Conditions: Gallbladder Carcinoma Metastatic Cholangiocarcinoma Stage III Intrahepatic Cholangiocarcinoma AJCC v8 Stage IV Intrahepatic Cholangiocarcinoma AJCC v8 Unresectable Cholangiocarcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 86
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well atezolizumab with or without cobimetinib works in treating patients with bile duct cancer that has spread to other places in the body (metastatic) and cannot be removed by surgery (unresectable) or gallbladder cancer. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cobimetinib is used in patients whose cancer has a mutated (changed) form of a gene called BRAF. It is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving atezolizumab with cobimetinib may work better at treating patients with bile duct and gallbladder cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. To assess the progression free survival (PFS) of patients receiving atezolizumab monotherapy and cobimetinib in combination with atezolizumab for unresectable cholangiocarcinoma.

SECONDARY OBJECTIVES:

I. To assess the overall survival (OS) of patients receiving cobimetinib in combination with atezolizumab and atezolizumab monotherapy for unresectable cholangiocarcinoma.

II. To determine the objective response rate (ORR), defined as complete plus partial response, of cobimetinib in combination with atezolizumab and atezolizumab monotherapy in patients with unresectable cholangiocarcinoma.

III. To assess the safety and tolerability of cobimetinib in combination with atezolizumab and atezolizumab monotherapy in patients with unresectable cholangiocarcinoma.

IV. To determine the relationship between PD-L1 expression in tumor at baseline and on treatment, and response to treatment.

CORRELATIVE OBJECTIVES:

I. To determine the effect of cobimetinib on CD8+ T cell infiltration in tumor. II. To determine the effect of cobimetinib on T cell subpopulations systemically and in tumor, PD-1/PD-L1 expression on tumor, and MHC 1/2 expression.

III. To determine the effect of cobimetinib on markers of immune exhaustion and pro-apoptotic factors in CD8+ effector T cells.

IV. To explore the effect of cobimetinib on local and systemic immune activation pathways and immune suppressive pathways through expression profiling.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) and collection of blood samples throughout the trial and undergo tumor biopsy on study.

ARM B: Patients receive atezolizumab IV over 30-60 minutes on days 1 and 15 and cobimetinib orally (PO) once daily (QD) on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and collection of blood samples throughout the trial and undergo tumor biopsy on study.

After completion of study treatment, patients are followed up every 3 months until death, withdrawal of consent, or study closure, whichever occurs first.

Arms:
arm 1: Patients receive atezolizumab IV over 30-60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and collection of blood samples throughout the trial and undergo tumor biopsy on study. arm 2: Patients receive atezolizumab IV over 30-60 minutes on days 1 and 15 and cobimetinib PO QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and collection of blood samples throughout the trial and undergo tumor biopsy on study.

Interventions: intervention 1: Atezolizumab intervention 2: Biopsy intervention 3: Biospecimen Collection intervention 4: Cobimetinib intervention 5: Computed Tomography intervention 6: Magnetic Resonance Imaging
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo tumor biopsy intervention 3: Undergo collection of blood samples intervention 4: Given PO intervention 5: Undergo CT intervention 6: Undergo MRI

Protocol document:
Prot_SAP_000.pdf: 
NCI Protocol #: 10139 
 
Protocol Version Date: October 10, 2022 
 
i 
 
 
DATE: 
October 10, 2022 
 
TO:  
CTEP Protocol and Information Office 
 
FROM:  
Nilofer Azad, MD 
 
SUBJECT: 
Amendment in response to 
 notice regarding atezolizumab 
drug information updates and update the LAO Protocol Liaison. No 
changes to the Consent Forms. 
 
 
SUMMARY OF CHANGES - Protocol: 
I. 
Response to 
 notice regarding atezolizumab drug information updates, 
dated 10/06/2022: 
# 
Section 
Comments 
1. 
8.1.1 
Updated atezolizumab drug information as provided in the notice. 
 
II. 
Requested changes by the PI: 
# 
Section 
Comments 
2. 
Header,       
Title Page 
Updated protocol version.  
3. 
Title Page 
Updated the LAO Protocol Liaison. 
 
SUMMARY OF CHANGES – Consent Form: 
# 
Section 
Comments 
1. 
Header 
Updated protocol version. 
 
SUMMARY OF CHANGES – Consent Form Beyond Progression: 
# 
Section 
Comments 
1.  
Header 
Updated protocol version. 
 
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NCI Protocol #: 10139 
 
Protocol Version Date: October 10, 2022 
 
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NCI Protocol #: 10139 
 
Local Protocol #: ETCTN10139 
 
ClinicalTrials.gov Identifier: NCT03201458 
 
TITLE: A Randomized Phase 2 Study of Atezolizumab in Combination with Cobimetinib 
versus Atezolizumab Monotherapy in Participants with Unresectable Cholangiocarcinoma 
 
Corresponding Organization: LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer 
Center  
 
Study Principal Investigator: 
Nilofer S. Azad, MD 
Johns Hopkins Sidney Kimmel Comprehensive Cancer 
1650 Orleans Street, Room 4M10 
Baltimore, Maryland 21287 
Office: 410-614-9169 
Fax: 410-614-9006 
nazad2@jhmi.edu 
 
: 
, MD 
Johns Hopkins Sidney Kimmel Comprehensive Cancer 
1650 Orleans Street, CRB1 186 
Baltimore, Maryland 21287 
 
 
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-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey 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 
 
 
 
 
 
 
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NCI Protocol #: 10139 
 
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STUDY SCHEMA 
 
 
 
 This is an open-label randomized phase 2 trial evaluating atezolizumab monotherapy and 
cobimetinib in combination with atezolizumab.  
 Each treatment cycle = 28 days 
 Patients randomized to Arm A will receive treatment with atezolizumab 840 mg IV every 2 
weeks.  
 Patients randomized to Arm B will receive oral cobimetinib 60 mg daily (21 days on/7 days 
off) plus atezolizumab 840 mg IV every 2 weeks. Therapy on either treatment arm will be 
continued without interruption until progression or intolerance to therapy. 
 For all patients, imaging scans will be performed at baseline and every 8 weeks thereafter, 
irrespective of the treatment schedule. 
 
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TABLE OF CONTENTS 
 
STUDY SCHEMA...........................................................................................................................3 
1. 
OBJECTIVES ..........................................................................................................................6 
1.1 
Primary Objectives......................................................................................................6 
1.2 
Secondary Objectives..................................................................................................6 
1.3 
Correlative Objectives ................................................................................................6 
2. 
BACKGROUND ......................................................................................................................7 
2.1 
Study Disease(s)..........................................................................................................7 
2.2 
CTEP IND Agents ......................................................................................................7 
2.3 
Rationale ...................................................................................................................13 
2.4 
Correlative Studies Background ...............................................................................14 
3. 
PATIENT SELECTION .........................................................................................................16 
3.1 
Eligibility Criteria .....................................................................................................16 
3.2 
Exclusion Criteria .....................................................................................................17 
3.3 
Inclusion of Women and Minorities .........................................................................21 
3.4 
Stratification factors ..................................................................................................22 
4. 
REGISTRATION PROCEDURES ........................................................................................23 
4.1 
Investigator and Research Associate Registration with CTEP .................................23 
4.2 
Site Registration ........................................................................................................23 
4.3 
Patient Registration ...................................................................................................25 
4.4 
General Guidelines....................................................................................................27 
5. 
TREATMENT PLAN ............................................................................................................27 
5.1 
Agent Administration................................................................................................27 
5.2 
General Concomitant Medication and Supportive Care Guidelines .........................30 
5.3 
Duration of Therapy ..................................................................................................32 
5.4 
Duration of Follow Up ..............................................................................................33 
5.5 
Criteria for Removal from Study ..............................................................................33 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ....................................................................34 
6.1 
Atezolizumab ............................................................................................................34 
6.2 
Cobimetinib...............................................................................................................49 
6.3 
Management of Cobimetinib plus Atezolizumab−Associated Adverse 
Events of particular concern .....................................................................................50 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ..................................63 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ..................63 
7.2 
Adverse Event Characteristics ..................................................................................69 
7.3 
Expedited Adverse Event Reporting .........................................................................70 
7.4 
Routine Adverse Event Reporting ............................................................................73 
7.5 
Secondary Malignancy..............................................................................................73 
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7.6 
Second Malignancy ...................................................................................................74 
8. 
PHARMACEUTICAL INFORMATION ..............................................................................74 
8.1 
CTEP IND Agent(s) ..................................................................................................74 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .............................................79 
9.1 
Hypotheses and background .....................................................................................79 
9.2 
Preliminary data ........................................................................................................79 
9.3 
Methods.....................................................................................................................80 
10. STUDY CALENDAR ............................................................................................................87 
11. MEASUREMENT OF EFFECT ............................................................................................89 
11.1 Antitumor Effect – Solid Tumors .............................................................................89 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS 96 
12.1 Study Oversight ........................................................................................................96 
12.2 Data Reporting ..........................................................................................................96 
12.3 CTEP Multicenter Guidelines ...................................................................................98 
12.4 Collaborative Agreements Language ........................................................................98 
13. STATISTICAL CONSIDERATIONS .................................................................................100 
13.1 Study Design/Endpoints..........................................................................................100 
13.2 Sample Size/Accrual Rate .......................................................................................101 
13.3 Stratification Factors ...............................................................................................101 
13.4 Analysis of Secondary Endpoints ...........................................................................102 
13.5 Reporting and Exclusions .......................................................................................102 
14. REFERENCES .....................................................................................................................104 
APPENDIX A PERFORMANCE STATUS CRITERIA .........................................................106 
APPENDIX B PATIENT DRUG INFORMATION HANDOUTS AND WALLET CARDS 107 
APPENDIX C STUDY CHECKLIST FOR CTEP-SUPPORTED EARLY PHASE TRIALS 
WITH BIOMARKER ASSAYS AND BIOASSAY TEMPLATES ...................................113 
APPENDIX D IMMUNE-RELATED RESPONSE CRITERIA ..............................................116 
APPENDIX E PATIENT MEDICATION DIARY - COBIMETINIB ....................................118 
 
 
 
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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To assess the progression free survival (PFS) of patients receiving atezolizumab 
monotherapy and cobimetinib in combination with atezolizumab for unresectable 
cholangiocarcinoma. 
 
1.2 
Secondary Objectives 
 
1.2.1 To assess the overall survival (OS) of patients receiving cobimetinib in combination with 
atezolizumab and atezolizumab monotherapy for unresectable cholangiocarcinoma.  
1.2.2 To determine the objective response rate (ORR), defined as complete plus partial 
response, of cobimetinib in combination with atezolizumab and atezolizumab 
monotherapy in patients with unresectable cholangiocarcinoma. 
1.2.3 To assess the safety and tolerability of cobimetinib in combination with atezolizumab and 
atezolizumab monotherapy in patients with unresectable cholangiocarcinoma. 
1.2.4 To determine the relationship between PD-L1 expression in tumor at baseline and on 
treatment, and response to treatment. 
 
1.3 
Correlative Objectives 
 
1.3.1 To determine the effect of cobimetinib on CD8+ T cell infiltration in tumor. 
1.3.2 To determine the effect of cobimetinib on T cell subpopulations systemically and in 
tumor, PD-1/PD-L1 expression on tumor, and MHC 1/2 expression. 
1.3.3 To determine the effect of cobimetinib on markers of immune exhaustion and pro-
apoptotic factors in CD8+ effector T cells. 
1.3.4 To explore the effect of cobimetinib on local and systemic immune activation pathways 
and immune suppressive pathways through expression profiling. 
 
 
 
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2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
Cholangiocarcinoma refers to cancers of the bile duct that arise in the intrahepatic, perihilar, or 
distal (extrahepatic) biliary tree and is the second most common primary liver tumor. 
Cholangiocarcinoma is a relatively rare cancer, accounting for approximately 3 percent of all 
gastrointestinal malignancies (or approximately 3500 new cases per year in the US), although the 
incidence is increasing globally (Khan et al. 2008, Patel 2001, Siegel et al. 2016). A small subset 
of patients with cholangiocarcinoma can be cured with surgical resection, but the majority of 
patients have unresectable disease at the time of presentation. Overall survival for this disease 
(which includes resectable patients) is poor, with less than 5% of patients surviving to 5 years 
(Shaib & El-Serag 2004). The most commonly used frontline therapy in patients with 
unresectable cholangiocarcinoma and a good performance status is palliative gemcitabine plus 
cisplatin. No regimen has ever conclusively shown benefit in second line treatment of 
cholangiocarcinoma (Lamarca et al. 2014) and the current treatment guidelines do not provide a 
recommendation for second line therapy. Prior retrospective studies suggest that the progression-
free survival of second-line chemotherapy is only 2-3 months (Lamarca et al. 2014, Rogers et al. 
2014). Therefore, cholangiocarcinoma remains a key area of unmet medical need. 
 
2.2 
CTEP IND Agents 
 
2.2.1 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. 
 
 
 
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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; 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 
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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 (21−89 years), body 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%) 
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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 ≥10% 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 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 7.1.1.1. 
 
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). 
 
 
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2.2.2 Cobimetinib 
 
Cobimetinib is a reversible, potent, and highly selective inhibitor of MEK1 and MEK2. 
Cobimetinib is approved in the United States, European Union, Switzerland, and in 
multiple other countries across the world for use with vemurafenib for the treatment of 
advanced BRAF-mutated melanoma.  
 
2.2.2.1 
Summary of Nonclinical Studies with Cobimetinib  
 
Cobimetinib inhibits proliferation of a variety of human tumor cell lines through 
inhibition of MEK1 and MEK2. In addition, cobimetinib inhibits ERK phosphorylation 
in xenograft tumor models and stimulates apoptosis. Cobimetinib accumulates in tumor 
xenografts and remains at high concentrations in the tumor after plasma concentrations 
have declined. The activity of cobimetinib to inhibit ERK1 phosphorylation is more 
closely correlated with its concentration in tumor tissue than in plasma; in general, there 
is a good correlation between reduced ERK1 phosphorylation and efficacy in tumor 
xenograft models. Tumor regression has been observed in several human tumor xenograft 
models. This regression was dose dependent with up to 100% regression at the highest 
doses tested. The models studied included CRC, malignant melanoma, breast carcinoma, 
and anaplastic lung carcinoma.  
 
A characterization of the pharmacologic and PK properties of cobimetinib was performed 
in a series of nonclinical studies that are summarized in the cobimetinib Investigator’s 
Brochure.  
 
The nonclinical toxicity of cobimetinib was characterized in single− and repeat−dose 
general toxicity studies in rats and dogs, in vitro genotoxicity studies,  
embryolethality/teratogenicity studies in rat, and cardiovascular, neurobehavioral, and  
respiratory safety pharmacology studies. The studies are summarized in the cobimetinib 
Investigator’s Brochure.  
 
