A Randomized Phase 2 Study of Rituxan Hycela in Patients With Advanced Melanoma Undergoing Combination Immune Checkpoint Blockade With Nivolumab and Ipilimumab
Phase: PHASE2
Conditions: Cutaneous Melanoma, Stage III, Cutaneous Melanoma, Stage IV, Stage III Melanoma, Stage IIIA Skin Melanoma, Stage IIIB Skin Melanoma, Stage IIIC Skin Melanoma, Stage IV Skin Melanoma, Unresectable Melanoma
Sponsor: Emory University

1
Winship Protocol #: 4457-18; Version 6.0 04 05 2021
TITLE:  A Randomized Phase 2 Study of Rituxan Hycela in patients with advanced 
melanoma undergoing combination immune checkpoint blockade with nivolumab and 
ipilimumab.
*Principal Investigator:
Kavita Dhodapkar, M.D.
1760 Haygood Drive, N.E, HSRB-E326
Atlanta, GA 30322
404-727-9191 (phone)
404-727-9311 (fax)
kavita.dhodapkar@emory.edu
Co-Investigators:
Ragini Kudchadkar, M.D.
1365 Clifton Road, NE
Atlanta, GA 30322
404-778-2407(phone)
404-778-5676 (fax)
rkudcha@emory.edu
David Lawson, M.D.
Melinda Yushak, MPH, M.D.
Michael Lowe, M.D.
Keith Delman, M.D.
Madhav Dhodapkar, MD 
Statistician:
Study Coordinator:
Ashley Trumbull
1365C Clifton Road, NE Suite 3012
Atlanta, GA 30322
404-778-3969 (phone)
404-778-4389 (fax)
Ashley.lynn.Trumbull@emory.edu
Subir Goyal Ph.D
Winship Cancer Institute of Emory University
718 Gatewood Rd, N.E 
Atlanta, GA 30322
Tel (O): (404) 778-1098
subir.goyal@emory.edu

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Supplied Agent:  Rituximab (supplied by Genentech, South San Francisco, CA)
IND: Exempt

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R
A
N
D
O
M
I
Z
E
Ipilimumab+Nivolumab
Standard of care
No Additional Therapy
+
Rituxan-4 weekly doses
Week 1-Intravenous Rituxan (loading dose)
Weeks 2-4 Subcutaneous Rituxan Hycela
Ipilimumab+Nivolumab
Standard of care
+
Trial Design. All patients have chosen ipi/nivo as standard of care (SOC) treatment. They will be 
randomized prior to the first dose of ipi/nivo to receive either ARM A: SOC Ipilimumab + Nivolumab 
only with no additional therapy or ARM B: Standard of care Ipilimumab and Nivolumab, + 4 weekly 
doses of Rituxan (first dose of IV Rituxan followed by 3 weekly doses of subcutaneous Rituximab 
hycela) beginning 1-2 days following the first dose of Ipilimumab and Nivolumab.
SOC Ipi/Nivo is ipilimumab 3mg/kg every 3 weeks for 4 doses and nivolumab 1mg/kg every 3 weeks 
for 4 doses followed by nivolumab 480 mg IV  every 4 weeks x 12 doses or until disease progression 
or intolerant adverse event.
SCHEMA
This is a prospective randomized trial to test the efficacy of preemptive Rituxan in melanoma 
patients in reducing Immune-related adverse events (IRAEs) following combination checkpoint 
blockade (CCB). All eligible patients will undergo baseline evaluation to assess the status of 
disease as well as a baseline tumor biopsy. Combination checkpoint blockade will be 
administered as per current FDA approved standard of care, consisting of nivolumab at a dose of 
1 mg/kg and ipilimumab at a dose of 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab 
maintenance at a dose of 480 mg every 4 weeks x 1 year. Patients will be randomly assigned to 
no additional therapy (ARM A control) or 4 weekly doses of Rituxan for B cell depletion (ARM 
B). Rituxan will be administered as 375 mg/m2 IV for the first dose followed by weekly 
subcutaneous dosing at 1400 mg dose of Rituxan Hycela for weeks 2-4, as per recommended 
dosing for the FDA approval in the setting of lymphoma. All patients will be clinically 
monitored for the development of IRAEs utilizing NCI Common Toxicity Criteria v5.0. Any 
patient who received at least one dose of study drug will be included in safety analysis, and 
safety assessment will continue through treatment phase and up to 100 days after the last dose of 
study drug. Tumor response will be assessed according to the Response Evaluation Criteria in 
Solid Tumors (RECIST v1.1) and irRECIST at 12 weeks and every 12 weeks thereafter. All 
patients will also undergo pre treatment and post treatment biopsies if possible. 
ARM A
ARM B

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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................3
1.
OBJECTIVES......................................................................................................................6
1.1
Primary Objectives...................................................................................................6
1.2
Secondary Objectives...............................................................................................6
2.
BACKGROUND .................................................................................................................6
2.1
Study Disease(s).......................................................................................................6
2.2
IND Agent(s) ...........................................................................................................6
2.3
Rationale ..................................................................................................................7
2.4
Correlative Studies Background ..............................................................................8
3.
PATIENT SELECTION......................................................................................................8
3.1
Eligibility Criteria....................................................................................................8
3.2
Inclusion of Women and Minorities ......................................................................10
4.
REGISTRATION PROCEDURES ...................................................................................10
4.1
Central Registration Process..................................................................................10
4.1 a  Local Winship Procedures .......................................................................................10
4.2a Local Site ...................................................................................................................10
5.
TREATMENT PLAN........................................................................................................10
5.1
Agent Administration.............................................................................................11
5.2
Duration of Therapy...............................................................................................14
5.3
Duration of Follow Up...........................................................................................14
5.4
Criteria for Removal from Study...........................................................................14
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................14
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................15
7.1
Comprehensive Adverse Events and Potential Risks List.....................................15
7.2
Adverse Event Characteristics...............................................................................19
7.3
Expedited Adverse Event Reporting......................................................................24
7.4
Routine Adverse Event Reporting .........................................................................26
8.
Reporting to Regulatory Authorities, Ethics Committees and Investigators.....................28
8.1
Secondary Malignancy...........................................................................................28
8.2
Second Malignancy................................................................................................29
9.
PHARMACEUTICAL INFORMATION..........................................................................30
9.1
Investigational Agent(s).........................................................................................30
9.2
Commercial Agent(s) .............................................................................................31
10.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................32

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10.1
Laboratory Correlative Studies..............................................................................33
11.
STUDY CALENDAR .......................................................................................................34
12.
MEASUREMENT OF EFFECT .......................................................................................36
12.1
Antitumor Effect....................................................................................................36
13.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................41
13.1
Data Reporting.......................................................................................................41
14.
STATISTICAL CONSIDERATIONS...............................................................................42
14.1
Study Design/Endpoints ........................................................................................42
14.2
Sample Size/Accrual Rate......................................................................................42
REFERENCES ..............................................................................................................................44
APPENDIX A
PERFORMANCE STATUS CRITERIA ..................................................46

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1. OBJECTIVES
1.1
Primary Objectives

To compare rates for Grade 3-4 IRAEs in the first 6 months in patients treated with 
combination checkpoint blockade (CCB) therapy (anti-CTLA4 and anti-PD1) as a part of 
standard of care for advanced melanoma who are treated with a single course of 4 weekly 
doses of Rituxan therapy versus those who are not treated with Rituxan. 
1.2
Secondary Objectives

To evaluate the safety and tolerability (in terms of Rituxan-related adverse events) in patients 
with melanoma receiving CCB.

To compare objective response rate in patients receiving CCB therapy + Rituxan versus CCB 
therapy alone.

To compare 1 year overall and progression-free survival in patients receiving CCB therapy + 
Rituxan versus CCB therapy alone.

To compare changes in CD21lo B cells in patients receiving CCB therapy + Rituxan versus 
CCB therapy alone.

To compare changes in T cells in patients receiving CCB therapy + Rituxan versus CCB 
therapy alone.
Exploratory Objectives

To compare treatment induced changes in tumor tissue in patients receiving CCB therapy + 
Rituxan versus CCB therapy alone.
2. BACKGROUND
2.1
Study Disease(s)
Stage IIII or IV unresectable melanoma 
2.2
IND Agent(s)
Rituxan Hycela
Rituxan Hycela is a combination of rituximab, a CD20-directed cytolytic antibody, and 
hyaluronidase human, an endoglycosidase, indicated for the treatment of adult patients with 
Follicular Lymphoma (FL), Diffuse Large B-cell Lymphoma (DLBCL), and Chronic 
Lymphocytic Leukemia (CLL). Rituxan has also been extensively utilized for therapy of 
autoimmune disorders such as immune thrombocytopenic purpura. The proposed use of Rituxan 
in this study is based on new data from the PI regarding the role of CD21loCD20+ B cells in the 
pathogenesis of immune related adverse events following combination checkpoint blockade. 
Please note Rituxan Hycela is always given as Rituximab IV as the first dose, if no reaction can 
proceed to Rituxan Hycela.

