Baptiste, et al. (2020). Cachexia – sarcopenia as a detriment of 
disease control rate and survival in non-small lung cancer patients receiving immune-checkpoint 
inhibitors. Lung Cancer. 143:19-26. 
 
Rogers, J.E., L. Law, V.D. Nguyen, et al. (2014). Second-line systemic treatment for advanced 
cholangiocarcinoma. J Gastrointest Oncol. 5:408-413. 
 
Romero, I., Garrido, C., Algarra, I., Chamorro, V., Collado, A., Garrido, F., & Garcia-Lora, A. 
M. (2018). MHC intratumoral heterogeneity may predict cancer progression and response to 
immunotherapy. Frontiers in Immunology. 9, 102. 
 
Rubinstein, J.C., Sznol, M., Pavlick, A.C., et al. (2010). Incidence of the V600K mutation 
among melanoma patients with BRAF mutations, and potential therapeutic response to the 
specific BRAF inhibitor PLX4032. J Transl Med. 8:67. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
198 
 
 
 
Sanghavi, K., J. Zhang, X. Zhao, et al. (2019). Population pharmacokinetics of ipilimumab in 
combination with nivolumab in patients with advanced solid tumors. CPT Pharmacometrics 
Syst Pharmacol. 9:29-39. 
 
Sanjabi, S., & Lear, S. (2021). New cytometry tools for immune monitoring during cancer 
immunotherapy. Cytometry. Part B, Clinical Cytometry. 100(1), 10-18. 
 
Shapira-Frommer, R., M.G.J. van Dongen, K. Dobrenkov, et al. (2020). O83 Phase 1 study of 
an anti-CD27 agonist as monotherapy and in combination with pembrolizumab in patients with 
advanced solid tumors. J Immunother Cancer. 8:A2. 
 
Shaib, Y., and H. El-Serag. (2004). The epidemiology of cholangiocarcinoma. Semin Liver 
Dis. 24:115-125. 
 
Shao, H., Yuan, C.M., Xi, L., et al. (2010). Minimal residual disease detection by flow 
cytometry in adult T-cell leukemia/lymphoma. Am J Clin Pathol. 133(4):592-601. 
 
Shek, D., S.A. Read, L. Akhuba, et al. (2020). Non-coding RNA and immune checkpoint 
inhibitors: friends or foes? Immunotherapy. 12:513-529. 
 
Siegel, R.L., Miller, K.D., and Jemal, A.. (2017). Cancer statistics. CA Cancer J Clin. 67:7-30. 
 
Solit, D.B., Garraway, L.A., Pratilas, C.A., et al. (2006). BRAF mutation predicts sensitivity to 
MEK inhibition. Nature. 439:358-62. 
 
Sosman, J.A., Kim, K.B., Schuchter, L., et al. (2012). Survival in BRAF V600–mutant 
advanced melanoma treated with vemurafenib. N Engl J Med. 366:707-714. 
 
Spagnolo, F., Ghiorzo, P., Orgiano, L., et al. (2015). BRAF-mutant melanoma: treatment 
approaches, resistance mechanisms, and diagnostic strategies. Onco Targets Ther. 8:157-68. 
 
Stevens, G., Fife, K. Cerebral metastases. (2004). In: Thompson JF, Morton DL, Kroon BBR, 
eds. Textbook of Melanoma: Pathology, Diagnosis, and Management. Independence, KY: Taylor 
& Francis. 519-29. 
 
Stroh M., H. Winter, M. Marchand, et al. (2017). Clinical Pharmacokinetics and 
Pharmacodynamics of Atezolizumab in Metastatic Urothelial Carcinoma. Clin Pharmacol Ther. 
102(2):305-312. 
 
Su, F., Viros, A., Milagre, C., et al. (2012). RAS mutations in cutaneous squamous-cell 
carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 366:207-15. 
 
Sumimoto, H., Hirata, K., Yamagata, S., et al. (2006). Effective inhibition of cell growth and 
invasion of melanoma by combined suppression of BRAFV599E and Skp2 with lentiviral RNAi. 
Int J Cancer. 118:472-6. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
199 
 
 
 
Suntharalingam, G., M.R. Perry, S. Ward, et al. (2006). Cytokine storm in a phase 1 trial of the 
anti-CD28 monoclonal antibody TGN1412. NEJM. 355:1018-1028. 
 