2.2.2.2 
Summary of Clinical Studies with Cobimetinib Monotherapy  
 
As of October 2015, cobimetinib had been administered alone or with other agents to 
more than 1000 adult cancer patients and approximately 120 healthy volunteers in 18 
clinical trials; the vast majority of patients had been treated with cobimetinib plus other 
agents, such as vemurafenib. These include one trial of cobimetinib as a single agent, 
seven clinical pharmacology studies, and nine trials of cobimetinib with other agents.  
Study MEK4592g was a Phase I, non-randomized, open-label, safety and PK dose-
escalation study. The study was conducted in patients with metastatic or unresectable 
solid tumors for which standard curative or palliative measures did not exist or were no 
longer effective. A total of 115 patients were treated, and the study has since been 
completed.  
 
The study consisted of five treatment stages:  
• 
Stage I: Dose-escalation cohorts; patients were treated on a 21-days-on, 7-days-off 
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(21/7) schedule to determine the MTD.  
• 
Stage IA: Dose-escalation cohorts; patients were treated on a 14-days-on, 14-days-off 
(14/14) schedule to determine the MTD on an alternate dosing regimen.  
• 
Stage II: Expansion cohort with the MTD determined in Stage I (60 mg daily [QD] 
21/7) in patients harboring a BRAF, NRAS, or KRAS mutation.  
• 
Stage IIA: Expansion cohort with the MTD determined in Stage IA (100 mg QD 
14/14) in patients harboring a BRAF, NRAS, or KRAS mutation.  
• 
Stage III: A dedicated drug-drug interaction study at the MTD determined in Stage I  
(60 mg QD 21/7) in approximately 20 patients with solid tumors.  
  
Dose-Limiting Toxicities  
 
Four DLTs were observed in Stage I (21/7 dosing schedule) of Study MEK4592g. At the 
40-mg dose level, a DLT of Grade 4 hepatic encephalopathy and Grade 3 elevated 
ammonia was reported in a patient with pre-existing liver metastases. At the 60-mg dose 
level, a DLT of Grade 3 rash was reported that improved with skin toxicity management 
and drug holiday. At the 80-mg dose level, two DLTs were reported: 1 patient with Grade 
3 diarrhea despite treatment with anti-diarrheal medications and 1 patient with Grade 3 
rash.  
 
Two DLTs were observed in Stage IA (14/14 dosing schedule), both at the 125-mg dose 
level. One patient had Grade 3 rash and another had Grade 3 blurred vision associated 
with neurosensory detachment of the retina.  
 
Adverse Events  
 
All patients in Study MEK4592g experienced an adverse event. The most frequent 
adverse events were diarrhea (67.0%), fatigue (50.4%), rash (49.6%), nausea and 
vomiting (33.9% each), and edema peripheral (28.7%). Other events that occurred in ≥ 
10% of patients included anemia, abdominal pain, constipation, hypokalemia, decreased 
appetite, headache, dizziness, back pain, increased AST, dermatitis acneiform, pruritus, 
and dry skin. Among the patients who received cobimetinib 60 mg 21/7, the most 
frequent treatment−emergent adverse events were diarrhea (64.4%), rash (53.3%), fatigue 
(48.9%), nausea and edema peripheral (31.1% each), and vomiting (28.9%).  
 
Grade ≥ 3 Adverse Events  
 
Among all cobimetinib-treated patients, 5 patients (4.3%) experienced a  
Grade 4 adverse event, and 53 patients (46.1%) experienced a Grade 3 adverse event. The 
most frequent Grade 3 and Grade 4 adverse events were hyponatremia (9.6%), fatigue 
(8.7%), anemia (7.8%), and diarrhea and hypokalemia (6.1% each).  
Serious Adverse Events  
 
A total of 49 patients (42.6%) experienced a serious adverse event. The most common 
types of serious adverse events were gastrointestinal disorders (n = 17), but there were no 
trends in specific preferred terms. The gastrointestinal serious adverse events, such as 
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intestinal obstructions and gastrointestinal hemorrhages, occurred in patients with 
gastrointestinal malignancies. Serious adverse events reported for more than 2 patients 
among all patients in the study were anemia, bile duct obstruction, dehydration, syncope, 
and respiratory arrest (3 patients each [2.6%]).  
 
Efficacy  
 
Best overall response (BOR) was assessed for 74 of 97 patients in Stages I, IA, II, and 
IIA. Overall 6 patients (all of whom had melanoma; 6.2%) had a confirmed partial 
response (PR), 28 patients (28.9%) had stable disease (SD), and 40 patients (41.2%) had 
progressive disease. Out of the 14 CRC patients, all patients experienced progressive 
disease. In Stage III of Study MEK4592g, 18 patients were accrued and BOR was 
assessed for 14 of 18 patients. Four patients (22.2%) had SD as their BOR, and 2 patients 
(11.1%) had unconfirmed tumor responses.  
 
For further clinical information on cobimetinib as monotherapy or with other anti-cancer 
agents, please see the cobimetinib Investigator’s Brochure. 
 
2.3 
Rationale 
 
As a single agent, anti-PD-1 therapies are most effective in tumors with high levels of effector T 
cell infiltration and PD-L1 expression (Taube et al. 2014). PD-L1 is expressed in high number of 
cholangiocarcinomas at baseline and is associated with poor survival, which suggests that 
cholangiocarcinoma may be particularly sensitive to a strategy that tweaks the tumor 
microenvironment and immune cellular compartments (Suleiman et al. 2015) (Mody et al. 2016). 
Preliminary activity of anti-PD-1 therapy in this disease is supported by a phase 1B trial 
pembrolizumab (Keynote 028). This trial, which only enrolled patients with positive PD-L1 tumor 
expression, had 4/23 partial responses (17% ORR). Therefore, further investigation of immune 
checkpoint inhibitors in cholangiocarcinoma is warranted.  
 
The MAPK/ERK signaling pathway is involved in the regulation of normal cell proliferation, 
survival and differentiation, and this pathway is often aberrantly upregulated in a wide number of 
human cancers including cholangiocarcinoma. The MEK 1/2 inhibitor MEK162 (ARRY-438162) 
was studied in cholangiocarcinoma in a phase 1 clinical trial; this study reported two objective 
responses including one complete response, as well as a 46% stable disease rate for a median 
duration of 5 months. Interestingly, no MAKP/ERK mutations were identified in either of the 
responders in this study. This study provided initial support for MEK inhibition in the treatment 
of cholangiocarcinoma. Preliminary signs of activity were also observed in studies of another 
MEK inhibitor, selumetinib (AZD6244, ARRY-142886), alone and in combination with 
gemcitabine and cisplatin in patients with cholangiocarcinoma (Bekaii-Saab et al. 2011), and 
additional efforts to advance MEK inhibitors in cholangiocarcinoma are ongoing. 
 
While these preliminary clinical data provide a basis for studying MEK inhibitors and anti-PD-1 
therapies individually cholangiocarcinoma, there is emerging preclinical data that the activity of 
MEK inhibitors and anti-PD-1 therapies may be synergistic, by modulating immune function 
and/or priming the tumor microenvironment. Several studies have demonstrated that MEK 
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inhibitors upregulate the expression of MHC and downregulate certain immunosuppressive 
mechanisms within the tumor (Kakavand et al. 2015, Liu et al. 2015, Reddy et al. 2016). 
Additionally, Ebert and colleagues recently demonstrated that MEK inhibition may also directly 
potentiate T-cell based anti-tumor immunity (Ebert et al. 2016). They demonstrated in an animal 
model that MEK inhibition can reverse T cell signal-driven apoptotic ‘‘exhaustive’’ T cell death 
within a tumor by blocking the upregulation of certain pro-apoptotic factors; this results in the 
accumulation of CD8+ T cells within tumors. In the aggregate, these data provide mechanistic 
rationale for combination treatment with a MEK inhibitor and an immunomodulator targeting PD-
1. 
 
The preliminary clinical data of combination therapy with a MEK inhibitor and an anti-PD-1 
therapy has been encouraging. The MEK inhibitor cobimetinib and the PD-L1 inhibitor 
atezolizumab were recently studied in combination in a phase 1 study of mismatch repair proficient 
(MMR-p) colorectal carcinoma (Bendell et al. 2016). The combination of cobimetinib and 
atezolizumab was well tolerated and full dose escalation was achieved [cobimetinib 60 mg daily 
(21 days on/7 days off) plus atezolizumab 800 mg IV q2w]. While neither therapy has previously 
demonstrated activity in MMR-p colorectal carcinoma when used as monotherapy, the 
combination of these agents resulted in a 17% overall response rate (4/23 evaluable patients). 
Correlative work from this study demonstrated that treatment with cobimetinib resulted in 
increased PD-L1 expression, increased tumor infiltration with CD8 T-cells, and increased MHC I 
expression. These findings support the hypothesis that MEK inhibition can prime a cancer to 
become a checkpoint sensitive tumor. 
 
In summary, the available clinical data suggest that a subset of patients with cholangiocarcinoma 
may benefit from therapies blocking the PD-1 pathway. MEK inhibitors have also shown evidence 
of activity in cholangiocarcinoma and may synergize with immune checkpoint inhibitor therapy, 
supporting a combinatorial approach to the development of these therapies in cholangiocarcinoma. 
 
2.4 
Correlative Studies Background 
 
A series of correlative studies are proposed to examine the impact of MEK inhibition with 
cobimetinib on biomarkers within the tumor microenvironment and systemically. Our primary 
objective will be to compare infiltration of CD8+ T cells into the tumor microenvironment 
between patients receiving atezolizumab alone and those receiving atezolizumab in combination 
with cobimetinib. This metric will be considered an integrated biomarker for the clinical study. 
The rationale for this is based on pre-clinical studies demonstrating the MEK inhibition can 
enhance T cell infiltration into tumors in murine models, limit their apoptosis and subsequently 
enhance the efficacy of immune checkpoint blockade. We hypothesize that patients receiving the 
combination of atezolizumab and cobimetinib will have increased CD8+ T cell infiltration in 
tumors as compared to patients receiving atezolizumab alone. Further, we hypothesize that 
patients with increased CD8+ T cell infiltration will have a better clinical outcome regardless of 
treatment group.  
 
In addition to this integrated biomarker, we will assess a number of exploratory biomarkers in 
the context of correlative laboratory studies. These are based on the rationale that (1) patients 
with greater PD-L1 expression or antigen presenting capacity (as measured by MHC expression) 
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will have a better response to immunotherapy; (2) MEK inhibitors may reverse exhaustive T cell 
death by reducing MEK-mediated phosphorylation of Nur77; and (3) Peripheral blood levels of 
immune suppressive T regulatory or myeloid derived suppressor cells may impact the response 
to regimens containing atezolizumab. Based on these observations we also propose a series of 
correlative studies that will help us better understand the mechanism(s) underlying MEK’s role 
in modulating tumor immunity, and to identify biomarkers that may predict response to therapy 
in the context of this clinical trial. 
 
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3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
All answers must be ‘Yes’ to eligible. 
 
3.1.1 Pathologically confirmed metastatic or unresectable cholangiocarcinoma or gallbladder 
carcinoma (GBC), 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 adjuvant therapy in resected patients will be considered the 
first line of therapy). 
• Includes intrahepatic cholangiocarcinoma (IHC), extrahepatic 
cholangiocarcinoma (EHC), and gallbladder carcinoma (GBC), but not Ampulla 
of Vater cancers.  
 
3.1.2 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) with conventional 
techniques or as ≥10 mm (≥1 cm) with spiral CT scan, MRI, or calipers by clinical exam. 
See Section 11 for the evaluation of measurable disease. Assessment must be completed 
within 4 weeks of Randomization. 
 
3.1.3 Age ≥ 18 years. Because no dosing or adverse event data are currently available on the 
use of cobimetinib in combination with atezolizumab in patients < 18 years of age, 
children are excluded from this study. 
 
3.1.4 ECOG performance status ≤ 1 (Karnofsky ≥ 80%, see Appendix A) 
 
3.1.5 Life expectancy of greater than 2 months. 
 
3.1.6 Patients must have normal organ and marrow function as defined below within 2 weeks 
of Randomization: 
 
− 
leukocytes 
≥ 2,500/mcL 
− 
absolute neutrophil count 
≥ 1,500/mcL 
− 
platelets 
≥ 75,000/mcL 
− 
hemoglobin 
≥ 8 g/dL 
− 
total bilirubin 
≤ 1.5 × institutional upper limit of normal (ULN) 
(however, patients with known Gilbert disease who 
have serum bilirubin level ≤3 × ULN may be enrolled) 
− 
AST(SGOT)/ALT(SGPT) 
≤ 3 × ULN 
− 
creatinine clearance 
≥ 30 mL/min/1.73 m2 by Cockcroft-Gault: 
(140 − age) × (weight in kg) × (0.85 if female) 
72 × (serum creatinine in mg/dL) 
 
OR 
 
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Creatinine < 1.5 x ULN 
 
− 
INR and aPTT 
≤ 1.5 × 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.) 
 
3.1.7 Administration of atezolizumab and cobimetininb may have an adverse effect on 
pregnancy and poses a risk to the human fetus, including embryo-lethality. Women of 
childbearing potential must agree to use either two adequate barrier methods or a barrier 
method plus a hormonal method of contraception to prevent pregnancy, or to abstain 
from heterosexual activity (complete abstinence) prior to study entry, for the duration of 
study participation, and for 5 months (150 days) after the last dose of study agent. 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. Male 
patients must agree to use an adequate method of contraception, or to abstain from 
heterosexual activity (complete abstinence), prior to study entry, for the duration of study 
participation, and for 5 months (150 days) after the last dose of study agent. 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent document. 
 
3.1.9 Patients positive for human immunodeficiency virus (HIV) are allowed on study, but 
HIV-positive patients must have: 
a. A stable regimen of highly active anti-retroviral therapy (HAART) 
b. No requirement for concurrent antibiotics or antifungal agents for the prevention of 
opportunistic infections 
c. A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-
based tests 
 
3.1.10 Oxygen saturation ≥ 92% on room air 
 
3.2 
Exclusion Criteria 
All answers must be ‘No’ to be eligible. 
 
3.2.1 Received chemotherapy or radiotherapy within 3 weeks prior to Randomization or those 
who have not recovered to ≤ grade 1 adverse events (other than alopecia) due to agents 
administered more than 3 weeks earlier. Herbal therapy intended as anticancer therapy 
must be discontinued at least 1 week prior to randomization. For patients who received 
prior immunotherapy (eg anti-CTLA-4), at least five drug half-lives must have passed 
before the patient may enroll on this study. However, the following therapies are allowed: 
• 
Hormone-replacement therapy or oral contraceptives. 
• 
Palliative radiotherapy for bone metastases ≥ 2 weeks prior to randomization. 
 
3.2.2 Prior treatment with a MEK inhibitor or ERK inhibitor. 
 
3.2.3 Prior treatment with any anti-PD-1 or anti-PD-L1 antibody, prior allogeneic bone marrow 
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transplantation, or prior solid organ transplantation. 
 
3.2.4 Treatment with any investigational agent within 4 weeks prior to Cycle 1, Day 1, or five 
drug half-lives (whichever is longer).  
 
3.2.5 Treatment with systemic immunosuppressive medications (including, but not limited to, 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor [anti-TNF] agents) within 6 weeks prior to Cycle 1, Day 1. 
• Patients who have received acute, low dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. 
• The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) 
for patients with orthostatic hypotension or adrenocortical insufficiency is 
allowed. 
 