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2.3
Rationale
Immune related adverse events (IRAEs) as a limiting toxicity of combination checkpoint 
blockade:
Blockade of T cell immune checkpoints PD-1/PD-L1 and CTLA-4 has emerged as an effective 
therapy for melanoma(1-4). Immune checkpoint blockade with monotherapy (anti-CTLA4 or 
anti-PD-1 alone) leads to tumor regression in only a subset of patients and combination therapy 
has therefore, been explored as a strategy to enhance clinical efficacy. The best studied 
combination therapy (concurrent administration of PD-1 and CTLA-4 blockade) leads to high 
response rates in advanced melanoma(5-10). However, increase in tumor regressions following 
combination therapy is associated with a marked increase in Grade 3 and 4 IRAEs resulting in 
significant morbidity and discontinuation of therapy in up to one third of patients(11, 12). 
Reduction in antibody dosages may be one way to partly reduce the risk for IRAEs with 
combination therapy, however the impact of such strategy on clinical efficacy remains to be 
resolved(13). There remains an urgent need to better understand the pathogenesis of IRAEs 
following CCB therapy and how/whether they can be prevented. Ability to prevent these IRAEs 
will have a major impact on the applicability of combination immune checkpoint blockade as 
therapy in melanoma as well as other cancers. This is not just because of short-and long-term 
morbidity and costs associated with IRAEs, but also because IRAEs often prevent delivery of 
planned therapy in several patients. 
Importance of human studies to test biomarkers and prevention of IRAEs following 
checkpoint blockade:
As discussed above, clinical studies have shown that immune checkpoint blockade therapies can 
lead to distinct patterns of autoimmunity in the clinic. Importantly, the pattern or spectrum of 
autoimmune manifestations observed in the clinic were not entirely predictable from preclinical 
studies of immune checkpoint blockade(14-16). Whether these differences related to species-
specific (human versus mouse) differences in the biology of the target organ(s), or the immune 
system remain to be clarified. A relevant example are the findings about changes in B cells in 
humans with CTLA4 deficiency, which were not anticipated from prior studies in CTLA4-
deficient mice. In addition, the biology of the specific immune cell types may also potentially 
differ between mouse and man. However, these considerations do raise the importance of 
directly studying patients to gain fundamental insights into effects of immune checkpoint 
blockade. Mechanistic studies in humans are limited, but controlled studies that link targeted 
manipulation of specific cell types or pathways provide an opportunity to gain fundamental 
mechanistic insights with immediate translational potential. 
Changes in B cells and risk of IRAEs following combination checkpoint blockade:
Our studies are among the first to identify that early changes in circulating B cells correlate with 
the development of IRAEs following checkpoint blockade(17). Much of the attention in terms of 
understanding biomarkers of response or efficacy in this setting has to date been focused on T 
cell responses. Changes in B cells have received less attention(18). In our preliminary studies, 
changes in B cells not only correlated with the development and severity of IRAEs, these 

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changes preceded the clinical manifestations of IRAEs by several weeks. Our studies will 
therefore provide a novel biomarker to help identify patients at risk for the development of 
IRAEs following checkpoint blockade. Importantly, these studies involve flow-based assays on 
circulating immune cells, and therefore can be easily incorporated into routine clinical practice. 
B cell depletion as a preemptive strategy to lower IRAEs:
The discovery that patients who experience early changes in B cells following CCB therapy are 
at higher risk for subsequent development of IRAEs provides the opportunity to prevent IRAEs 
in this cohort. These studies will test a novel strategy of B cell depletion to reduce the risk of 
autoimmunity following combination checkpoint blockade. This is feasible because CCB-
emergent changes in B cells not only precede autoimmune complications but are also directly 
amenable to targeting via anti-CD20 antibodies. It is important to note that even if this approach 
does not work clinically, it will provide biologically and clinically important information. For 
example, it would then suggest a role of other immune cells in mediating IRAEs. Recent studies 
have suggested that B cell depletion may also enhance anti-tumor effects in melanoma and 
therefore this combination may not only reduce toxicity but also improve efficacy(19). 
2.4
Correlative Studies Background
CD21lo B cells as targets in IRAEs following combination checkpoint blockade:
Our studies are also among the first to identify a role for CD21lo subset of B cells in CCB-
induced IRAEs. Our preliminary data indeed identified this as a specific subset of human B cells 
that express PD1. Improved understanding of the biology of this specific B cell subset in 
melanoma patients and changes in these cells following CCB will therefore provide novel 
mechanistic insights into CCB-induced IRAEs. These studies may also suggest novel approaches 
to specifically target this specific subset, as opposed to the current strategy targeting all B cells to 
lower the risk of IRAEs.
Contributions of B cells to protective immunity mediated by combination checkpoint 
blockade:
While the role of T cells in protective immunity is well established, the relative contribution of B 
cells to the anti-tumor effects of checkpoint blockade remain to be clarified, particularly in 
human studies. In preclinical models, depletion of B cells did not lead to reduction in anti-tumor 
effects of checkpoint blockade(19). The application of B cell depleting antibody with Rituxan in 
patients undergoing CCB will provide direct and novel insights into the role of B cells in both 
IRAEs and tumor immunity. The latter is particularly relevant because approaches targeting 
IRAEs will only be clinically viable if they do not adversely impact protective tumor immunity 
or alter the frequency or durability of clinical tumor regressions following CCB therapy. 
3. PATIENT SELECTION
3.1
Eligibility Criteria 
Inclusion Criteria
Subjects must meet all of the inclusion criteria before enrollment can occur. 

Clinically eligible to receive FDA approved standard of care combination immune 

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checkpoint therapy with Ipilimumab and Nivolumab for unresectable Stage III or 
stage IV melanoma.

Age ≥18 years. 

Patients with progression on anti-PD-1 as a single agent are allowed to enroll on the 
study

No therapy with immune checkpoint inhibitors other than anti-PD-1 within 1 year 
prior to starting combination checkpoint therapy. Prior adjuvant ipilimumab as single 
agent is allowed if greater than 1 year since last treatment. Patient had no Grade 3 or 
4 toxicities from the checkpoint inhibitors including prior single agent PD-1 or anti-
CTLA4 therapy. History of adjuvant interferon is allowed. 

Patients must have the following required values for laboratory tests obtained within 
three weeks prior to randomization (ULN: institutional upper limit of normal): 
o
-Adequate blood counts: White Blood Count > 3,000/uL ANC >1,500/uL, 
Platelet Count > 100,000/uL, Hemoglobin > 9 g/dL, 
o
-Adequate renal function: Serum creatinine <1.5 x ULN or serum creatinine 
clearance (CrCl) > 40ml/min. (CrCl= Wt (kg) x (140- age)*/72 x Cr. level, 
*female x 0.85)
o
-Adequate liver function: AST and ALT <3 x ULN ( <5 x ULN for patients 
with documented liver metastases), Alkaline phosphatase < 2X ULN 
(<5XULN for those with bone metastasis), Total bilirubin < 1.5 X ULN 
except those with direct bilirubin or gilberts syndrome, serum LDH <10 X 
ULN).
Exclusion Criteria
Subjects will be ineligible for enrollment if they meet any of the following criteria.

Allergy to Rituximab, or any of the ingredients in Rituximab injection or Rituximab 
and hyaluronidase human injection. 

Patients with active CNS metastatic disease or leptomeningeal disease. Patients with 
CNS metastatic disease that has been treated with surgical resection or stereotactic 
radiosurgery are eligible if lesions are stable. If patient required steroid therapy for his 
CNS metastatic disease, the patient maybe enrolled 2 weeks after stopping steroids. 
Prior therapy with immune checkpoint blocking antibodies (monotherapy given at 
least 1 year prior to starting combination therapy and no Grade 3-4 toxicities while on 
monotherapy are allowed, prior vaccines or IL2 given at least one year prior is also 
allowed) 

Patients may have had prior systemic therapy in the adjuvant setting (e.g. interferon, 
BRAF, or MEK agents). Adjuvant ipilimumab as single agent is allowed if greater 
than 1 year since last treatment and patient had no Grade 3 or 4 toxicities from the 
checkpoint inhibitors. Prior anti-PD-1 therapy is allowed if patients progress and have 
had no grade 3 or 4 toxicities related to anti-PD-1 therapy.

Women must not be pregnant or lactating. Must have negative urine or blood 
pregnancy test within 1 week of starting therapy.

Patients with known HIV are ineligible

Patients with active Hepatitis B Virus (HBV) or Hepatitis C virus (HCV) are 
ineligible. Patients with prior history of, or serology suggestive of prior infection with 

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Hepatitis B Virus (HBV) or Hepatitis C virus (HCV) are also ineligible.

Patients with active, known or suspected autoimmune disorders including lupus and 
type I diabetes are ineligible. Patients with history of vitiligo, thyroiditis are eligible. 

Patients with active or history of inflammatory bowel disease are ineligible.

Patients cannot be on corticosteroid therapy except as physiologic replacement 
therapy.

Patients receiving ongoing corticosteroid therapy for autoimmune disorders are 
ineligible. Occasional steroid inhaler use or nasal spray are allowed. Patients 
receiving replacement doses of steroids for adrenal insufficiency are eligible.