Thompson, R.H., S.M. Kuntz, B.C. Leibovich, et al. (2006). Tumor B7-H1 is associated with 
poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res. 66:3381- 
3385. 
 
Turner, D.C., A.G. Kondic, K.M. Anderson, et al. (2018). Pembrolizumab Exposure–Response 
assessments challenged by association of cancer cachexia and catabolic clearance. Clin Cancer 
Res. 24:5841-5849. 
 
Trentin, .L, Zambello, R., Sancetta, R., et al. (1997). B lymphocytes from patients with chronic 
lymphoproliferative disorders are equipped with different costimulatory molecules. Cancer 
research. 57(21):4940-4947. 
 
Ueno, M., H.C. Chung, A. Nagrial, et al. (2018). Pembrolizumab for advanced biliary 
adenocarcinoma: Results from the multicohort, phase II KEYNOTE-158 study. Annal Oncol. 
29:viii210. 
 
Ueno, M., M. Ikeda, C. Morizane, et al. (2019). Nivolumab alone or in combination with 
cisplatin plus gemcitabine in japanese patients with unresectable or recurrent biliary tract cancer: 
A non-randomised, multicentre, open-label, phase 1 study. Lancet Gastroenterol. 4:611-621. 
 
Valle, J., H. Wasan, D.H. Palmer, et al. (2010). Cisplatin plus gemcitabine versus gemcitabine 
for biliary tract cancer. NEJM. 362:1273-1281. 
 
van Montfrans, J.M., Hoepelman, A.I., Otto, S., et al. (2012). CD27 deficiency is associated 
with combined immunodeficiency and persistent symptomatic EBV viremia. J Allergy Clin 
Immunol. 129(3):787-793. 
 
van Oers, M.H., Pals, S.T., Evers, L.M., et al. (1993). Expression and release of CD27 in 
human B-cell malignancies. Blood. 82(11):3430-3436. 
 
Vella, L.J., A. Pasam, N. Dimopoulos, et al. (2014). MEK inhibition, alone or in combination 
with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and 
dendritic cells. Cancer Immunol Res. 2:351-360. 
 
Villanueva, J., Vultur, A., Lee, J.T., et al. (2010). Acquired resistance to BRAF inhibitors 
mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF- 
1R/PI3K. Cancer Cell. 18:683-95. 
 
Vonderheide, R.H., and M.J. Glennie. (2013). Agonistic CD40 antibodies and cancer therapy. 
Clin Cancer Res. 19:1035-1043. 
 
Wellbrock, C., Ogilvie, L., Hedley, D., et al. (2004). V599EB-RAF is an oncogene in 
melanocytes. Cancer Res. 64:2338-42. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
200 
 
 
 
Wilkins, J.J., B. Brockhaus, H. Dai, et al. (2019). TimeဨVarying clearance and impact of 
disease state on the pharmacokinetics of avelumab in merkel cell carcinoma and urothelial 
carcinoma. CPT Pharmacometrics Syst Pharmacol. 8:415-427. 
 
Wischhusen, J., Jung, G., Radovanovic, I., et al. (2002). Identification of CD70-mediated 
apoptosis of immune effector cells as a novel immune escape pathway of human glioblastoma. 
Cancer Res. 62(9):2592-2599. 
 
Wolchok, J.D., A. Hoos, S. O’Day, et al. (2009). Guidelines for the evaluation of immune 
therapy activity in solid tumors: immune-related response criteria. Clin Can Res. 15:7412-7420. 
 
Wong, H., Vernillet, L., Peterson, A., et al. (2012). Bridging the gap between preclinical and 
clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a 
MEK inhibitor. Clin Cancer Res. 18:3090-9. 
 
Yarchoan, M., L. Cope, R. Anders, et al. (2020a). Abstract CT043 - A multicenter randomized 
phase 2 trial of atezolizumab as monotherapy or in combination with cobimetinib in biliary tract 
cancers (BTCs): A NCI experimental therapeutics clinical trials network (ETCTN) study. 
Cancer Res. 80:CT043. 
 