3.2.6 Patients with known primary central nervous system (CNS) malignancy or symptomatic 
CNS metastases, with the following exceptions:  
• Patients with asymptomatic treated CNS metastases may be enrolled, provided all 
the criteria listed above are met as well as the following: 
o Radiographic demonstration of clinical stability 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 ≥ 4 weeks from completion of 
radiotherapy and ≥ 2 weeks from discontinuation of corticosteroids. 
 
3.2.7 Has a known concurrent malignancy that is expected to require active treatment within 
two years, or may interfere with the interpretation of the efficacy and safety outcomes of 
this study in the opinion of the treating investigator. Superficial bladder cancer, non-
melanoma skin cancers, or low grade prostate cancer not requiring therapy should not 
exclude participation in this trial.  
 
3.2.8 Known hypersensitivity to Chinese hamster ovary cell products or other recombinant 
human antibodies. 
 
3.2.9 Allergy or hypersensitivity to components of the cobimetinib formulations. 
 
3.2.10 History of congenital long QT syndrome or corrected QT interval (QTc) > 450 msec 
within 2 weeks of Randomization. 
 
3.2.11 LVEF below institutional LLN or below 50%, whichever is lower, as determined by 
echocardiogram or MUGA scan within 4 weeks of randomization. 
 
3.2.12 Patients who meet any of the following exclusion criteria related to ocular disease will be 
excluded from study entry: 
• Known risk factors for ocular toxicity, consisting of any of the following: 
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– History of serous retinopathy 
– History of retinal vein occlusion (RVO) 
– Evidence of ongoing serous retinopathy or RVO at screening 
 
3.2.13 Patients receiving any medications or substances that are strong inhibitors or inducers of 
CYP3A4 enzymes are ineligible. These include St. John’s wort or hyperforin (potent 
CYP3A4 enzyme inducer) and grapefruit juice (potent cytochrome P450 CYP3A4 
enzyme inhibitor). Such substances can significantly increase or decrease the serum level 
of cobimetinib. Because the lists of these agents are constantly changing, it is important 
to regularly consult a frequently-updated list such as 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. 
 
3.2.14 Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis; cirrhosis; fatty liver; and inherited liver disease. 
• 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. 
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction (PCR) is negative for HCV RNA. 
 
3.2.15 History or risk of autoimmune disease, including, but not limited to, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s 
syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid 
disease, vasculitis, or glomerulonephritis. 
• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible. 
• Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may 
be eligible. 
• 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 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). 
 
3.2.16 History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, 
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etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) 
scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
3.2.17 Severe infections within 4 weeks prior to randomization, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia. 
 
3.2.18 Signs or symptoms of infection within 2 weeks prior to randomization. 
 
3.2.19 Received oral or intravenous (IV) antibiotics within 2 weeks prior to randomization. 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection 
or chronic obstructive pulmonary disease) are eligible. 
 
3.2.20 Major surgical procedure within 4 weeks prior to randomization or anticipation of need 
for a major surgical procedure during the course of the study. 
 
3.2.21 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. 
• Influenza vaccination should be given during influenza season only 
(approximately October to March). Patients must not receive live, attenuated 
influenza vaccine within 4 weeks prior to Cycle 1, Day 1 or at any time during the 
study. 
 
3.2.22 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
active tuberculosis (TB), symptomatic congestive heart failure (CHF), unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
• Symptomatic CHF is defined as New York Heart Association (NYHA) CHF 
Class II or higher disease. 
 
3.2.23 Pregnant women are excluded from this study because both atezolizumab and 
cobimetinib are expected to cause fetal harm if used during pregnancy. Because there is 
an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with cobimetinib or atezolizumab, breastfeeding should be 
discontinued if the mother is treated with either therapy. These potential risks may also 
apply to other agents used in this study. 
 
3.2.24 Inability or unwillingness to swallow pills 
 
3.2.25 History of malabsorption syndrome or other condition that would interfere with enteral 
absorption 
 
3.2.26  Clinically significant ascites, defined as ascites that is symptomatic or has resulted in a 
paracentesis in the past 3 months 
 
 
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3.4 
Stratification factors 
 
Eligible subjects will be stratified according to the site of disease: 1) gallbladder cancer (GBC); 
2) intrahepatic (IHC); or 3) extrahepatic cholangiocarcinoma (EHC). There will be no further 
stratification based on other patient or tumor characteristics (such as age, sex) in this trial. 
 
 
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Regulatory Support System (RSS) uses extensive data to make a determination of whether a site 
has fulfilled all regulatory criteria including but not limited to the following: 
 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements. 
• In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally. 
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office. In order 
for the SSW approval to be processed, the Signatory Institution must inform the CTSU which 
CIRB-approved institutions aligned with the Signatory Institution are participating in the study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the NCI protocol #10139 protocol page 
located on the CTSU Web site. Permission to view and download this protocol is 
restricted and is based on person and site roster data housed in the CTSU RSS. To 
participate, Investigators and Associates must be associated with the Corresponding or 
Participating protocol organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-MD017, 
and protocol NCI protocol #10139. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided. (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Requirements For NCI protocol #10139 Site Registration: 
 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 
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• Internal Site initiation visit (SIV) conducted by the site Study PI with the site 
research team 
-SIV checklist and sign-in sheet must be completed and signed by site Study PI 
and sent back to the Protocol Liaison of the lead LAO.  
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.  
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab 
Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
website.  
 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available to users on a 24/7 basis. It is 
integrated with the CTSU Enterprise System for regulatory and roster data interchange 
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and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability. Registration staff should ensure that a slot is available 
and secured for the patient before completing an enrollment. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records.  
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations: Be on an ETCTN Corresponding or 
Participating Organization roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type. 
• To approve slot reservations or access cohort management: Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.  
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 Patient Enrollment Instructions 
 
In order to verify eligibility, the following documents should be submitted to the Protocol 
Liaison of the Lead Organization at least 48 hours prior to treatment initiation:  
 
• Completed Request for Registration form, along with requested supporting 
documents  
• Signed consent form 
• Signed eligibility checklist 
 
After approval by the Lead Organization, the patient may be enrolled in OPEN. 
 
 
4.3.4 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab 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.  
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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 609-619-7802 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. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Reported adverse events and potential risks are described in Section 7. Appropriate dose 
modifications are described in Section 6. No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the patient's 
malignancy. 
 
 
Arm A Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Atezolizumab Premeds are not 
permitted for the first 
infusion. If patient 
experienced an 
Infusion-Related 
Reaction (IRR) during 
any previous  
infusion, pre-
medication with 
antihistamines may be 
administered for 
Cycles ≥ 2 at the 
discretion of the 
treating physician.  
840 mg IV over 60 (± 15) 
min. If the patient 
tolerated the first 
infusion well 
without infusion-
associated AEs, 
subsequent infusions 
may be delivered 
over 30 (± 10) min. 
Days 1, 15 
28 days 
(4 weeks) 
 
 
 
 
 
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Arm B Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Atezolizumab Premeds are not 
permitted for the first 
infusion. If patient 
experienced an 
Infustion-Related 
Reaction (IRR) during 
any previous  
infusion, pre-
medication with 
antihistamines may be 
administered for 
Cycles ≥ 2 at the 
discretion of the 
treating physician.  
840 mg IV over 60 (± 15) 
min. If the patient 
tolerated the first 
infusion well 
without infusion-
associated AEs, 
subsequent infusions 
may be delivered 
over 30 (± 10) min. 
Days 1, 15 
28 days 
(4 weeks) 
 
Cobimetinib Cobimetinib should be 
taken at the same time 
every morning. It can 
be taken with or 
without food.  
60 mg 
PO once daily in the 
a.m.  
Days 1−21 
 
 
NOTE: For patients receiving cobimetinib, the cobimetinib may be taken before or after the 
scheduled dose of atezolizumab on the days when both are to be administered (i.e., the drugs do 
not need to be sequenced in any particular order).  
 
For patients receiving cobimetinib, patient 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. 
 
5.1.1 Atezolizumab 
 
Atezolizumab has the potential to cause infusion reactions and therefore administration of 
atezolizumab will be performed in a setting with emergency medical facilities and staff 
who are trained to monitor for and respond to medical emergencies. 
 
The initial dose of atezolizumab will be delivered over 60 (±15) minutes. If the 
first infusion is tolerated without infusion-associated AEs, the second infusion may be 
delivered over 30 (±10) minutes. If the 30-minute infusion is well tolerated, 
all subsequent infusions may be delivered over 30 (±10) minutes.  
 
For the first infusion, the patient’s vital signs (heart rate, respiratory rate, blood pressure, 
and temperature) should be determined within 60 minutes before the infusion, every 15 
[±5] minutes during the infusion, and 30 (±10) minutes after the infusion.  
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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 if 
clinically indicated.  
 
Patients will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms. 
 
Premedication is not permitted for the first dose of atezolizumab. Premedication with 
antihistamines or antipyretics/analgesics (e.g., acetaminophen) may be administered for 
subsequent infusions at the discretion of the treating physician. The management of 
Infusion Related Reactions will be according to severity as follows: 
 
• In the event that a patient experiences a Grade 1 Infusion Related Reaction during 
Cycle 1, the infusion rate should be reduced to half the rate being given at the 
time of event onset. Once the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate. If tolerated, the 
infusion rate may then be increased to the original rate. 
 
• In the event that a patient experiences a Grade 2 Infusion Related Reaction, or 
flushing, fever, or throat pain, the infusion should be immediately interrupted and 
the patient should receive aggressive symptomatic treatment. The infusion should 
be restarted only after the symptoms have adequately resolved to baseline grade. 
The infusion rate at restart should be half of the infusion rate that was in progress 
at the time of the onset of the Infusion Related Reaction. For subsequent 
infusions, administer oral premedication with antihistamine and anti-pyretic and 
monitor closely for Infusion Related Reactions. 
 
• For Grade 3 or 4 Infusion Related Reactions, the infusion should be stopped 
immediately, and aggressive resuscitation and supportive measures should be 
initiated (e.g., oral or IV antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). Atezolizumab should be permanently discontinued. 
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-related event; retreatment 
requires consultation with, and consent of, the trial Principal Investigator (PI). 
 
For anaphylaxis precautions, use the following procedure: In event of an anaphylactic 
reaction, follow institutional procedures. 
 
 
5.1.2 Cobimetinib 
 
Patients randomized to cobimetinib will receive 60 mg (three tablets of 20 mg each) 
orally once daily in the morning for Days 1−21 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 6.  
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Cobimetinib should be taken at the same time every day. It can be taken with or without 
food. If a dose of cobimetinib is not taken within 1 hour 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.  
 
For patients receiving cobimetinib, the patient 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.  
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Concomitant medication guidelines for atezolizumab and cobimetinib are provided below.  
 
Because there is a potential for interaction of cobimetinib 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, including 
medications or substances that are inhibitors or inducers of CYP450 enzymes. The study team 
should check a frequently-updated medical reference for a list of drugs to avoid or minimize use 
of. Appendix B (Patient Drug Information Handout and Wallet Card) for the assigned treatment 
arm should be provided to each participant. 
 
5.2.1 General Concomitant Medication Guidelines for All Participants 
 
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 β2-adrenergic agonists; 
see Section 5.1.1). 
 
Systemic corticosteroids and TNFα 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.  
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Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or 
therapeutic anticoagulation therapy (such as low-molecular-weight heparin, warfarin at a 
stable dose level, or a non–vitamin K antagonist oral anticoagulants), should continue 
their use. Males and females of reproductive potential should use highly effective means 
of contraception. 
 
5.2.2 Excluded Therapies for Patients Receiving Atezolizumab (Study Arms A and B) 
 
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: 
• Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational 
agents, or herbal therapy (except for maintenance therapies outlined in Section 5.2.1). 
o After completion of Cycle 1, external beam radiotherapy may be considered for 
pain palliation under a case-by-case basis (e.g., treatment of known symptomatic 
bony metastases). Prior to pursuing radiotherapy, the treating physician should 
review with the study chair: 1) the reason for radiotherapy, 2) the tumor status 
(whether progressive disease criteria has been met) and 3) whether resumption of 
protocol therapy will be considered after completion of radiotherapy. 
Administration of protocol treatment must be suspended during radiotherapy 
treatment.  
 
It is strongly recommended that:  
• 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-α, IFN-γ, 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-TNFα 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. 
 
 
 
 
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5.2.3 Excluded Therapies for Participants Receiving Cobimetinib (Study Arm B Only) 
 
Concomitant use of strong and moderate inhibitors of CYP3A (e.g., clarithromycin, 
grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and 
voriconazole) should be avoided as cobimetinib is a sensitive substrate of CYP3A and 
exposures will be increased in presence of these agents (approximately 7-fold increase in 
presence of itraconazole in healthy subjects).  
 
Avoid strong and moderate CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine, 
phenobarbital, and St. John’s wort) as they increase the metabolism of cobimetinib. 
Strong inducers of CYP3A4 should be avoided, or selection of an alternate concomitant 
medicinal product, with no or minimal potential to induce CYP3A4 should be considered. 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• 
Disease progression not meeting criteria dosing of study treatment beyond disease 
progression (see 5.3.1). 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s), as defined in section 6.1.1, or at the discretion of the 
treating physician,  
 
• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.3.1 Dosing of Study Treatment Beyond Disease Progression  
 
Study treatment beyond disease progression on an imaging scan is allowed for patients on both 
treatment arms. However, participants who meet criteria for continued treatment must 
discontinue treatment upon documentation of disease progression on the second scan (relative to 
the scan that initially showed progression). Patients must also meet all of the following criteria to 
receive study treatment beyond disease progression:  
 
• 
Evidence of clinical benefit as assessed by the investigator. 
 
• 
Absence of symptoms and signs indicating unequivocal progression of disease.  
 
• 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that are life threatening and cannot be managed by protocol−allowed medical 
interventions. 
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• 
No evidence of clinical deterioration and no evidence of progressive disease at critical 
anatomical sites (e.g., cord compression) requiring urgent alternative medical 
intervention. 
 
• 
Patients treated beyond progression should receive their next follow-up scan 6-8 
weeks following the initial assessment of radiological progression. 
 
5.4 
Duration of Follow Up 
 
All subjects should continue to be monitored for disease status at least every three months until 
death, withdrawal of consent, or study closure, whichever occurs first. Patients removed from 
study for unacceptable adverse event(s) will be followed until resolution or stabilization of the 
adverse event. 
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from study at the time of death, withdrawal of consent, or study 
closure, whichever comes first. 
 
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6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Atezolizumab 
 
6.1.1 General AE Management and Dose Modification Guidelines 
 
There will be no dose reduction for atezolizumab in this study.  
 
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 is held because of AEs for > 84 days beyond 
the scheduled date of infusion, the patient will be discontinued from atezolizumab 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 may be held for longer than 84 days (up to 4 weeks or for a total of 112 
days) 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 for up to 84 days. The appropriate length of interruption will be at the discretion 
of the study PI in consultation with CTEP. Patients receiving surgery or other procedures 
for unequivocal progression of disease (for example, malignant bowel obstruction) must 
be permanently removed from study treatment. 
 
