Clinical trial NCT03636503
Conditions: Follicular Lymphoma
Keywords: Lymphoma
Sponsor: Dana-Farber Cancer Institute
Start date: 2018-10-30; Completion date: 2023-07-30
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study is studying several new investigational drug combinations as a possible treatment for follicular lymphoma.

The drugs involved are:

* Rituximab
* Utomilumab
* Avelumab
* PF-04518600

Detailed description:
This research study is a Phase 1 clinical trial. Phase 1 clinical trials test the safety of an investigational intervention and also try to define the appropriate dose of the investigational intervention to use for further studies. "Investigational" means that the intervention is being studied.

Utomilumab and avelumab are drugs which may stimulate the immune system against tumor cells. Because they activate the immune system, they are sometimes called immunotherapy drugs. The FDA (the U.S. Food and Drug Administration) has not approved utomilumab or avelumab for treatment of this cancer.

Rituximab is approved by the FDA (the U.S. Food and Drug Administration) as a treatment option for this disease.

The purpose of this research is to learn about the effects of combining the immunotherapy drugs utomilumab and avelumab with rituximab in follicular lymphoma. The investigators hope to learn how safe the combinations of treatments are for participants with follicular lymphoma.

Arms: arm 1: * Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only
* Utomilumab is administered intravenously over 1 hour once every 4 weeks
* Avelumab is administered intravenously over 1 hour once every 2 weeks, 3mg/kg arm 2: * Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only
* Utomilumab is administered intravenously over 1 hour once every 4 weeks
* Avelumab is administered intravenously over 1 hour once every 2 weeks, 10mg/kg arm 3: -PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg arm 4: * Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only
* PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg arm 5: * Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only
* Utomilumab is administered intravenously over 1 hour once every 4 weeks
* PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg arm 6: * Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only
* Utomilumab is administered intravenously over 1 hour once every 4 weeks
* Avelumab is administered intravenously over 1 hour once every 2 weeks, 3mg/kg arm 7: * Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only
* Utomilumab is administered intravenously over 1 hour once every 4 weeks
* Avelumab is administered intravenously over 1 hour once every 2 weeks, 10mg/kg
Interventions: intervention 1: Rituximab intervention 2: Utomilumab intervention 3: Avelumab intervention 4: PF04518600
Intervention descriptions: intervention 1: Rituximab works by targeting the CD20 antigen on normal and malignant B-cells. Then the body's natural immune defenses are recruited to attack and kill the marked B-cells. Stem cells (young cells in the bone marrow that will develop into the various types of cells) do not have the CD20 antigen. This allows healthy B-cells to regenerate after treatment intervention 2: Utomilumab is a drug which may stimulate the immune system against tumor cells. Because it activate the immune system, it is sometimes called immunotherapy drug intervention 3: Avelumab is a drug which may stimulate the immune system against tumor cells. Because it activate the immune system, it is sometimes called immunotherapy drug intervention 4: In the presence of tumor-associated antigens (TAAs), this may promote a T-cell-mediated immune response against TAA-expressing tumor cells. OX40

Protocol documents:
Prot_SAP_000.pdf: 
DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
 
 
 
 
NCI Protocol #: 
N/A 
 
DF/HCC Protocol #: 18-311 
 
TITLE:  A Multi-Cohort Phase 1b Clinical Trial of Rituximab in Combination with 
Immunotherapy in Untreated and Previously Treated Follicular Lymphoma 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
*Principal Investigator (PI): 
Caron Jacobson, MD 
 
Dana-Farber Cancer Institute 
 
450 Brookline Avenue, Boston MA 02215 
 
(p): 617-632-5847 
 
(f): 617-582-7890 
 
Caron_Jacobson@DFCI.HARVARD.EDU  
 
Other Investigators: 
DFCI: Philippe Armand, MD, PhD; Arnold Freedman, MD; 
Ann LaCasce, MD; David C Fisher, MD; Matthew Davids, 
MD; Jennifer R. Brown, MD, PhD; Eric Jacobsen, MD; Oreofe 
Odejide, MD; Samuel Ng, MD, PhD; Austin Kim, MD; 
Jennifer Crombie, MD; Reid Merryman, MD; Benjamin 
Lampson, MD, PhD; Erin Parry, MD, PhD; Katherine 
Stephans, NP; Barbara Virchick, APRN; Josie Bazemore, NP; 
Sharyn Kurtz, PA-C; Kaitlen Reyes, DNP 
 
City of Hope: Matthew Mei, MD 
 
Emory: Jonathon Cohen, MD 
 
University of Chicago: Justin Kline, MD 
 
Washington University: Neha Mehta-Shah, MD 
 
Yale University: Iris Isufi, MD  
 
Statistician: 
Robert Redd 
 
 
 
 
 
Dana-Farber Cancer Institute 
 
Robert_Redd@DFCI.HARVARD.EDU  
  
 
 
Agents:  Rituximab (commercial supply); Utomilumab (investigational, supplied by Pfizer); PF-
04518600 (investigational, supplied by Pfizer); Avelumab (investigational, supplied by 
Pfizer) 
 
IND #:  138620 
IND Sponsor: Caron Jacobson, MD 
 
Protocol Version # / Version Date: Version 11 / 18 February 2021 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
1 
 
SCHEMA 1: RELAPSED/REFRACTORY DOSE ESCALATION AND EXPANSION DESIGN 
 
 
A1a, dose level 1: Rituximab (or rituximab biosimilar) 375mg/m2 IV q7 days x 4 doses, utomilumab 100mg IV q28d, avelumab 3mg/kg IV q14 days;  
A1a, dose level 2: Rituximab (or rituximab biosimilar) 375mg/mg2 IV q7 days x 4 doses, utomilumab 100mg IV q28d, avelumab 10mg/kg IV q14 days;  
A2a, dose level 0: PF-04518600 0.3mg/kg IV q14 days;  
A2a, dose level 1: Rituximab (or rituximab biosimilar) 375mg/m2 IV q7 days x 4 doses, PF-04518600 0.3mg/kg IV q14 days;  
A2a, dose level 2: Rituximab (or rituximab biosimilar) 375mg/m2 IV q7 days x 4 doses, PF-04518600 0.3mg/kg IV q14 days, utomilumab 100mg IV q28 days;  
A3a, dose level 1: Rituximab (or rituximab biosimilar) 375mg/m2 IV q7 days x 4 doses, PF-04518600 0.3mg/kg IV q14 days, avelumab 3mg/kg IV q14 days;  
A3a, dose level 2: Rituximab (or rituximab biosimilar) 375mg/m2 IV q7 days x 4 doses, PF-04518600 0.3mg/kg IV q14 days, avelumab 10mg/kg IV q14 days;  
RP2D: recommended phase 2 dose (if 0/3 or 1/6 DLTs at dose level 2 for a given cohort, this will be dose level 2; if 2+/6 DLTs at dose level 2 for a given cohort, this will be dose 
level 1; n=15 patients in total at a given dose) 
 
0/3 or 1/6 DLTs 


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Protocol Version Date: 18 February 2021 
 
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SCHEMA 2: CRITERIA TO OPEN, AND EARLY STOPPING RULES FOR, PREVIOUSLY UNTREATED COHORTS  
 
 
 
B1: Rituximab (or rituximab biosimilar) 375mg/mg2 IV q7 days x 4 doses, utomilumab 100mg IV q28d, avelumab at the RP2D IV q14 days;  
B2: Rituximab (or rituximab biosimilar) 375mg/m2 IV q7 days x 4 doses, PF-04518600 0.3mg/kg IV q14 days, utomilumab 1.2mg/kg IV q28 days;  
Early stopping rule: a cohort will be closed if >2 patients at any point meet the criterion for DLT. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
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SCHEMA 3: TREATMENT CYCLES AND RESPONSE ASSESSMENTS ON STUDY 
 
Tumor Restaging 
Tumor Restaging 
If no PD, observation 
and follow-up for 2 
years 
 
Then survival follow-up 
for 3 years 
PR       Partial remission 
SD       Stable disease 
PD       Progressive disease 
IR        Indeterminate 
CR, PR, SD, or IR by LyRIC criteria 
Cohort 
A1:  
x3 cycles 
Cohort A2:  
x3 cycles 
Cohort 
A3:  
x3 cycles 
CR, PR, SD, or IR by LyRIC criteria 
Cohort 
B1:  
x3 cycles 
Cohort B2:  
x3 cycles 
Off Study 
Tumor Restaging 
Tumor Restaging 
PD by 
LyRIC 
Cohort 
A1:  
x3 cycles 
Cohort A2:  
x3 cycles 
Cohort 
A3:  
x3 cycles 
Cohort 
B1:  
x3 cycles 
Cohort B2: 
x3 cycles 
Previously Untreated Follicular Lymphoma 
Relapsed/Refractory Follicular Lymphoma 


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Protocol Version Date: 18 February 2021 
 
4 
 
TABLE OF CONTENTS 
 
SCHEMA 1: RELAPSED/REFRACTORY DOSE ESCALATION AND EXPANSION 
DESIGN ...............................................................................................................................1 
SCHEMA 2: CRITERIA TO OPEN, AND EARLY STOPPING RULES FOR, PREVIOUSLY 
UNTREATED COHORTS ..................................................................................................2 
SCHEMA 3: TREATMENT CYCLES AND RESPONSE ASSESSMENTS ON STUDY ...........3 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Study Design ............................................................................................................8 
1.2 
Primary Objectives ...................................................................................................8 
1.3 
Secondary Objectives ...............................................................................................8 
1.4 
Exploratory Objectives ............................................................................................9 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Follicular Lymphoma (FL) ......................................................................................9 
2.2 
General Rationale for Study ...................................................................................10 
3. 
PARTICIPANT SELECTION ...........................................................................................15 
3.1 
Eligibility Criteria ..................................................................................................15 
3.2 
Exclusion Criteria ..................................................................................................16 
3.3 
Inclusion of Women and Minorities ......................................................................18 
4. 
REGISTRATION PROCEDURES ...................................................................................19 
4.1 
General Guidelines for DF/HCC Institutions ........................................................19 
4.2 
Registration Process for DF/HCC Institutions .......................................................19 
4.3 
General Guidelines for Other Investigative Sites ..................................................19 
4.4 
Registration Process for Other Investigative Sites .................................................19 
5. 
TREATMENT PLAN ........................................................................................................20 
5.1 
Study Design ..........................................................................................................20 
5.2 
Treatment Regimen ................................................................................................23 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................26 
5.4 
Criteria for Taking a Participant Off Protocol Therapy .........................................28 
5.5 
Duration of Follow Up ...........................................................................................29 
5.6 
Criteria for Taking a Participant Off Study ...........................................................29 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................29 
6.1 
Special Precautions for Avelumab Administration ................................................30 
6.2 
Management of Avelumab Infusion-Related Reactions ........................................31 
6.3 
Immune-Related Adverse Events ..........................................................................32 


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6.4 
Recommended Treatment Modifications ...............................................................38 
6.5 
Treatment Delays ...................................................................................................40 
6.6 
Dose Reductions ....................................................................................................40 
6.7 
Management of Immune-Related Adverse Events ................................................40 
6.8 
Management of Infusion-Related Reactions ..........................................................41 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................41 
7.1 
Expected Toxicities ................................................................................................41 
7.2 
Adverse Event Reporting .......................................................................................45 
7.3 
Reporting to the Food and Drug Administration (FDA) .......................................46 
7.4 
Expedited Reporting to Pfizer ................................................................................46 
7.5 
Reporting to Hospital Risk Management ...............................................................48 
7.6 
Routine Adverse Event Reporting .........................................................................48 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................48 
8.1 
Investigational Product ..........................................................................................48 
8.2 
Other Agent(s) .......................................................................................................63 
9. 
BIOMARKER STUDIES ..................................................................................................65 
10. 
STUDY CALENDAR .......................................................................................................67 
10.1 
Required Data for Study Screening .......................................................................78 
10.2 
Required Data During Study ..................................................................................78 
10.3 
Required at End of Treatment (4-6 weeks from last study treatment) ...................80 
10.4 
Required during Follow-Up (every 3 months +/- 2 weeks from the end of 
treatment) ...............................................................................................................81 
11. 
MEASUREMENT OF EFFECT........................................................................................81 
11.1 
Disease Response Assessments .............................................................................81 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................83 
12.1 
Data Reporting .......................................................................................................83 
12.2 
Data Safety Monitoring ..........................................................................................83 
12.3 
Multi-Center Guidelines ........................................................................................83 
13. 
STATISTICAL CONSIDERATIONS...............................................................................84 
13.1 
Study Design/Endpoints.........................................................................................84 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................85 
13.3 
Reporting and Exclusions ......................................................................................86 
13.4 
Disclosures and Confidentiality .............................................................................86 
14. 
PUBLICATION PLAN .....................................................................................................87 
REFERENCES ..............................................................................................................................88 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................92 
APPENDIX B 
CAIRO-BISHOP CLINICAL TUMOR LYSIS SYNDROME 


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DEFINITION AND GRADING ........................................................................................93 
APPENDIX C 
DF/HCC Multi-center Data and Safety monitoring plan ...........................94 
1. 
INTRODUCTION .............................................................................................................94 
1.1 
Purpose ...................................................................................................................94 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ..................................94 
2. 
GENERAL ROLES AND RESPONSIBILITIES .............................................................95 
2.1 DF/HCC Sponsor .........................................................................................................95 
2.2 Coordinating Center .....................................................................................................96 
2.3 Participating Institution ................................................................................................96 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS..............................97 
3.1 
Protocol Distribution ..............................................................................................97 
3.2 
Protocol Revisions and Closures ...........................................................................97 
3.3 
Informed Consent Requirements ...........................................................................98 
3.4 
IRB Documentation ...............................................................................................98 
3.5 
IRB Re-Approval ...................................................................................................98 
3.6 
Participant Confidentiality and Authorization Statement ......................................98 
3.7 
DF/HCC Multi-Center Protocol Registration Policy .............................................99 
3.8 
DF/HCC Protocol Case Number ..........................................................................100 
3.9 
Safety Assessments and Toxicity Monitoring .....................................................101 
3.10 
Data Management ................................................................................................102 
4. 
REQUISITIONING INVESTIGATIONAL DRUG........................................................102 
5. 
MONITORING: QUALITY CONTROL ........................................................................103 
5.1 
Ongoing Monitoring of Protocol Compliance .....................................................103 
5.2 
Monitoring Reports ..............................................................................................103 
5.3 
Accrual Monitoring ..............................................................................................103 
6. 
AUDITING: QUALITY ASSURANCE .........................................................................103 
6.1 
DF/HCC Internal Audits ......................................................................................104 
6.2 
Audit Notifications ...............................................................................................104 
6.3 
Audit Reports .......................................................................................................104 
6.4 
Participating Institution Performance ..................................................................104 
APPENDIX D 
RESPONSE CRITERIA FOR lYMPHOMA: LUGANO 2014 and LYRIC .
 
..................................................................................................................105 
 
 
 
 
 
 
 
 


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LIST OF TABLES 
 
Table 1.  Avelumab Treatment Modifications for Symptoms of Infusion Related Reactions…31 
Table 2.  Management of Immune Related Adverse Events…………………………………...33 
Table 3.  Treatment Modifications for Treatment-Related Hematologic Toxicities …………..39  
Table 4.  Treatment of Modifications for Treatment-Related Non-Hematologic Toxicities…..39 
Table 5.  DF/HCC Reportable Adverse Events (AEs) ………………………………………...46 
 
LIST OF FIGURES 
 
Figure 1  A20 Lymphoma Model Data Showing Synergy of Simultaneous PD-L1, Anti-4-1BB, 
and Rituximab Blockade……………………………………………………………..12 
 
 


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1. OBJECTIVES 
 
1.1 
Study Design 
 
This is a multi-cohort Phase 1b open label study to assess efficacy and safety of immunotherapy 
in combination with rituximab in relapsed/refractory (R/R) and untreated follicular lymphoma 
(FL).  This study is designed to rapidly test various combinations of immunotherapeutic or 
immunomodulatory agents in both R/R and untreated FL.  For a given combination, pre-defined 
safety and efficacy benchmarks must be met in the R/R cohort before the combination can be 
tested in untreated disease.  The goals of this study are: 
1. to determine whether any of the combinations are promising enough to justify further 
testing in subsequent phase 2 studies; 
2. to explore the efficacy in untreated patients of combinations that are promising in R/R 
patients; 
3. through correlative studies, to further our understanding of the immunobiology of FL 
and the determinants of response/resistance to checkpoint blockade. 
 
Immunotherapy will consist of a combination of drugs, including utomilumab, avelumab, and 
PF-04518600. All combinations will be administered for ~6 months.  Response will be assessed 
with PET/CT scans following the completion of treatment.  Minimal residual disease (MRD) and 
progression-free survival (PFS) will be monitored as a key secondary endpoint. 
 