Patients must not have any serious underlying medical conditions or take medications 
that in the investigators opinion may interfere with compliance or interpretation of 
IRAEs.
3.2
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.  Due to melanoma 
being at a much higher incidence in Caucasians as compared to other races, we expect the vast 
majority of subjects to be Caucasian.  
4. REGISTRATION PROCEDURES
4.1
Central Registration Process   
This occurs at the time a subject is consented. 
4.1 a  Local Winship Procedures
To register a patient, the following documents should be completed by the Study 
Coordinator and e-mailed to Clinical Research (OCR) ocr@emory.edu and Winship 
Central Subject Registration (WCSR) winshipcsr@emory.edu within 24 hours or 1 
business day:

Signed patient consent form

HIPAA authorization form

Emory Research Management System (ERMS) Enrollment Fax Cover 
o
printed from ERMS (https://erms.emory.edu) after subject registered
Enrolling a subject requires careful screening and determination of eligibility. 
Eligible patients will be enrolled on study centrally at Winship Cancer Institute by the Study 
Coordinator.  
Agents may be ordered by a participating site only after the initial IRB approval.
4.2a Local Site
When all required test results are available, complete the eligibility checklist and provide 
the checklist and the supporting documentation to the IRB approved investigator for 
review and sign-off. Once the investigator has signed the eligibility checklist, 
randomization and or enrollment may proceed. Oncore and ERMS must be updated to 

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reflect eligibility and on treatment status. 
5. TREATMENT PLAN
5.1
Agent Administration
Once the investigator has signed the eligibility checklist, randomization may proceed.  Patients 
meeting study entry criteria will be randomized to treatment ARM A or Arm B by the study 
statistician, Dr. Goyal.  Eligible subjects (eligibility confirmed and checklist signed) will be 
assigned to a treatment arm until 44 subjects (22 in each arm) have been enrolled.  The study 
coordinator will update Oncore and ERMS reflect randomization information. 
Following randomization, patients should begin protocol treatment within 5 business days.  
Issues that would cause treatment delays should be discussed with the Principal Investigator.  
Treatment will be administered on an outpatient basis.  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.
Patients will be randomly assigned 1:1 using block randomization with a block of 6 patients. 
Randomization schema will be kept in the research pharmacy.
Patients with unresectable stage III or stage IV melanoma being treated with FDA approved 
standard of care immune checkpoint combination therapy with Ipilimumab and Nivolumab are 
eligible for this trial. 
Patients will be randomized 1:1 to either continue therapy with standard of care Ipilimumab and 
Nivolumab (ARM A) or standard of care Ipilimumab and Nivolumab plus 4 doses of weekly 
Rituxan (ARM B).
Patients enrolling on this study following treatment failure on single agent anti-PD-1 will be 
distributed equally between arms A and B of the study.
Induction Phase:
ARM A: Cycles 1-4
Each cycle is 21 days and includes Ipilimumab (3 mg/kg) on day 1 plus Nivolumab (1 mg/kg) on 
Day 1.
ARM B. Cycles 1-4
Each cycle is 21 days and includes Ipilimumab (3 mg/kg) on day 1 plus Nivolumab (1 mg/kg) on 

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Day 1. In addition, patients will receive 4 weekly doses of Rituxan (first dose 375 mg/m2 IV and 
then 3 weekly doses of 1400 mg Rituxan Hycela subcutaneous, as per current label for Rituxan 
Hycela).
First dose of Rituxan will be administered 1 week after start of Ipi/Nivolumab therapy. 3rd dose 
of Rituxan will be administered on day 2 of cycle 2 after infusion of Ipi/Nivo on week4. 
Continuation Phase:
All patients will receive Nivolumab 480 mg every 4weeks for up to 13 doses (52 weeks) until 
disease progression or intolerable adverse events. 
All treatments will have a +/-3 business day window for administration. 
5.1.1
IND Agent(s)
Rituximab (RITUXAN) (for IV use)
Dosage and administration:
Do not administer as an intravenous push or bolus.  RITUXAN should only be administered by a
healthcare professional with appropriate medical support to manage severe infusion-related 
reactions that can be fatal if they occur. Pre-medicate before each infusion.
Prior to First Infusion: Screen all patients for HBV infection by measuring HBsAg and anti-
HBc before initiating treatment with RITUXAN.  Obtain complete blood counts including 
platelets (CBC) prior to the first dose.
During RITUXAN Therapy: In patients with lymphoid malignancies, during treatment with 
RITUXAN monotherapy, obtain complete blood counts (CBC) with differential and platelet 
counts prior to each RITUXAN course.  During treatment with RITUXAN and chemotherapy, 
obtain CBC with differential and platelet counts at weekly to monthly intervals and more 
frequently in patients who develop cytopenias.  In patients with RA, GPA or MPA, obtain CBC 
with differential and platelet counts at two to four month intervals during RITUXAN therapy. 
Continue to monitor for cytopenias after final dose and until resolution.
First Infusion:  Initiate infusion at a rate of 50 mg/hr.  In the absence of infusion toxicity,
increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.
Storage and Handling:
RITUXAN vials [100 mg/10 mL single-use vials (NDC 50242-051-21) and 500 mg/50 mL 
single-use vials (NDC 50242-053-06)] are stable at 2°C–8°C (36°F–46°F). RITUXAN vials 
should be protected from direct sunlight. Do not freeze or shake.
Rituxan Hycela:
RITUXAN HYCELA is for subcutaneous use only. RITUXAN HYCELA should only be 
administered by a healthcare professional with appropriate medical support to manage severe 
reactions that can be fatal if they occur. All patients must first receive at least one full dose of a 
rituximab product by intravenous infusion without experiencing severe adverse reactions before 

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starting treatment with RITUXAN HYCELA. If patients are not able to receive one full dose by 
intravenous infusion, they should continue subsequent cycles with a rituximab product by 
intravenous infusion and not switch to RITUXAN HYCELA until a full intravenous dose is 
successfully administered. Refer to the prescribing information for a rituximab product for 
intravenous infusion for additional information (Rituxan prescribing information, Genentech). 
Premedicate approximately 30 minutes before each dose of RITUXAN HYCELA. Dose 
reductions of RITUXAN HYCELA are not recommended. The recommended dose is RITUXAN 
HYCELA 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) 
subcutaneously at a fixed dose irrespective of patient’s body surface area. The dosing for 
Rituxan Hycela utilized in this protocol is similar to that FDA approved for follicular 
lymphoma. 
Recommended Premedication and Prophylactic Medications:
Premedicate with acetaminophen and an antihistamine before each dose of RITUXAN 
HYCELA. 
Administration and Storage 
RITUXAN HYCELA is ready to use. To avoid needle clogging, attach the hypodermic injection 
needle to the syringe immediately prior to administration. RITUXAN HYCELA is compatible 
with polypropylene and polycarbonate syringe material and stainless steel transfer and injection 
needles. Use the product immediately. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration. RITUXAN HYCELA should be a 
clear to opalescent and colorless to yellowish liquid. Do not use vial if particulates or 
discoloration is present. 
Administration
 Inject RITUXAN HYCELA into the subcutaneous tissue of the abdomen over approximately 
5–7 minutes and never inject into areas where the skin is red, bruised, tender or hard, or areas 
where there are moles or scars. No data are available on performing the injection at other sites of 
the body. 
 Inject 11.7 mL of RITUXAN HYCELA 1,400 mg/23,400 Units vial (1,400 mg rituximab and 
23,400 Units hyaluronidase human) subcutaneously into the abdomen over approximately 5 
minutes.
If administration of RITUXAN HYCELA is interrupted, continue administering at the same site, 
or at a different site, but restricted to the abdomen.
During treatment with RITUXAN HYCELA, do not administer other medications for 
subcutaneous use at the same sites as RITUXAN HYCELA.
Storage:
After the solution of RITUXAN HYCELA is withdrawn from the vial, it should be labeled with 
the peel-off sticker and used immediately. If not used immediately, prepare in controlled and 
validated aseptic conditions. Once transferred from the vial into the syringe, store the solution of 
RITUXAN HYCELA in the refrigerator at 2°C–8°C (36°F–46°F) up to 48 hours and 

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subsequently for 8 hours at room temperature up to 30°C (86°F) in diffuse light.
5.2
Duration of Therapy
The protocol-specific therapy in this study is restricted to only 4 weekly doses of rituximab in 
patients randomized to the Rituximab-arm. 
In the absence of treatment delays due to adverse event(s), treatment may continue for 4 weekly 
doses of Rituxaimab  (or observation) or until one of the following criteria applies:

Disease progression,

Intercurrent illness that prevents further administration of treatment,

Unacceptable adverse event(s),

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
Duration of Follow Up
Patients will be followed for 4 weeks after removal from study or until death, whichever occurs 
first.  Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event.
5.4
Criteria for Removal from Study
Patients will be removed from study when any of the criteria listed in Section 5.2 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form.
6. DOSING DELAYS/DOSE MODIFICATIONS
There is no dose modification for Rituxan in this study. Patients who experience Rituxan-related 
grade 3 or greater toxicity will not receive further Rituxan, and will be followed on the Rituxan-
arm on an intent to treat basis. 
Management of Ipilimumab and Nivolumab therapy in this protocol will be as per FDA 
approved standard of care guidelines and per the discretion of the treating investigator. 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 