Yarchoan, M. (2020b). A multicenter randomized phase 2 trial of atezolizumab as monotherapy 
or in combination with cobimetinib in biliary tract cancers (BTCs) [unpublished manuscript]. 
 
Yonezawa, A., S. Dutt, C. Chester, et al. (2015). Boosting cancer immunotherapy with anti- 
CD137 antibody therapy. Clin Cancer Res. 21:3113-3120. 
 
Zhang, W., Shi, J., Wang, Y., et al. (2020). Next-generation sequencing-guided molecular- 
targeted therapy and immunotherapy for biliary tract cancers. Cancer Immunology. 
Immunotherapy : CII, https://10.1007/s00262-020-02745-y [doi] 
 
Zheng, Y., R. Narwal, C. Jin, et al. (2018). Population modeling of tumor kinetics and overall 
survival to identify prognostic and predictive biomarkers of efficacy for durvalumab in patients 
with urothelial carcinoma. Clin Pharmacol Ther. 103:643-652. 
 
Zubrilov, I., Sagi-Assif, O., Izraely, S., et al. (2015). Vemurafenib resistance selects for highly 
malignant brain and lung-metastasizing melanoma cells. Cancer Lett. 361:86-96. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
201 
 
 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
 
 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
 
 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
202 
 
 
 
APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING SERUM 
CREATININE 
 
Formulas to estimate renal function using serum creatinine provided by the NCI’s Investigational Drug 
Steering Committee (IDSC) Pharmacological Task Force in table below. 
 
1. Estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) (Levey et al., 2009). 
 
Formulae: 
 
Race and 
Serum Creatinine (SCr), 
Equation 
Sex 
μmol/L (mg/dL) 
Black 
Female 
62 (0.7) 
GFR = 166 × (SCr/0.7)í0.329 × (0.993)Age 
>62 (>0.7) 
GFR = 166 × (SCr/0.7)í1.209 × (0.993)Age 
Male 
80 (0.9) 
GFR = 163 × (SCr/0.9)í0.411 × (0.993)Age 
>80 (>0.9) 
GFR = 163 × (SCr/0.9)í1.209 × (0.993)Age 
 
White or 
other 
Female 
62 (0.7) 
GFR = 144 × (SCr/0.7)í0.329 × (0.993)Age 
>62 (>0.7) 
GFR = 144 × (SCr/0.7)í1.209 × (0.993)Age 
Male 
80 (0.9) 
GFR = 141 × (SCr/0.9)í0.411 × (0.993)Age 
>80 (>0.9) 
GFR = 141 × (SCr/0.9)í1.209 × (0.993)Age 
 
SCr in mg/dL; Output is in mL/min/1.73 m2 and needs no further conversions. 
2. eGFR using the Modification of Diet in Renal Disease (MDRD) Study (Levey et al., 2006). 
 
175 x SCr–1.154 × age–0.203 × 0.742 (if female) × 1.212 (if black) 
Output is in mL/min/1.73 m2 and needs no further conversions. 
3. Estimated creatinine clearance (ClCr) by the Cockcroft-Gault (C-G) equation (Cockcroft and 
Gault, 1976). 
 
 
 
Followed by conversion to a value normalized to 1.73 m2 with the patient’s body surface area 
(BSA). 
 
References 
1. Levey, A.S., L.A. Stevens, C.H. Schmid, et al. (2009). A new equation to estimate glomerular 
filtration rate. Ann Inter Med. 150:604-612. 
2. Levey, A.S., J. Coresh, T. Greene, et al. (2006). Using standardized serum creatinine values in the 
modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann 
Intern Med. 145:247-254. 
3. Cockcroft, D.W. and M.H. Gault. (1976). Prediction of creatinine clearance from serum 
creatinine. Nephron. 16:31-41. 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
203 
 
 
 
APPENDIX C 
PATIENT CLINICAL TRIAL WALLET CARD 
 
 
 
CLINICALTRIALWALLETCARD
 
Showthiscardtoallofyour
healthcareprovidersandkeep
itwithyouincaseyougoto
theemergencyroom.
 