Atezolizumab must be permanently discontinued if the patient experiences any of the 
following events, regardless of benefit: 
 
• Grade 4 pneumonitis 
• AST or ALT > 5×ULN or total bilirubin > 3×ULN  
• Grade 4 diarrhea or colitis 
• Grade 4 hypophysitis 
• Any grade myasthenic syndrome/myasthenia gravis, Guillain-Barré or 
meningoencephalitis 
• Grade 4 ocular inflammatory toxicity 
• Grade 4 pancreatitis or any grade of recurrent pancreatitis 
• Grade 4 rash 
• Any grade myocarditis  
 
Treatment may, under limited and compelling circumstances, be resumed in patients who 
have recovered from the following events, but only after consultation with the Study 
Principal Investigator: 
• Grade 3 pneumonitis 
• Grade 3 ocular inflammatory toxicity 
• Grade 3 or 4 infusion-related reactions 
 
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Any toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice. Additional tests, such as autoimmune 
serology or biopsies, may be used to determine a possible immunogenic etiology. 
Although most immune-related adverse events (irAEs) observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications (Di Giacomo et al., 2010). 
Discontinuation of atezolizumab may not have an immediate therapeutic effect, and there 
is no available antidote for atezolizumab. In severe cases, immune-related toxicities may 
be acutely managed with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents. The investigator should consider the benefit-risk balance 
prior to further administration of atezolizumab.  
 
For detailed information regarding management of adverse events associated with 
atezolizumab, please refer to the most current version of the Atezolizumab Investigator’s 
Brochure and the FDA product label. 
 
The primary approach to grade 1 to 2 irAEs is supportive and symptomatic care with 
continued treatment with atezolizumab; for higher-grade irAEs, atezolizumab should be 
withheld and oral and/or parenteral steroids administered. Recurrent grade 2 irAEs may 
also mandate withholding atezolizumab or the use of steroids. Assessment of the 
benefit-risk balance should be made by the investigator, with consideration of the totality 
of information as it pertains to the nature of the toxicity and the degree of clinical benefit 
a given patient may be experiencing prior to further administration of atezolizumab. 
Atezolizumab should be permanently discontinued in patients with life-threatening irAEs. 
 
Patients should be assessed clinically (including review of laboratory values) for toxicity 
prior to, during, and after each infusion. If unmanageable toxicity due to atezolizumab 
occurs at any time during the study, treatment with atezolizumab should be discontinued. 
 
Systemic Immune Activation 
 
Systemic immune activation is a rare condition characterized by an excessive immune 
response. Given the mechanism of action of atezolizumab, systemic immune activation is 
considered a potential risk when given in combination with other immunomodulating 
agents. 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 the initial evaluation should include the 
following: 
• CBC with peripheral smear 
• PT, PTT, fibrinogen, and D-dimer 
• Ferritin 
• Triglycerides 
• AST, ALT, and total bilirubin 
• LDH 
• Complete neurologic and abdominal examination (assess for 
hepatosplenomegaly) 
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If systemic immune activation is still suspected after the initial evaluation, contact the 
Principal Investigator for additional recommendations. 
 
6.1.2 Management of Specific AEs 
 
Management of certain AEs of concern, including immune-related pneumonitis, hepatitis, 
colitis, endocrinopathies, pancreatitis, neuropathies, meningoencephalitis, and potential 
ocular toxicities are presented in the Atezolizumab Investigator’s Brochure. See Section 
6.1.1 for guidelines for the management of Infusion Related Reactions and Anaphylaxis. 
 
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. 
 
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 obtained to determine whether thyroid abnormalities are present. TSH, 
prolactin, and a morning cortisol level will help to differentiate primary adrenal 
insufficiency from primary pituitary insufficiency. 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. 
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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. 
 
 
The table below presents management and dose modification guidelines for specific AEs. 
For recommendations to hold atezolizumab and begin corticosteroid treatment, use the 
following guidance for tapering the corticosteroid and resuming atezolizumab therapy 
after resolution of the event: 
 
• Corticosteroids must be tapered to ≤10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
• Atezolizumab may be held for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to ≤10 mg/day oral prednisone or equivalent. 
 
AE Management and Dose Interruption Guidelines for Specific Toxicities in Treatment  
Toxicity 
Severity/ Duration 
Management 
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 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). 
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AE Management and Dose Interruption Guidelines for Specific Toxicities in Treatment  
Toxicity 
Severity/ Duration 
Management 
Adrenal 
insufficiency 
Grade 2+ 
(symptomatic) 
Hold atezolizumab. 
 
Refer patient to endocrinologist. 
 
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. 
 
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 according to the guidelines above. 
 
Permanently discontinue atezolizumab 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. 
 
Monitor amylase and lipase prior to dosing. 
Grade 2  
Continue atezolizumab. 
 
Monitor amylase and lipase weekly. 
 
For prolonged elevation (e.g., >3 weeks), 
consider treatment with 10 mg/day oral 
prednisone or equivalent. 
Grade 3  
Hold atezolizumab. 
 
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 according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
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AE Management and Dose Interruption Guidelines for Specific Toxicities in Treatment  
Toxicity 
Severity/ Duration 
Management 
does not resolve to grade 1 or better within 12 
weeks. 
 
For recurrent events, permanently discontinue 
atezolizumab. 
Dermatologic 
toxicity/rash 
(e.g., 
maculopapular or 
purpura) 
Grade 1  
Continue atezolizumab. 
 
Initiate symptomatic therapy with antihistamine 
PRN.  
 
Consider topical steroids and/or other 
symptomatic therapy (e.g., antihistamines).  
 
Grade 2  
Continue atezolizumab.  
 
Consider consultation with a dermatologist.  
 
Administer topical steroids.  
 
Consider higher potency topical steroids if rash 
does not improve.  
 
Grade 3  
Hold atezolizumab.  
 
Consult dermatologist.  
 
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. 
 
Restart atezolizumab at fixed dose and 
cobimetinib at 1 dose reduction if rash resolves to 
≤ tolerable grade 2, and systemic dose is < 10 mg 
oral prednisone equivalent per day.  
 
Grade 4 
Permanently discontinue treatment. 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. 
Diarrhea or 
Any grade 
Patients should be advised to inform the 
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AE Management and Dose Interruption Guidelines for Specific Toxicities in Treatment  
Toxicity 
Severity/ Duration 
Management 
colitis 
investigator if any diarrhea occurs, even if it is 
mild. 
 
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. 
Grade 1 
Continue atezolizumab. 
 
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.  
 
Endoscopy is recommended if symptoms persist 
for >7 days. 
 
Monitor closely. 
Grade 2 
Hold atezolizumab. 
 
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.  
 
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AE Management and Dose Interruption Guidelines for Specific Toxicities in Treatment  
Toxicity 
Severity/ Duration 
Management 
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 is recommended. 
 
For recurrent events or events that persist >5 
days, initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent.  
 
If event resolves to grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to grade 1 or better within 12 
weeks.  
 
Resumption of atezolizumab may be considered, 
after consultation with the trial PI, in patients 
who are deriving benefit and have fully recovered 
from the immune-related event. 
Grade 3 
Hold atezolizumab. 
 
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. 
 
If event resolves to grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to Grade 1 or better within 12 
weeks.  
 
Resumption of atezolizumab may be considered, 
after consultation with the trial PI, in patients 
who are deriving benefit and have fully recovered 
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AE Management and Dose Interruption Guidelines for Specific Toxicities in Treatment  
Toxicity 
Severity/ Duration 
Management 
from the immune-related event. 
Grade 4  
Permanently discontinue atezolizumab. Patient 
may not resume treatment, regardless of benefit. 
 
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. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent.  
 
If event resolves to grade 1 or better, taper 
corticosteroids over ≥1 month.  
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. 
 
Symptoms of abdominal pain associated with 
elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the 
administration of atezolizumab. The differential 
diagnosis of acute abdominal pain should also 
include pancreatitis, as described below. 
Grade 1 hepatic event 
Continue atezolizumab. 
 
Monitor LFTs until values resolve to within 
normal limits. 
Grade 2 hepatic event, 
≤5 days 
Continue atezolizumab. 
 
Monitor LFTs more frequently until values 
resolve to baseline values. 
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AE Management and Dose Interruption Guidelines for Specific Toxicities in Treatment  
Toxicity 
Severity/ Duration 
Management 
Grade 2 hepatic event, 
>5 days 
Hold atezolizumab. 
 
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 if event 
does not resolve to Grade 1 or better within 12 
weeks. 
Grade 3 or 4 hepatic 
event 
Permanently discontinue atezolizumab. 
 
Consider patient referral to GI specialist for 
evaluation and liver biopsy to establish etiology 
of hepatic injury.  
 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 
If event resolves to grade 1 or better, taper 
corticosteroids over ≥1 month. 
Hyperglycemia 
Grade 1 or 2 
Continue atezolizumab. 
 
Initiate treatment with insulin if needed. 
 
Monitor for glucose control. 
Grade 3 or 4 
Hold atezolizumab. 
 
Initiate treatment with insulin. 
 
Monitor for glucose control. 
 
Resume atezolizumab when symptoms resolve 
and glucose levels are stable. 
Hyperthyroidism 
Grade 1 
(asymptomatic) 
TSH ≥ 0.1 mU/L and < 0.5 mU/L: 
Continue atezolizumab. Monitor TSH every 4 
weeks. 
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AE Management and Dose Interruption Guidelines for Specific Toxicities in Treatment  
Toxicity 
Severity/ Duration 
Management 
 
TSH < 0.1 mU/L: 
Follow guidelines for symptomatic 
hyperthyroidism. 
Grade 2+ 
(symptomatic) 
Hold atezolizumab. 
 
Initiate treatment with anti-thyroid drug such as 
methimazole or carbimazole as needed. 
 
Consider patient referral to endocrinologist. 
 
Resume atezolizumab when symptoms are 
controlled and thyroid function is improving. 
 
Permanently discontinue atezolizumab for 
life-threatening immune-related hyperthyroidism. 
Hypothyroidism 
Grade 1 
(asymptomatic) 
Continue atezolizumab.  
 
Start thyroid-replacement hormone.  
 
Monitor TSH weekly. 
Grades 2+ 
(symptomatic) 
Hold atezolizumab.  
 
Start thyroid-replacement hormone. Consider 
referral to an endocrinologist.  
 
Monitor TSH weekly. 
 
Restart atezolizumab when symptoms are 
controlled and thyroid function is improving.  
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AE Management and Dose Interruption Guidelines for Specific Toxicities in Treatment  
Toxicity 
Severity/ Duration 
Management 
Meningo-
encephalitis, 
immune-related 
 
(signs and 
symptoms in 
absence of an 
identified 
alternate 
etiology) 
 
All grades 
Permanently discontinue atezolizumab. Patient 
may not resume treatment, regardless of benefit. 
 
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 does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 
If event resolves to grade 1 or better, taper 
corticosteroids over ≥1 month. 
 
Myasthenia 
gravis and 
Guillain-Barré 
syndrome 
All grades 
Permanently discontinue atezolizumab. Patient 
may not resume treatment, regardless of benefit. 
 
Refer patient to neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
Consider initiation of 1−2 mg/kg/day oral or IV 
prednisone or equivalent. 
Myocarditis 
All grades  
Permanently discontinue atezolizumab. Patient 
may not resume treatment, regardless of benefit. 
Myositis 
All grades 
Permanently discontinue atezolizumab. Patient 
may not resume treatment, regardless of benefit. 
Neuropathy, 
immune-related 
 
(sensory and/or 
motor) 
Grade 1 
Continue atezolizumab. 
 
Evaluate for alternative etiologies. 
Grade 2 
Hold atezolizumab. 
 
Evaluate for alternative etiologies. 
 
Initiate treatment as per institutional guidelines. 
 
Resume atezolizumab if event resolves to grade 1 
or better within 12 weeks. 
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AE Management and Dose Interruption Guidelines for Specific Toxicities in Treatment  
Toxicity 
Severity/ Duration 
Management 
 
Permanently discontinue atezolizumab if event 
does not resolve to grade 1 or better within 12 
weeks. 
Grade 3 or 4 
Permanently discontinue atezolizumab. 
 
Initiate treatment as per institutional guidelines. 
Ocular event 
(e.g., uveitis, 
retinal events) 
Grade 1 
Continue atezolizumab. 
 
Patient referral to ophthalmologist is strongly 
recommended. 
 
Initiate treatment with topical corticosteroid eye 
drops and topical immunosuppressive therapy. 
 
If symptoms persist for more than 1 week, treat 
as a grade 2 event. 
Grade 2 
Hold atezolizumab. 
 
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 according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to grade 1 or better within 
12 weeks. 
Grade 3 or 4 
Permanently discontinue atezolizumab.  
 
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 ≥1 month. For grade 3 AEs, 
patient may only resume treatment after 
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AE Management and Dose Interruption Guidelines for Specific Toxicities in Treatment  
Toxicity 
Severity/ Duration 
Management 
consultation with the trial PI; for grade 4, patient 
cannot resume treatment, regardless of benefit. 
Pancreatitis, 
immune-related 
Grade 2 or 3 
Hold atezolizumab if radiologic findings or 
physical exam findings are suggestive of 
immune-related pancreatitis.  
 
Note: If amylase/lipase ≥ 2X ULN, refer to GI 
specialist and consider scan to evaluate for 
immune-mediated pancreatitis. 
 
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. 
 
If event resolves to grade 1 or better within 12 
weeks, taper corticosteroids and resume 
atezolizumab according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to grade 1 or better within 
12 weeks. Patient may only resume treatment 
after consultation with the trial PI. 
 
For recurrent events, permanently discontinue 
atezolizumab. Patient may not resume treatment, 
regardless of benefit. 
Grade 4 
Permanently discontinue atezolizumab. Patient 
may not resume treatment, regardless of benefit. 
 
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. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 
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AE Management and Dose Interruption Guidelines for Specific Toxicities in Treatment  
Toxicity 
Severity/ Duration 
Management 
If event resolves to grade 1 or better, taper 
corticosteroids over ≥1 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. 
Grade 1 
Continue atezolizumab and monitor closely.  
 
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.  
 
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 according to the guidelines above. 
 
Permanently discontinue atezolizumab if event 
does not resolve to grade 1 or better within 
12 weeks. 
 
For recurrent events, treat as a Grade 3 or 4 
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AE Management and Dose Interruption Guidelines for Specific Toxicities in Treatment  
Toxicity 
Severity/ Duration 
Management 
event. 
Grade 3 or 4 
Hold atezolizumab. 
 
Bronchoscopy or BAL is recommended. 
 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 
If event resolves to grade 1 or better, taper 
corticosteroids over ≥1 month.  
 
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. 
 