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following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting in addition to routine reporting.
7.1
Comprehensive Adverse Events and Potential Risks List
The Adverse Event and Potential Risks list provides a single list of reported and/or potential 
adverse events (AE) associated with an agent using a uniform presentation of events by body 
system.  
Rituxan Hycela:
The information below describes the potential warnings, precautions and adverse events with 
Rituxan Hycela. Please refer to the prescribing drug information for details. (Genentech, South 
San Francisco, CA).
WARNINGS AND PRECAUTIONS
Severe Mucocutaneous Reactions 
Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab 
containing products, including RITUXAN HYCELA. These reactions include paraneoplastic 
pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and 
toxic epidermal necrolysis. Discontinue RITUXAN HYCELA in patients who experience a 
severe mucocutaneous reaction. The safety of re-administration of a rituximab-containing 
product, including RITUXAN HYCELA, to patients with severe mucocutaneous reactions has 
not been determined. 
Hepatitis B Virus Reactivation 
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic 
failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic 
antibodies, including rituximab-containing products. HBV reactivation is defined as an abrupt 
increase in HBV replication manifesting as a rapid increase in serum HBV DNA levels or 
detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. 
Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase 
levels. In severe cases increase in bilirubin levels, liver failure, and death can occur. Screen all 
patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with a 
rituximab-containing product. For patients who show evidence of prior hepatitis B infection 
(HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), 
consult with physicians with expertise in managing hepatitis B regarding monitoring and 
consideration for HBV antiviral therapy before and/or during treatment with a rituximab 
containing product. Monitor patients with evidence of current or prior HBV infection for clinical 
and laboratory signs of hepatitis or HBV reactivation during and for several months following 
RITUXAN HYCELA. HBV reactivation has been reported up to 24 months following 
completion of therapy containing rituximab. In patients who develop reactivation of HBV while 
on RITUXAN HYCELA, immediately discontinue treatment and any concomitant 
chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of 
resuming RITUXAN HYCELA treatment in patients who develop HBV reactivation. 

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Resumption of RITUXAN HYCELA treatment in patients whose HBV reactivation resolves 
should be discussed with physicians with expertise in managing HBV.
Progressive Multifocal Leukoencephalopathy (PML) 
JC virus infection resulting in PML and death has been observed in patients receiving rituximab 
containing products, including RITUXAN HYCELA. Consider the diagnosis of PML in any 
patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is 
not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue 
RITUXAN HYCELA and consider discontinuation or reduction of any concomitant 
chemotherapy or immunosuppressive therapy in patients who develop PML.
Hypersensitivity and other Administration Reactions 
Systemic Reactions Patients must receive at least one full dose of a rituximab product by 
intravenous infusion before receiving RITUXAN HYCELA due to the higher risk of 
hypersensitivity and other acute reactions during the first infusion. Beginning therapy with a 
rituximab product by intravenous infusion allows management of hypersensitivity and other 
administration reactions by slowing or stopping the intravenous infusion. Rituximab-containing 
products, including RITUXAN HYCELA, are associated with hypersensitivity and other 
administration reactions, which may be related to release of cytokines and/or other chemical 
mediators. Cytokine release syndrome may be clinically indistinguishable from acute 
hypersensitivity reactions. This set of reactions which includes syndrome of cytokine release, 
tumor lysis syndrome and anaphylactic and hypersensitivity reactions are described below. They 
are not specifically related to the route of administration of a rituximab-containing product. 
Severe infusion-related reactions with fatal outcome have been reported with the use of 
intravenous formulations of rituximab products, with an onset ranging within 30 minutes to 2 
hours after starting the first intravenous infusion. They were characterized by pulmonary events 
in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms. 
Anaphylactic and other hypersensitivity reactions can also occur. In contrast to cytokine release 
syndrome, true hypersensitivity reactions typically occur within minutes after starting infusion. 
Severe cytokine release syndrome is characterized by severe dyspnea, often associated by 
bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This 
syndrome may be associated with acute respiratory failure and death. Cytokine release syndrome 
may occur within 1–2 hours of initiating the infusion. Patients with a history of pulmonary 
insufficiency or those with pulmonary tumor infiltration may be at a greater risk of poor 
outcome. Rituximab product administration should be interrupted immediately and aggressive 
symptomatic treatment initiated. During RITUXAN HYCELA administration, the injection 
should be interrupted immediately when observing signs of a severe reaction and aggressive 
symptomatic treatment should be initiated. Closely monitor the following patients: those with 
pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary 
adverse reactions, and those with high numbers of circulating malignant cells (≥ 25,000/mm3). 
Premedicate patients with an antihistamine and acetaminophen prior to each administration of 
RITUXAN HYCELA. Premedication with glucocorticoids should also be considered in the event 
of severe anaphylaxis or per treating physician. Observe patients for at least 15 minutes 
following RITUXAN HYCELA. A longer period may be appropriate in patients with an 
increased risk of hypersensitivity reactions.

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Local Cutaneous Reactions 
Local cutaneous reactions, including injection site reactions, have been reported in patients 
receiving RITUXAN HYCELA. Symptoms included pain, swelling, induration, hemorrhage, 
erythema, pruritus, and rash. Some local cutaneous reactions occurred more than 24 hours after 
RITUXAN HYCELA administration. The incidence of local cutaneous reactions following 
administration of RITUXAN HYCELA was 16%. Reactions were mild or moderate and resolved 
without any specific treatment. Local cutaneous reactions of any Grade were most common 
during the first RITUXAN HYCELA cycle (Cycle 2; 5%) with the incidence decreasing with 
subsequent injections.
Tumor Lysis Syndrome (TLS)
TLS can occur within 12–24 hours after administration of a rituximab-containing product, 
including RITUXAN HYCELA. A high number of circulating malignant cells (≥ 25,000/mm3) 
or high tumor burden confers a greater risk of TLS. Administer aggressive intravenous hydration 
and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte 
abnormalities, monitor renal function and fluid balance, and administer supportive care, 
including dialysis as indicated. 
Infections
Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur 
during and following the completion of therapy with rituximab-containing products, including 
RITUXAN HYCELA. The incidence of infections with RITUXAN HYCELA vs rituximab was 
56% and 49% respectively in patients with CLL, and 46% and 41% respectively in patients with 
FL/DLBCL in combination with chemotherapy. Infections have been reported in some patients 
with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia > 11 months 
after rituximab exposure). New or reactivated viral infections included cytomegalovirus, herpes 
simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. 
Discontinue RITUXAN HYCELA for serious infections and institute appropriate anti-infective 
therapy. 
Cardiovascular Adverse Reactions
Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and 
cardiogenic shock may occur with rituximab-containing products, including RITUXAN 
HYCELA. Discontinue RITUXAN HYCELA for serious or life threatening cardiac arrhythmias. 
Perform cardiac monitoring during and after all administrations of RITUXAN HYCELA for 
patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or 
angina.
Renal Toxicity
Severe, including fatal, renal toxicity can occur after administration of rituximab-containing 
products, including RITUXAN HYCELA. Renal toxicity has occurred in patients who 
experience tumor lysis syndrome and in patients with administered concomitant cisplatin therapy 
during clinical trials. The combination of cisplatin and RITUXAN HYCELA is not an approved 
treatment regimen. Monitor closely for signs of renal failure and discontinue RITUXAN 
HYCELA in patients with a rising serum creatinine or oliguria.

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Bowel Obstruction and Perforation
Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in 
patients receiving rituximab-containing products, including RITUXAN HYCELA, in 
combination with chemotherapy. In postmarketing reports, the mean time to documented 
gastrointestinal perforation was 6 (range 1–77) days. Evaluate if symptoms of obstruction such 
as abdominal pain or repeated vomiting occur. 
Immunization The safety of immunization with live viral vaccines following rituximab-
containing products, including RITUXAN HYCELA, therapy has not been studied and 
vaccination with live virus vaccines is not recommended before or during treatment. 
Embryo-Fetal Toxicity
Based on human data, rituximab-containing products can cause fetal harm due to B-cell 
lymphocytopenia in infants exposed to rituximab in-utero. Advise pregnant women of the risk to 
a fetus. Females of childbearing potential should use effective contraception while receiving 
RITUXAN HYCELA and for 12 months following the last dose of rituximab-containing 
products, including RITUXAN HYCELA.
Immunogenicity 
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody 
formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the 
observed incidence of antibody (including neutralizing antibody) positivity in an assay may be 
influenced by several factors including assay methodology, sample handling, timing of sample 
collection, concomitant medications, and underlying disease. For these reasons, comparison of 
the incidence of antibodies to RITUXAN HYCELA and rituximab in the studies described below 
with the incidence of antibodies in other studies or to other products may be misleading. In the 
SABRINA study, where previously untreated patients with follicular lymphoma were treated 
with RITUXAN HYCELA or rituximab in combination with CVP or CHOP, the incidence of 
treatment-induced/enhanced anti-rituximab antibodies in the RITUXAN HYCELA group was 
similar to that observed in the rituximab group (2.0% RITUXAN HYCELA vs. 1.5% rituximab). 
The incidence of treatment-induced/enhanced anti-recombinant human hyaluronidase antibodies 
was 13% in the RITUXAN HYCELA group compared with 8% in the rituximab group, and the 
overall proportion of patients found to have anti-recombinant human hyaluronidase antibodies 
remained generally constant over the follow-up period in both cohorts. All patients who tested 
positive for anti-recombinant human hyaluronidase antibodies at any point during the study were 
negative for neutralizing antibodies. In the SAWYER study, where previously untreated patients 
with CLL were treated with RITUXAN HYCELA or rituximab in combination with FC, the 
incidence of treatment induced/enhanced anti-rituximab antibodies was 2.4% in the RITUXAN 
HYCELA group vs. 6.7% in rituximab group. The incidence of treatment-induced/enhanced anti- 
recombinant human hyaluronidase antibodies was 10.6% in the RITUXAN HYCELA treatment 
arm. None of the patients who tested positive for anti-recombinant human hyaluronidase 
antibodies tested positive for neutralizing antibodies. The clinical relevance of the development 
of anti-rituximab or anti-recombinant human hyaluronidase antibodies after treatment with 
RITUXAN HYCELA is not known.
Postmarketing Experience