1.2 
Primary Objectives 
 
• To determine the recommended phase 2 dosing (RP2D) of immunotherapy 
combinations with rituximab for the treatment of relapsed/refractory or untreated 
follicular lymphoma 
• To evaluate clinical efficacy of immunotherapy in combination with rituximab in 
relapsed/refractory or untreated FL as measured by the complete response (CR) rate 
using the 2014 Lugano criteria1 
 
1.3 
Secondary Objectives 
 
• To evaluate clinical efficacy of immunotherapy in combination with rituximab in 
relapsed/refractory or untreated FL as measured by: 
o Objective response rate (2014 Lugano1) 
o Overall and complete response rate (LyRIC2) 
o PFS, overall survival (OS), and time to next treatment (TTNT)   
 PFS will be analyzed by both 2014 Lugano1 and LyRIC2 criteria 
o Objective response rate, complete response rate, and MRD negativity will be 
stratified by grade (1-2 versus 3A) and by FL International Prognostic Index 
(FLIPI)3 
• Evaluate safety of these combinations in relapsed/refractory FL and previously 
untreated FL. 
o Rate of grade 3 or higher toxicity regardless of attribution 
o Rate of grade 3 or higher toxicity at least possibly related to study treatment 


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o Rate of grade 2 or higher toxicity at least probably related to study treatment 
 
1.4 
Exploratory Objectives 
 
• 
To perform correlative laboratory studies using pre-treatment and on-treatment 
peripheral blood and tumor samples to evaluate for biomarkers of response and 
resistance 
• 
To analyze pre-treatment fecal microbiome to investigate relationship with response 
or resistance to immunotherapy 
• 
Rate of MRD negativity at 6 and 12 months 
 
 
2. BACKGROUND 
 
2.1 
Follicular Lymphoma (FL) 
 
There will be approximately 70,000 new cases of non-Hodgkin lymphoma (NHL) this year in the 
United States, and 20,000 deaths. Follicular lymphoma is the second most common B cell NHL, 
with approximately 25,000 new cases diagnosed each year in the United States.  It is the most 
common indolent B cell NHL and generally presents at advanced stage and is incurable with 
conventional therapies. Though incurable, it does tend to be chemotherapy responsive with high 
rates of initial response, but it exhibits progressively lower rates of response and remission 
duration with subsequent lines of therapy, and always with invariable relapse.  
 
Of the many effective treatment modalities for FL, overall survival benefits have not been 
demonstrated favoring one treatment approach over another, with the exception of rituximab-
containing chemotherapy versus chemotherapy alone.4,5 Increased intensity regimens have been 
shown to improve CR rates and PFS without improvement in OS. Choice of therapy has thus 
been based upon balancing efficacy and tolerability. Available treatment approaches currently 
employed in chemotherapy naïve patients include rituximab monotherapy, R-bendamustine, R-
CVP (rituximab, cyclophosphamide, vincristine, prednisone), and R-CHOP (rituximab, 
cyclophosphamide, adriamycin, vincristine, prednisone).  For the relapsed/refractory setting, 
these options remain but additional options include fludarabine-based regimens, 
radioimmunotherapy, and targeted therapies with the immunomodulatory drug lenalidomide and 
the PI3 kinase inhibitor idelalisib.6,7 Furthermore, lenalidomide has been used in combination 
with rituximab in the upfront setting and has excellent response rates, including a CR rate of 
87%.8   
 
Both autologous and allogeneic stem cell transplantation have been used for the treatment 
relapsed FL.9,10  The former may consolidate a second or third line chemotherapy remission and 
results in a median progression free survival (PFS) of 4-5 years.  The latter is currently the only 
potentially curative therapy for advanced stage FL, with a long term PFS of 60-80%, but with a 
considerable risk of morbidity and mortality.  It is thus reserved for multiply relapsed disease 
with suboptimal depth and/or duration of response.  Its efficacy, however, supports the use of 
immune strategies for the treatment of this disease.   
 


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2.2 
General Rationale for Study 
 
The success of allogeneic transplantation in FL mentioned above, as well as the preliminary 
successes of checkpoint blockade and co-stimulatory agonism mentioned below, strongly 
support the hypothesis that FL is an inherently immunosensitive malignancy.  Despite this, most 
existing therapies are cytotoxic or targeted therapies, leaving a wide opening for immunotherapy 
studies in this disease.  Fortunately, there are now a number of available therapeutic agents that 
target specific agonist and checkpoint pathways and that so far have shown very good tolerability 
in patients with cancer.  The experience to date in FL (and more broadly in non-Hodgkin 
lymphoma) suggests that while these drugs can lead to meaningful responses, any of these drugs 
given alone will be unlikely to provide effective and durable responses in FL in the majority of 
patients.11  One of the likely reasons for this is that tumor cells can use alternative checkpoint or 
agonist pathways as escape mechanism for single pathway inhibition.  This understanding has 
paved the way for combination studies of immunotherapeutic drugs, which have already shown 
success (for example the combination of CTLA-4 and PD-1 blockade in melanoma).12  At the 
present time, we do not understand the immunobiology of FL enough to rationally predict which 
particular combination is most likely to be effective.   
 
Based on the above, we have therefore designed the present study to allow the rapid testing of 
multiple attractive combinations of co-stimulatory agonists/checkpoint 
blockade/immunomodulatory drugs, all administered in combination with CD20 blockade.  This 
will allow the empiric selection of the most promising combination(s) for further testing.  
Importantly, the extensive correlative studies that are planned may allow us to build the scientific 
understanding of FL immunobiology that should help to optimize immunotherapy combinations 
in future trials. 
 
In the following sections, we describe the various agents used in this study, and then expand on 
the rationale for their use in combination in R/R and untreated FL. 
 
2.2.1 Rationale for rituximab combined with immunotherapy in relapsed/refractory and 
previously untreated follicular lymphoma 
 
Follicular lymphoma is sensitive to immunotherapy as evidenced by the ability of allogeneic 
stem cell transplantation (alloSCT) to cure a majority of patients with advanced disease.13  
AlloSCT, however, is often prohibitively toxic.  Similarly, anti-CD19 directed CAR T cell 
therapy has yielded long term remissions in this disease but is complicated by cytokine release 
syndrome and neurotoxicity.14  This supports the investigation into novel forms of 
immunotherapy to successfully engage the patient’s own immune system to deliver long-lasting 
disease control with improved morbidity and mortality.   
Both inhibitory antibodies against the T cell inhibitory receptor PD1, and activating antibodies 
against the T cell costimulatory molecule 4-1BB have shown some promise in the clinic in this 
disease, but as single agents their efficacy appears to be limited to undefined subsets.  The anti-
PD1 antibody, nivolumab, was tested in a phase 1 study in refractory lymphoma and myeloma.11  
Ten patients had follicular lymphoma and four patients achieved a response (CR rate 10%); the 
median duration of response was not yet reached at nearly 2 years of follow-up.  Combining 
rituximab and pidilizumab, a putative anti-PD1 antibody, in patients with relapsed, rituximab 


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sensitive, follicular lymphoma yielded complete responses in just over half of patients (52%); the 
median duration of response was 20 months and the combination was well tolerated.15  However, 
these patients had disease that was sensitive to rituximab and so it is unclear the degree to which 
this response was due to pidilizumab.  Additionally, we have since learned that the mechanism of 
action of pidilizumab does not appear to work through inhibition of PD1 but is instead unknown.   
As previously mentioned, the combination of utomilumab and rituximab has been tested in 
rituximab-refractory follicular lymphoma.  This is based on preclinical data demonstrating an 
enhancement of the anti-lymphoma NK cell ADCC activity of rituximab by anti-4-1BB agonist 
mAbs.16  Using CD20+ lymphoma cell lines, it was shown that recognition of rituximab-coated 
tumor B cells induces CD137 up-regulation on human NK cells, and that subsequent stimulation 
of these NK cells with anti-CD137 mAb enhances anti-lymphoma ADCC.16  These results were 
confirmed in vivo using a syngeneic immunocompetent mouse model, and a human 
xenotransplant model of lymphoma.  The combination of utomilumab with rituximab, then, may 
restore rituximab sensitivity in patients with refractory disease.   In a phase 1/1b clinical trial, the 
combination of utomilumab and rituximab has yielded deep and durable responses in a subset of 
patients but the objective response rate has been disappointing.   
The follicular lymphoma microenvironment may hold the key to the lack of generalizable 
efficacy of immunotherapy agents when used alone or in combination with rituximab.  It is rich 
in immune cells, including PD1+ T cells and PD-L1 positive macrophages, as well as regulatory 
T (Treg) cells, all of which may result in a net inhibitory signal on tumor-directed T cells.17  We 
hypothesize that combining immunotherapy agents to shift this net inhibitory signal to an 
activation signal will improve response rates while preserving a tolerable safety profile.   
PD1 blockade and 4-1BB agonism work synergistically 
 
There is preclinical data to support the combination of anti-PD1 therapy with agonist antibodies 
against 4-1BB, although this data is in animal models that have not been validated as surrogates 
for clinical disease.  A 4-1BB agonist antibody resistant mouse MC38 colon cancer tumor model 
expressing PD-L1 was used to examine anti-tumor activity using the combination of a 4-1BB 
agonist antibody with PD-1 antagonist antibody compared with either agent alone.  Combination 
treatment of animals with 4-1BB agonist in combination with a PD-1 antagonist resulted in 
63.2% reduction in tumor growth as compared with vehicle controls (unpaired t test *p = 
0.0125).  Significant tumor growth inhibition by either agent dosed individually was not 
observed.  Consistent with the proposed mechanism for the combination, significant increases in 
CD8+ effector memory cells and tumor responsive IFN-γ producing cells were found in the 
spleens of mice treated with the combination.  In addition, preliminary toxicology data in mice 
suggest that the toxicity of an anti-4-1BB agonist is not increased by the addition of an anti-PD-1 
antagonist.  
Other pre-clinical studies indicate that PD-L1 expression confers resistance to therapeutic anti-4-
1BB antibody in mice with established tumors.  The resistance is accompanied by failure of 
antigen specific CD8+ cytotoxic TLs to destroy tumor cells without impairment of cytotoxic TL 
function.  Blockade of PD-L1 or PD-1 using mAbs could reverse this resistance and enhance 
therapeutic efficacy.18  A mastocytoma cell line negative for PD-L1, was either mock transfected 
or transfected with a PD-L1 construct.  The cells were then injected into the strain of mouse 


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where the tumor cells were derived (DBA/2).  Anti-PD-L1 mAbs were shown to abrogate the 
response to anti-4-1BB mAbs, suggesting that PD-L1 blockade might enhance the response to 
anti-4-1BB.  
The hypothesis that a triplet comprising avelumab, rituximab and utomilumab might provide 
enhanced clinical activity in B cell lymphoma has been tested in an A20 lymphoma model 
(Unpublished Pfizer data on file).  In this model the triplet combination of avelumab, 
anti-4-1BB, and rituximab resulted in a higher frequency of tumor-free mice than either of the 
corresponding doublets or monotherapy (Figure 1). 
 
Figure 1. A20 Lymphoma Model Data Showing Synergy of Simultaneous PD-L1, 
Anti-4-1BB, and Rituximab Blockade 
 
 
Doublet and triplet combinations of agonist antibodies to OX40 and 4-1BB with or without 
anti-PD1 therapy, respectively, improve efficacy preclinically 
 
Similarly, OX40 is expressed in the FL microenvironment, including on PD1+ T cells, and 
preclinical studies suggest that OX40 targeting therapy may enhance the effect of immune 
checkpoint blockade therapy.19  Specifically, high circulating and intratumoral regulatory T 
(Treg) cell levels pre-treatment has been associated with decreased PFS following chemotherapy 
and immunotherapy (rituximab and pidilizumab).  These intratumoral Tregs are activated and 
suppress the function of anti-tumoral T cells, but this suppression could be overcome in vitro 
through the addition of toll-like receptor ligands, including OX40.19   Similarly, while OX40 and 
4-1BB/PD-L1/CD20 Triplet Regress Large A20 Lymphomas
Treatments
# Tumor-Free Mice
Isotypes
0 / 8
Anti-CD20
0 / 8
Avelumab
0 / 8
Avelumab / Anti-CD20
0 / 8
Anti-4-1BB
3 / 8
Anti-4-1BB / Avelumab
4 / 8
Anti-4-1BB / Anti-CD20
4 / 8
Anti-4-1BB / Avelumab / Anti-CD20
7 / 8
1 8
2 1
2 4
2 7
3 0
3 3
0
3 0 0
6 0 0
9 0 0
1 2 0 0
1 5 0 0
1 8 0 0
A 2 0  L y m p h o m a
(S ta rtin g  tu m o r v o lu m e  ~  3 0 0  m m 3)
D a y s  P o s t T u m o r In o c u la tio n
T u m o r  V o lu m e  (m m
3 ±  S E M )
Is o ty p e e s
A n ti-4 -1 B B
A n ti-C D 2 0
A v e lu m ab
A n ti-4 -1 B B  / A n ti-C D 2 0
A n ti-4 -1 B B  / A v e lu m a b
A v e lu m a b  / A n ti-C D 2 0
A n ti-4 -1 B B  / A v e lu m a b  / A n ti-C D 2 0


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
13 
4-1BB are from the same TNFR superfamily of costimulatory molecules, they have 
complementary mechanisms that elicit distinct immune functions. Indeed, dual targeting of 
OX40 and 4-1BB has been shown to synergistically induce CD8 and cytotoxic CD4 T cell clonal 
expansion.20-22 In studies by Lee et al.20, a combination of OX40 and 4 1BB agonists induced 
tumor growth inhibition in an immunologically resistant fibrosarcoma model. In preclinical 
studies conducted by Pfizer, a combination of anti-OX40 (OX86 mIgG1) and anti-4-1BB IgG1 
mouse surrogate antibodies inhibited tumor growth by 96.4%, compared with 63.3% (4-1BB) 
and 35.3% (OX86) inhibition following single antibody treatment. In a less immunogenic B16-
F10 murine melanoma model, a combination of OX40 and 4-1BB agonists significantly 
enhanced tumor T-cell infiltration and T-cell proliferation. PF-04518600 is currently being 
tested alone and in combination with avelumab and utomilumab in advanced solid tumor 
malignancies.   
 
Preclinical studies of triplet therapy with anti-PDL1 antibodies combined with agonist antibodies 
against OX40 and 4-1BB demonstrated antitumor synergy over single or double antibody 
treatments in the MC38 colon cancer model and the B16F10 melanoma model.  The increase in 
activity seen with the triplet therapy was associated with an increased CD8 T -cell infiltration as 
well as increased T cell activation and proliferation in the peripheral blood.  In these models, 
there was no increased toxicity observed in the triplet therapy group compared to animals treated 
with any of the antibodies alone. 
 
2.2.2 Rationale for Study Design 
 
We hypothesize that although follicular lymphoma is highly sensitive to immunotherapy in the 
form of allogeneic stem cell transplant and CAR T cell therapy, the tumor microenvironment is 
sufficiently immune suppressive such that immunotherapeutic agents, including immune 
checkpoint inhibitors, as single agents have had limited success.  The long natural history of this 
disease, along with the morbidity and mortality risk of allogeneic stem cell transplant and CAR T 
cell therapy, however, make finding effective yet tolerable therapies a high priority and an unmet 
need.  Combining therapy targeting several different checkpoint pathways, in association with 
standard immunotherapy targeting CD20 (rituximab) has the potential to overcome the FL 
immunosuppressant microenvironment and could provide significant therapeutic benefit while 
retaining the relatively high tolerability characteristic of rituximab and checkpoint targeting 
monoclonal antibodies.  In addition, the incurable nature of this disease with a long natural 
history makes finding a non-chemotherapy regimen that is well tolerated a goal both in the 
upfront and relapsed setting, but it also makes accrual to clinical trials more difficult, and leads 
to a delay in moving experimental regimens into the clinic.   
 
In this study we will rapidly test a variety of immunotherapy combinations with rituximab in 
small cohorts of patients with untreated and relapsed follicular lymphoma in order to identify 
regimens with a promising efficacy and safety profile to explore further in a larger clinical trial.  
By enrolling patients sequentially into cohorts testing different immunotherapy combinations in 
the relapsed setting, and quickly moving combinations that meet a pre-specified safety and 
efficacy benchmark into testing in the upfront setting we will be able to identify combinations 
that are worth further exploration, either in cohort expansion within the current study, or in a 
larger clinical trial.  The parallel testing in both the relapsed/refractory and upfront testing will 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
14 
substantially shorten the duration of the study so that the results will be clinically useful and 
meaningful in a disease with a long natural history with many available treatment options.  