6.2 
Cobimetinib 
 
Cobimetinib may be dose reduced in this study for drug-related toxicity. Management of 
certain AEs of particular concern for patients on cobimetinib plus atezolizumab are 
presented in 6.3. For other AEs, refer to general recommended dose modifications for 
cobimetinib (presented below, 6.2.1) and atezolizumab (6.1.1). Patients may temporarily 
suspend cobimetinib treatment for up to 84 days (12 weeks) if study drug-related toxicity 
requiring dose suspension is experienced. If cobimetinib is held because of AEs for >84 
days, the patient will be discontinued from cobimetinib therapy.  
 
Patients experiencing adverse events attributable to cobimetinib therapy may continue 
atezolizumab therapy while cobimetinib is held. Patients discontinued from cobimetinib 
therapy may continue atezolizumab therapy, and will be followed for safety and efficacy 
as specified in this protocol.  
 
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. 
 
6.2.1 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 are 
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included in section 6.3. 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 3 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.  
 
 
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 
 
6.3 
Management of Cobimetinib plus Atezolizumab−Associated Adverse Events of 
particular concern 
 
In general, patients discontinued from combination therapy due to intolerance or adverse events 
that are attributable to only one of the two drug therapies may continue monotherapy with the 
therapy that is not causing the adverse event. For example, a patient removed from cobimetinib 
therapy after developing retinal vein occlusion may continue atezolizumab monotherapy. Below, 
recommended management of specific adverse events of particular concern with combination 
therapy are provided. 
 
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.  
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Diarrhea or colitis 
Management 
Any grade 
Patients should be advised to inform the investigator if any 
diarrhea occurs, even if it is mild. 
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. 
Grade 1 
Continue atezolizumab and cobimetinib. 
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 
Endoscopy is recommended if symptoms persist for 
>7 days. 
Monitor closely. 
Grade 2 
Hold atezolizumab and cobimetinib. 
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.  
If Grade ≤ 2 diarrhea persists after 48 hr total treatment 
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with Lomotil and loperamide, consider second-line agents 
(e.g., octreotide, budesonide, tincture of opium).  
Patient referral to GI specialist is recommended. 
For recurrent events or events that persist >5 days, initiate 
treatment with 1−2 mg/kg/day oral prednisone or 
equivalent.  
If event resolves to grade 1 or better within 12 weeks, 
taper corticosteroids and resume atezolizumab and 
cobimetinib according to the guidelines above. 
Permanently discontinue atezolizumab if event does not 
resolve to grade 1 or better within 12 weeks.  
Resumption of atezolizumab may be considered, after 
consultation with the trial PI, in patients who are deriving 
benefit and have fully recovered from the immune-related 
event. 
Grade 3 
Hold atezolizumab and cobimetinib. 
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. 
If event resolves to grade 1 or better within 12 weeks, 
taper corticosteroids and restart atezolizumab at fixed 
dose and cobimetinib at 1 dose reduction once at baseline 
stool frequency.  
Permanently discontinue atezolizumab and cobimetinib if 
event does not resolve to Grade 1 or better within 12 
weeks.  
Resumption of atezolizumab and cobimetinib may be 
considered, after consultation with the trial PI, in patients 
who are deriving benefit and have fully recovered from 
the immune-related event. 
Grade 4  
Permanently discontinue atezolizumab and cobimetinib. 
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Patient may not resume treatment, regardless of benefit. 
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. 
Consider TNF antagonists for refractory diarrhea.  
GI = gastrointestinal; IV = intravenous; LLN = lower limit of normal; NSAID = nonsteroidal 
anti-inflammatory drug; TNF = tumor necrosis factor.  
  
 
Amylase and/or lipase 
increased 
Management 
Grade 1 
Continue atezolizumab and cobimetinib. 
 
Monitor amylase and lipase prior to dosing. 
Grade 2 
Continue atezolizumab and cobimetinib. 
 
Monitor amylase and lipase weekly. 
 
For prolonged elevation (e.g., >3 weeks), consider 
treatment with 10 mg/day oral prednisone or equivalent. 
Grade 3 or 4 
Hold atezolizumab and cobimetinib. 
 
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 according 
to the guidelines above. 
 
Permanently discontinue atezolizumab if event does not 
resolve to grade 1 or better within 12 weeks.  
 
For recurrent events, permanently discontinue 
atezolizumab. 
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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. 
 
 
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. 
 
Symptoms of abdominal pain associated with elevations of 
amylase and lipase, suggestive of pancreatitis, have been 
associated with the administration of atezolizumab. The 
differential diagnosis of acute abdominal pain should also 
include pancreatitis, as described below. 
Grade 1 hepatic event 
Continue atezolizumab and cobimetinib. 
 
Monitor LFTs until values resolve to within normal limits. 
Grade 2 hepatic event, ≤5 
days 
Continue atezolizumab and cobimetinib. 
 
Monitor LFTs more frequently until values resolve to baseline 
values. 
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Grade 2 hepatic event, >5 
days 
Hold atezolizumab and cobimetinib. 
 
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 and cobimetinib at 1 
dose reduction. 
 
Permanently discontinue atezolizumab if event does not 
resolve to Grade 1 or better within 12 weeks. Resumption of 
cobimetinib may be considered after discussion with the 
sponsor provided there is evidence of clinical benefit and 
continued therapy is of interest. 
 
Grade 3 or 4 hepatic event 
Permanently discontinue atezolizumab and hold cobimetinib. 
 
Consider patient referral to GI specialist for evaluation and 
liver biopsy to establish etiology of hepatic injury.  
 
Initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent. 
 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 
If event resolves to grade 1 or better, taper corticosteroids over 
≥1 month.  
 
Resumption of cobimetinib may be considered after discussion 
with the sponsor provided there is evidence of clinical benefit 
and continued therapy is of interest. 
 
IV = intravenous; LFT = liver function test; q4w = every 4 weeks; TNF = tumor necrosis factor; 
ULN = upper limit of normal.  
  
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. 
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A dermatologist should 
evaluate persistent and/or 
severe rash or pruritus. A 
biopsy should be considered 
unless contraindicated. 
Dermatologic Toxicity/Rash 
(e.g., maculo-papular or 
purpura)  
Management  
Grade 1  
Continue atezolizumab and cobimetinib 
 
Initiate symptomatic therapy with antihistamine PRN.  
 
Consider topical steroids and/or other symptomatic 
therapy (e.g., antihistamines).  
 
For acneiform rash, consider topical corticosteroids  
(hydrocortisone 2.5%, alclometasone) and oral antibiotics 
(minocycline, doxycycline, or antibiotics covering skin 
flora) BID for at least 4 weeks.  
 
Grade 2  
Continue atezolizumab and cobimetinib.  
 
Consider consultation with a dermatologist.  
 
Administer topical steroids.  
 
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. 
  
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Grade 3  
Hold atezolizumab and cobimetinib.  
 
Consult dermatologist.  
 
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. 
 
Restart atezolizumab at fixed dose and cobimetinib at 1 
dose reduction if rash resolves to ≤ tolerable grade 2, and 
systemic dose is < 10 mg oral prednisone equivalent per 
day.  
 
For acneiform rash, consider continuation of topical 
corticosteroids 2.5%, alclometasone) and oral antibiotics 
(minocycline, doxycycline or antibiotics covering skin 
flora) when restarting cobimetinib.  
 
Grade 4 
Permanently discontinue atezolizumab and 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. 
BID = twice daily; BSA = body surface area; PRN = as needed.  
  
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:  
• Measurement of oxygen saturation (i.e., arterial blood gas)  
• High-resolution computed tomography (CT) scan of the chest  
• Bronchoscopy with bronchoalveolar lavage and biopsy (if clinically feasible)  
• Pulmonary function tests (diffusion capacity of the lung for carbon monoxide)  
• 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. 
 
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. 
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Grade 1 
Continue atezolizumab and cobimetinib and monitor closely.  
 
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 and cobimetinib.  
 
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 at fixed dose and 
cobimetinib at 1 dose reduction if GGO/infiltrates improving.  
 
Permanently discontinue atezolizumab and cobimetinib if 
event does not resolve to grade 1 or better within 12 weeks. 
 
For recurrent events, treat as a Grade 3 or 4 event. 
Grade 3 or 4 
Hold atezolizumab and cobimetinib. 
 
Bronchoscopy or BAL is recommended. 
 
Initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent. 
 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 
If event resolves to grade 1 or better, taper corticosteroids over 
≥1 month.  
 
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. 
 
  
 
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POTENTIAL EYE TOXICITY  
An ophthalmologist should evaluate visual complaints.  
 
Uveitis or episcleritis and other immune−mediated ocular disease may be associated with 
atezolizumab and may be treated with topical corticosteroid eye drops. Atezolizumab should be 
permanently discontinued for immune-mediated ocular disease that is unresponsive to local 
immunosuppressive therapy.  
 
Serous retinopathy have been associated with cobimetinib.  
 
Eye Toxicities  
Management  
Symptomatic eye toxicity 
(autoimmune uveitis, iritis 
or episcleritis)  
Hold atezolizumab and cobimetinib.  
 
Consult ophthalmologist and start topical corticosteroid eye 
drops.  
 
Consider starting prednisone 60 mg/day or equivalent. 
  
Taper steroids over ≥ 1 month once symptoms improve to 
Grade 0/1 (asymptomatic).  
 
Atezolizumab may be restarted following resolution of the 
events with careful monitoring for recurrence.  
 
Permanently discontinue atezolizumab for immune−mediated 
ocular disease that is unresponsive to immunosuppressive 
therapy.  
 
Retinal vein occlusion  
 Any grade  
If RVO (any grade) is diagnosed, cobimetinib dosing should be 
permanently discontinued and RVO treated per institutional 
guidelines. Atezolizumab therapy may be continued.  
  
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 and cobimetinib without dose change.  
 
Continue ophthalmology follow-up as clinically indicated.  
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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 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 and 
cobimetinib dosing should be held until  
symptoms improve to Grade 1. Restart atezolizumab at fixed 
dose 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, cobimetinib should be permanently discontinued.  
  
Grade 4: Sight-threatening 
consequences; urgent 
intervention indicated; 
blindness (20/200 or worse) 
in the affected eye  
Permanently discontinue atezolizumab and cobimetinib.  
ADL = activities of daily living; NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events version 5.0; RVO = retinal vein occlusion; OCT = optical coherence 
tomography.  
  
GUIDELINES FOR MANAGEMENT OF PATIENTS WHO EXPERIENCE 
DECREASED LEFT VENTRICULAR EJECTION FRACTION  
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.  
 
Asymptomatic, absolute 
decrease in LVEF from 
baseline of greater than 
10% and less than 
institutional lower limit of 
normal (LLN) 
Withhold cobimetinib for 2 weeks; repeat LVEF 
 
Resume at next lower dose if all of the following are present 
• LVEF is at or above LLN, and 
• Absolute decrease from baseline LVEF is more than 10% 
 
Permanently discontinue is any of the following are present 
• LVEF is less than LLN, or 
• Absolute decrease from baseline LVEF is more than 10% 
Symptomatic LVEF 
decrease from baseline 
Withhold cobimetinib for up to 4 weeks; repeat LVEF 
 
Resume at next lower dose if all of the following are present 
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• Symptoms resolved, and 
• LVEF is at or above LLN, and 
• Absolute decrease from baseline LVEF is 10% or less 
 
Permanently discontinue if any of the following are present 
• Symptoms persist, or 
• LVEF is less than LLN, or 
• Absolute decrease from baseline LVEF is more than 10% 
 
LVEF = left ventricular ejection fraction; LLN = lower limit of normal  
 
Decreased LVEF may also result from immune related cardiomyopathy, a potential risk of 
atezolizumab therapy. For this reason, atezolizumab 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 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 may be restarted only if the patient is clinically stable, and after consultation with 
the trial PI. 
 
GUIDELINES FOR MANAGEMENT OF PATIENTS WHO EXPERIENCE ELEVATED 
CPK  
Elevated CPK has been reported with cobimetinib. Recommended Dose Modifications for 
Cobimetinib in Patients with CPK Elevations are presented below. 
Description  
Management  
CPK elevations  
  
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).  
 
Consider permanent discontinuation of atezolizumab 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.  
 
For Grade 3 CPK elevations 
that are asymptomatic and 
deemed not clinically 
significant  
Hold atezolizumab 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 and cobimetinib may be restarted at previous 
dose and schedule only if cardiac etiology is ruled out.  
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Recheck CPK at least once a week. If CPK remains Grade 3 or 
decreases, continue cobimetinib at current dose and schedule.  
For Grade 4 CPK elevations 
that are asymptomatic and 
deemed not clinically 
significant  
Hold atezolizumab and cobimetinib. 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. 
 
Recheck CPK within 3 days. When CPK is Grade ≤ 3 and 
cardiac immune-related cardiomyopathy has been ruled out, 
atezolizumab 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 elevation recurs after 1 dose reduction, 
cobimetinib may be reduced by another dose level (e.g., 40 to 
20 mg).  
 
Permanently discontinue cobimetinib if Grade 4 CPK 
elevation recurs after 2 dose reductions of cobimetinib. 
Atezolizumab may be continued after consultation with the 
trial PI. 
IM = intramuscular.  
 
 
 
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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:  
 
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. 
7.2 
Adverse Event Characteristics  
 
• 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 
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to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
 
• 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 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site: https://eapps-
ctep.nci.nih.gov/ctepaers. The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm.  
These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when 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 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 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.  
 
7.3.3 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 
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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: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
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 
 
7.3.4 Adverse Events of Special Interest 
 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event). Adverse 
events of special interest for this study include the following: 
 
• Pneumonitis [atezolizumab] 
• Colitis [atezolizumab] 
• Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism 
or hypophysitis [atezolizumab] 
• Systemic lupus erythematosus [atezolizumab] 
• Neurologic: Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, 
meningoencephalitis [atezolizumab] 
• Nephritis [atezolizumab] 
• Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, influenza-like illness, systemic inflammatory response syndrome, and 
systemic immune activation [atezolizumab] 
• Ocular events 
• 
Retinal vein occlusion [cobimetinib] 
o Serous retinopathy, including events of retinal detachment, retinal pigment 
epithelium detachment, neurosensory retinal detachment, and central serous 
chorioretinopathy [cobimetinib] 
• 
Ocular inflammatory toxicities (e.g., uveitis, retinitis) [atezolizumab] 
• Significant muscular toxicities 
• 
Rhabdomyolysis or Grade ≥ 3 CPK elevation [cobimetinib] 
• 
Myopathies including myositis [atezolizumab] 
• 
Grade ≥ 3 hemorrhage or any grade cerebral hemorrhage [cobimetinib] 
• 
Grade ≥ 3 rash [cobimetinib and atezolizumab] 
• Grade ≥ 2 cardiac events including: 
• 
Symptomatic heart failure or Grade ≥ 3 left ventricular ejection fraction reduction 
[cobimetinib] 
• 
Myocarditis, pericarditis, or atrial fibrillation [atezolizumab] 
• Vasculitis [atezolizumab] 
• Significant liver toxicity [concern for cobimetinib and atezolizumab] 
• 
Hepatitis, including AST and/or ALT > 10 ×ULN 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
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in combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law: 
 Treatment emergent ALT or AST > 3× ULN in combination with either an 
elevated total bilirubin (> 2× ULN) or clinical jaundice, without initial 
findings of cholestasis (elevated serum alkaline phosphatase) 
 No other reason can be found to explain the combination of increased 
ALT/AST and total bilirubin, such as: liver metastasis; viral hepatitis A, 
B, or C; alcoholic and autoimmune hepatitis; other liver diseases; or 
exposure to other drugs known to cause liver injury 
• Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent. A transmission of an infectious agent may be suspected from clinical symptoms or 
laboratory findings that indicate an infection in a patient exposed to a medicinal product. 
This term applies only when a contamination of the study drug is suspected. 
 