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The following adverse reactions have been identified during post-approval use of rituximab 
containing products. Because these reactions are reported voluntarily from a population of 
uncertain size, it is not always possible to reliably estimate their frequency or establish a causal 
relationship to drug exposure. 
 Hematologic: prolonged pancytopenia, marrow hypoplasia, Grade 3–4 prolonged or late onset 
neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia, prolonged 
hypogammaglobulinemia 
 Cardiac: fatal cardiac failure 
 Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like 
syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. 
 Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), 
increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of 
Grade 3 and 4 infections 
 Neoplasia: disease progression of Kaposi’s sarcoma. 
 Skin: severe mucocutaneous reactions. 
 Gastrointestinal: bowel obstruction and perforation.
 Pulmonary: fatal bronchiolitis obliterans and fatal interstitial lung disease.
7.2
Adverse Event Characteristics 
SAFETY REPORTING OF ADVERSE EVENTS
ASSESSMENT OF SAFETY
Specification of Safety Variables
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) per protocol. This includes all events of death, and any study specific issue 
of concern.
Adverse Events
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal product 
(IMP) or other protocol-imposed intervention, regardless of attribution.
This includes the following:

AEs not previously observed in the subject that emerges during the protocol-specified  
AE reporting period, including signs or symptoms associated with melanoma those were 
not present prior to the AE reporting period.

Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations)

If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention.

Preexisting medical conditions (other than the condition being studied) judged by the 

Investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period.

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Serious Adverse Events
An AE should be classified as an SAE if the following criteria are met:

It results in death (i.e., the AE actually causes or leads to death).

It is life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe form, 
might have caused death.).

It requires or prolongs inpatient hospitalization.

It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions).

It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the IMP.

It is considered a significant medical event by the investigator based on medical judgment 
(e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one 
of the outcomes listed above).
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc.in 
accordance with CFR 312.32 (IND Safety Reports). 
Adverse Event Reporting Period
The study period during which AEs and SAEs must be reported begins after informed consent is 
obtained and initiation of study treatment and ends 30 days following the last administration of 
study treatment or study discontinuation/termination, whichever is earlier. After this period, 
investigators should only report SAEs that are attributed to prior study treatment.
Assessment of Adverse Events
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the Rituxan 
IV/Rituxan Hycela (see following guidance), and actions taken.
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline:
Yes
There is a plausible temporal relationship between the onset of the AE and administration of 
Rituxan IV/Rituxan Hycela , and the AE cannot be readily explained by the subject’s clinical 
state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to Rituxan IV/Rituxan Hycela; and/or the AE abates or resolves upon discontinuation 
of Rituxan IV/Rituxan Hycela, or dose reduction and, if applicable, reappears upon re- 
challenge.

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No
Evidence exists that the AE has an etiology other than Rituxan IV/Rituxan Hycela  (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to Rituxan IV/Rituxan 
Hycela administration (e.g., cancer diagnosed 2 days after first dose of study drug).
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert (P.I) or current Investigator Brochure (I.B).
Unexpected adverse events are those not listed in the P.I or current I.B or not identified. This 
includes adverse events for which the specificity or severity is not consistent with the 
description in the P.I. or I.B. For example, under this definition, hepatic necrosis would be 
unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis.
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy.
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS
Eliciting Adverse Events
A consistent methodology for eliciting AEs at all subject evaluation time points should be 
adopted. Examples of non-directive questions include:

“How have you felt since your last clinical visit?”

“Have you had any new or changed health problems since you were last here?”
Specific Instructions for Recording Adverse Events
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations.
a.   Diagnosis vs. Signs and Symptoms
If known at the time of reporting, a diagnosis should be reported rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, it is 
acceptable to report the information that is currently available. If a diagnosis is subsequently 
established, it should be reported as follow-up information.
b.   Deaths
All deaths that occur during the protocol-specified AE reporting period (see Section I), 
regardless of attribution, will be reported to the appropriate parties. When recording a death, the 
event or condition that caused or contributed to the fatal outcome should be reported as the 
single medical concept. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, report “Unexplained Death”.
c.   Preexisting Medical Conditions

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A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be re-
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”).
d.   Hospitalizations for Medical or Surgical Procedures
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE.
Hospitalizations for the following reasons do not require reporting:

Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions

Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study or

Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the 
study
e.   Pregnancy
If a female subject becomes pregnant while receiving  Rituxan IV/Rituxan Hycela or within 12 
months after the last dose of Rituxan IV/Rituxan Hycela, or if the female partner of a male study 
subject becomes pregnant while the study subject is receiving Rituxan IV/Rituxan Hycela or 
within 160 days after the last dose of Rituxan IV/Rituxan Hycela, a report should be completed 
and expeditiously submitted to Genentech, Inc. 
Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, whether 
accidental, therapeutic, or spontaneous, should always be classified as serious, and expeditiously 
reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female 
subject exposed to the study drug should be reported as an SAE.
f. AEs of Special Interest (AESIs)
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the 
product, for which ongoing monitoring and rapid communication by the Investigator to 
Genentech is required. Such an event might require further investigation in order to characterize 
and understand it. Depending on the nature of the event, rapid communication by the trial 
Sponsor to other parties (e.g., Regulatory Authorities) may also be warranted.
Though there are no specific adverse event of special interest for Rituxan IV/Rituxan Hycela.
Adverse events of special interest for this study include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law:

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o
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN
o
Treatment-emergent ALT or AST  3  ULN in combination with clinical 
jaundice

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
g. Other Special Situations Reports
The following other Special Situations Reports should be collected even in the absence of an 
Adverse Event and transmitted to Genentech:

Data related to the Product usage during breastfeeding

Data related to overdose, abuse, misuse or medication error (including potentially 
exposed or intercepted medication errors)

In addition, reasonable attempts should be made to obtain and submit the age or age 
group of the patient, in order to be able to identify potential safety signals specific to a 
particular population
h. Product complaints
A Product Complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial.
i.
Post-Study Adverse Events 
For studies involving collection of survival data the investigator after the end of the adverse 
event reporting period (defined as 30 days after the last dose of study drug) should report all 
deaths, (regardless of cause), and any serious adverse event including development of cancer or a 
congenital anomaly in a subsequently conceived offspring of a female subject including 
pregnancy occurring in the partner of a male study subject who participated in the study that is 
believed to be related to prior exposure to study drug.
Case Transmission Verification will be performed by both parties during this period to ensure 
successful transmission of Single case reports. 

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 

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will be utilized for AE reporting.  All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0.  
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI 
CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention 
indicated; or limiting age-appropriate instrumental activities of 
daily living a
3
Severe or medically significant, but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; or limiting self-care 
activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAE  National Cancer Institute Common Terminology Criteria for 
Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be 
found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a.
Instrumental activities of daily living refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.
b. Examples of self-care activities of daily living include bathing, dressing and 
undressing, feeding oneself, using the toilet, and taking medications, as 
performed by patients who are not bedridden.
c.
If an event is assessed as a "significant medical event," it must be reported as a 
serious adverse event 
d. Grade 4 and 5 events must be reported as serious adverse events 

For expedited reporting purposes only:  
-
AEs related to the agent should be reported to the FDA/IRB within 24 hours of 
awareness. Other AEs for the protocol that do not require expedited reporting are 
outlined in section 7.3.4.