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
15 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
 
3.1.1 Patients must have histologically determined follicular lymphoma, grade 1-3A, 
with pathologic review at the participating institutions, that has either: 
• Relapsed or primary refractory after at least one line of therapy including anti-
CD-20 monoclonal antibody treatment (part A) or; 
• Has had no previous anti-lymphoma therapy other than corticosteroids or 
radiotherapy (part B).  
3.1.2 Patients with active histologic transformation are excluded.  Relapsed/refractory 
patients with prior transformation may be included as long as there is no evidence 
of transformation at the time of study entry by pathology, imaging, or clinical 
status 
3.1.3 Patients in part B, without prior anti-lymphoma therapy, must be in need of 
treatment as defined by any of the following criteria: 
• Symptomatic adenopathy 
• Organ function impairment due to disease involvement, including cytopenias 
due to marrow involvement (WBC <1.5x109/L; absolute neutrophil count 
[ANC] <1.0x109/L, Hgb <10g/dL; platelets <100x109/L) 
• Constitutional symptoms 
• Maximum diameter of disease > 7cm 
• >3 nodal sites of involvement 
• Risk of local compressive symptoms 
• Splenomegaly (craniocaudal diameter > 16cm on CT imaging) 
• Clinically significant pleural or peritoneal effusion 
• Leukemic phase (>5x109/L circulating malignant cells) 
• Rapid generalized disease progression 
• Renal infiltration 
• Bone lesions 
3.1.4 Patients may have had a prior autologous stem cell transplant and may have been 
treated with autologous chimeric antigen receptor T-cells (CAR T-cells). 
3.1.5 Not in need of urgent cytoreductive therapy in the opinion of the investigator 


DF/HCC Protocol #: 18-311 
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16 
3.1.6 Measurable disease that has not been previously irradiated on CT scans of at least 
1.5 cm, OR if the patient has had previous radiation to the marker lesion(s), there 
must be evidence of progression since the radiation. Imaging must be completed 
no greater than 6 weeks prior to study enrollment. 
3.1.7 Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see 
Appendix A) 
3.1.8 Adequate hematologic and organ function: 
• Absolute neutrophil count > 1.0x109/L unless due to marrow involvement by 
lymphoma in which case ANC must be >0.5x109/L 
• Platelets > 75 x109/L, unless due to marrow involvement by lymphoma, in 
which case platelets must be >50 x109/L 
• Creatinine < 1.5 x ULN (upper limit of normal) or estimated GFR > 40ml/min 
• Total bilirubin < 1.5 X ULN, unless Gilbert syndrome, in which case direct 
bilirubin must be < 3 x ULN 
3.1.9 AST/ALT < 2.5 X ULN, unless documented liver involvement by lymphoma, in 
which case AST/ALT must be <5 x ULN 
3.1.10 Age >18 years 
3.1.11 Ability to understand and the willingness to sign a written informed consent 
document. 
3.1.12 Willingness to provide pre-treatment (or recent archival w/o intervening therapy), 
and on-treatment tumor samples by core needle or excisional surgical biopsy 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not eligible for 
admission into the study: 
 
3.2.1 Patients currently receiving anticancer therapies or who have received anticancer 
therapies within 28 days of the start of study drug (including chemotherapy, 
radiation therapy, antibody based therapy, etc.), or 56 days for 
radioimmunotherapy. Steroids for symptom palliation are allowed, but must be 
either discontinued or on stable doses of < 10mg daily of prednisone (or the 
equivalent) at the time of initiation of protocol therapy. 
 
 


DF/HCC Protocol #: 18-311 
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17 
3.2.2 Patients may not be receiving any other investigational agents, or have received 
investigational agents within 4 weeks (or 3 half-lives, whichever is longer) of 
beginning treatment. 
3.2.3 History of severe allergic or anaphylactic reactions to monoclonal antibody 
therapy unless in consultation with an allergy specialist they are deemed eligible 
for retreatment with desensitization. 
3.2.4 Patients who have previously received therapy with any drug that works by a 
similar mechanism of action as any drug being tested in a given cohort will be 
excluded from that cohort but will be allowed to enroll in other open cohorts.  
3.2.5 Patients who have undergone prior allogeneic stem cell transplantation 
3.2.6 Patients with a history of or active autoimmune disease (except controlled asthma, 
Hashimoto thyroiditis, atopic dermatitis, and/or vitiligo), or requiring systemic 
corticosteroids at a dose of 10mg prednisone equivalent daily.  Patients with a 
history of autoimmune disease who never required corticosteroids and with no 
evidence of disease activity, and in whom the risk of reactivation is felt not to be 
serious, may be enrolled after discussion with the overall study chair.  Exceptions 
to this are patients with a history of inflammatory bowel disease (ulcerative colitis 
and Crohn’s disease).  These patients are excluded regardless of whether their 
disease is active or inactive. 
3.2.7 Patients with active pneumonitis or colitis, or patients with chronic liver disease 
and/or cirrhosis 
3.2.8 Patients, who have had a major surgery or significant traumatic injury within 4 
weeks of start of study drug, patients who have not recovered from the side 
effects of any major surgery (defined as requiring general anesthesia) or patients 
that may require major surgery during the course of the study. 
3.2.9 Patients with known leptomeningeal or brain metastases. Imaging or spinal fluid 
analysis to exclude CNS involvement is not required, unless there is clinical 
suspicion by the treating investigator. 
3.2.10 Patients with known HIV infection or hepatitis B or C infection.  Testing for HIV 
is optional.  Testing for hepatitis B and C is mandatory.  Patients with hepatitis B 
core Ab positivity but negative surface antigen and negative viral load may be 
enrolled if they can be treated with a prophylactic agent (eg, entecavir); patients 
with hepatitis C seropositivity who have undergone successful treatment with 
negative viral load can also be enrolled. 
3.2.11 Patients with a systemic fungal, bacterial, viral, or other infection not controlled 
(defined as exhibiting ongoing signs/symptoms related to the infection and 
without improvement, despite appropriate antibiotics or other treatment). 
3.2.12 Prior history of another malignancy (except for non-melanoma skin cancer or in 
situ cervical or breast cancer) unless disease free for at least three years. Patients 
with prostate cancer are allowed if PSA is less than 1. 
3.2.13 Patients should not have received immunization with attenuated live vaccine 
within one week of study entry or during study period. 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
18 
3.2.14 Female patients who are pregnant or breast feeding, or adults of reproductive 
potential who are not using effective birth control methods. Women of child 
bearing potential (WOCBP) or male study participants of reproductive potential 
must agree to use double barrier birth control method of contraception during the 
course of the study treatment period and for 3 months after completing study 
treatment. WOCBP are defined as sexually mature women who have not 
undergone a hysterectomy or who are not postmenopausal (no menses) for at least 
12 consecutive months. WOCBP must have a negative urine or serum pregnancy 
test within 14 days prior to administration of treatment. 
3.2.15 History of noncompliance to medical regimens. 
3.2.16 Patients who have any severe and/or uncontrolled medical conditions or other 
conditions that could affect their participation in the study such as: 
• New York Heart Association Class III or IV cardiac disease, including pre-
existing clinically significant arrhythmia, congestive heart failure, or 
cardiomyopathy 
• Patients with a history of previous anthracycline treatment and are at risk of 
cardiac failure (New York Heart Association Class II or above) are excluded 
from cohorts A2, A3, and B2 (cohorts that include PF-04518600) 
• Unstable angina pectoris, symptomatic congestive heart failure, myocardial 
infarction within 6 months of start of study drug, serious uncontrolled cardiac 
arrhythmia or any other clinically significant cardiac disease 
3.2.17 Patients with any one of the following currently on or in the previous 6 months 
will be excluded from cohorts A2, A3, and B2 (any cohort that includes treatment 
with PF-04518600) myocardial infarction, congenital long QT syndrome, 
torsade’s de points, left anterior hemiblock (bifascicular block), unstable angina, 
coronary/peripheral artery bypass graft, cerebrovascular accident, transient 
ischemic attack or symptomatic pulmonary embolism or other clinically 
significant episode of thrombo-embolic disease*.  Ongoing cardiac dysrhythmias 
of NCI CTCAE grade > 2, atrial fibrillation of any grade, or QTcF interval 
>470msec at screening (except in case of right bundle branch block, these cases 
must be discussed with the principal investigator). *Cases must be discussed in 
detail with the principal investigator to judge eligibility.  Anticoagulation (heparin 
only, no vitamin K antagonists or factor Xa inhibitors will be allowed if indicated. 
3.2.18 Other uncontrolled intercurrent illness that would limit adherence to study 
requirements. 
 
3.3 
Inclusion of Women and Minorities 
 
Women, minorities and underrepresented populations should be eligible for this trial at a similar 
rate to men and patients not from underrepresented populations.  The inclusion and exclusion 
criteria should not be affected by gender or ethnicity, except for the exclusion of pregnant or 
lactating women. 
 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
19 
4. REGISTRATION PROCEDURES  
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off-study in the CTMS (OnCore) with an appropriate date and reason 
entered.   
 
4.2 
Registration Process for DF/HCC Institutions 
 
Applicable DF/HCC policy (REGIST-101) must be followed.   
 
4.3 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
Project Manager.  All sites should email the Project Manager at 
Samantha_Pazienza@dfci.harvard.edu to verify dose level availabilities.   
 
Following registration, participants should begin protocol therapy within 72 hours or as soon as 
possible. Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator.  Issues that would cause treatment delays should be discussed with the Principal 
Investigator. If a participant does not receive protocol therapy following registration, the 
participant’s protocol status must be changed. The Project Manager should be notified of 
participant status changes as soon as possible. Except in very unusual circumstances, each 
Participating Institution will order the study agent(s) directly from the supplier. A Participating 
Institution may order the agent(s) only after the initial IRB approval for the site has been 
forwarded by Coordinating Center to the supplier. 
 
4.4 
Registration Process for Other Investigative Sites 
 
To register a participant, the following documents should be completed by the participating site 
and or e-mailed to Samantha_Pazienza@dfci.harvard.edu: 
• Copy of required laboratory tests required at screening (see study calendar) 
• Signed informed consent document 
• HIPAA authorization form (if separate from the informed consent document) 


DF/HCC Protocol #: 18-311 
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20 
• Completed Eligibility Checklist  
 
The participating site will then e-mail Samantha_Pazienza@dfci.harvard.edu to verify eligibility.  
The Project Manager will follow DF/HCC policy (REGIST-101) and register the participant on 
the protocol.  The Project Manager will e-mail the participant study number, and if applicable the 
dose treatment level, to the participating site.  The Project Manager will also contact the 
participating site and verbally confirm registration 
 
Treatment may not begin without confirmation from the Coordinating Center that the 
participant has been registered.  
 
5. TREATMENT PLAN 
 
5.1 
Study Design 
 
This study will consist of 3 cohorts (A1-A3) in the relapsed/refractory setting tested in two 
stages: 1) dose escalation and 2) dose expansion.  If a combination meets prespecified safety and 
efficacy endpoints in the expansion stage, and after discussion with regulatory authorities, 2 
additional cohorts (B1, B2) will open testing these combinations in the upfront setting in 
previously untreated FL patients.  
 
The cohorts for this study will be as follows: 
• Dose escalation stage:  
 
Rituximab (or 
rituximab 
biosimilar) 
Utomilumab 
Avelumab 
PF-04518600 
Cohort A1a 
Dose Level 1 
375mg/m2 IV 
q7d for 4 doses 
(cycle 1 only) 
100mg IV q28d 
cycle 1-6 
3mg/kg IV q14d 
cycle 1-6 
n/a 
Dose Level 2 
375mg/m2 IV 
q7d for 4 doses 
(cycle 1 only) 
100mg IV q28d 
cycle 1-6 
10mg/kg IV 
q14d cycle 1-6 
n/a 
Cohort A2a 
Dose Level 0 
n/a 
n/a 
n/a 
0.3mg/kg IV 
q14d cycle 1-6 
Dose Level 1 
375mg/m2 IV 
q7d for 4 doses 
(cycle 1 only) 
n/a 
n/a 
0.3mg/kg IV 
q14d cycle 1-6 
Dose Level 2 
375mg/m2 IV 
q7d for 4 doses 
(cycle 1 only) 
100mg IV q28d 
cycle 1-6 
n/a 
0.3mg/kg IV 
q14d cycle 1-6 
Cohort A3a 
Dose Level 1 
375mg/m2 IV 
q7d for 4 doses 
(cycle 1 only) 
n/a 
3mg/kg IV q14d 
cycle 1-6 
0.3mg/kg IV 
q14d cycle 1-6 
Dose Level 2 
375mg/m2 IV 
q7d for 4 doses 
(cycle 1 only) 
n/a 
10mg/kg IV 
q14d cycle 1-6 
0.3mg/kg IV 
q14d cycle 1-6 
 
 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
21 
• Dose Expansion Cohorts  
o Cohort A1b: Rituximab (or rituximab biosimilar), utomilumab, avelumab at the 
recommended phase 2 dose  
o Cohort A2b: Rituximab (or rituximab biosimilar), utomilumab, PF-04518600 at 
the recommended phase 2 dose  
o Cohort A3b: Rituximab (or rituximab biosimilar), avelumab, PF04516800 at the 
recommended phase 2 dose  
• Upfront Cohorts (B1, B2) (n=up to 15) 
o Cohort B1: Rituximab (or rituximab biosimilar), utomilumab, avelumab at the 
recommended phase 2 dose 
o Cohort B2: Rituximab (or rituximab biosimilar), utomilumab, PF-04518600 at the 
recommended phase 2 dose 
 
Enrollment will begin with the phase 1 dose escalation stage to test the safety of these 
combinations in relapsed/refractory FL and to determine the recommended phase 2 dose (RP2D) 
to use for the phase 1b dose expansion cohorts as well as for the potential upfront cohorts.   The 
cohorts in the phase 1 dose escalation stage will follow a 3+3 dose escalation schema, such that 
there will be a safety pause and evaluation after the first 3 patients at any given dose level have 
completed 6 weeks of therapy.  If there are no dose limiting toxicities (DLTs) seen, the next dose 
level will open.  If there is 1 DLT, an additional 3 patients will be enrolled at that dose level with 
a safety pause and evaluation after all 3 have completed 6 weeks of treatment. If there are 2 or 
more DLTs at any time in a given dose level, no further testing of that dose level will be done.  
If, however, there are no additional DLTs at that dose level, the next dose level will open.   The 
next dose levels will follow the same 3+3 dose escalation schema (Schema 1).  Once a 
recommended phase 2 dose is determined, this dose will be used in both the dose expansion 
cohorts as well as in the potential upfront dosing cohorts. 
 
Enrollment will begin with cohorts A1a, dose level 1, and A2a, dose level 0 in an alternating 
fashion.  Each subsequent cohort will be filled sequentially beginning with cohort A1a dose level 
2, followed by cohort A2a dose level 1, then A2a dose level 2, then A3a dose level 1, and finally 
A3a dose level 2.  If a patient is not eligible for the cohort that is being filled preferentially at the 
time of enrollment due to prior treatment history, they may be enrolled in the next cohort for 
which they are eligible.  Note, if a patient in cohort A2a, dose level 0, has not had a response by 
the midtreatment response assessment following cycle 3, they will be allowed to received 
rituximab 375mg/m2 q7d for 4 weeks during cycle 4 (C4D1, C4D8, C4D15, C4D22). 
 
Dose limiting toxicities (DLTs) are defined as any grade 3 or greater toxicity unless directly, and 
incontrovertibly, related to progressive disease with the exception of the following: 
• Grade 3 hematologic abnormalities 
• Grade 4 hematologic abnormalities that recover to grade 2 or lower with supportive 
treatment (including transfusion, IVIg, or growth factor) within 7 days 
• Non-hematologic abnormalities: 
o Transient (≤24 hours) Grade 3 fatigue, local reactions, or headache that 
resolves to Grade ≤1; 
o Grade 3-4 nausea and vomiting controlled by optimal medical therapy within 
72 hours; 


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22 
o Grade 3 hypertension controlled by medical therapy; 
o Grade 3 diarrhea that improves to Grade ≤2 within 72 hrs after medical 
management has been initiated;  
o Grade 3 skin toxicity that resolves to Grade ≤1 in less than 7 days after 
medical management (eg, immunosuppressant treatment) has been initiated; 
o Any Grade ≥3 amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis; 
o Grade 3 endocrinopathies controlled with medical therapy; 
o Tumor flare phenomenon defined as local pain, irritation, or rash localized at 
sites of known or suspected tumor. 
• Non-hematologic Grade ≥3 laboratory abnormality if medical intervention is 
required to treat the patient or the abnormality leads to hospitalization.  
o Single laboratory values out of normal range that are unlikely related to trial 
treatment according to the Investigator, do not have any clinical correlate, and 
resolve to Grade ≤1 within 7 days with adequate medical management are not 
to be considered DLTs; 
• ALT or AST >3 x upper limit of normal (ULN) (if normal at baseline) or >3 x ULN 
and doubling the baseline (if > ULN at baseline) associated with bilirubin >2 x ULN 
 
For part B (untreated disease cohorts), enrollment will open following the completion of the 
corresponding dose expansion cohort in part A (cohorts A1b and A2b), assuming that the 
corresponding cohort in part A meets its efficacy and safety criteria for success (> 3 complete 
responses and < 3 DLTs).  
 