 
7.4 
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. 
 
7.5 
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:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• 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.  
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7.6 
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. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the agents administered in this 
study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 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 in 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 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 
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2°C-8°C for up to 24 hours or at ambient ≤25⁰C (77⁰F) 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-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 premedications 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. 
 
Availability: 
Atezolizumab is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Atezolizumab is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
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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 
and a “current” password.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
8.1.2 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. 
 
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. 
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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.  Females of 
reproductive potential should use adequate contraception during treatment and for a 
minimum of 2 weeks after the last dose of cobimetinib. 
 
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 
and a “current” password.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution. Pharmaceutical 
Management Branch (PMB) policy requires that agent be shipped directly to the 
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institution where the patient is to be treated. PMB does not permit the transfer of 
agents between institutions (unless prior approval from PMB is obtained). The 
CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents. The responsible investigator at each participating 
institution must be registered with CTEP, DCTD through an annual submission of 
FDA Form 1572 (Statement of Investigator), Biosketch/Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), 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 investigator at that institution. 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can 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 and a “current” password. 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.  
 
8.1.3.2 
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. 
 
8.1.3.3 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm  
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help: 
ctepreghelp@ctep.nci.nih.gov  
• PMB email: PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
• IB Coordinator:  IBCoordinator@mail.nih.gov  
 
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9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Hypotheses and background 
A series of correlative studies are proposed to examine the impact of MEK inhibition with 
cobimetinib on the tumor microenvironment and systemically. Our primary objective will be to 
compare infiltration of CD8+ T cells into the tumor microenvironment between patients 
receiving atezolizumab alone and those receiving atezolizumab in combination with cobimetinib. 
This metric will be considered an integrated biomarker for the clinical study. The rationale for 
this is based on pre-clinical studies demonstrating the MEK inhibition can enhance T cell 
infiltration into tumors in murine models, limit their apoptosis and subsequently enhance the 
efficacy of immune checkpoint blockade. We hypothesize that patients receiving the 
combination of atezolizumab and cobimetinib will have increased CD8+ T cell infiltration in 
tumors as compared to patients receiving atezolizumab alone. Further, we hypothesize that 
patients with increased CD8+ T cell infiltration will have a better clinical outcome regardless of 
treatment group.  
 
In addition to this integrated biomarker, we will assess a number of exploratory biomarkers in 
the context of correlative laboratory studies to better define the impact of these agents on the 
TME. These are based on the rationale that (1) patients with greater PD-L1 expression or antigen 
presenting capacity (as measured by MHC expression) will have a better response to 
immunotherapy; (2) MEK inhibitors may reverse exhaustive T cell death by reducing MEK-
mediated phosphorylation of Nur77; and (3) Peripheral blood levels of immune suppressive T 
regulatory or myeloid derived suppressor cells may impact the response to regimens containing 
atezolizumab. Based on these observations we propose a series of studies to address the 
hypothesis that these factors may serve as biomarkers to predict response to therapy in the 
context of this clinical trial. 
 
This clinical trial is a 2-arm randomized Phase II study that will incorporate a series of both 
intratumoral biomarkers that can be assessed from patient biopsy materials as well as those 
within the peripheral blood. The randomized nature of this trial has a number of inherent 
advantages whereby the contribution of MEK inhibitor on immune modulation can be accurately 
compared to a relevant control arm in which patients receive atezolizumab alone. 
 
9.2 
Preliminary data 
 
It has been demonstrated in other malignancies that the presence of CD8+ effector T cells within 
tumors increases the likelihood of responding to PD-1/PD-L1 antibody blockade. Pre-clinical 
studies demonstrate that the inclusion of a MEK inhibitor may enhance the access of these T 
cells to the tumors, while concurrently promoting their survival (Ebert et al. 2016). Together 
these data justify the choice of CD8+ T cells as an integrated biomarker that should be assessed 
in the context of this clinical study. This assay is conducted routinely on FFPE tissue in our 
clinical pathology laboratory, from which we have implemented the protocol with additional 
biologic and quality controls for the purpose of this study. 
 
We propose a series of correlative studies that will be used concurrently to identify other 
potential biomarkers that deserve further investigation in future studies. 
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Depending on the quantity of tissue obtained from each patient enrolled in this study, we 
estimate that a portion of FFPE or frozen blocks sufficient for another 8-10 slides cut at 3-4 µM 
will be remaining. In addition, it is likely that an additional cryopreserved vial of peripheral 
blood mononuclear cells (~3 x 106 total) and 3 – 5 mL of patient plasma will remain following 
our immune phenotyping studies. In previous studies with paired core biopsies we have obtained 
an average of 3-4 cores per patient. 
 
9.3 
Methods 
 
9.3.1 Archival Tumor Tissues  
 
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). 
 
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, 30 unstained sections, cut 
at 4 micrometers and mounted in poly-l-lysine-coated or plus (+) slides, and 30 sections 
containing at least 50% tumor cut at 10 micrometers and mounted on glass slides. If the tissue is 
small (< 1cm2), then 12 unstained sections cut at 4 micrometers of thickness are requested. These 
latter slides will be air dried (not oven-dried). The slides will be stored at room temperature 
(>16°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. 
 
 
The following guidelines should be used for preparation of slides:  
• Slides #1: to be regular 4 microns, positively charged slide, H&E, with cover 
• Slides #2 and above: 4 microns, positively charged slides, unstained, NO COVER 
• Blades need to be changed between blocks, if more than one block is being cut.  
• If possible, slides and process need to be DNAase free and tissue should be mounted on 
the bottom third of the slide.  
 
 
 
 
 
 
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9.3.2 Fresh Tumor Specimens 
 
9.3.2.1 
Collection of Specimens 
 
 
Supplies 
- 
10% Neutral Buffered Formalin (ambient/room temperature) (VWR #16004-115) 
- 
RNAlaterTM (refrigerated at 4ºC for ≥16 hours prior to biopsy procedure) 
- 
Cryovial tubes – 1.8 ml cryotubes/vials (e.g., Nunc Code #377267 or equivalent) 
- 
Conical tubes – 15 mL (e.g., Sarstedt Code #62.554.001 PP or equivalent) 
 
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). A maximum of 6 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. The biopsies will be used to prepare paraffin embedded and 
frozen samples. A total of 6 biopsies is preferred, when possible. The first pass will generally be 
used for on-site examination of the material, to determine presence and quality of lesional tissue. 
The remaining biopsy tissue will be paraffin embedded and frozen at each respective institution. 
If a limited amount of tumor tissue is obtained, paraffin embedded tissue should be prioritized 
over frozen tissue. Archived or freshly obtained paraffin embedded formalin fixed (FFPE) or 
frozen tissues of biopsied specimens are needed for the purposes of: 
• Pathological examination (for conventional pathology examination, such as H&E stain) 
• Examination of immune and inflammatory fibroblast biomarkers via IHC or IF analysis, 
as appropriate.  
• Future analysis of genomic and transcriptome features within the tumor 
microenvironment. 
 
Samples will be collected in this order:  
Core 1 – Formalin-fixed paraffin-embedded (FFPE)  
Core 2 – FFPE  
Core 3 – Snap Frozen 
Core 4 – FFPE  
Core 5 – FFPE  
Core 6 – Frozen in RNAlaterTM  
 
For example, if only 2 cores are obtained, both should be set aside and preserved for IHC 
analysis (FFPE). If 5 cores are obtained, four should be set aside and preserved for IHC 
analysis and one core should be snap frozen.  
 
9.3.2.2 
RNAlaterTM samples 
• The cryovial containing a single core biopsy in RNAlaterTM must be placed back in 
the refrigerator (4ºC) for ≥16-24 hours after the biopsy procedure. 
• After ≥16-72 hours at 4ºC, the RNAlaterTM samples/vials must be transferred to -
80oC or below for storage.  
• Frozen samples should never be thawed until RNA isolation. 
 
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9.3.2.3 
Shipping of Tumor Specimens 
 
• Tissue samples (archival and fresh tumor biopsies) should be shipped to JHU 
biannually. Tissues for correlative research studies will be shipped from each 
institution to Dr. Nilo Azad at Johns Hopkins University, for analysis of integrated 
(CD8+, PD-L1 staining) and exploratory biomarkers outlined below. Please call 
ahead or email (nazad2@jhmi.edu, 
, and 
) 
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. 
 
• Frozen tissue samples must be shipped frozen and maintained in the frozen state. All 
shipments should be made in freezer boxes containing DRY ICE, and labeled as 
HUMAN SAMPLES: NONINFECTIOUS. 
 
• Each tumor sample must be clearly labelled with the study number (10139), 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 (i.e. frozen RNA Later) 
 
The shipping address for Tissue Samples (NOT RESEARCH BLOODS) is as follows: 
 
 
Attn: NCI 10139 
1550 Orleans Street 
CRBI Room 
 
Baltimore, MD 21287 
 
3. Immunohistochemical analysis of tumor tissue 
 
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 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 +/- cobimetinib. 
For the integrated biomarker of CD8+ staining, IHC assays will be conducted in a Central 
Reference CLIA Laboratory using the Cell Marque, CD8 (C8/144B), mouse monoclonal antibody, 
Ref#108M-98, Status IVD. Further technical details for this biomarker are listed in appendix C. 
PD-L1 expression will be another integrated biomarker and will be conducted in a Reference CLIA 
Laboratory. 
 
In addition to these integrated biomarkers, 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 
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tissue obtained. In addition to this panel, we will explore the impact of cobimetinib on a subset of 
CD8+ T cells identified by Dr. 
 (CD8+Ki67+) that displays a 
proliferative burst after PD-1 blockade and may be a potential biomarker of response to anti-PD-
1 therapy (Kamphorst et al. 2017). This panel can also be expanded for other co-stimulatory or 
immune checkpoint molecules on cell subsets (i.e. CD8, Tim3, LAG3) (Tsujikawa et al. 2017). 
Briefly, we will utilize a validated quantitative multiplex immunohistochemical platform co-
developed at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and the Knight Cancer 
Institute at Oregon Health and Science University that has previously been used to characterize 
the tumor microenvironment. This technology incorporates a computational image processing 
workflow, including image cytometry, that enables simultaneous evaluation of 12 biomarkers in 
one formalin fixed paraffin-embedded tissue section. This platform is readily adaptable to assess 
a variety of markers including lymphoid and myeloid lineage markers, in addition to those listed 
below (Tsujikawa et al. 2017). 
 
 
Table I. Planned Immunohistochemical (IHC) and Immunofluorescence (IF) analysis 
(*denotes integrated biomarker) 
IHC Stains 
IF Stains 
 
CD8* 
PD-L1* 
CD4 
CD8+Ki67+ 
CD8+Nur77+ 
Priority 1 
CD11c 
CD19 
CD68 
CD163 
CTLA4 
PD1 
PD-L2 
IDO1 
LAG3 
pERK 
ERK 
CD4+FoxP3+ 
CD33+S100+ 
CD4+IL-17+ 
 
Priority 2 
 
4. Analysis of IHC/IF data 
After staining, slides will be analyzed in the Cell Imaging Core Facility at Johns Hopkins Sidney 
Kimmel Comprehensive Cancer Center to quantitate the percentage and intensity of cells for 
each marker(s) in the TME.  
 
For analysis of CD8+ cells as an integrated biomarker, the specific image measurement/ analysis 
strategy is described in the appendix.  
 
The exploratory biomarker data will be captured for samples according to a digital image 
workflow. Briefly, this encompasses three steps: image preprocessing, visualization, and 
quantitative image analysis using state-of-the-art software in the Core Lab. This system allows 
for true quantitative data on dual staining in patient samples. These IHC and IF analyses will be 
conducted under the guidance of Dr.
 To ensure the rigor of these analyses, 
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9.3.2.7 
Immune suppressor cell analyses 
 
The expansion of immune suppressive cytokines and particular cell populations represent 
important barriers that likely limit the full potential of immune-based therapies or endogenous host 
responses to tumors. We hypothesize that this state of elevated immune suppressor cells in cancer 
patients can be manipulated via MEK inhibition to provide an advantage for the maximal 
therapeutic effect of immune checkpoint blockade. For these experiments, multiparameter flow 
cytometry will be utilized to phenotype immune effector cells to determine whether cobimetinib 
containing regimens downregulate T regulatory cells (based on expression of CD4, CD25, CD127, 
CD49d and FoxP3), IL-10-producing B regulatory cells (based on expression of CD5, CD19, 
CD1d, CD24, CD25, CD27, CD38 and IL-10) and myeloid derived suppressor cells 
(CD33+HLADR-CD11b+ plus CD14+ or CD15+) as these populations can neutralize host anti-
tumor responses and could be modulated in response to cobimetinib. Namely, it is possible that 
cobimetinib could directly interact with these cells, or the ability of this agent to limit tumor 
growth, and indirectly reduce expansion of these cell populations. Briefly, these freshly procured 
cells will be aliquoted at 5 x 105 – 1 x 106 cells/flow tube in PBS containing 5% FBS (flow buffer). 
Cells will be incubated at 4°C with the following fluorochrome conjugated Ab for 45 minutes. 
Cells will then be washed twice with 2 mL flow buffer and pelleted via centrifugation at 805 x g 
for 10 minutes. Following decanting of flow buffer from the final wash, cells will be resuspended 
in 300 uL 1% formalin and stored in the dark at 4°C. Samples will be analyzed on a BD LSR II 
flow cytometer in the Emory University School of Medicine Flow Cytometry Core Facility. All 
data will be expressed as the percentage of total circulating peripheral blood cells with each 
respective phenotype. Appropriate fluorochrome labeled isotype control antibodies will be utilized 
for determination of background staining and for compensation. The phenotypes chosen represent 
the most well-accepted and published phenotypic definitions to date, and will be modified as 
concordance among the tumor immunology community becomes more apparent. 
 