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

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7.3.1
Expedited AE reporting for this study must be reported to the FDA/IRB and Genentech 
within 24 hours of awareness of the event.    These requirements are briefly outlined in 
the tables below (Section 7.3.2).
7.3.2
Expedited Reporting Guidelines
Use the protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports.
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided.
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” 
under the system organ class (SOC) of the same name.  Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with a disease process) should be 
submitted. 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE:  Investigators MUST immediately report ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:  
1)
Death
2)
A life-threatening adverse event 
3)
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours 
4)
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
5)
A congenital anomaly/birth defect. 
6)
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the Sponsoring 
IRB/FDA and Genentech within the timeframes detailed in the table below.
Hospitalization
Grade 1 and Grade 2 Timeframes
Grade 3-5
Timeframes
Resulting in 
Hospitalization 
≥ 24 hrs
10 Calendar Days
Not resulting in 
Hospitalization 
≥ 24 hrs
Not required
24-Hour 5 Calendar 
Days

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Expedited AE reporting timelines are defined as:

“24-Hour; 5 Calendar Days” - The AE must initially be reported to the IRB/FDA and  
Genentech within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar 
days of the initial 24-hour report.

“10 Calendar Days” - A complete expedited report on the AE must be submitted within 
10 calendar days of learning of the AE.
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for:

All Grade 3, 4, and Grade 5 AEs
Expedited 10 calendar day reports for:

Grade 2 AEs resulting in hospitalization or prolongation of hospitalization
7.4
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions.  ALL AEs are to be 
reported through ONCORE.
EXCHANGE OF SINGLE CASE REPORTS TO GENENTECH
Dr. Kavita Dhodapkar will be responsible for collecting all protocol-defined Adverse Events 
(AEs)/Serious Adverse Events (SAEs), pregnancy reports (including pregnancy occurring in the 
partner of a male study subject), other Special Situation reports, AESIs and Product Complaints 
with an AE where the patient has been exposed to the Product. The completed MedWatch form 
should be sent to the Genentech contact specified below. Transmission of these reports (initial 
and follow-up) will be either electronically via email or by fax and within the timelines specified 
below:
Fax: 650-238-6067
Email: usds_aereporting-d@gene.com
All Product Complaints without an AE should call via:
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST)
Transmission of these reports (initial and follow-up) will be either electronically or by fax and 
within the timelines specified below:
Serious Adverse Drug Reactions (SADRs)
15 calendar days of the awareness date
Other SAEs
30 calendar days of the awareness date.
Special Situation Reports (Pregnancy) 
Special Situation Reports (Other) 
30 calendar days of the awareness date.
30 calendar days of the awareness date.
Product Complaints 
15 calendar days of the awareness date.
AESIs
15 calendar days of the awareness date.

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
Serious Adverse Drug Reactions (SADRs)
Serious AE reports that are related to the Product or where the causality is assessed as unknown 
or not provided shall be transmitted to Genentech within fifteen (15) calendar days of the 
awareness date.

Other SAEs
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech within 
thirty (30) calendar days of the awareness date.

Special Situation Reports
o
Pregnancy reports
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as defined 
herein, any reports of pregnancy (including pregnancy occurring in the partner of a male study 
subject), where the fetus may have been exposed to the Product, shall be transmitted to Genetech 
within thirty (30) calendar days of the awareness date. Pregnancies will be followed-up until the 
outcome of the pregnancy is known, whenever possible, based upon due diligence taken to 
obtain the follow-up information.
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately inform the 
investigator if their partner becomes pregnant during the study or within 160 days after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to Genentech within thirty (30) calendar days of the awareness date.
o
Other Special Situation Reports, as defined above, shall be transmitted to 
Genentech within thirty (30) calendar days of the awareness date.

Product Complaints 
All Product Complaints (with or without an AE) shall be forwarded to Genentech within fifteen 
(15) calendar days of the awareness date.

AESIs 
AESIs requiring expedited reporting (related or possibly related to Genentech product or where 
the causality is assessed as unknown or not provided) shall be forwarded to Genentech within 
fifteen (15) calendar days of the awareness date. Others (non-related to Genentech product) shall 
be sent within thirty (30) calendar days.
Case Transmission Verification of Single Case Reports
The Sponsor agrees to conduct  the Case Transmission verification to ensure that all single case 
reports have been adequately received by Genentech  via  Dr. Kavita Dhodapkar
emailing Genentech a Quarterly line-listing documenting single case reports sent by Dr. Kavita 
Dhodapkar to Genentech in the preceding time period. 
The periodic line-listing will be exchanged within seven (7) calendar days of the end of the 
agreed time period. Confirmation of receipt should be received within the time period mutually 
agreed upon.
                   
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the 

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discrepancies. The responsible individuals for each party shall handle the matter on a case-by-
case basis until satisfactory resolution.  The sponsor shall receive reconciliation guidance 
documents within the ‘Activation Package’.
Following Case Transmission Verification, single case reports which have not been received by 
Genentech shall be forwarded by Dr. Kavita Dhodapkar to Genentech within five (5) calendar 
days from request by Genentech.
At the end of the study, a final cumulative Case Transmission Verification report will be sent to 
Genentech.
MEDWATCH 3500A REPORTING GUIDELINES
In addition to completing appropriate patient demographic (Section A) and suspect medication 
information (Section C & D), the report should include the following information within the 
Event Description (Section B.5) of the MedWatch 3500A form:

Protocol number and title description 

Description of event, severity, treatment, and outcome if known

Supportive laboratory results and diagnostics (Section B.6)

Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication
Follow-Up Information

Additional information may be added to a previously submitted report by any of the 
following methods:

Adding to the original MedWatch 3500A report and submitting it as follow-up

Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form

Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-up 
information is being submitted (The patient identifiers are important so that the new 
information is added to the correct initial report)
MedWatch 3500A (Mandatory Reporting) form is available at 
https://www.fda.gov/media/69876/download
8. REPORTING TO REGULATORY AUTHORITIES, ETHICS COMMITTEES AND 
INVESTIGATORS
Genentech as the Marketing Authorization Holder will be responsible for the reporting of 
individual case safety reports from the study to the regulatory authority in compliance with 
applicable regulations.

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Dr. Kavita Dhodapkar will be responsible for the expedited reporting of safety reports 
originating from the Study to the Ethics Committees and Institutional Review Boards (IRB), 
where applicable.
Dr. Kavita Dhodapkar, as the Sponsor of the Study, will be responsible for the expedited 
reporting of safety reports originating from the Study to the EMA through Eudravigilance 
Clinical Trial Module (EVCTM).
Dr. Kavita Dhodapkar will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations. 
Dr. Kavita Dhodapkar will be responsible for the distribution of safety information to Emory 
IRB:
Emory IRB
1599 Clifton Rd NE, 5th Floor
Atlanta GA 30322
Tel: 404-712-0720
Fax: 404-727-1358
For questions related to safety reporting, please contact Genentech Drug Safety:
Tel: (888) 835-2555
Fax: (650) 225-4682 or (650) 225-4630
Other REPORTS 
 
Investigator will forward a copy of the Publication to Genentech upon completion of the Study.
8.1
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. 
All secondary malignancies that occur following treatment with an agent under an IND/IDE 
must be reported through ONCORE.  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. 
8.2
Second Malignancy

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A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  
STUDY CLOSE-OUT
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech. Copies of such reports should be mailed to the assigned Clinical Operations contact 
for the study:
[Clinical Operations Contact Information 
] rituxan-gsur@gene.com
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com
QUERIES
Queries related to the Study will be answered by the Dr. Kavita Dhodapkar or study 
staff. However,  responses  to  all  safety  queries  from  regulatory  authorities  or  
for publications will be discussed and coordinated between the Parties. The Parties 
agree that Genentech shall have the final say and control over safety queries relating 
to the Product. Dr. Kavita Dhodapkar agrees that it shall not answer such queries 
from regulatory authorities and other sources relating to the Product independently 
but shall redirect such queries to Genentech.
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent requests 
for information or review of data are met. The Parties will clearly indicate on the request the 
reason for urgency and the date by which a response is required.
SAFETY CRISIS MANAGEMENT
In case of a safety crisis, e.g., where safety issues have a potential impact on the 
indication(s), on the conduct of the Study, may lead to labeling changes or 
regulatory actions that limit or restrict the way in which the Product is used, or 
where there is media involvement, the Party where the crisis originates will contact 
the other Party as soon as possible.  
The Parties agree that Genentech shall have the final say and control over safety crisis 
management issues relating to the Product. Dr. Kavita Dhodapkar agrees that it shall not answer 
such queries from media and other sources relating to the Product but shall redirect such queries 
to Genentech.
COMPLIANCE WITH PHARMACOVIGILANCE AGREEMENT / AUDIT
The Parties shall follow their own procedures for adherence to AE reporting timelines. 