All cohorts in part B will have an early stopping rule if >2 patients at any point meet the criterion 
for a DLT. 
 
Toxicity will be continuously monitored and recorded using CTCAE 4 criteria, up to 30 days 
following the last dose of the study treatment or until resolution of toxicity to grade 1 or baseline, 
whichever occurs last.  Response will be assessed 4-6 weeks after the completion of therapy 
(either after cycle 6 of therapy for patients who complete the planned cycles of therapy, or after 
their last dose of treatment for patients who discontinue treatment before cycle 6) by PET and 
CT scans of the neck (if involved at baseline), chest, abdomen, and pelvis, as well as at 6, 12, 
and 18 months from the end of treatment (+/- 2 weeks)  in the absence of disease recurrence or 
progression (PET may be omitted once patient is in CR).  In addition, CT scans of the chest, 
abdomen, and pelvis +/- neck will be obtained 4 weeks (+/- 1 week) after the completion of cycle 
3 while on therapy.  If patients experience evidence of progressive disease confirmed by imaging 
while on treatment, they will be allowed to complete treatment if they meet the definition of an 
indeterminate response according to LyRIC criteria.2   
 
Expected toxicities and potential risks for all drugs are described in Section 6 (Dosing 
Delays/Dose Modifications).  No investigational or commercial agents or therapies other than 
those described below may be administered with the intent to treat the participant's malignancy.  
 
 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
23 
5.2 
Treatment Regimen 
 
It is expected that treatment will be administered on an outpatient basis.  A cycle will be 28 days 
and there will be a planned 6 cycles of therapy.  Therapy will consist of the following, with each 
cohort consisting of 15 patients each: 
 
5.2.1 Cycle 1 
 
Cohort A1a: 
(i) 
Rituximab (or rituximab biosimilar) 375 mg/m2/dose intravenously per institutional 
standards for four weekly treatments for cycle 1 only, starting on day -6.   
(ii) Utomilumab 100mg intravenously over 1 hour on day 2.  
(iii) Avelumab 3mg/kg (dose level 1) or 10mg/kg (dose level 2) intravenously over 1 hour 
on day 16.   
 
Cohort A1b and B1:  
(i) 
Rituximab (or rituximab biosimilar) 375 mg/m2/dose intravenously per institutional 
standards for four weekly treatments for cycle 1 only, starting on day -6.   
(ii) Utomilumab 100mg intravenously over 1 hour on day 2.  
(iii) Avelumab at the recommended phase 2 dose intravenously over 1 hour on day 16.   
 
Cohort A2a, Dose Level 0: 
(i) 
PF-04518600 0.3mg/kg intravenously over 1 hour on day 1 and day 15. 
 
Cohort A2a, Dose Level 1:   
(i) 
Rituximab (or rituximab biosimilar) 375 mg/m2/dose intravenously per institutional 
standards for four weekly treatments for cycle 1 only, starting on day -6.   
(ii) PF-04518600 0.3mg/kg intravenously over 1 hour on day 2 and day 16.   
 
Cohort A2a, Dose Level 2: 
(i) 
Rituximab (or rituximab biosimilar) 375 mg/m2/dose intravenously per institutional 
standards for four weekly treatments for cycle 1 only, starting on day -6.   
(ii) Utomilumab 100mg intravenously over 1 hour on day 2.   
(iii) PF-04518600 0.3mg/kg intravenously over 1 hour on day 16.   
 
Cohort A2b and B2: 
(i) 
Rituximab (or rituximab biosimilar) 375 mg/m2/dose intravenously per institutional 
standards for four weekly treatments for cycle 1 only, starting on day -6.   
(ii) Utomilumab 100mg intravenously over 1 hour on day 2.   
(iii) PF-04518600 0.3mg/kg intravenously over 1 hour on day 16.   
 
Cohort A3a: 
(i) 
Rituximab (or rituximab biosimilar) 375 mg/m2/dose intravenously per institutional 
standards for four weekly treatments for cycle 1 only, starting on day -6.   


DF/HCC Protocol #: 18-311 
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24 
(ii) PF-04518600 0.3mg/kg intravenously over 1 hour on day 2 and day 15.  PF-04518600 
will be given first and must have completed administration at least 30 minutes (but a 
maximum of 28 hours) prior to rituximab (day 15)  
(iii) Avelumab 3mg/kg (dose level 1) or 10mg/kg IV (dose level 2) over 1 hour on day 16.   
 
Cohort A3b: 
(i) 
Rituximab (or rituximab biosimilar) 375 mg/m2/dose intravenously per institutional 
standards for four weekly treatments for cycle 1 only, starting on day -6.   
(ii) PF-04518600 0.3mg/kg intravenously over 1 hour on day 2 and day 15.  PF-04518600 
will be given first and must have completed administration at least 30 minutes (but a 
maximum of 28 hours) prior to rituximab (day 15)  
(iii) Avelumab at the recommended phase 2 dose intravenously over 1 hour on day 16.   
 
5.2.2 Cycle 2-6 
 
Cohort A1a: 
(i) 
Utomilumab 100mg intravenously over 1 hour once every 4 weeks x 5 (up to 5 
additional doses) on day 1 of each cycle.  Utomilumab must have completed 
administration at least 30 minutes (but a maximum of 28 hours) prior to avelumab. 
(ii) Avelumab 3mg/kg (dose level 1) or 10mg/kg (dose level 2) intravenously over 1 hour 
once every 2 weeks x 10 (up to 10 additional doses), on day 1 and day 15 of each cycle.  
On days when avelumab will be given in combination with utomilumab it must be 
given at least 30 minutes (maximum 24+/-4 hours) following the completion of 
utomilumab. 
 
Cohort A1b and B1:  
(i) 
Utomilumab 100mg intravenously over 1 hour once every 4 weeks x 5 (up to 5 
additional doses) on day 1 of each cycle.  Utomilumab must have completed 
administration at least 30 minutes (but a maximum of 28 hours) prior to avelumab. 
(ii) Avelumab at the recommended phase 2 dose intravenously over 1 hour once every 2 
weeks x 10 (up to 10 additional doses), on day 1 and day 15 of each cycle.  On days 
when avelumab will be given in combination with utomilumab it must be given at least 
30 minutes (maximum 24+/-4 hours) following the completion of utomilumab. 
 
Cohort A2a, Dose level 0: 
(i) 
PF-04518600 0.3mg/kg intravenously over 1 hour on day 1 and day 15.   
**If there is no response on midtreatment scans following cycle 3, patients may get 
Rituximab (or rituximab biosimilar) 375mg/m2 intravenously on day 1, 8, 15, and 22 of 
cycle 4, with PF-04518600 0.3mg/kg intravenously over 1 hour on day 1 and day 15 of 
this cycle. On days when rituximab will be given in combination with PF-04518600 it 
must be given at least 30 minutes (maximum 28 hours) following the completion of PF-
04518600. 
 
Cohort A2a, Dose level 1:   
(i) 
PF-04518600 0.3mg/kg intravenously over 1 hour on day 1 and day 15.   
 


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25 
Cohort A2a, Dose level 2: 
(i) 
Utomilumab 100mg intravenously over 1 hour once every 4 weeks x 5 (up to 5 
additional doses), on day 1 of each cycle.  Utomilumab must have completed 
administration at least 30 minutes (but a maximum of 28 hours) prior to PF-04518600. 
(ii) PF-04518600 0.3mg/kg intravenously over 1 hour once every 2 weeks x 10 (up to 10 
additional doses), on day 1 and day 15 of each cycle.  On days when PF-04518600 will 
be given in combination with utomilumab it must be given at least 30 minutes 
(maximum 28 hours) following the completion of utomilumab. 
 
Cohort A2b and B2: 
(i) 
Utomilumab 100mg intravenously over 1 hour once every 4 weeks x 5 (up to 5 
additional doses), on day 1 of each cycle.  Utomilumab must have completed 
administration at least 30 minutes (but a maximum of 28 hours) prior to PF-04518600. 
(ii) PF-04518600 0.3mg/kg intravenously over 1 hour once every 2 weeks x 10 (up to 10 
additional doses), on day 1 and day 15 of each cycle.  On days when PF-04518600 will 
be given in combination with utomilumab it must be given at least 30 minutes 
(maximum 28 hours) following the completion of utomilumab. 
 
Cohort A3a: 
(i) 
PF-04518600 0.3mg/kg intravenously over 1 hour once every 2 weeks x 10 (up to 10 
additional doses), on day 1 and day 15 of each cycle.  PF-04518600 will be given first 
and must have completed administration at least 30 minutes (but a maximum of 28 
hours) prior to avelumab 
(ii) Avelumab 3mg/kg (dose level 1) or 10mg/kg (dose level 2) intravenously over 1 hour 
once every 2 weeks x 10 (up to 10 additional doses), on day 1 and day 15 of each cycle.  
Avelumab will be given at least 30 minutes (maximum 28 hours) following the 
completion of PF-04518600.   
 
Cohort A3b: 
(ii) 
PF-04518600 0.3mg/kg intravenously over 1 hour once every 2 weeks x 10 (up to 10 
additional doses), on day 1 and day 15 of each cycle.  PF-04518600 will be given first 
and must have completed administration at least 30 minutes (but a maximum of 28 
hours) prior to avelumab 
(iii) 
Avelumab at the recommended phase 2 dose intravenously over 1 hour once every 2 
weeks x 10 (up to 10 additional doses), on day 1 and day 15 of each cycle.  Avelumab 
will be given at least 30 minutes (maximum 28 hours) following the completion of 
PF-04518600.   
 
 
 


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26 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are also not allowed 
during the active treatment period, except for administration of inactivated vaccines (for 
example, inactivated influenza vaccine).  If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the trial, permanent discontinuation 
from study therapy may be required.  The Investigator should consult with the Principal 
investigator about individual cases.  The final decision on any supportive therapy or vaccination 
rests with the Investigator and/or the patient’s primary physician.  However, the decision to 
continue the patient on study therapy or medication/vaccination schedule requires the mutual 
agreement of the Investigator, the Principal investigator, and the patient. Prior/concomitant 
treatment considered necessary for the patient’s well-being may be given at discretion of the 
treating physician. 
 
Concomitant medications and treatments, including herbal supplements, will be recorded from 
28 days prior to the start of study treatment and up to 90 days after the last dose of study 
treatment (at Days 30, 60, and 90 post-treatment +3 days).  Non-Drug Supportive Interventions 
should be recorded in the CRF including supportive care drugs (eg, antiemetic treatment and 
prophylaxis), and the drugs used to treat adverse events or chronic diseases, and non-drug 
supportive interventions (eg, transfusions). 
Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol acetate for 
anorexia) are allowed. 
5.3.1 Pre-medications 
 
Participants will be premedicated as outlined in Section 8.1.2.8 prior to each dose of avelumab 
and by institutional standards prior to each dose of rituximab, or as needed for utomilumab 
and/or PF-04518600. On days when patients are receiving multiple infusions, premedications do 
not need to be redosed prior to subsequent infusions unless it has been > 4 hours since their 
previous administration or since administration of medications to treat a hypersensitivity 
reaction. 
 
5.3.2 Antibiotics 
 
Prophylactic antibiotics or anti-virals are not required on this trial. 
 
5.3.3 Hydration 
 
No pre-hydration or hydration is required with this regimen. 
 
5.3.4 Tumor lysis prevention and management 
 
Participants with bulky disease (>10cm in maximal tumor diameter) and/or circulating disease ≥ 
25,000 circulating malignant cells/ mm3 will receive allopurinol 300mg orally daily for 14 days 
starting with the first dose of rituximab.  All participants will have a complete metabolic panel, 
phosphorus, LDH and uric acid checked pre-treatment and at each study visit in cycle 1.  For 


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27 
patients deemed at risk for tumor lysis syndrome (TLS) these labs will also be monitored more 
closely according to institutional practices.  The management of established tumor lysis (see 
appendix B for definition and grading of tumor lysis) should follow standard institutional 
practice.   
 
5.3.5 Other supportive treatments 
 
Growth factors, blood product transfusions, and the use of bisphosphonates are permitted at the 
discretion of the treating physician. 
 
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to any available American Society of Clinical Oncology 
(ASCO) guidelines. 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
Investigator including but not limited to the items outlined below:  
• Diarrhea: All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion; 
• Nausea/Vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Patients 
should be strongly encouraged to maintain liberal oral fluid intake.  
• Anti-infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating Investigator for a given infectious condition, according to standard 
institutional practice.  Prophylactic administration should be considered for the cases 
outlined in Table 2, Management of Immune Related Adverse Events; 
• Anti-inflammatory or narcotic analgesics may be offered as needed.  
Patients who need to be on anticoagulant therapy during treatment should be treated with low 
molecular weight heparin.  If low molecular weight heparin cannot be administered, coumadin or 
other coumadin derivatives or other anticoagulants (including direct Xa inhibitors) may be 
allowed; however, appropriate monitoring of prothrombin time/international normalized ratio 
(PT/INR) should be performed. 
5.3.6 Other Prohibited Concomitant Medications and Treatments 
 
Patients are prohibited from receiving the following therapies during the treatment phase of this 
trial:  
• Anti-cancer systemic chemotherapy or biological therapy. 
• Immunotherapy not specified in this protocol.  
• Investigational agents other than avelumab and utomilumab.  
• Radiation therapy. 


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• Immunosuppressive drugs, unless otherwise indicated for the treatment of irAEs and 
for premedication (see Table 2 and Clarification About Steroid Use below), or for 
treatment of issues unrelated to study drug after consultation with study chair. 
• Medications or vaccinations specifically prohibited in the exclusion criteria are also 
not allowed during the active treatment period; however, the administration of 
inactivated vaccines (eg, influenza vaccine) is allowed during the study. 
• Herbal remedies or vitamins used as anticancer treatments. 
• Herbal remedies with immunostimulating properties (eg, mistle toe extract) or known 
to potentially interfere with major organ function (eg, hypericin). 
• Daily intake over 2 grams acetaminophen/paracetamol. 
 
Clarifications About Steroid Use with Utomilumab, Avelumab and/or PF-04518600: Data 
have indicated that corticosteroids have an adverse effect on T-cell function and that they inhibit 
and damage lymphocytes.23  Furthermore, as with all immunotherapies intended to augment cell 
mediated immunity, there is a risk that concomitant immunosuppressives such as steroids will 
counteract the intended benefit of the proposed study treatment.  However, studies with 
anti-CTLA-4 compounds have indicated that short-term use of steroids may be employed 
without compromising clinical outcomes.24  Therefore, the use of steroids during this trial is 
restricted as follows: 
• Therapeutic use: for the treatment of infusion related reactions, premedication for the 
prevention of an infusion reaction, and short-term treatment of irAEs, steroids are 
permitted according to the modalities indicated in Table 2: Management of 
Immune-Related Adverse Events. 
• Physiologic use: steroid replacement for adrenal insufficiency at doses equivalent to 
≤10 mg prednisone daily is acceptable. 
 
5.4 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
25 weeks or until one of the following criteria applies: 
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
• 
Participant decides to withdraw from the protocol therapy 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 


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29 
 
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore. 
 
5.5 
Duration of Follow Up 
 
Patients who complete treatment or come off treatment for reasons other than progressive disease 
(PD) will have active follow up through 24 months or until death, PD, or next treatment, 
whichever comes first. After 24 months, PD, or next treatment, patients will enter survival follow 
up.  Participants removed from protocol therapy for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. 
 
5.6 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure Off 
Treatment/Off Study information is updated in OnCore in accordance with DF/HCC policy 
REGIST-101. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Every effort should be made to administer investigational products using the planned dose and 
schedule.  
Dose modifications may occur in one of two ways during study conduct: 
• Within a cycle, dosing may be interrupted until adequate recovery from toxicities;  
• Next cycle administration may be delayed due to persisting toxicity when a new cycle 
is due to commence.  
 
Patients whose treatment is delayed due to adverse events should be evaluated at intervals of one 
week or less until adequate recovery has been documented or no further improvement is 
expected.  No dose reductions are allowed for avelumab, utomilumab, PF-04518600, or 
rituximab.  Intra-patient dose escalation is not allowed for any of the study drugs at any time.  
Any suspected immune-related adverse event should be managed according to the Management 
of Immune Related Adverse Events (irAEs) guidance (see Table 2). 
 