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(visit window +/-7 days), then every 3 months (visit window +/-7 days), while on cobimetinib only (study arm B only). 
I: Ophthalmologic examination will be performed for all participants < 4 weeks prior to randomization (study arms A and B). Repeat 
ophthalmologic examination will be performed every 2 months for 1 year, then every 6 months while on cobimetinib (visit 
window +/- 14 days); (study arm B only). Eye exam should include retinal exam, slit lamp exam, and visual fields (preferably 
Humphrey Visual Field or Goldmann Visual Field, if available) for evidence of retinal pathology and other abnormalities. 
Patients with ocular symptoms occurring during study treatment should be examined by an opthamologist 
J: 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. Imaging will be repeated every 8 weeks (+/-4 days), irrespective of 
dosing schedule or treatment delays. For patients continuing treatment past progression, the subsequent scan should be 
performed 6-8 weeks following the initial scan demonstrating progression (see section 5.3.1.). If this repeat scan does not show 
further progression, imaging frequency can revert to every 8 weeks (+/-4 days). 
K: Only for subjects with tumor that in the opinion of the study treatment team is safely accessible for biopsy. 
L: Baseline research blood collection will be collected prior to dosing of any study therapy (visit window day -7 to 0, prior to 
dosing). Additional on-treatment research bloods will be collected on cycle 1 day 15 (day -4 to 0), on cycle 2 day 1 (day -4 to 0), 
and at the time of progression (+/-7 days). No research blood is needed for day 1 of any cycle beyond cycle 2. Research blood 
samples should be collected and shipped on Monday-Thursday only to avoid problems with weekend/holiday delivery. For 
additional details, see section 9 3 1. 
M: For patients randomized to cobimetinib plus atezolizumab (study arm B only). 
N: Off-study evaluations will be completed 4 weeks after meeting at least one of the criteria listed in section 5.3. 
O: Patients receiving cobimetinib (study arm B only). 
P: Adverse events will be assessed at least 90 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. 
Q: Scans do not need to be repeated if a scan has been performed within 8 weeks. 
 
 
 
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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks. 
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) (Eisenhauer et al., 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. 
 
This study will [also] evaluate response and progression using immune-related response criteria 
(irRC) (Wolchok et al., 2009). See Appendix D for a detailed description of the evaluation 
criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with cobimetinib or atezolizumab. 
 
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.  
 
11.1.2 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter 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 may not be 
considered measurable unless there is evidence of progression in the irradiated site. 
 
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 
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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. 
 
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.  
 
11.1.3 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. 
 
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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 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 
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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. 
 
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 
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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. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<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. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes 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 
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Investigator). 
 
11.1.4.3 
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. 
 
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 
 
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. 
** 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 
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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 
 
11.1.5 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. 
 
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, or until 
death. 
 
 
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.  
 
11.1.6 Progression-Free Survival (PFS) 
 
PFS is defined as the duration of time from date of randomization to time of progression 
or death, whichever occurs first.  
 
Note: For participants who receive treatment beyond disease progression (as described in 
5.3.1), 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. 
 
11.1.7 Overall Survival (OS) 
 
OS is defined as the duration of time from date of randomization to time of death.  
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12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section. The Study 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 Study Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.  
 
The Study Principal Investigator will have, at a minimum, quarterly conference calls with the site 
Investigators, study collaborators, and the CTEP Medical Officer(s) to review accrual, progress, 
and pharmacovigilance.  
 
All Site Principal Investigators 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. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave. Access to the trial 
in Rave is granted through the iMedidata application to all persons with the appropriate roles 
assigned in the Regulatory Support System (RSS). To access Rave via iMedidata, the site user 
must have an active CTEP IAM account (check at https://ctepcore.nci.nih.gov/iam and the 
appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site Investigator) on 
either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA 
role or CRA Lab Admin role, the user must hold a minimum of an AP registration type.  To hold 
the Rave Site Investigator role, the individual must be registered as an NPIVR or IVR.  
Associates can hold read-only roles in Rave.  
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Please note, site users 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 link in the 
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upper right pane of the iMedidata screen.  
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
In addition, the Protocol Principal Investigator will have at least monthly conference calls with 
the site Study Investigators and study teams to review accrual, progress, adverse events, and 
unanticipated problems.  
 
12.2.1 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) 799-7580 
or by email at CTMSSupport@theradex.com for additional support with Rave and 
completion of CRFs. 
 
12.2.2 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 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 
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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. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 
recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs).  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
). 
 
12.3 
CTEP Multicenter Guidelines 
 
• N/A 
 
12.4 
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 
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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. 
 
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 
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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. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
The proposed study is an open-label, randomized phase 2 multicenter trial evaluating 
cobimetinib in combination with atezolizumab compared with atezolizumab monotherapy in 
unresectable cholangiocarcinoma.  
 
The primary clinical endpoint is progression free survival and the primary objective of the trial is 
to determine whether the combination of cobimetinib in combination with atezolizumab yields a 
clinically compelling antitumor activity measured as progression free survival (PFS). Additional 
secondary endpoints include safety, objective response rate (ORR, assessed by RECIST 1.1), 
overall survival (OS), and other immunologic correlates. 
 
The principle correlative objective of the trial is to determine whether the combination of 
cobimetinib and atezolizumab increases immune response compared to atezolizumab 
monotherapy.  The change CD8+ density within tumor after 21 days of treatment, as compared 
to baseline, is an integrated biomarker for this clinical trial. 
 
The study is planned with 76 evaluable subjects (38 subjects per treatment arm), to achieve 90% 
power using a 1-sided test with alpha=0.05. Both of these drugs are in common use and will be 
given at full dose. The combination of cobimetinib and atezolizumab was previously tested, and 
well tolerated in a similar population of patients with metastatic colorectal cancer, so 
unacceptable rates of toxicity are not expected, but the present study will be continuously 
monitored for adverse events. The primary study team made up of the study PI Dr. Azad, 
 
 Dr. 
, and lead study nurse and coordinator at the lead site Johns 
Hopkins will meet weekly to discuss adverse events.  In addition, the primary study team will 
have bimonthly calls with representatives at all the enrolling sites to monitor toxicity 
continuously. 
 
Progression-free survival is defined as the duration of time from date of randomization to time of 
progression or death. The evaluable population includes all subjects who have completed at least 
one dose of therapy and have received at least one follow-up scan. Patients who come off of 
study treatment for clinical progression prior to the first follow-up scan (i.e. clinical progression) 
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will also be considered evaluable and will be coded as progressors for the analysis. 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 groups, under the assumption of Cox proportional hazards, 
using the stratified log-rank test to account for tumor site. An interim analysis will be conducted 
when half the required PFS events have been observed (35).  The trial will be stopped early for 
futility if the p-value from the log-rank statistic is greater than 0.5 (i.e., the PFS is worse for 
study arm B than for study arm A).  
 
The analysis will be stratified on site of disease (gallbladder cancer, intrahepatic 
cholangiocarcinoma, and extrahepatic cholangiocarcinoma). An interim analysis will be 
conducted when half the required PFS events have been seen (35), and the trial will be stopped 
early for futility if median PFS is lower by any amount, under the combination therapy than 
under monotherapy. 
 
13.2 
Sample Size/Accrual Rate 
 
Approximately 82 patients with unresectable cholangiocarcinoma will be enrolled in this 
randomized phase 2 trial with the goal of accruing at least 76 evaluable subjects, with 
progression free survival (PFS) as the primary endpoint. We plan to enroll approximately 6 
patients per month across the multiple trial sites, and because of the rapid progression of the 
disease, expect little or no censoring. We anticipate fully enrolling this trial within 18 months, 
permitting an average of 12 months of follow up, and completing the study within 3 years. This 
design yields 90% power at a one-sided type I error rate of 5% assuming a difference in median 
PFS between the arms of 2 months (2 months vs. 4 months), and assuming that 71 events will 
have occurred among 76 patients over the study period. Calculations were performed without 
stratification, as it is not known whether outcome varies by site. 
 
Patients with tumor that is safely accessible for biopsy will obtain a biopsy at study baseline and 
a repeat on-treatment biopsy at treatment day 21. Based on previous clinical experience, we 
anticipate that paired biopsy samples will be successfully obtained in at least 50% of 
participants. We anticipate obtaining approximately 20 subjects in each treatment arm with 
paired samples available for analysis, offering 80% power for detecting an increase in CD8+ 
density equal to 0.8s.d., using a one-sided t-test with alpha=0.05, and more than 90% power for 
detecting an effect size of 1.0s.d.  
 
13.3 
Stratification Factors 
 
After the screening phase, eligible subjects will be stratified according to the site of disease: 1) 
gallbladder cancer (GBC); 2) intrahepatic (IHC); and 3) extrahepatic cholangiocarcinoma 
(EHC). 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 
it is not known whether outcome varies by site. 
 
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13.4 
Analysis of Secondary Endpoints 
 
Overall survival is defined as the duration of time from date of randomization to time of death. 
Subjects lost to follow-up or whose vital status is unknown, will be right-censored at the date the 
subject was last known to be alive. Every effort will be made to determine outcome, including 
phone calls, certified mail, and the checking of public records as necessary. The evaluable 
population is as defined for the primary endpoint. Results will be summarized descriptively using 
Kaplan-Meier plots, and compared between groups, under the assumption of proportional 
hazards, using the stratified log-rank test to account for tumor site. 
 
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 s.d. 
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 cobimetinib plus atezolizumab) than in treatment arm A (ateozolizumab 
monotherapy).  
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
The safety analysis will be performed in all subjects who receive any amount of study 
drug. 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 
version 5.0 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. 
 
13.5.2 Evaluation of Response 
 
All subjects who have completed at least one dose of therapy will be included in the 
evaluation of response. Each patient will be assigned 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).  
 
The objective response rate is 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 is as defined for the primary 
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endpoint. Response rates will be reported for each group along with exact confidence 
intervals, and an exact binomial test will be used to compare response rates across 
treatment groups.  
 
Evaluation of Correlative Aims 
Correlative studies will be performed: 
• To measure the baseline expression and on treatment expression of PD-L1 and correlate 
these variables with treatment response. 
• To measure the baseline levels of immune markers including CD8+ T effector cells and 
CD4+FoxP3+ T regulatory cells, and tumor infiltrating lymphocytes (TILs), major 
histocompatibility complex (MHC) class I and II expression, and natural killer (NK) cell 
receptors and ligands expression and correlate these variables with treatment response 
and toxicity. 
• To characterize changes in the immune markers described above after treatment 
• To measure changes in circulating immune suppressor cells (MDSC, Treg) in peripheral 
blood by flow cytometry and test for association with response to therapy. 
 
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 cholangiocarcinoma, 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.  
 
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.  
 
 
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14. REFERENCES 
 
Bekaii-Saab T, Phelps MA, Li X, Saji M, Goff L, et al. 2011. Multi-institutional phase II study 
of selumetinib in patients with metastatic biliary cancers. J. Clin. Oncol. 29(17):2357–63 
Bendell J, Won KT, Ean CC, Yung-Jue B, Lee C, et al. 2016. Safety and efficacy of cobimetinib 
(cobi) and atezolizumab (atezo) in a Phase 1b study of metastatic colorectal cancer 
(mCRC). Ann. Oncol. 27(suppl 2):ii140-ii140 
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. 
Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, et al. 2012. Safety and activity of 
anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366(26):2455–65 
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. 
Ebert PJR, Cheung J, Yang Y, McNamara E, Hong R, et al. 2016. MAP Kinase Inhibition 
Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint 
Blockade. Immunity. 44(3):609–21 
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. 
Farren MR, Mace TA, Geyer S, Mikhail S, Wu C, et al. 2016. Systemic Immune Activity 
Predicts Overall Survival in Treatment-Nai ve Patients with Metastatic Pancreatic 
Cancer. Clin. Cancer Res. 22(10):2565–74. 
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. 
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. 
Investigator’s Brochure, Atezolizumab (MPDL3280A). Version 9, August 2016. 
Kakavand H, Wilmott JS, Menzies AM, Vilain R, Haydu LE, et al. 2015. PD-L1 expression and 
tumor-infiltrating lymphocytes define different subsets of MAPK inhibitor-treated 
melanoma patients. Clin. Cancer Res. 21(14):3140–48 
Kamphorst AO, Wieland A, Nasti T, Yang S, Zhang R, et al. 2017. Rescue of exhausted CD8 T 
cells by PD-1–targeted therapies is CD28-dependent. Science (80-. ). 355(6332) 
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. 
Khan SA, Toledano MB, Taylor-Robinson SD. 2008. Epidemiology, risk factors, and 
pathogenesis of cholangiocarcinoma. HPB (Oxford). 10(2):77–82 
Lamarca A, Hubner RA, David Ryder W, Valle JW. 2014. Second-line chemotherapy in 
advanced biliary cancer: a systematic review. Ann. Oncol. 25(12):2328–38 
Liu L, Mayes PA, Eastman S, Shi H, Yadavilli S, 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(7):1639–51 
Mody K, Feldman R, Reddy SK, Reynolds GA, McMillan JM, Johnson E. 2016. PD-1/PD-L1 
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expression and molecular associations in HPB malignancies. | 2016 Gastrointestinal 
Cancers Symposium | Abstracts | Meeting Library. J Clin Oncol. 34(suppl 4S):abstr 289 
Okazaki, T., T. Honjo. (2007). PD-1 and PD-1 ligands: from discovery to clinical application. Int 
Immunol. 9:813-824. 
Patel T. 2001. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in 
the United States. Hepatology. 33(6):1353–57 
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. 
Reddy SM, Reuben A, Wargo JA. 2016. Influences of BRAF Inhibitors on the Immune 
Microenvironment and the Rationale for Combined Molecular and Immune Targeted 
Therapy. Curr. Oncol. Rep. 18(7):42 
Rogers JE, Law L, Nguyen VD, Qiao W, Javle MM, et al. 2014. Second-line systemic treatment 
for advanced cholangiocarcinoma. J. Gastrointest. Oncol. 5(6):408–13 
Shaib Y, El-Serag HB. 2004. The epidemiology of cholangiocarcinoma. Semin. Liver Dis. 
24(2):115–25 
Siegel RL, Miller KD, Jemal A. 2016. Cancer statistics, 2016. CA. Cancer J. Clin. 66(1):7–30 
Suleiman Y, Coppola D, Juan T, Lee JK, Soliman HH, et al. 2015. The influence of tumor-
infiltrating lymphocytes (TILs) and their prognostic value in cholangiocarcinoma. ASCO 
Meet. Abstr. 33(15_suppl):4087 
Taube JM, Klein A, Brahmer JR, Xu H, Pan X, et al. 2014. Association of PD-1, PD-1 ligands, 
and other features of the tumor immune microenvironment with response to anti-PD-1 
therapy. Clin. Cancer Res. 20(19):5064–74 
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. 
Tsujikawa T, Kumar S, Borkar RN, Gray JW, Flint PW, et al. 2017. Quantitative Multiplex 
Immunohistochemistry Reveals Myeloid-Inflamed Tumor-Immune Complexity 
Associated with Poor Prognosis. Cell Rep. 19(4):203–17 
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. 
 
 
 
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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. 
 
 
 
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APPENDIX B 
PATIENT DRUG INFORMATION HANDOUTS AND WALLET 
CARDS 
 
PATIENTS ON STUDY ARM A (ATEZOLIZUMAB MONOTHERAPY) 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug atezolizumab (trade name Tecentriq). This clinical trial is sponsored by 
the National Cancer Institute. This form is addressed to the patient, but includes important 
information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
• The patient is on an immunotherapy clinical trial, designed to help the immune system 
attack cancer. There is a risk of developing autoimmune side effects from the study 
drugs, and these autoimmune side effects may be serious and challenging to diagnose. 
Examples of autoimmune side effects previously observed in clinical trials of 
immunotherapy drugs include:  
o Endocrinopathies (eg, hypothyroidism, adrenal insufficiency, panhypopituitarism, 
new onset type 1 diabetes) 
o Inflammation of various organs (colitis, pneumonitis, hepatitis, myocarditis) 
o Rheumatologic diseases (for example, rheumatoid arthritis, myositis) 
 
When evaluating this patient for an acute medical complaint, please consider that the 
patient may be experiencing an immune-related adverse event. 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.  
 