PatientName:
Diagnosis:
StudyDoctor:
StudyDoctorPhone#:
NCITrial#: 10476
StudyDrug(S):Atezolizumab
Varilimub
Cobimetinib
Formoreinformation:1Ͳ800Ͳ4ͲCANCER
cancer.gov|clinicaltrials.gov

204 
 
 
NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
 
APPENDIX D 
PRE-BIOPSY ASSESSMENT 
 
A pre-biopsy lesion assessment can increase trial safety and efficiency. By agreement between 
all investigators, an attempt at biopsy will be made if the clinical trial team determines that a 
biopsy poses minimal relative risk, provides potential clinical gain to the participant, and will 
likely yield sufficient tissue for analysis. 
 
Pre-biopsy assessments will be reported and tracked through a trial-specific CRF within the 
CTEP Medidata Rave system. Additional information can be found in the Investigational 
Radiology SOP available at: 
https://ctep.cancer.gov/initiativesPrograms/docs/ETCTN_IR_Research_Biopsy_SOP.pdf. 
 
Individual Patient Pre-Biopsy Assessment. IR co-investigators are encouraged to apply this 
pre-biopsy scoring and correlation system to assist in the determination of biopsy 
appropriateness. 
 
x IR co-investigators assign a subjective score of 1-3 based on likelihood of success due to 
lesion characteristics. 
 
1. Biopsy should not be done 
A. Due to safety concerns 
B. Due to lack of suitable lesion for biopsy 
 
2. Uncertainty about success 
A. Due to access path to lesion 
B. Due to lesion characteristics 
 
3. Likely successful 
 
x Lesion characteristics to be considered 
x Size (small) (<2 cm) 
x Location/path to lesion 
x Morphologic features (necrosis, sub-solid, sclerosis, ill-defined/infiltrative) 
x PET (+/-), avidity 
x Organ/site (sclerotic bone is low yield; fine needle aspiration to be used) 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
205 
 
 
 
APPENDIX E 
MEDICATION DIARY 
 
 
PATIENT’S MEDICATION DIARY – Cobimetinib 
 
Cycle  
 Start date  
 
 
Agent Cobimetinib 
Patient’s Initials 
Patient Study ID 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each cycle. 
2. You will take your dose of cobimetinib each day in the morning. You will take  
 20 mg tablets. 
3. You will take your dose of cobimetinib prior to your IV therapy appointments on Days 1 and 15. 
4. If your dosing time is missed by greater than four hours from your regularly scheduled time, consider the 
dose missed and do not take it. Resume your dose at next scheduled day/time. 
5. If you vomit, do not retake the cobimetinib. Take you next dose as scheduled. 
6. Record the date, the number of tablets you took, and when you took them. 
7. If you have any comments or notice any side effects, please record them in the Comments column. 
8. Please return the forms to your physician when you go for your next appointment. 
 
 
Day 
 
 
Date 
 
Time of 
morning dose 
 
# of tablets 
taken 
 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
X 
X 
X 
Do Not Take 
23 
X 
X 
X 
Do Not Take 
24 
X 
X 
X 
Do Not Take 
25 
X 
X 
X 
Do Not Take 
26 
X 
X 
X 
Do Not Take 
27 
X 
X 
X 
Do Not Take 
28 
X 
X 
X 
Do Not Take 
 
CTEP-assigned Protocol #10476 
Local Protocol #  
 

NCI Protocol #: 10476 
Version Date: Octobe 9, 2023 
206 
 
 
 
 
 
 
 
Patient’s Initials/Date  
 
Physician’s Office will complete this section: 
Date patient started study drug this 
cycle 
 
Date patient last took the study 
drug 
 
Patient’s planned daily 
dose 
 
Patient’s planned total dose this cycle (i.e. 60 mg daily dose x 21 days is 1260 mg) 
Total number of tablets taken this 
cycle 
 
Total actual dose taken this cycle  
 
Physician/Nurse/Data Manager’s Signature/Date