The same irAEs management guidelines will apply to utomilumab, avelumab and PF-04518600.  
In addition, in the event of an irAE, dosing with rituximab should continue per protocol if 


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30 
applicable for the current cycle, but may be interrupted for the same duration as utomilumab, 
avelumab, and/or PF-04518600, or for longer at the discretion of the Investigator, following prior 
discussion with the Principal investigator.   
In the event of significant toxicity; dosing may be delayed and/or reduced as outlined below.  In 
the event of multiple toxicities, dose modifications should be based on the worst observed 
toxicity.  Patients must be instructed to notify Investigators at the first occurrence of any adverse 
symptom/s. 
All treatment modification recommendations must be followed unless previously discussed with 
and agreed by the Principal investigator.  All dose modifications/adjustments must be clearly 
documented in the patient's notes and in the CRF. 
6.1 
Special Precautions for Avelumab Administration 
 
As with all monoclonal antibody therapies, there is a risk of allergic reaction including 
anaphylactic shock. 
In order to mitigate the risk of avelumab related infusion-related reactions, a pre-medication 
regimen comprising 25 to 50 mg IV (or oral equivalent) diphenhydramine, and 650 mg IV (or 
oral equivalent) acetaminophen/paracetamol (per local practice) is mandatory and should be 
administered approximately 30 to 60 minutes prior to each dose of avelumab.  This may be 
modified, as appropriate, according to local treatment practice and guidelines. 
If the avelumab is administered more than 1 hour after the preceding drug and/or if no 
premedication has already been administered, then the premedication must be repeated and/or 
initiated.  The line should be flushed, according to local practice, between infusions, and a new 
administration set should be used for avelumab. 
Avelumab should be administered in a setting that allows for immediate access to an intensive 
care unit or equivalent environment and administration of therapy for anaphylaxis, such as the 
ability to implement immediate resuscitation measures.  Steroids (dexamethasone 10 mg), 
epinephrine (1: 1,000 dilution), allergy medications (IV antihistamines), bronchodilators or 
equivalents and oxygen should be available for immediate access.  Infusion of avelumab will be 
stopped in case of Grade ≥2 infusion-related, allergic, or anaphylactic reactions.  Following 
avelumab infusion, patients must be observed for 2 hours for potential infusion-related reactions.  
If an allergic reaction occurs, the patient should be treated according to the best available 
medical practice.  Patients should be instructed to report any delayed reactions to the Investigator 
immediately. Monitoring may be reduced to 30 minutes after cycle 1 at the investigator’s 
discretion. 
Investigators should additionally monitor patients closely for potential irAEs, which may only 
become apparent following several weeks of treatment.  Immune-related adverse events 
described with this class of drugs include pneumonitis, colitis, hepatitis, endocrinopathies 
including thyroid disorders (hyperthyroidism, hypothyroidism, thyroiditis), adrenal insufficiency, 
hypophysitis, and diabetes mellitus, renal dysfunction, encephalitis, eye disorders (uveitis, iritis), 
myositis and myocarditis.  Treatment recommendations for the management of irAEs are 


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31 
outlined in Section 6.3 and Table 2. 
6.2 
Management of Avelumab Infusion-Related Reactions 
 
Symptoms may include one or more of the following: fever, chills, rigors, diaphoresis, and 
headache.  
Once the avelumab infusion rate has been decreased by 50% due to an infusion-related reaction, 
the same decreased infusion rate must be used for all subsequent infusions.  
 
Table 1. Avelumab Treatment Modifications for Symptoms of Infusion Related Reactions 
 
NCI-CTCAE Grade  
Treatment Modification for Avelumab 
Grade 1 – mild 
• Mild transient reaction; infusion interruption not 
indicated; intervention not indicated 
 
• Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening 
Grade 2 – moderate 
• Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for ≤ 24h 
 
• Temporarily discontinue avelumab infusion 
• Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased 
to at least Grade 1 in severity, and monitor closely 
for any worsening  
Grade 3 or Grade 4 – severe or life-threatening 
• Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms 
following 
initial 
improvement; 
hospitalization 
indicated for clinical sequelae 
• Grade 4: Life-threatening consequences; urgent 
intervention indicated 
 
• Stop the avelumab infusion immediately and 
disconnect infusion tubing from the subject 
• Subjects have to be withdrawn immediately from 
avelumab treatment and must not receive any 
further avelumab treatment 
IV: intravenous; NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Event; 
NSAIDs: nonsteroidal anti-inflammatory drugs. 
 
6.2.1 Additional Avelumab Treatment Modifications for Patients with Grade 2 Infusion-
Related Reactions 
 
In the event of a Grade 2 infusion-related reaction that does not improve or that worsens 
following implementation of the modifications indicated in Table 1 (including reducing the 
infusion rate by 50%), the Investigator may consider treatment with corticosteroids per local 
guidelines, and the infusion should be stopped for that day.  At the time of the next cycle, the 
Investigator may consider adding H2-blocker antihistamines (eg, famotidine or ranitidine) and/or 
hydrocortisone 100mg IV, or the steroid equivalent, to the mandatory pre-medication.   
If the patient has a second infusion-related reaction of Grade ≥2 on the reduced infusion rate, 
with or without the addition of further medication/s to the mandatory pre-medication, the 
infusion should be stopped, and the patient discontinued from avelumab treatment. 
6.2.2 Management of Avelumab Severe Hypersensitivity Reactions and Flu-Like Symptoms 
 


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32 
Symptoms of hypersensitivity may include impaired airway, decreased oxygen saturation 
(<92%), confusion, lethargy, hypotension, pale or clammy skin, and cyanosis.  These symptoms 
may, if necessary, be managed with epinephrine and dexamethasone.  Oxygen therapy should be 
administered as appropriate.  Patients should be immediately placed on a cardiac monitor, and 
the intensive care unit (ICU) alerted for possible transfer if required.  In extreme cases, 
intubation may be necessary. 
For prophylaxis of flu-like symptoms, 25 mg of indomethacin or a comparable nonsteroidal 
anti-inflammatory drug (NSAID) dose (for example, ibuprofen 600 mg, naproxen sodium 
500 mg) may be administered 2 hours prior to and 8 hours after the start of each avelumab IV 
infusion.  Alternative treatments for fever (eg, paracetamol) may be given to patients at the 
discretion of the Investigator. 
6.3 
Immune-Related Adverse Events 
 
NOTE: The same irAE management guidelines apply to utomilumab, avelumab and PF-
04518600. 
As these drugs stimulate the immune system, irAEs may occur.  Treatment of irAEs is dependent 
upon their severity (NCI-CTCAE grade): 
• Grade 1 to 2:  
treat symptomatically or with moderate dose 
steroids, and more frequent monitoring; 
• Grade 1 to 2 (persistent):  
manage as per high-grade (ie, Grade 3 to 4) AEs; 
• Grade 3 to 4:  
 
treat with high-dose corticosteroids. 
 
Any event suspected to be immune-related should be managed according to the guidance for 
management of immune-related adverse events in this section and in Table 2. There are no dose 
modifications on this protocol of any of the agents. However, treatment may be temporarily or 
permanently discontinued following the recommendations in Table 2. Also note that the 
recommendations may be superseded by the judgement of the treating clinician, although this 
should be discussed with the Study Chair. 
 
Immune-related adverse events described with this class of drugs include:  pneumonitis, colitis, 
hepatitis, endocrinopathies including thyroid disorders (hyperthyroidism, hypothyroidism, 
thyroiditis), adrenal insufficiency, hypophysitis, and diabetes mellitus or hyperglycemia, rash, 
nephritis and renal dysfunction, encephalitis, eye disorders (including uveitis, iritis), and other 
immune-mediated reactions including myositis and myocarditis. 
Any adverse event which may have an underlying immune-mediated mechanism including those 
described above, and without other confirmed etiologies, should be considered immune-related 
and managed according to guidelines described in this section. 
 
 


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33 
Table 2. Management of Immune Related Adverse Events 
Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue immunotherapy 
agent 
Symptomatic treatment (e.g. 
loperamide) 
Close monitoring for worsening symptoms 
Educate subject to report worsening 
immediately 
If worsens: 
Treat as Grade 2, 3 or 4.  
Grade 2  
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated < 24 
hours; not interfering with ADL 
Colitis: abdominal pain; blood in 
stool  
 
Withhold all immunotherapy 
agents 
Symptomatic treatment 
If improves to Grade ≤ 1:  
Resume immunotherapy agents 
 
If persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools per 
day over Baseline; incontinence; IV 
fluids ≥ 24 h; interfering with ADL 
Colitis (Grade 3):  severe abdominal 
pain, medical intervention indicated, 
peritoneal signs 
Grade 4: life-threatening, perforation 
Withhold all immunotherapy 
agents for Grade 3. 
Permanently discontinue 
immunotherapy agents for 
Grade 4 or recurrent Grade 3. 
 
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider lower endoscopy  
If improves:  
Continue steroids until Grade ≤ 1, then taper 
over at least 1 month; resume 
immunotherapy agents following steroids 
taper (for initial Grade 3).  
 
If worsens, persists > 3 to 5 days, or recurs 
after improvement: 
Add infliximab 5mg/kg (if no contraindication). 
Note: infliximab should not be used in cases 
of perforation or sepsis.  
Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body surface area  
Continue immunotherapy 
agents 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
If persists > 1 to 2 weeks or recurs:  
Withhold all immunotherapy agents  
Consider skin biopsy  
 
Consider 0.5-1.0 mg/kg/day prednisone or 
equivalent. Once improving, taper steroids 
over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and 
resume immunotherapy agents following 
steroids taper. 
If worsens:  
Treat as Grade 3 to 4.  


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34 
Grade 3 to 4 
Grade 3: Covering > 30% body 
surface area;  
Grade 4: Life threatening 
consequences  
Withhold all immunotherapy 
agents for Grade 3. 
Permanently discontinue for 
Grade 4 or recurrent Grade 3.  
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month; resume 
immunotherapy agents following steroids 
taper (for initial Grade 3). 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes only  
Consider withholding all 
immunotherapy agents  
Monitor for symptoms every 
2 to 3 days  
Consider Pulmonary and 
Infectious Disease consults  
Re-assess at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4.  
Grade 2 
Mild to moderate new symptoms  
Withhold all immunotherapy 
agents 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
Re-assess every 1 to 3 days  
If improves:  
When symptoms return to Grade ≤ 1, taper 
steroids over at least 1 month, and then 
resume all immunotherapy agents following 
steroids taper  
If not improving after 2 weeks or worsening:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4:  Life-threatening  
Permanently discontinue all 
immunotherapy agents. 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month  
If not improving after 48 hours or worsening:  
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, IV 
immunoglobulin, or mycophenolate mofetil)  
Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Continue immunotherapy 
agents 
Continue liver function monitoring  
If worsens:  


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35 
Grade 1 AST or ALT > ULN to 3.0 x 
ULN and/or Total bilirubin > ULN to 
1.5 x ULN  
 Treat as Grade 2 or 3 to 4.  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 x 
ULN  
Withhold all immunotherapy 
agents 
Increase frequency of 
monitoring to every 3 days. 
 
If returns to Grade ≤ 1: 
Resume routine monitoring; resume 
immunotherapy agents. 
If elevation persists > 5 to 7 days or worsens:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT > 5 x ULN and/or total 
bilirubin > 3 x ULN  
Permanently discontinue all 
immunotherapy agents  
Increase frequency of 
monitoring to every 1 to 
2 days  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consult gastroenterologist/ 
hepatologist 
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted  
If returns to Grade ≤ 1:  
Taper steroids over at least 1 month  
If does not improve in > 3 to 5 days, worsens 
or rebounds:  
Add mycophenolate mofetil 1 gram (g) twice 
daily  
If no response within an additional 3 to 5 
days, consider other immunosuppressants 
per local guidelines. 
Renal irAEsƗ 
Grade of Creatinine Increased 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 1.5 x 
ULN 
Continue immunotherapy agents 
Continue renal function monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 6 x 
ULN 
 
 
 
 
 
Withhold all immunotherapy agents 
Increase frequency of monitoring to 
every 3 days 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to Grade ≤1: 
Taper steroids over at least 1 month, 
and resume immunotherapy agents 
following steroids taper. 
If worsens:  
Treat as Grade 4. 
Grade 4 
Creatinine increased > 6 x ULN 
 
 
 
 
 
 
 
Permanently discontinue all 
immunotherapy agents 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
If returns to Grade ≤1: 
Taper steroids over at least 1 month. 


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ƗFor pts with a baseline Cr 1-1.5x ULN, management of specific changes in Cr are at the discretion of the treating 
physician 
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (e.g. 
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive 
of myocarditis.  
Withhold all immunotherapy agents. 
Hospitalize. 
In the presence of life threatening cardiac 
decompensation, consider transfer to a 
facility experienced in advanced heart 
failure and arrhythmia management. 
Cardiology consult to establish etiology 
and rule-out immune-mediated 
myocarditis.  
Guideline based supportive treatment as 
per cardiology consult. * 
 
Consider myocardial biopsy if 
recommended per cardiology consult. 
If 
symptoms 
improve 
and 
immune-mediated etiology is ruled 
out, re-start immunotherapy agents. 
 
If symptoms do not 
improve/worsen, viral myocarditis 
is excluded, and immune-mediated 
etiology is suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis. 
Immune-mediated myocarditis 
Permanently discontinue all 
immunotherapy agents. 
Guideline based supportive treatment as 
appropriate as per cardiology consult. * 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids over 
at least 1 month. 
 
If no improvement or worsening, 
consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A). 
*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue immunotherapy agents 
Endocrinology consult if needed 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate. 


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Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold all immunotherapy agents 
Consider hospitalization 
Endocrinology consult 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Resume all immunotherapy agents 
once symptoms and/or laboratory 
tests improve to Grade ≤ 1 (with or 
without hormone 
replacement/suppression). 
 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate.  
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e. 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately low 
ACTH) : 
• 
Refer to endocrinologist for 
dynamic testing as indicated 
and measurement of other 
hormones (FSH, LH, GH/IGF-
1, PRL, testosterone in men, 
estrogens in women)  
• 
Hormone 
replacement/suppressive 
therapy as appropriate  
• 
Perform pituitary MRI and 
visual field examination as 
indicated 
 
If hypophysitis confirmed: 
• 
Continue all immunotherapy 
agents if mild symptoms with 
normal MRI. Repeat the MRI in 1 
month 
• 
Withhold all immunotherapy 
agents if moderate, severe or life-
threatening symptoms of 
hypophysitis and/or abnormal 
MRI. Consider hospitalization. 
Initiate corticosteroids (1 to 2 
mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during at 
least 1 month. 
• 
Add prophylactic antibiotics for 
opportunistic infections. 
Resume all immunotherapy agents 
once symptoms and hormone tests 
improve to Grade ≤ 1 (with or 
without hormone replacement). 
 
In addition, for hypophysitis with 
abnormal MRI, resume avelumab 
only once shrinkage of the pituitary 
gland on MRI/CT scan is 
documented.  
 
Continue hormone 
replacement/suppression therapy 
as appropriate. 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 


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Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE 
Withhold all immunotherapy agents 
pending clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-starting 
all immunotherapy agents 
If irAE is confirmed, treat as Grade 
2 or 3 irAE. 
Grade 2 irAE  or first occurrence 
of Grade 3 irAE 
Withhold all immunotherapy agents 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent   
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month 
and resume all immunotherapy 
agents following steroids taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue all 
immunotherapy agents 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month. 
Grade 4  
 
Permanently discontinue all 
immunotherapy agents 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent and/or other 
immunosuppressant as needed 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult. 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
Permanently discontinue all 
immunotherapy agents 
Specialty consult 
 
 
6.4 
Recommended Treatment Modifications 
 
Dose delays for drug-related non-immune related toxicities related to utomilumab, avelumab, 
PF-04518600, and rituximab are detailed in Table 3 and Table 4.  If a toxicity can be attributed 
just to one of the drugs in the combination, dose delays can be implemented independently for 
each drug.  In instances where it is not possible to attribute the toxicity to only one of the three 
drugs, the treatment modifications detailed in Table 3 and Table 4 should be followed for 
all drugs. 
 
 


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Table 3. Treatment Modifications for Treatment-Related Hematologic Toxicities* 
 
Hematologic 
Toxicity (NCI 
CTCAE 
version 4.03) 
Utomilumab 
Avelumab 
PF-04518600 
Rituximab 
Grade 1 
Continue per schedule 
Continue per 
schedule 
Continue per 
schedule 
Continue per 
schedule 
Grade 2 
Continue per schedule 
Continue per 
schedule 
Continue per 
schedule 
Continue per 
schedule 
Grade 3 
Hold treatment up to 
4 weeks until 
Grade ≤1, or baseline 
then rechallenge. 
 
Permanent 
discontinuation if 
recurrence to Grade 3 
(Unless resolve to 
Grade ≤1 or baseline 
within 7 days 
following appropriate 
medical management). 
 
Hold treatment up to 
4 weeks until Grade 
≤1, or baseline, then 
rechallenge. 
 
Permanent 
discontinuation if 
recurrence to 
Grade 3. 
(Unless resolve to 
Grade ≤1 or baseline 
within 7 days 
following 
appropriate medical 
management 
Hold treatment up to 
4 weeks until Grade 
≤1, or baseline, then 
rechallenge. 
 
Permanent 
discontinuation if 
recurrence to 
Grade 3. 
(Unless resolve to 
Grade ≤1 or baseline 
within 7 days 
following 
appropriate medical 
management 
Hold treatment up to 
4 weeks until Grade 
≤1, or baseline, then 
rechallenge. 
 