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Each Party shall monitor and, as applicable, request feedback from the other Party regarding AE 
report timeliness in accordance with its own procedures. The Parties agree to provide written 
responses in a timely manner to inquiries from the other Party regarding AE reports received 
outside the agreed upon Agreement timelines. If there is any detection of trends of increasing or 
persistent non-compliance to transmission timelines stipulated in this Agreement, both Parties 
agree to conduct ad hoc or institute a regular joint meeting to address the issue.
In case of concerns related to non-compliance of processes, other than exchange timelines, with 
this Agreement, the Parties will jointly discuss and collaborate on clarifying and resolving the 
issues causing non-compliance. Every effort will be made by the non-compliant Party to solve 
the non-compliance issues and inform the other Party of the corrective and preventative actions 
taken.
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an audit 
under the provisions of this Agreement can be requested by either Party. The Parties will then 
discuss and agree in good faith upon the audit scope, agenda and execution of the audit. The 
requesting Party will bear the cost of the audit.
How to file a complaint?
For all Investigator Initiated Studies (interventional and non-interventional):

For Non-Interventional Investigator Initiated Studies:
us-acmo-d@gene.com
9. PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1.
9.1
Investigational Agent(s)
Rituxan Hycela:
Mechanism of Action 
Rituximab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of 
pre-B and mature B-lymphocytes. Upon binding to CD20, rituximab mediates B-cell lysis. 
Possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and 
antibody dependent cell mediated cytotoxicity (ADCC). Hyaluronan is a polysaccharide found in 
the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring 
enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, 
hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase human increases 
permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses 
administered, hyaluronidase human in RITUXAN HYCELA acts locally. 
The effects of hyaluronidase human are reversible and permeability of the subcutaneous tissue is 
restored within 24 to 48 hours. 

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Hyaluronidase human has been shown to increase the absorption rate of a rituximab product into 
the systemic circulation when given in the subcutis of Göttingen Minipigs.
Rituxan Hycela is given IV Rituximab as first dose followed by rituxan hycela subcutaneously 
for subsequent doses for those without severe infusion reactions.
DESCRIPTION 
RITUXAN HYCELA is a combination of rituximab and hyaluronidase human. Rituximab is a 
genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed 
against the CD20 antigen. Rituximab has an approximate molecular weight of 145 kD. 
Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM. Rituximab is 
produced by mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium 
that may contain the antibiotic gentamicin. Gentamicin is not detectable in the final product. 
Recombinant human hyaluronidase is an endoglycosidase used to increase the dispersion and 
absorption of co-administered drugs when administered subcutaneously. It is produced by 
mammalian (Chinese Hamster Ovary) cells containing a DNA plasmid encoding for a soluble 
fragment of human hyaluronidase (PH20). It is a glycosylated single-chain protein with an 
approximate molecular weight of 61 kD. 
RITUXAN HYCELA (rituximab and hyaluronidase human) Injection is a colorless to yellowish, 
clear to opalescent solution supplied in sterile, preservative-free, single-dose vials for 
subcutaneous administration. 
RITUXAN HYCELA is supplied as 1,400 mg rituximab and 23,400 Units hyaluronidase human 
per 11.7 mL in single-dose vials or 1,600 mg rituximab and 26,800 Units hyaluronidase human 
per 13.4 mL in single-dose vials. Each mL of solution contains rituximab (120 mg), 
hyaluronidase human (2,000 Units), L-histidine (0.53 mg), L-histidine hydrochloride 
monohydrate (3.47 mg), L-methionine (1.49 mg), polysorbate 80 (0.6 mg), α,α-trehalose 
dihydrate (79.45 mg), and Water for Injection.
9.1.1
Agent Ordering and Agent Accountability
9.1.1.1
Rituxan be requested by the Principal Investigator (or their authorized designee) at 
Emory.  
9.1.1.2
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, will maintain a careful record of the inventory and disposition of all 
agents 
9.2
Commercial Agent(s)
The following commercial agents used to treat melanoma will be utilized as part of standard of 
care. Please refer to the manufacturer package insert for details.

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Nivolumab, commercial supply.
 Preparation for Administration
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. Nivolumab is a clear to opalescent, colorless to pale-yellow solution. Discard
the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than 
a few translucent-to-white, proteinaceous particles. Do not shake the vial.
• Withdraw the required volume of nivolumab and transfer into an intravenous container.
• Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, 
USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL.
• Mix diluted solution by gentle inversion. Do not shake.
• Discard partially used vials or empty vials of nivolumab.
Storage of Infusion
The product does not contain a preservative. After preparation, store the nivolumab infusion 
either:
• at room temperature for no more than 4 hours from the time of preparation. This includes room 
temperature storage of the infusion in the IV container and time for administration of the 
infusion or
• under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from
the time of infusion preparation. Do not freeze.
Administration
Administer the infusion over 30 minutes through an intravenous line containing a
sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 
micrometer). Do not coadminister other drugs through the same intravenous line. Flush the 
intravenous line at end of infusion.  
Dosage forms
Injection: 40 mg/4 mL (10 mg/mL) and 100 mg/10 mL (10 mg/mL)  and 240mg/24mL 
(10mg/mL) solution
Ipilimumab, commercial supply.
Preparation for administration
Do not shake product.
• Inspect parenteral drug products visually for particulate matter and discoloration prior to 
administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution may 
have pale-yellow color), or there is foreign particulate matter other than translucent-to-white, 
amorphous particles.
• Allow the vials to stand at room temperature for approximately 5 minutes prior to preparation 
of infusion.
• Withdraw the required volume of ipilimumab and transfer into an intravenous bag.
• Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP
to prepare a diluted solution with a final concentration ranging from 1 mg/mL to
2 mg/mL. Mix diluted solution by gentle inversion.

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Storage of infusion
• Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 36°F to 
46°F) or at room temperature (20°C to 25°C, 68°F to 77°F).
• Discard partially used vials or empty vials of ipilimumab.
Administration Instructions
• Do not mix ipilimumab with, or administer as an infusion with, other medicinal products.
• Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose
Injection, USP after each dose.
• Administer diluted solution over 90 minutes through an intravenous line containing a
sterile, non-pyrogenic, low-protein-binding in-line filter. 
Dosage forms
Injection: 50 mg/10 mL (5 mg/mL)
Injection: 200 mg/40 mL (5 mg/mL)
10. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
This protocol involves extensive correlative studies to gain fundamental insights into the effects 
of B cell depletion in the setting of immune checkpoint blockade. 
Specimens:
Both blood and tissue specimens will be analyzed.
Time-points:
Pre and Post treatment tissue samples
Pre and Post-treatment peripheral blood mononuclear cells.
Assays:
Mass cytometry.
Gene expression, including single cell sequencing.
B and T cell receptor sequencing
Functional assays
Immunohistochemistry
Change cycle below to show nivo being administered on week 13
10.1
Laboratory Correlative Studies
10.1.1 Title – Peripheral Blood for immune analysis to be drawn any time prior to the cycle of 
treatment as long as it’s the same day as treatment 
10.1.1.1
Collection of Specimen(s): collect 40-60 ml in green top heparin anticoagulant.
10.1.1.2
Handling of Specimens(s): keep at room temperature. 
10.1.1.3
Shipping of Specimen(s): call Dhodapkar lab for pickup. 
10.1.1.4
Site(s) Performing Correlative Study; Dhodapkar lab

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10.1.2 Title – Tissue for immune analysis
10.1.2.1
Collection of Specimen(s): Fresh tissue from operating room
10.1.2.2
Handling of Specimens(s): keep at room temperature.
10.1.2.3
Shipping of Specimen(s): call Dhodapkar lab for pickup.
10.1.2.4
Site(s) Performing Correlative Study: Dhodapkar lab.  

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11. STUDY CALENDAR
Schedules shown in the Study Calendar below are provided as an example and should be 
modified as appropriate.
Baseline evaluations are to be conducted within 3 weeks prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.
All protocol visits have a plus or minus 3 business day window.
Rituxan should be given after ipi/nivo infusion for subjects on Arm B. The timing of Rituxan is 
1-2 days (preferably 1 day) following ipi-nivo infusion. 
Pre-
Study
Wk
1
Wk
2
Wk
3
Wk
4
Wk
5
Wk
6
Wk
7
Wk
8
Wk
9
Wk
10
WK
12
Wk
13
WK
17
WK
21
Off Study
IPI 3mg/kg + Nivo 1mg/kg
X
X
X
X
Nivo 480mg IVa
X
X
X
Rituxan IV (loading dose)
X
Rituxan SQ
X
X
X
Informed consent
X
Demographics
X
Medical history
X
Con Medications
X
X
X
X
X
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
CBC w/diff, plts
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry with LDH
X
X
X
X
X
X
X
X
X
X
X
EKG (12-lead)
X
Adverse Event
X
X
X
X
X
X
X
X
X
X
X
Radiologic Evaluationb
X
X
B-HCG
X
Hepatitis B (HepB surface 
antigen and HepB core 
antibody), Hep C and HIV 
serology
X
TSH, Free T, ACTH, cortisol
X
X
X
X
X
X
X
X
Blood correlative 
X
X
X
X
X
X
Fresh Tissue Biopsyc
X
X

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a given every 4 weeks starting at Week 13 for up to 13 doses.
b CT scans n/c/a/p with contrast every 12 weeks for the first two years, then every 6 months for 
five years. MRI brain with contrast should be done at baseline, then every 6 months for patients 
with no history of CNS mets as per standard of care; every 3 months for those with a history of 
CNS metastases for two years, then every 6 months. CT head can be used for patients with a 
contraindication to MRI. 
C Tissue biopsy before week 4 is optional but encouraged whenever possible.