Atezolizumab (trade name Tecentriq®) may interact with other drugs, which can cause side 
effects. For this reason, it is very important to tell your study doctors of any medicines you are 
taking before you enroll onto this clinical trial. It is also very important to tell your doctors if you 
stop taking any regular medicines, or if you start taking a new medicine while you take part in 
this study. When you talk about your current medications with your doctors, include medicine 
you buy without a prescription (over-the-counter remedy), or any herbal supplements such as St. 
John’s Wort. It is helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions. You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
Your regular health care provider should check a frequently updated medical reference or call 
your study doctor before prescribing any new medicine or discontinuing any medicine. Your 
study doctor’s name is: 
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_____________________________________ and he or she can be contacted at  
 
_____________________________________. 
 
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STUDY DRUG INFORMATION WALLET CARD  
You are enrolled on a clinical trial using the experimental study  
drug atezolizumab. This clinical trial is sponsored by the NCI.  
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 This study drug can sometimes cause autoimmune problems that 
can sometimes become serious or life-threatening. Getting medical 
treatment right away may keep these problems from becoming more 
serious. Tell all of your health care providers (doctors, physician 
assistants, nurse practitioners, or pharmacists) that you are taking 
part in a clinical trial. 
 
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements.  
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for 
a list of drugs to avoid, or contact your study doctor.  
 
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  
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PATIENTS ON STUDY ARM B (ATEZOLIZUMAB PLUS COBIMETINIB) 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drugs, atezolizumab (trade name Tecentriq®), and cobimetinib (trade name 
Cotellic®). This clinical trial is sponsored by the National Cancer Institute. This form is 
addressed to the patient, but includes important information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
• The patient is on an immunotherapy clinical trial, designed to help the immune system 
attack cancer. There is a risk of developing autoimmune side effects from the study 
drugs, and these autoimmune side effects may be serious and challenging to diagnose. 
Examples of autoimmune side effects previously observed in clinical trials of 
immunotherapy drugs include:  
o Endocrinopathies (eg, hypothyroidism, adrenal insufficiency, panhypopituitarism, 
new onset type 1 diabetes) 
o Inflammation of various organs (colitis, pneumonitis, hepatitis, myocarditis) 
o Rheumatologic diseases (for example, rheumatoid arthritis, myositis) 
 
When evaluating this patient for an acute medical complaint, please consider that the 
patient may be experiencing an immune-related adverse event. 
 
• Cobimetinib is a substrate of substrate of CYP3A4 (major). Therefore, cobimetinib is 
broken down by this enzyme and may be affected by other drugs that inhibit or induce 
this enzyme. 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.  
 
Atezolizumab (trade name Tecentriq®) and cobimetinib (trade name Cotellic®) may interact 
with other drugs which can cause side effects. For this reason, it is very important to tell your 
study doctors of any medicines you are taking before you enroll onto this clinical trial. It is also 
very important to tell your doctors if you stop taking any regular medicines, or if you start taking 
a new medicine while you take part in this study. When you talk about your current medications 
with your doctors, include medicine you buy without a prescription (over-the-counter remedy), 
or any herbal supplements such as St. John’s Wort. It is helpful to bring your medication bottles 
or an updated medication list with you. 
 
Many health care providers can write prescriptions. You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
 
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These are the things that you and they need to know:  
 
Cobimetinib (trade name Cotellic®) must be used very carefully with other medicines that use 
certain liver enzymes to be effective or to be cleared from your system. Before you enroll onto 
the clinical trial, your study doctor will work with your regular health care providers to review 
any medicines and herbal supplements that are considered strong inducers/inhibitors or 
substrates of CYP3A4. 
 
• Please be very careful! Over-the-counter drugs (including some herbal supplements such as 
St. John’s wort) may contain ingredients that could interact with your study drug. Speak 
to your doctors or pharmacist to determine if there could be any side effects.  
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine. Your study doctor’s name is  
_____________________________________ and he or she can be contacted at  
 
_____________________________________. 
 
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STUDY DRUG INFORMATION WALLET CARD  
You are enrolled on a clinical trial using the experimental study  
drugs atezolizumab and cobimetinib. This clinical trial is sponsored by 
the NCI. Cobimetinib may interact with drugs that are processed by 
your liver. Because of this, it is very important to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 
 
 
Cobimetinib interacts with a specific liver enzyme called CYP3A4 and 
must be used very carefully with other medicines that interact with 
this enzyme. 
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered strong 
inducers/inhibitors or substrates of CYP3A4.  
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for 
a list of drugs to avoid, or contact your study doctor.  
 
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  
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APPENDIX C 
STUDY CHECKLIST FOR CTEP-SUPPORTED EARLY PHASE 
TRIALS WITH BIOMARKER ASSAYS AND BIOASSAY TEMPLATES 
 
 
1. 
Name of marker:  
 
CD8 
 
2. 
For an integral or integrated assay, indicate the role(s) of the biomarker assay in the 
trial: 
 
This is an INTEGRATED assay aimed at evaluate the effect of MEK inhibition on CD8+ T cell 
infiltration in patients with cholangiocarcinoma. Across many tumor types the extent of CD8+ T 
cell infiltration may predict clinical benefit from treatment with PD-1/PD-L1 blockade (Taube et 
al. 2014). Increasing CD8+ T cell infiltration is therefore one potential strategy for increasing 
response rates to anti-PD-1 therapies. In preclinical studies, work from the Mellman group (Ebert 
et al. 2016) demonstrated that MEK inhibition can reverse T cell signal-driven apoptotic 
‘‘exhaustive’’ T cell death within a tumor by blocking the upregulation of certain pro-apoptotic 
factors resulting in the accumulation of CD8+ T cells within tumors. We postulate that MEK 
inhibition may represent a novel approach to re-program the tumor microenvironment in a manner 
that favors responsiveness to PD-L1 blockade. 
In this proposal we will utilize an immunohistochemical (IHC) platform to assess CD8+ T cell 
infiltration in biopsy samples from patients on anti-MEK/PD-L1 combination therapy and anti-
PD-L1 monotherapy. As a result of these studies, we will be able to test the following 
hypotheses:  
 
 Patients with cholangiocarcinoma receiving a combination of a MEK inhibitor and a PD-
L1 inhibitor will have a greater increase in CD8+ T cells in tumor than patients receiving 
a PD-L1 inhibitor as monotherapy. 
 
 Greater treatment-related changes in CD8+ T cell infiltration in cholangiocarcinoma 
tumors will correlate with a favorable clinical response to therapy. 
 
3. 
Identify the specific individual(s) and laboratory(ies) who are being considered for 
conducting the assay(s) for the trial. 
 
This assay will be conducted at Johns Hopkins University. Staining for the described assay will 
be performed by research technicians in a Central Reference CLIA laboratory, at The Sidney 
Kimmel Comprehensive Cancer Center at the Johns Hopkins University. Oversight of the digital 
analysis for this assay will be performed on the laboratory of Dr. 
. PI oversight 
will be performed by Dr. 
 and Dr. Nilo Azad. 
 
4. 
Biomarker assay templates  
 
The CD8 IHC biomarker assay template has been completed and is appended to the end of this 
section.  
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Staining for the proposed biomarker has been optimized at the Johns Hopkins Central Reference 
CLIA laboratory for standard clinical practice across multiple solid tumor types. In order to 
optimize and validate this assay, this laboratory has performed test runs of more than 50 samples 
in duplicate that included multiple samples tumors with high lymphocytic infiltrate (kidney 
cancer, melanoma, tonsil tissue), and samples from multiple tumor types with less apparent 
infiltrates (MSS colon cancer, pancreatic cancer). The described analyses have now been 
validated and successfully performed on hundreds of clinical samples at Johns Hopkins. The 
group at Johns Hopkins that will perform this assay has rigorously validated and previously 
published with this assay (Le et al. 2016, Lutz et al. 2014, N Cuka, HA Hempel, KS Sfanos, AM 
De Marzo 2014, Thompson et al. 2017). As with most IHC the reactions are run to saturation, 
thus there is little range of intensity as lymphocytes are either positive or negative. The described 
assay will only be performed at a single institution (Johns Hopkins University). 
 
5. 
Provide data on the clinical utility of the integral/integrated assay as it will be used 
in the trial: 
 
Preclinical data demonstrate the potential for synergy between MEK inhibitors and PD-1 
checkpoint inhibitors. Several studies have demonstrated that MEK inhibitors upregulate HLA and 
downregulate certain immunosuppressive mechanisms within the tumor (Kakavand et al. 2015; 
Liu et al. 2015; Reddy et al. 2016). Additionally, Mellman et al. recently demonstrated that MEK 
inhibition may also directly potentiate T-cell based anti-tumor immunity. In an animal model, this 
group showed that MEK inhibition can reverse T cell signal-driven apoptotic ‘‘exhaustive’’ T cell 
death within a tumor by blocking the upregulation of certain pro-apoptotic factors; this results in 
the accumulation of CD8+ T cells within tumors. In the aggregate these data provide mechanistic 
rationale for combination treatment with a MEK inhibitor and an immunomodulator targeting PD-
1. These data support the use of CD8+ T cell infiltration as a biomarker that may be relevant to 
this treatment combination.  
 
Based on previous clinical experience, we anticipate that paired biopsy samples will be 
successfully obtained in at least 50% of participants. We anticipate obtaining approximately 20 
subjects in each treatment arm with paired samples available for analysis, offering 80% power 
for detecting an increase in CD8+ density equal to 0.8s.d., using a one-sided t-test with 
alpha=0.05, and more than 90% power for detecting an effect size of 1.0s.d. The change in CD8 
density will be captured and reported as a continuous variable, rather than a categorical variable. 
 
As the described biomarker results are experimental in this context and are not currently 
applicable to the care of the patient, they will not be made available to the treating physicians or 
patients. 
 
 
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The IHC bioassay template is attached to this protocol. 
 
 
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APPENDIX D 
IMMUNE-RELATED RESPONSE CRITERIA 
 
Introduction 
Increasing clinical experience indicates that traditional response criteria (e.g., Response 
Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1] and World Health Organization 
[WHO]) may not be sufficient to fully characterize activity in the new era of target therapies 
and/or biologics. In studies with cytokines, cancer vaccines, and monoclonal antibodies, 
complete response, partial response, or stable disease has been shown to occur after an increase 
in tumor burden as characterized by progressive disease by traditional response criteria. 
Therefore, conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents because progressive disease (by initial radiographic evaluation) does 
not necessarily reflect therapeutic failure. Long-term effect on the target disease must also be 
captured. The immune-related response criteria (irRC) are criteria that attempt to do that by 
enhancing characterization of new response patterns that have been observed with 
immunotherapeutic agents (i.e., ipilimumab) (Wolchok et al., 2009). (Note: The irRC only index 
and measurable new lesions are taken into account.) 
 
Glossary 
Term 
Definition 
SPD 
sum of the products of the two largest perpendicular diameters 
Tumor burden 
SPDindex lesions + SPDnew, measurable lesions 
Nadir 
minimally recorded tumor burden 
irCR 
immune-related complete response 
irPD 
immune-related progressive disease 
irPR 
immune-related partial response 
irSD 
immune-related stable disease 
irBOR 
immune-related best overall response 
 
Baseline Assessment Using irRC 
Step 1. Identify the index lesions (five lesions per organ, up to ten visceral lesions and 
five cutaneous lesions). 
 
Step 2. Calculate the SPD of all of these index lesions: 
 
SPD = ෍(Largest diameter of lesion i)
i
× (Second largest diameter of lesion i) 
 
Post-Baseline Assessments Using irRC 
Step 1. Calculate the SPD of the index lesions.  
 
Step 2. Identify new, measurable lesions (≥5 × 5 mm; up to five new lesions per organ: five new 
cutaneous lesions and ten visceral lesions).  
 
Step 3. Calculate the SPD of the new, measurable lesions. 
 
Step 4. Calculate the tumor burden: 
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Tumor burden = SPDindex lesions + SPDnew, measurable lesions 
 
Step 5. Calculate the change in tumor burden relative to baseline and the change in tumor burden 
relative to nadir. 
 
Step 6. Derive the overall response using the table below. 
 
Overall Response Criterion 
irCR 
Complete disappearance of all lesions (whether measurable or not, and no 
new lesions) confirmed by a repeat, consecutive assessment ≥4 weeks 
from the date first documented 
irPR 
Decrease in tumor burden ≥50% relative to baseline confirmed by a 
consecutive assessment ≥4 weeks from the date first documented 
irSD 
Criteria for irCR, irPR, and irPD are not met; does not require 
confirmation 
irPD 
Increase in tumor burden ≥25% relative to nadir confirmed by a 
consecutive assessment ≥4 weeks from the date first documented 
irCR = immune-related complete response; irPD = immune-related progressive disease; 
irPR = immune-related partial response; irSD = immune-related stable disease. 
 
Determination of irBOR 
Once a patient has completed all tumor assessments, his/her irBOR may be determined: 
 
Condition 
irBOR 
At least one irCR 
irCR 
At least one irPR and no irCR 
irPR 
At least one irSD and no irCR and no irPR 
irSD 
At least one irPD and no irCR, no irPR, and no irSD 
irPD 
irBOR = immune-related best overall response; irCR = immune-related complete response; 
irPD = immune-related progressive disease; irPR = immune-related partial response; 
irSD = immune-related stable disease. 
 
 
 
 
 
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APPENDIX E 
PATIENT MEDICATION DIARY - COBIMETINIB 
 
PATIENT ID  
CYCLE NUMBER  
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each 4 week-period while you take cobimetinib. Each cycle of 
therapy is 4 weeks (28 days). 
2. Take your dose of cobimetinib at about the same time each morning for the first 21 days. 
Do not take cobimetinib on days 22 through 28. 
3. Record the date, the number of tablets you took, and when you took them. Record doses as 
soon as you take them; do not batch entries together at a later time. 
4. If you miss taking your dose and remember within 1 hour of your scheduled dose, you may 
take it late. If it has been more than 1 hour, do not make up the dose; resume dosing with the 
next scheduled dose. If vomiting occurs, do not make up the dose; resume dosing with the next 
scheduled dose. 
5. Take cobimetinib tablets orally in the morning with or without food. The tablets should be 
swallowed whole and must not be crushed or broken. 
6. If you have any comments or notice any side effects, please record them in the Comments 
column. If you make a mistake while you write, please cross it out with one line, put your 
initials next to it, and then write the corrected information next to your initials. Example: 
10:30 am SB 9:30 am 
7. Please return this form to your physician when you go for your next appointment. 
 
Day 
Date 
Time of Daily Dose 
# of Tablets Taken 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
Day 
Date 
Time of Daily Dose 
# of Tablets Taken 
Comments 
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Use of this document is governed by the terms of use on the first page of this document.