Permanent 
discontinuation if 
recurrence to 
Grade 3. 
(Unless resolve to 
Grade ≤1 or baseline 
within 7 days 
following 
appropriate medical 
management 
Grade 4 
Permanent 
discontinuation 
(Unless resolve to 
Grade ≤1, or baseline 
within 7 days 
following appropriate 
medical management). 
Permanent 
discontinuation 
(Unless resolve to 
Grade ≤1, or baseline 
within 7 days 
following 
appropriate medical 
management). 
Permanent 
discontinuation 
(Unless resolve to 
Grade ≤1, or baseline 
within 7 days 
following 
appropriate medical 
management). 
Permanent 
discontinuation 
(Unless resolve to 
Grade ≤1, or baseline 
within 7 days 
following 
appropriate medical 
management). 
* Patients with baseline hematologic abnormalities due to lymphoma involvement of the bone marrow or spleen 
need not follow these guidelines if the ongoing cytopenias are felt to be due to lymphoma.  Management of 
cytopenias in these cases are at the discretion of the treating physician. 
 
Table 4. Treatment Modifications for Treatment-Related Non-Hematologic Toxicities 
 
Non-Hematologic Toxicity (NCI 
CTCAE v. 4.03) 
Utomilumab 
Avelumab 
PF-04518600 
Rituximab 
Progressive multi-focal leuco-
encephalopathy (PML) – any 
grade 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Viral Hepatitis B – any grade 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Grade >3 infection 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Grade >3 cardiac arrhythmia 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Grade >3 renal toxicity (eg, acute 
kidney injury, urine output 
decreased) 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
 
 


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Grade >3 muco cutaneous reactions 
including paraneoplastic pemphigus, 
Steven Johnson syndrome, lichenoid 
dermatitis, vesciculobullous 
dermatitis, and toxic epidermal 
necrolysis 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Any Grade ≥3 liver function test 
abnormality 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Other - Grade 1 or 2 
Continue per 
schedule 
Continue per 
schedule 
Continue per 
schedule 
Continue per 
schedule 
Other- Grade 3 
Hold until 
resolved to 
grade 1 or 
baseline 
Hold until 
resolved to 
grade 1 or 
baseline 
Hold until 
resolved to 
grade 1 or 
baseline 
Hold until 
resolved to 
grade 1 or 
baseline 
Other-Grade 4 
Permanently 
discontinue* 
Permanently 
discontinue* 
Permanently 
discontinue* 
Permanently 
discontinue* 
irAEs 
See Table 2 
See Table 2 
See Table 2 
 
Infusion-related reactions 
See section 6.2 
See section 6.2 
See section 6.2 
 
*For asymptomatic grade 4 laboratory abnormalities including lipase, amylase, CK elevations, the subject may be 
restarted on treatment if the abnormality resolves to grade 1 or baseline, in cases where the investigator judges that 
the benefit of resuming treatment outweighs the risk, and after discussion with the Study Chair. 
6.5 
Treatment Delays 
 
A new treatment cannot start unless the ANC is ≥1.0 x109/L, the platelet count is ≥75 x109/L (or 
an ANC > 0.5x109/L and platelets >50x109/L if due to marrow involvement by the lymphoma), 
and non-hematologic toxicities have returned to baseline or Grade ≤1 severity. 
A new treatment may be delayed for a maximum duration of 4 weeks to allow for ANC and 
platelet count recovery.  In the event that recovery does not occur within 4 weeks, all study drugs 
must be permanently discontinued.  The 4-week recovery window commences on the day of the 
planned treatment. 
If avelumab, utomilumab, and/or PF-04518600 treatment is delayed due to toxicities attributable 
to avelumab and/or utomilumab or PF-04518600 (eg, pneumonitis or hypothyroidism), rituximab 
administration does not need to be delayed.  If the start of rituximab administration is delayed 
due to toxicities attributable to rituximab, administration of other drugs does not need to be 
delayed.  
6.6 
Dose Reductions 
 
No dose reductions are permitted for utomilumab, avelumab, PF-04518600, or rituximab.   
 
6.7 
Management of Immune-Related Adverse Events 
 
The irAE management guidelines outlined in Section 6.3 apply to utomilumab, avelumab and 
PF-04518600.  Any event suspected to be immune related should be managed according to the 
guidance for management of immune related adverse event in Table 2. 


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In case of a potential irAE, besides the management related to utomilumab, avelumab and PF-
04518600 therapy, rituximab doses may also be modified or interrupted based on the guidance 
provided for combination toxicity management in Table 3 and Table 4, product labeling and 
institutional guidelines according to Investigator’s best medical judgment. 
6.8 
Management of Infusion-Related Reactions 
 
For utomilumab and/or PF-04518600, the rates of infusion reactions are rare and no empiric 
premedication is recommended.  If an infusion related reaction occurs following these infusions, 
the same management guidelines outlined in Section 6.2 for avelumab are applicable.   
 
Rituximab may cause severe, including fatal, infusion reactions.  Severe reactions typically occur 
during the first infusion, with time to onset typically being 30-120 minutes. Patients with 
pre-existing cardiac or pulmonary conditions, those who have experienced prior 
cardio-pulmonary adverse reactions, and those with high numbers of circulating malignant cells 
(≥25,000/mm3) should be closely monitored.  In order to mitigate infusion related reactions, a 
premedication with an antihistamine and with paracetamol (acetaminophen) approximately 30 to 
60 minutes prior to each dose of rituximab (if more than 60 minutes have passed since the 
completion of the prior infusion and/or if no prior premedication has been given) is mandatory 
(for example, 25-50 mg diphenhydramine and 500-650 mg paracetamol [acetaminophen] IV or 
oral equivalent).  This may be modified based on local treatment standards and guidelines, as 
appropriate.  
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs and the characteristics of an observed AE (Section 
9) will determine whether the event requires expedited reporting in addition to routine reporting. 
 
7.1 
Expected Toxicities 
 
7.1.1 Adverse Events List(s) 
 
7.1.1.1 
Utomilumab 
 
Frequent (reported in at least 10% of patients): 
 
• Fatigue  
 
Occasional (Between a 1-10% chance that this will happen). These cases were generally 
mild to moderate:  
 
• Dizziness 
• Gastrointestinal symptoms: abdominal pain, decreased appetite, diarrhea, nausea, and/or 
vomiting 


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• Anemia 
• Thrombocytopenia. 
• Back pain 
• Chills/Flu-like illness 
• Shortness of breath  
• Ear discomfort 
• Inflammation of the intestines (enterocolitis) 
• Eye irritation 
• Swelling and pain in the joints 
• Headache 
• Hypertension 
• Hyponatremia 
• Insomnia 
• Muscle spasm and/or pain 
• Sore throat 
• Neuropathy 
• Pneumonitis 
• Fever  
• Maculo-papular rash 
• Vaginal infection 
• Weight loss 
• Abnormal liver tests 
 
7.1.1.2 
Avelumab 
 
Very common (Observed in greater than or equal to 10% of patients) 
• Infusion reactions 
• Fatigue 
• Gastrointestinal side effects including diarrhea, constipation, decreased appetite, nausea, 
belly pain 
• Weight loss 
• Anemia 
• Fever 
• Respiratory side effects including cough, shortness of breath 
• Swelling of the feet and legs 
• Back pain 
• Joint pain 
 
Common (Observed in 2-9% of patients) 
• Chills and/or fever with or without flu-like symptoms of body aches and weakness 
• Hypothyroidism. 
• Skin symptoms including itchy skin, rash 
• Abnormal liver function tests 
• Muscle pain 


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• Weakness 
• Headache 
 
Side effects resulting from an increased activity of the immune system following treatment with 
avelumab have also been observed. Most of these side effects are reversible, which means they 
will stop once treatment with avelumab is discontinued, however in some cases these reactions 
may be severe (approximately 2% of patients) and could lead to death in rare cases. The 
reactions that are more severe may require treatment with drugs that decrease the immune system 
function, also called immunosuppressant drugs (like corticosteroids or more potent drugs, such 
as infliximab). The side effects resulting from an increased activity of the immune system that 
were observed in patients receiving avelumab include the following: 
 
Immune side effects observed in less than 1% of patients: 
• Inflammation of the liver 
• Adrenal insufficiency 
• Uveitis 
• Myositis 
• Myocarditis or pericarditis 
• Nephritis 
• Diabetes 
• Guillain-Barre syndrome 
 
Immune side effects observed in 1% to less than 5% of patients: 
• Pneumonitis 
• Colitis 
 
Immune side effects observed in 5% to less than 10% of patients: 
• Inflammation of the skin (could include skin rash, itchy skin, redness or blisters in the skin) 
• Autoimmune thyroid dysfunction 
 
7.1.1.3 
PF-04518600 
 
Common (10-50%) 
• Fatigue 
• Fever 
• Gastrointestinal symptoms: Nausea, vomiting, constipation, diarrhea, abdominal pain 
• Anorexia 
• Abnormalities in liver function tests 
• Respiratory symptoms: shortness of breath, cough 
• Itching of the skin 
• Headache 
• Insomnia 
• Anemia 
 
 
 


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Rare (<1%-10%) 
• Chills 
• Congestive heart failure  
• Dry mouth 
• Hypophosphataemia 
• Muscle pain (myalgia) 
• Pain (whole body) 
• Proteinuria 
• Rash 
 
7.1.1.4 
Rituximab 
 
Common (>20%) 
• Nausea 
• Infusion reactions. This risk is greatest with the first infusion. 
• Fatigue 
 
Occasional (4-20%) 
• Anemia 
• Bruising or bleeding 
• Leukopenia 
• Diarrhea 
• Vomiting 
• Body and/or joint pain 
• Cough 
• Stuffy nose 
• Rash, itching or hives 
• Increased blood sugar  
• Dizziness 
 
Rare (<4%) 
• Stevens-Johnson syndrome 
• Pneumonitis 
• Viral infections including hepatitis in participants who are carriers of the hepatitis virus 
• Progressive multifocal leukoencephalopathy (PML)  
• Tumor lysis syndrome 
• Abnormal heartbeat 
 
7.1.2 Adverse Event Characteristics 
 


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• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• 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. 
 
• Expectedness: 
- 
Expected adverse events are those adverse events that are listed or characterized in 
the current adverse event list, the Package Insert, the Investigator Brochure or is 
included in the informed consent document as a potential risk. 
- 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (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 
 
7.2 
Adverse Event Reporting  
 
In the event of an unanticipated problem or life-threatening complications treating investigators 
must immediately notify the Overall PI. 
 
Investigators must report to the Overall PI any adverse event (AE) that occurs after the initial 
dose of study treatment, during treatment, or within 30 days of the last dose of treatment on the 
local institutional SAE form.  
 
The study period, during which AEs and SAEs must be reported, begins after starting the first 
dose 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 study treatment. 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 assessed and reported, when appropriate. 
Abnormal laboratory values will not be reported unless deemed to be clinically significant. 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 study therapy, expectedness, and 
actions taken.  
 
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events.  These requirements are delineated for 3 types of events: (1) SAEs; 


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(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under study 
during pregnancy or breastfeeding, and occupational exposure.  
For Multi-Center Trials where a DF/HCC investigator is serving as the Sponsor, each 
participating institution must abide by the reporting requirements set by the DF/HCC. This 
applies to any medical event equivalent to an unexpected grade 2 or 3 with a possible, probable 
or definite attribution, unexpected grade 4 toxicities, and grade 5 (death) regardless of study 
phase or attribution. 
 
7.2.1 DF/HCC Adverse Event Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
Other investigative sites will report AEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the submitted institutional AE 
form should be forwarded to the Overall PI within the timeframes detailed in the table below.   
 
 
 
 
 
Attribution 
Table 5. DF/HCC Reportable Adverse Events(AEs) 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
10 working days# 
10 working days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
10 working days 
 
10 working days# 
 
10 working days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 1 business day of learning of the event. 
 
 
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS according to 
DFCI IRB policies and procedures in reporting adverse events.  
 
7.3 
Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.4 
Expedited Reporting to Pfizer 
 
Within 24 hours of first awareness of the event (immediately if the event is fatal or life-
threatening), the study team will report to Pfizer by facsimile any Serious Adverse Event 


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(“SAE,” as defined below) for which reporting is required under this provision (as described 
below).  Such SAEs are to be reported for study subjects or individuals otherwise exposed to the 
Pfizer Product as described below.  The study teams should report SAEs as soon as they are 
determined to meet the definition, even if complete information is not yet available. 
 
Study teams will report SAEs using Form FDA 3500A (MedWatch). The Reportable Event Fax 
Cover Sheet provided by Pfizer must also be included with each SAE submitted.   
 
7.4.1 SAE Definition for Reporting to Pfizer   
 
An SAE is any adverse event, without regard to causality, that is life-threatening (ie, causes an 
immediate risk of death) or that results in any of the following outcomes: death; in-patient 
hospitalization or prolongation of existing hospitalization; persistent or significant disability or 
incapacity (i.e., substantial disruption of the ability to conduct normal life functions); or a 
congenital anomaly or birth defect.  Any other medical event that, in the medical judgment of the 
Principal Investigator, may jeopardize the subject or may require medical or surgical intervention 
to prevent one of the outcomes listed above is also considered an SAE.  A planned medical or 
surgical procedure is not, in itself, an SAE.   
 
7.4.2 Exposure During Pregnancy, Exposure During Lactation, Occupational Exposure  
 
Even though there may not be an associated SAE, exposure to Utomilumab, Avelumab, and/or 
PF-04518600 during pregnancy, exposure to Utomilumab, Avelumab, and/or PF-04518600 
during lactation, and occupational exposure to Utomilumab, Avelumab and/or PF-04518600 are 
reportable to Pfizer.   
 
7.4.3 Hy’s Law Cases 
 
Cases of potential drug-induced liver injury as assessed by laboratory test values (“Hy’s Law 
Cases”) are also reportable to Pfizer.  If a participant develops abnormal values in aspartate 
transaminase (AST) or alanine transaminase or both, concurrent with abnormal elevations in 
total bilirubin and no other known cause of liver injury, that event would be classified as a Hy’s 
Law Case. 
  
7.4.4 Exclusions from SAE Reporting Requirements 
 
Specifically excluded from the reporting requirements for SAEs under this provision is any SAE 
identified in the Protocol as anticipated to occur in the Study population at some frequency 
independent of drug exposure, unless the Principal Investigator assesses such an event as related 
to study medication.  Also, specifically excluded from the reporting requirements is any SAE 
judged by the Overall Investigator to represent progression of the malignancy under study, unless 
it results in death within the SAE Reporting Period.   
 
7.4.5 SAE Reporting Period 
 
The SAEs that are subject to this reporting provision are those that occur from after the first dose 


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of study medication(s) through 30 calendar days after the last administration of the study 
medication(s). In addition, if a Principal Investigator becomes aware of an SAE occurring within 
30 days of last dose of study medication in Utomilumab and PF-0451600 and within 90 days of 
avelumab the Principal Investigator should report that SAE to Pfizer if the Principal Investigator 
suspects a causal relationship between the study drug and the SAE.  In addition, if the 
investigator determines that an SAE is associated with study procedures, the investigator must 
record this causal relationship in the source documents.  
 
7.5 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports, sentinel events or unanticipated problems that require reporting per institutional 
policy.  
 
7.6 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational other agent(s) 
administered in this study can be found in Section 7.1. 
 
8.1 
Investigational Product 
 
Administration of investigational products should be performed by an appropriately qualified, 
Good Clinical Practice (GCP) trained, and experienced member of the study staff (eg, physician, 
nurse, physician’s assistant, practitioner, pharmacist, or medical assistant) as allowed by local, 
state, and institutional guidance.  All trial treatments will be administered at the Investigational 
site. 
Investigational product administration details will be recorded on the CRF. 
8.1.1 Utomilumab 
 
Utomilumab is an intravenous (IV) fully human IgG2 monoclonal antibody (mAb) that binds to 
the extracellular domain of human 4-1BB with high affinity and specificity and is capable of 4-
1BB agonism. 4-1BB (CD137, TNFRSF9), is a membrane spanning glycoprotein of the Tumor 
Necrosis Factor (TNF) receptor superfamily. It is an inducible costimulatory receptor expressed 
on activated T cells. Current understanding of 4-1BB indicates that expression is generally 
activation dependent and encompasses a broad subset of immune cells including activated NK 
and NKT cells; regulatory T cells; dendritic cells (DC) including follicular DC; stimulated mast 
cells, differentiating myeloid cells, monocytes, neutrophils, eosinophils25, and activated B cells26.  
4-1BB expression has also been demonstrated on tumor vasculature27,28 and atherosclerotic 


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endothelium.29 The ligand that stimulates 4-1BB (4-1BBL) is expressed on activated antigen-
presenting cells (APCs), myeloid progenitor cells and hematopoietic stem cells. 
 