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12. MEASUREMENT OF EFFECT
12.1
Antitumor Effect 
For the purposes of this study, patients should be re-evaluated for response every 12 weeks.  
Please see study calendar for details on scan requirements. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
12.1.1 Definitions
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with ipilimumab/nivolumab. 
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. 
12.1.2 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 by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol.
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 

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lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered 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. 
12.1.3 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 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 or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).  
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.
12.1.4 Response Criteria
12.1.4.1
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.
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 

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20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
12.1.4.2
Evaluation of Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis).
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator).
12.1.4.3
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.
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
CR
Not evaluated
No
PR
PR
Non-CR/Non-
No
PR
>4 wks. Confirmation**

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PD/not 
evaluated
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks. from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        Only for non-randomized trials with response as primary endpoint.
***      In exceptional circumstances, unequivocal progression in non-target lesions may be
            accepted as disease progression.
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD

‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised
12.1.5 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).
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented.
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 

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12.1.6 Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or 
death or last follow-up, whichever occurs first.
12.1.7 Response Review
Response will be measured by RECIST criteria.  
13. 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).
13.1
Data Reporting
13.1.1 Method
Cumulative protocol- and patient-specific data will be submitted electronically into 
ONCORE monthly. 
13.1.2 Responsibility for Data Submission
Study staff are responsible for submitting data and/or data forms in ONCORE per 
Winship SOP 4.2 Data Completion Metrics.  Data completion will be reviewed monthly. 
In situations where there are significant delays of data completion, the PI may 
temporarily suspend enrollment. Data entry is to be completed within the designated 
timeframe, not to exceed 30 days of the subject visit. 
Queries will be resolved by the research staff within the time frame specified by the 
protocol, not to exceed 2 weeks. 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will 
provide oversight for the conduct of this study.  The DSMC functions independently within 
Winship Cancer Institute to conduct internal monitoring functions to ensure that research being 
conducted by Winship Cancer Institute Investigators produces high-quality scientific data in a 
manner consistent with good clinical practice (GCP) and appropriate regulations that govern 
clinical research.    Depending on the risk level of the protocol, the DSMC review may occur 
every 6 months or annually.  For studies deemed High Risk, initial study monitoring will occur 
within 6 months from the date of the first subject accrued, with 2 of the first 5 subjects being 
reviewed.  For studies deemed Moderate Risk, initial study monitoring will occur within 1 year 
from the date of the first subject accrued, with 2 of the first 5 subjects being reviewed.  
Subsequent monitoring will occur in routine intervals per the Winship Data and Safety 
Monitoring Plan (DSMP). 

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The DSMC will review pertinent aspects of the study to assess subject safety, compliance with 
the protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute 
Internal Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, 
accuracy and availability of source documents, AEs/SAEs, and essential regulatory documents.  
Following the monitoring review, monitors will provide a preliminary report of monitoring 
findings to the PI and other pertinent individuals involved in the conduct of the study.  The PI is 
required to address and respond to all the deficiencies noted in the preliminary report.  Prior to 
the completion of the final summary report, monitors will discuss the preliminary report 
responses with the PI and other team members (when appropriate).  A final monitoring summary 
report will then be prepared by the monitor.  Final DSMC review will include the final 
monitoring summary report with corresponding PI response, submitted CAPA (when applicable), 
PI Summary statement, and available aggregate toxicity and safety data.  
The DSMC will render a recommendation and rating based on the overall trial conduct.  The PI 
is responsible for ensuring that instances of egregious data insufficiencies are reported to the IRB.  
Continuing Review submissions will include the DSMC recommendation letter.  Should any 
revisions be made to the protocol-specific monitoring plan after initial DSMC approval, the PI 
will be responsible for notifying the DSMC of such changes.  The Committee reserves the right 
to conduct additional audits if necessary.
14. STATISTICAL CONSIDERATIONS
14.1
Study Design/Endpoints
Endpoints:
Primary:

Primary endpoint is the rate of CTC (v5.0) grade 3 or greater immune-related adverse 
events at 6 months of follow up.
Secondary:

Rate of CTC (v5.0) toxicity related to Rituxan.

Objective tumor response as assessed by RECIST v1.1 and irRECIST at 12 weeks and 
every 12 weeks thereafter.

Rates of overall and progression-free survival at 1 year following initiation of therapy.
14.2
Sample Size/Accrual Rate
This is an open-label, 2-arm phase Ⅱ clinical trial to study the differential effect in the risk of 
IRAEs between treatment and control groups. A sample size of 22 patients per arm (44 total) will 
provide us approximately 80% power to detect a 40% difference in the rates of developing 
>grade 3 IRAE within 6 months follow up between the control and the treatment arm (estimated 
to be 60% in the control arm, Callahan et al; J Clin Oncol. 2017 Dec 1;35(34):3815-3822). The 
sample size calculation is based on Fisher’s exact test at a one sided significance level of 0.05 
under the following assumptions:  1). Patients will be randomized in 1:1 ratio of the treatment to 
control arm. 2). Approximately 60% patients in the placebo arm will develop > grade 3 IRAE 

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within 6 months based on our pilot study. 3). The treatment will reduce the rate of > grade 3 
IRAE to 20% in the treatment arm. In a recent study, the rate of objective response following 
combination checkpoint blockade was 42% (Callahan et al; J Clin Oncol. 2017 Dec 
1;35(34):3815-3822). In order to monitor potentially adverse impact of Rituxan on checkpoint 
blockade, we will utilize early stopping rules based on an adaptive design wherein trial will be 
stopped if we have strong evidence of rates of objective response of <30%. The trial will be 
stopped early in the unlikely event that less than 2 patients among the first 12 patients treated by 
Rituxan respond to therapy. If the rate of objective response is > 30%, the probability that at least 
two out of first twelve patients will achieve an objective response of at least a PR for the first 12 
patients is approximately 92%. Hazard ratios and corresponding two-sided 95% confidence 
intervals will be estimated using Cox-proportional hazards model, with the treatment group as a 
single covariate. Progression-free and overall survival curves, median with 95% confidence 
intervals, and progression-free survival rates at 6 months will be estimated with the use of 
Kaplan-Meier method. Biostatistics support for the study will be provided by biostatistics core 
resource of Winship Cancer Center.
Newly diagnosed patients as well as patients that have previously received anti-PD-1 therapy in 
adjuvant setting will be randomized as separate groups equally between the two arms. This will 
allow us to normalize the ORR between the two groups. ORR will be calculated for every 10 
patients enrolled. The trial will be stopped early if there is a difference in ORR of greater than 
30% between the two arms. 

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REFERENCES
1.
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved 
survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 
2010;363(8):711-23.
2.
Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. 
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory 
melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 
2015;16(8):908-18.
3.
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab 
versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-32.
4.
Wolchok JD. PD-1 Blockers. Cell. 2015;162(5):937.
5.
D'Angelo SP, Larkin J, Sosman JA, Lebbe C, Brady B, Neyns B, et al. Efficacy and 
Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With 
Mucosal Melanoma: A Pooled Analysis. J Clin Oncol. 2017;35(2):226-35.
6.
Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. 
Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced 
melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, 
phase 2 trial. Lancet Oncol. 2016;17(11):1558-68.
7.
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined 
Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 
2015;373(1):23-34.
8.
Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. 
Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 
2015;372(21):2006-17.
9.
Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. 
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N 
Engl J Med. 2017;377(14):1345-56.
10.
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. 
Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-33.
11.
Sznol M, Ferrucci PF, Hogg D, Atkins MB, Wolter P, Guidoboni M, et al. Pooled 
Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients 
With Advanced Melanoma. J Clin Oncol. 2017:JCO2016721167.
12.
Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, Carbonnel F, et al. Safety 
profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin 
Oncol. 2016;13(8):473-86.
13.
Long GV, Atkinson V, Cebon JS, Jameson MB, Fitzharris BM, McNeil CM, et al. 
Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients 
with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol. 
2017;18(9):1202-10.
14.
Curran MA, Montalvo W, Yagita H, and Allison JP. PD-1 and CTLA-4 combination 
blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within 
B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107(9):4275-80.
15.
Uno T, Takeda K, Kojima Y, Yoshizawa H, Akiba H, Mittler RS, et al. Eradication of 
established tumors in mice by a combination antibody-based therapy. Nat Med. 

Winship Protocol #: Winship4457-18
Version Date: 04-05-2021  v6.0
47
2006;12(6):693-8.
16.
Dranoff G. Experimental mouse tumour models: what can be learnt about human cancer 
immunology? Nat Rev Immunol. 2011;12(1):61-6.
17.
Das R, Bar N, Ferreira M, Newman AM, Zhang L, Bailur JK, et al. Early B cell changes 
predict autoimmunity following combination immune checkpoint blockade. J Clin Invest. 
2018;128(2):715-20.
18.
Hopkins AM, Rowland A, Kichenadasse G, Wiese MD, Gurney H, McKinnon RA, et al. 
Predicting response and toxicity to immune checkpoint inhibitors using routinely 
available blood and clinical markers. Br J Cancer. 2017;117(7):913-20.
19.
Somasundaram R, Zhang G, Fukunaga-Kalabis M, Perego M, Krepler C, Xu X, et al. 
Tumor-associated B-cells induce tumor heterogeneity and therapy resistance. Nat 
Commun. 2017;8(1):607.

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