Interaction of 4-1BB on activated normal human B cells with its ligand at the time of B cell 
receptor engagement stimulates proliferation and enhances survival.26  The potential impact of 4-
1BB engagement in B cell lymphoma has been investigated in two published studies. Evaluation 
of several types of human primary NHL samples indicated that 4-1BB was expressed 
predominantly on infiltrating T cells rather than the lymphoma cells.30 The addition of 4-1BB 
agonists to in vitro cultures of B lymphoma cells with rituximab and NK cells resulted in 
increased lymphoma killing.16 In addition, B cell immunophenotyping was performed in two 
experiments using utomilumab in cynomolgus monkeys with doses from 0.001-100 mg/kg; in 
these experiments, peripheral blood B cell numbers were either unchanged or decreased. 
 
4-1BB is undetectable on the surface of naive T cells but expression increases upon 
activation. Based on homology to other members of the TNFRSF, ligand binding is expected to 
induce receptor trimerization resulting in activation.31 Some members of the TNFRSF can cleave 
the extracellular domain from the cell surface and exist in a soluble form. Soluble 4-1BB and 
soluble 4-1BBL have been demonstrated in the serum of some patients with autoimmune 
diseases and cancers (Michel et al. 1998; Furtner et al. 2005; Hentschel et al. 2006).32-34 
 
Upon 4-1BB activation, TRAF 1 and TRAF 2, pro-survival members of the TNFR associated 
factor (TRAF) family are recruited to the 4-1BB cytoplasmic tail resulting in downstream 
activation of NFkB and the Mitogen Activated Protein (MAP) Kinase cascade including Erk, 
Jnk, and p38 MAP kinases. NFkB activation leads to upregulation of Bfl-1 and Bcl-XL, pro-
survival members of the Bcl-2 family. The pro-apoptotic protein Bim is downregulated in a 
TRAF1 and Erk dependent manner.35 
 
Numerous studies of murine and human T cells indicate that 4-1BB promotes enhanced cellular 
proliferation, survival, and cytokine production.36 Reports have shown that 4-1BB agonist mAbs 
increase costimulatory molecule expression and markedly enhance cytolytic T lymphocyte 
responses, resulting in anti-tumor efficacy in various models. 4-1BB agonist mAbs have 
demonstrated efficacy in prophylactic and therapeutic settings and both monotherapy and 
combination therapy tumor models and have established durable anti-tumor protective T cell 
memory responses.37 4-1BB agonists also inhibit autoimmune reactions in a variety of 
autoimmunity models.38 This dual activity of 4-1BB offers the potential to provide anti-tumor 
activity while dampening autoimmune side effects that can be associated with immunotherapy 
approaches that break immune tolerance. 
 
Pre-clinical studies have demonstrated activity of utomilumab alone and in combination with 
mAbs in lymphoma models.  Injection with utomilumab has been shown to correlate with tumor 
cell line growth inhibition in xenogenic tumor models as a single agent. In addition, 4-1BB 
agonist mAbs demonstrate significant combinatorial efficacy with ADCC antibodies in 
lymphoma models. Preclinical studies support the use of this 4-1BB agonist mAb as a promising 
candidate for treatment of cancer, alone or in combination with ADCC-inducing mAbs.   
 
As a single agent, utomilumab has exhibited the ability to increase lymphocyte proliferation. In 


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small animal models developed to test the in vivo function of utomilumab, utomilumab was able 
to enhance expansion of human leukocytes in a dose dependent manner as evidenced by an 
increase in the proportion of human CD45+ cells in the peripheral blood of engrafted mice. 
Similarly, a dose dependent increase in the proportion of human leukocytes expressing the 
proliferation marker Ki-67 was noted. In addition, utomilumab treatment of cynomolgus 
monkeys in single or multiple dose studies increased proliferation among cytotoxic central 
memory T cells (CD8 TCM) in PBMC samples. Taken together, these data demonstrate evidence 
of utomilumab’s ability to enhance lymphocyte response in vivo. 
 
Utomilumab alone has also demonstrated anti-tumor activity in pre-clinical studies. Tumor cell 
lines representing melanoma, colon, and prostate tumor types were tested in a xenogenic tumor 
model. None of the tumor lines expressed 4-1BB; therefore, tumor cells were mixed with 
primary human PBMC from a healthy volunteer donor prior to injection in all cases. Once 
tumors were established, animals were treated with utomilumab. Utomilumab was found to be 
efficacious against all 3 tumor types. 
 
Utomilumab has been tested in combination with mAbs in animal models with resultant additive 
effects on cancer growth and survival.  Antibody dependent cellular cytotoxicity (ADCC) has 
been hypothesized as a mechanism of tumor destruction resulting in direct antigen presentation 
and in the induction of tumor antigen specific T cell responses (‘cross-priming”).39 This is 
supported by preclinical experiments demonstrating that the therapeutic efficacy of an anti-
HER2/neu antibody depends on both innate and adaptive immunity.40 
 
The combinatorial anti-tumor activity of ADCC inducing mAb with 4-1BB agonist mAbs was 
assessed. A mouse anti-mouse CD20 antibody with ADCC inducing activity was selected as a 
surrogate mAb for rituximab.41 MAB9371 was selected as a surrogate for utomilumab, as 
utomilumab does not cross react with murine 4-1BB. MAB9371 is a commercially available rat 
anti mouse 4-1BB agonist mAb (R & D Systems, Minneapolis MN). The binding affinity of 
MAB9371 for murine 4-1BB is similar to the affinity of utomilumab for human 4-1BB. In both 
models, treatment with a combination of surrogate mAbs at concentrations with limited single 
agent efficacy, showed significant tumor growth inhibition (A20 model) and/or enhanced 
survival (Eµ-myc model). 
 
8.1.1.1 
Clinical Experience 
 
The clinical experience with utomilumab has included five phase 1 or phase 1b/2 studies of 
utomilumab alone or in combination with pembrolizumab, mogamulizumab, avelumab, PF-
04518600, or rituximab in advanced solid tumors and B cell non-Hodgkin lymphoma.  The first 
of these studies is the phase 1 study of utomilumab alone in solid tumors, and utomilumab in 
combination with rituximab in relapsed or refractory CD20 positive NHL. 
 
8.1.1.2 
Pharmacokinetics 
 
Preliminary PK data following single dose of treatments are available from 81 patients (46 in 
Portion A (utomilumab monotherapy) and 35 in Portion B (utomilumab + rituximab) from the 
first in human Phase 1 study B1641001.  Following attainment of Cmax, PF-05082566 serum 


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concentrations showed a bi-exponential decline with a mean terminal elimination half-life of 
208-349 hrs, a low systemic clearance (CL = 0.271-0.372 mL/hr/kg) and a small volume of 
distribution (Vss = 83.3-231 mL/kg) in Cycle 1 of Portion A.  In Portion B, PF-05082566 also 
showed a bi-exponential decline with a mean terminal elimination half-life of 274-550 hrs, a low 
systemic clearance (CL = 0.175-0.335 mL/hr/kg) and a small volume of distribution (Vss = 
88.4-164 mL/kg).  A dose proportional increase in exposure was observed. 
Preliminary population PK analysis has been conducted using data from 68 patients (n=41 in 
Portion A and n=27 from Portion B) receiving utomilumab doses from 0.006 to 5 mg/kg Q4W 
using serial and sparse PK samples in Study B1641001.  A two-compartment model with linear 
elimination best described these data.  Among the covariates tested, both baseline body weight 
and treatment portion had statistically significant effect on clearance (CL).  Baseline body 
surface area and gender were found to significantly correlate with central volume of distribution 
(Vc).  No other covariates had a statistically significant effect on either CL or Vc. Simulations 
were performed at various dosing schedules which indicated that the exposure at dose levels 
higher than 0.12 mg/kg was above the assumed efficacious concentration (Ceff, 1730 ng/mL) 
with both once every 3 weeks (Q3W) and once Q4W schedule.  Although body weight was 
identified as a significant covariate on CL, it accounted for only a small percentage (~<7%) of 
the inter-individual variability in serum PF-05082566 exposure.  In addition, simulations 
indicated that utomilumab exposure is similar between body weight based and fixed dosing 
regimens.  Based on these data, and in accordance with emerging data for monoclonal antibodies 
which reveal that body weight-based dosing regimens do not result in less variability in measures 
of exposure over fixed dosing regimens, a fixed dosing regimen was proposed for future 
utomilumab clinical studies.  
The flat dose levels chosen for further exploration were based on the following data from Study 
B1641001. The highest planned dose of 10 mg/kg utomilumab was tested with no DLTs reported 
in Portion A or in Portion B and no further dose escalation was performed.  At utomilumab dose 
levels of 0.24 mg/kg and above, adequate exposure was achieved based on the simulation and 
biomarker data [circulating T and natural killer (NK) cells, and soluble 4-1BB] that indicated 
target modulation can be detected at utomilumab dose levels from 0.24 to 1.2 mg/kg.  In 
addition, early signs of clinical activity were reported with single-agent utomilumab dose levels 
between 0.24 mg/kg to 0.6 mg/kg in patients with Merkel cell carcinoma (MCC) and melanoma 
and responses were also observed with the combination of utomilumab and rituximab in NHL at 
dose levels as low as 0.03 mg/kg with the majority of responses observed at dose levels 
≤1.2 mg/kg.  Finally, exploratory exposure (dose) response analyses indicated that better efficacy 
is expected at utomilumab dose levels ≤1.2 mg/kg. Taken these data together, a few dose levels 
can be further evaluated based on emerging data: 0.24 mg/kg (20 mg) and 1.2 mg/kg (100 mg). 
Doses of 20mg and 100mg were tested in single agent and combination studies and based on PK 
and safety data, a dose of 100mg is being evaluated in all ongoing studies, both single agent and 
in combination with avelumab and PF-04518600 (see discussions of combinations below). 
 
8.1.1.3 
Immunogenicity 
 
Levels of anti-drug antibodies (ADA) to utomilumab in human serum were determined using a 
validated, quasi-quantitative bridging electro chemi-luminescence method.  Preliminary analyses 


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based on quality-controlled, non-quality-assured data are presented.  In Portion A, 8 out of 48 
(16.7%) patients exhibited positive ADA prior to treatment with utomilumab.  Thirty out of 
48 patients (63%) were positive for ADA for at least one time point regardless of baseline ADA 
status.  For patients with positive ADA at any time, the maximum fold increase in titer at 
post-treatment compared to baseline ranged from 1 to 3.1 fold. 
In Portion B, 2 out of 39 (5%) patients exhibited positive ADA against utomilumab prior to 
treatment with utomilumab plus rituximab.  Three out of 39 patients (8%) were positive for ADA 
for at least one time point regardless of baseline ADA status when administered in combination 
with rituximab.  For patients with positive ADA at any time, the maximum fold increase in titer 
at post-treatment versus baseline ranged from 1 to 1.5 fold.  
The impact of ADA on PK of utomilumab was characterized.  ADA negative patients were 
defined as those with negative antibody status for all samples collected during the study 
including baseline (pre-treatment).  ADA positive patients were defined as those with at least 
positive ADA sample anytime during the study including baseline (pre-treatment).  The CL was 
similar in ADA negative and ADA positive patients suggesting that ADA status had minimal 
impact on the PK of utomilumab. 
8.1.1.4 
Safety 
 
In Study B1641001, utomilumab was given as a single agent in patients with solid tumors or R/R 
B-cell lymphoma (Portion A), and was given in combination with rituximab in patients with R/R 
CD20+ NHL (Portion B).  The administered dose levels were 0.006 mg/kg to 10 mg/kg once 
every 4 weeks (Q4W) for Portion A, and 0.03 mg/kg to 10 mg/kg Q4W for Portion B.  The 
maximum tolerated dose (MTD) for utomilumab was not reached as a single agent or in 
combination with rituximab.  Rituximab was administered only in Cycle 1 at a fixed dose of 
375 mg/m2, once per week for a total of 4 weeks.  The first dose of rituximab was administered 
on Cycle 1 Day (-7) followed by the second dose a week later on Day (0) followed by 
utomilumab on C1D1.  No DLT or Grade 4 or 5 treatment-related AEs were observed in either 
study portion.  
Based on a data cutoff date of 05-May-2015, 47 patients in Portion A (29 male, 18 female, mean 
age of 59.7) and 40 patients in Portion B (24 male, 16 female, mean age of 60.8) were treated. 
A total of 19 (40.4%) patients out of 47 experienced treatment-related AEs in Portion A.  The 
most frequently reported treatment-related AE was pyrexia (5 patients, 10.6%), which was 
generally mild, followed by fatigue (4 patients, 8.5%), which was mild except for one patient 
treated at 10 mg/kg, the highest utomilumab dose studied.  This case was considered as a 
Grade 3, non-serious AE. 
For Portion B of this study, a total of 18 out of 40 treated patients (45%) experienced 
treatment-related AEs, with the most common AE being fatigue (22.5% of patients).  AEs were 
mild to moderate, with the exception of one case of Grade 3 thrombocytopenia (platelet count 
decreased), which lasted less than 7 days, and was not considered as a serious adverse event 
(SAE). 


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Additional information for utomilumab may be found in the SRSD, which for this study is the 
PF-05082566 (utomilumab) Investigator’s Brochure (IB).  
8.1.1.5 
Efficacy 
 
The anti-tumor activity of single agent utomilumab in patients with advanced malignancies and 
utomilumab in combination with rituximab in patients with B-cell NHL is being assessed in 
Study B1641001.  This study does not have a control arm, and tumor responses are reported by 
Investigators per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)42 for Portion A 
patients or International Working Group (IWG) criteria43 for Portion B.  Forty-seven patients in 
Portion A and 40 patients in Portion B (24 male, 16 female, mean age 60.8 years) have been 
treated.  
In the single-agent portion (Portion A) of the study, best objective responses observed have been 
1 CR and 1 PR in Merkel cell carcinoma (MCC) patients who were treated at 0.24 mg/kg and 
0.6 mg/kg, respectively. 
In patients treated with the combination of utomilumab and rituximab (Portion B), 8 patients 
with follicular lymphoma (7 patients were refractory to prior rituximab-containing regimen) 
achieved an objective response: 4 patients achieved a CR (2 treated at 1.2 mg/kg, 1 at 0.12 
mg/kg, and 1 at 0.03 mg/kg) and 4 patients achieved a PR (2 treated at treated at 0.18 mg/kg, 1 
treated at 1.2 mg/kg, and 1 treated at 5.0 mg/kg). One (1) patient with CD20 + Hodgkin’s 
lymphoma treated at 1.2 mg/kg achieved a PR and 1 patient with Mantle Cell Lymphoma (MCL) 
treated at 2.4 mg/kg achieved a PR.  
8.1.1.6 
Ordering 
 
Utomilumab will be supplied by Pfizer.  No patients or third-party payers will be charged. Use 
the Drug Supply Request Form provided to order utomilumab.  For all inquiries regarding 
utomilumab supplies, please contact: 
Donna Stocker 
100 Rt. 206 North 
SOM-PPK3-020323 
Peapack, NJ 07977 
Phone 908-901-7356 
 
Utomilumab is a sterile, colorless solution intended for IV administration.  The drug product 
provided will contain 100mg of utomilumab in a 10mL solution in single-use glass vials, 
stoppered with a rubber septum and sealed with an aluminum polypropylene flip-off seal. 
Packaging and labeling will be in accordance with applicable local regulatory requirements and 
applicable Good Manufacturing Practice (GMP) guidelines.   
 
Utomilumab will be packed in cartons each containing one vial.  The information on the labels 
will be in accordance with approved submission documents. Utomilumab will be shipped in 
transport cool containers (2°C to 8°C) that are monitored with temperature monitoring devices. 


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8.1.1.7 
Preparing and Dispensing 
 
The contents of the utomilumab vials are sterile and nonpyrogenic, and do not contain 
bacteriostatic preservatives.  Any spills that occur should be cleaned up using the facility’s 
standard cleanup procedures for biologic products. 
For administration in this trial, utomilumab must be diluted with 0.9% sodium chloride (normal 
saline solution).  Detailed information on infusion bags and medical devices to be used for the 
preparation of the dilutions and subsequent administration will be provided in the Investigational 
Product Manual (IP Manual).  Tubing with in line, low protein binding 0.2 micron filter made of 
polyether sulfone (PES) must be used during administration of utomilumab.  A fixed dose of 
utomilumab at 100mg will be used for all cohorts in this study. 
Utomilumab must not be used for any purpose other than for the trial.  The administration of trial 
drug to patients who have not been enrolled into the trial is prohibited.  Vials are for single use 
only.  Any unused portion of the solution must be discarded in a biohazard waste disposal 
container with final disposal according to accepted local and national standards of incineration. 
8.1.1.8 
Administration 
 
All study treatments will be administered at the investigational site on an outpatient basis as 
described in the IP Manual. 
Utomilumab is administered in this study as a 1 hour IV infusion at a dose of 100mg each 28-day 
cycle and must have completed administration at least 30 minutes prior to subsequent drug 
administration.   
Site staff should make every effort to target the timing of utomilumab infusion to be as close to 
1 hour as possible.  However, given the variability of infusion pumps from site to site, time 
windows of minus 10 minutes and plus 20 minutes is permitted (ie, infusion time is 
50-80 minutes).  The exact duration of infusion should be recorded in both source documents and 
CRFs. 
8.1.2 Avelumab 
 
Avelumab is a fully human monoclonal antibody of the immunoglobulin (Ig) G1 isotype against 
PD-L1. Avelumab selectively binds to PD-L1 and competitively blocks its interaction with PD 1. 
Unlike anti-PD-1 antibodies that target T cells, avelumab targets tumor cells, and therefore is 
expected to have fewer side effects, including a lower risk of autoimmune-related safety issues, 
as blockade of PD-L1 leaves the PD L2/PD 1 pathway intact to promote peripheral self-
tolerance.44  Avelumab is being developed jointly by Pfizer and Merck KGaA.    
 
8.1.2.1 
Clinical Experience 
 
The clinical development program for avelumab currently includes multiple ongoing studies in 


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patients with various solid tumors (Phase 1 studies in patients with solid tumors, as well as 
studies in Merkel cell carcinoma, non-small cell lung cancer (NSCLC), breast cancer, ovarian 
and endometrial cancer, urothelial cancer, renal cell cancer, glioblastoma multiforme, head and 
neck cancer, GI adenocarcinoma, classical Hodgkin lymphoma, diffuse large B cell lymphoma, 
and acute myeloid leukemia). The recommended phase 2 dose from the early phase studies is 
10mg/kg administered intravenously every 2 weeks. 
 
8.1.2.2 
Pharmacokinetics 
 
Pharmacokinetics following the first 1-hour infusion and dose proportionality of avelumab have 
been characterized in 77 Caucasian patients treated in the dose escalation and expansion cohort 
of Study EMR 100070-001 by standard non-compartmental analysis.  This analysis showed that 
the exposure parameters of Cmax and AUCτ increased in a dose proportionate fashion across the 
1, 3, 10, and 20 mg/kg doses.  Apparent half-life tended to increase with dose, likely due to 
target-mediated disposition at lower doses, but terminal half-life of 10 and 20 mg/kg doses were 
similar (102-120 hours).  This suggested that target-mediated elimination does not increase at 
these two doses, and that target occupancy is very high.  
Target occupancy on peripheral blood CD3+ T cells was investigated in human blood in vitro 
using flow cytometry after spiking of whole blood samples from eight healthy volunteers with 
avelumab over a concentration of 0.003-10 µg/mL.  Fifty percent (50%) receptor occupancy was 
observed at a drug concentration of 0.122 µg/mL ±0.042 µg/mL with a plateau indicating at least 
a (95% receptor occupancy reached in all blood samples at 1 µg/mL.  PK profiles obtained from 
the dose escalation phase of Trial EMR 100070-00 found all patients at 10 mg/kg dose reached 
or exceeded the serum level (mean Ctrough 22±12 µg /mL at Day 15) of avelumab required 
for >95% target occupancy.  For patients treated with 3 mg/kg of avelumab, 10 of 13 patients 
reached the required serum level (3.7-8.3 ug/mL). 
8.1.2.3 
Immunogenicity 
 
Based on the Phase 1/1b Trial EMR 100070-001, the incidence of anti-drug antibodies (ADA) 
was relatively low, observed in 1 out of 39 patients (2.6%) in the dose escalation cohorts and 10 
out of 338 patients (2.9%) in a non-small cell lung cancer (NSCLC) expansion cohort.  In 8 of 
these 10 patients, a positive signal was observed at a single time point and a decrease in 
avelumab plasma exposure was observed in the 2 patients with multiple positive samples.  
From these 11 positive patients, 2 patients had symptoms on the day of the infusion compatible 
with an immune reaction (chills and fever, nausea and vomiting) and, therefore, these AEs could 
be ADA-related.  For the other 9 ADA-positive patients, no such AEs were reported. 
Additional information for avelumab may be found in the SRSD, which for this study is the 
avelumab Investigator’s Brochure.  
8.1.2.4 
Safety 
 
As of April 11, 2017, 1738 patients have been treated with avelumab on clinical trials.  The most 
common AEs, observed in 10% or more of patients, include the following: Tiredness; Nausea; 


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Loose or watery stools (diarrhea); Constipation; Reduced appetite; Decrease in weight; 
Vomiting; Low number of red blood cells (anemia); Belly pain; Cough; Fever; Shortness of 
breath; Swelling of feet and legs; Back pain; Joint pain. 
In addition, over 10% of patients experienced at least 1 episode of infusion-related reaction.  
Most of the events were of Grade 1 or Grade 2 severity.  Fewer than 1% had severe reactions 
(Grade 3 or 4) and no Grade 5 events were reported.  Most of the infusion-related reactions 
occurred after the first or second infusion.  These reactions included chills or shaking, fever, 
flushing, back pain, belly pain, shortness of breath or wheezing, decrease in blood pressure, 
hives.   
Potential Immune-Related Adverse Events (irAEs): Potential irAEs (based on a list of pre-defined 
Preferred Terms without further clinical evaluation of individual cases), which were considered 
treatment-related occurred in <10% of patients based on investigator’s causality assessment.  The 
most frequent treatment-related potential irAEs were: hypothyroidism and skin 
inflammation/rash (occurring in 5-10% of patients).  Additionally, 1-5% of patients experienced 
the following: colitis, pneumonitis.  Fewer than 1% of patients experienced autoimmune 
hepatitis, nephritis, adrenal insufficiency, diabetes, uveitis, myositis, myocarditis, Guillain-Barre 
syndrome. The majority of potential irAEs were Grade 1 or Grade 2 in severity; approximately 
2% were severe.  
Additional information for avelumab may be found in the single reference safety document 
(SRSD), which for this study is detailed in the avelumab Investigator’s Brochure.  
Guidelines for the Management of Infusion-Related Reactions and Severe Hypersensitivity 
Reaction are found in Section 6.2.1 and Section 6.2.2. 
8.1.2.5 
Efficacy 
 
Avelumab itself has not been tested as a single agent in B cell non-Hodgkin lymphomas, but 
other checkpoint inhibitors, including the anti-PD1 antibody nivolumab, have.11 Ten patients had 
follicular lymphoma and four patients achieved a response (CR rate 10%); the median duration 
of response was not yet reached at nearly 2 years of follow-up. 
 
8.1.2.6 
Ordering 
 
Avelumab will be supplied for the study by the manufacturer.  No patients or third-party payers 
will be charged.  Use the Drug Supply Request Form provided to order avelumab.  For all 
inquiries regarding avelumab supplies, please contact: 
Donna Stocker 
100 Rt. 206 North 
SOM-PPK3-020323 
Peapack, NJ 07977 
Phone 908-901-7356 
 


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Avelumab is a sterile, clear, and colorless solution intended for IV administration.  Avelumab is 
formulated as a 20 mg/mL solution and will be supplied by Pfizer in single-use glass vials, 
stoppered with a rubber septum and sealed with an aluminum polypropylene flip-off seal. 
Packaging and labeling will be in accordance with applicable local regulatory requirements and 
applicable Good Manufacturing Practice (GMP) guidelines.  Avelumab will be packed in cartons 
each containing one vial.  The information on the labels will be in accordance with approved 
submission documents.  
Avelumab will be shipped in transport cool containers (2°C to 8°C) that are monitored with 
temperature monitoring devices. 
8.1.2.7 
Preparing and Dispensing 
 
The contents of the avelumab vials are sterile and nonpyrogenic, and do not contain 
bacteriostatic preservatives.  Any spills that occur should be cleaned up using the facility’s 
standard cleanup procedures for biologic products. 
For administration in this trial, avelumab must be diluted with 0.9% sodium chloride (normal 
saline solution).  Detailed information on infusion bags and medical devices to be used for the 
preparation of the dilutions and subsequent administration will be provided in the Investigational 
Product Manual (IP Manual).  Tubing with in line, low protein binding 0.2 micron filter made of 
polyether sulfone (PES) must be used during administration of avelumab. 
The dose amount required to prepare the avelumab infusion solution will be based on the 
patient’s weight in kilograms (kgs).  All patients should be weighed within 3 days prior to dosing 
for every cycle to ensure they did not experience either a weight loss or gain >10% from the 
weight used for the last dose calculation.  For weight change less than 10% the decision to 
recalculate the avelumab dose can be in accordance with institutional practice.  If the patient 
experienced either a weight loss or gain >10% compared to the weight used for the last dose 
calculation, the amount of study drug must be recalculated. 
Avelumab must not be used for any purpose other than for the trial.  The administration of trial 
drug to patients who have not been enrolled into the trial is prohibited.  Vials are for single use 
only.  Any unused portion of the solution must be discarded in a biohazard waste disposal 
container with final disposal according to accepted local and national standards of incineration. 
8.1.2.8 
Administration 
 
All study treatments will be administered at the investigational site on an outpatient basis as 
described in the IP Manual. 
 
Avelumab will be administered as a 1 hour IV infusion once every 2 weeks of each 28-day cycle.  
In order to mitigate infusion related reactions, a premedication with an antihistamine and with 
paracetamol (acetaminophen) approximately 30 to 60 minutes prior to each dose of avelumab is 
mandatory (for example, 25-50 mg diphenhydramine and 500-650 mg paracetamol 
[acetaminophen] IV or oral equivalent.  This may be modified based on local treatment standards 


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and guidelines, as appropriate.  
 
If the avelumab is administered more than 4 hours after premedication is administered for the 
preceding drug and/or if no premedication has been given, then the premedication must be 
repeated or dosed.  The line should be flushed, according to local practice, between infusions, 
and a new administration set should be used for avelumab. 
 
Site staff should make every effort to target the timing of avelumab infusion to be as close to 
1 hour as possible.  However, given the variability of infusion pumps from site to site, time 
windows of minus 10 minutes and plus 20 minutes is permitted (ie, infusion time is 
50-80 minutes).  The exact duration of infusion should be recorded in both source documents and 
CRFs.  Possible modifications of the infusion rate for the management of infusion related 
reactions are described in Section 6.2. 
 
8.1.3 Utomilumab and Avelumab Combination Therapy 
 
B9991004 is an ongoing Phase 1b/2 open-label, multi-center, multiple-dose study to evaluate the 
safety, pharmacokinetic (PK), pharmacodynamics, and preliminary antitumor activity of 
avelumab (anti-PD-L-1) at 10 mg/kg Q2W in combination with other cancer immunotherapies in 
patients with locally advanced or metastatic solid tumors.   
As of the 17 December 2016 cutoff date, the study has enrolled and treated 153 patients with the 
combination of utomilumab and avelumab.  There were 8 cases with 12 SAEs assessed as related 
to avelumab by the Investigator (PTs included 2 SAEs of infusion related reaction and 1 SAE 
each of pneumonitis, abdominal pain, chills/hyperthermia/hypertension/tachycardia, diarrhea, 
diabetic ketoacidosis/pancreatic disorder, vomiting).  There was no SAE with fatal outcome 
assessed as related to avelumab.  
The most common treatment-emergent, all-causality Grade 3, 4 AEs were dyspnea (16.7%), 
hypoxia (16.7%) and, nausea (5.6%).  There were no treatment-emergent, treatment-related 
Grade 3, 4 or 5 AEs reported.  There were 3 cases of fatal outcome (Grade 5) attributed to 
disease progression. 
8.1.4 PF-04518600 
 
PF-04518600 is a fully human IgG2 (immunoglobulin g2) agonistic monoclonal antibody (mAb) 
specific for human OX40. OX40 (CD134, TNFRSF4 [tumor necrosis factor receptor superfamily, 
member 4]), a member of the tumor-necrosis factor receptor (TNFR) superfamily like 4-1BB, is a 
co-stimulatory receptors that are expressed by antigen stimulated T cells but not native T 
cells.37,45,46 Following OX40 binding to OX40 ligand (also known as OX40L, CD252 or 
TNFSF4), OX40 signaling activates both the canonical and noncanonical NF-κB (nuclear factor 
kappa-light-chain enhancer of activated B cells) survival pathways, leading to an upregulation of 
anti-apoptotic molecules including Bcl-2 (B-cell lymphoma-2), Bcl-xL, and survivin.47  A number 
of studies support the potential for agonistic OX40 antibodies to reverse T cell’s anergic state, and 
enhance tumor immunity. This includes a number of published preclinical studies demonstrating 
eradication of tumor growth in syngeneic models of melanoma, sarcoma, glioma, colon, breast, 
prostate, and renal cancers.46,48-50 Preclinical studies completed at Pfizer support these published 


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59 
findings; using OX86 (a murine IgG1 surrogate anti-OX40 agonistic antibody), growth inhibition 
of colon tumors was demonstrated in a syngeneic mouse model.  
 
In vitro mechanism of action studies with PF-04518600 have been completed. PF-04518600 
showed minimal binding to resting human T cells compared with activated cells. Consistent with 
the binding data, PF 04518600 demonstrated dose-dependent induction of cell proliferation and 
pro-inflammatory cytokine release (TNF, IFNγ [interferon gamma] and IL-10 [interleukin-10]) in 
CD3 activated T cells but not in non-activated whole blood or peripheral blood mononuclear cells 
(PBMCs). Biacore experiments also confirmed PF-04518600 to be highly selective and specific 
for human OX40. PF-04518600 showed no significant binding to other members of the TNFR 
super-family, such as CD40, 4-1BB, and GITR (glucocorticoid-induced tumor necrosis factor 
receptor), and no binding crossreactivity for murine, rat, rabbit, or dog OX40.  
 
8.1.4.1 
Clinical Experience 
 
PF-04518600 has been tested in a first-in-human study in advanced solid tumor malignancies, 
with or without utomilumab.  There have been 2 confirmed partial responses (PRs); 1 PR was 
reported in a melanoma patient treated at 0.1 mg/kg dose level, and a second PR was reported in 
a hepatocellular carcinoma (HCC) patient treated at 0.3 mg/kg dose level. A total of 52% of 
patients, of the 49 evaluable patients treated in experienced a best overall response of stable 
disease (SD).  There is also an ongoing phase 1b/2 study of avelumab in combination with 
various immune modulators, including PF-04518600 alone or in combination with utomilumab, 
in locally advanced of metastatic solid tumors. 
 
8.1.4.2 
Pharmacokinetics 
 
Preliminary PK data are available for 52 patients at the 0.01, 0.1, 0.3, 1.5, 3.0, or 10 mg/kg dose 
levels of the ongoing FIP study. The preliminary PK results suggest that exposure increased with 
increasing dose in an approximately dose-proportional manner between the doses of 0.3 and 
10 mg/kg.  The mean half-life (t1/2) ranged from 4.0 to 10.1 days at the dose range of 0.1 to 
10 mg/kg.  Following multiple IV infusions of PF-04518600 once every 14 days, the mean 
(±SD) accumulation ratio was 1.4 ±0.5, 1.7 ±0.4, 1.8 ±0.2, 2.0±0.2 and 2.0 ±03. at the dose 
levels of 0.1, 0.3, 1.5, 3, and 10 mg/kg, respectively, based on a total of 28 patients with full PK 
profiles from both Cycle 1 and Cycle 3. 
The flat dose that is equivalent to 0.3 mg/kg was determined to be 25 mg in terms of matching 
the center of the distributions based on the population PK/PD analysis.  However, 30 mg was 
chosen as the low dose to ensure the 5th percentile of trough concentrations (Ctrough) to be at or 
above which the full receptor occupancy was observed.  The flat dose that is equivalent to 
3 mg/kg was determined to be 250 mg. 
8.1.4.3 
Immunogenicity 
 
Anti-drug antibody (ADA) against PF-04518600 was determined using a validated 
electrochemiluminescence assay based on a tiered approach with screening, confirmation and 
titer assays. As of 17 November, 2016, preliminary data were available for 46 patients who had 
the baseline and at least one post-dose ADA sample analyzed from the monotherapy portion of 


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B0601002 study. A total of 3 patients (6.5%) tested positive for ADA at baseline.  A total of 16 
patients (35%) were ADA positive at a minimum of one post-dose time point. The majority of 
ADA responses were transient with no noticeable effect on the PK of PF-04518600, except for 3 
patients at the 0.1 mg/kg dose level; these 3 patients had the highest titers in that group and the 
Ctrough of PF-04518600 appeared to be lower compared to the expected profiles. 
 
8.1.4.4 
Safety 
 
PF-04518600 as monotherapy has been well-tolerated in doses from 0.01 to 10 mg/kg.  Fifty-
two patients (43 male and 9 female, mean ages of 60.0 years) were treated with PF-04518600 
across 6 dose levels (0.01, 0.1, 0.3, 1.5, 3 and 10 mg/kg) in the FIP study. 
The most frequent treatment-emergent adverse events (TEAEs) regardless of causality that 
occurred in ≥10% of patients were: fatigue (46.2%), nausea (28.8%), decreased appetite (23.1%), 
pruritus (23.1%), anemia (21.2%), aspartate aminotransferase increase (21.2%), abdominal pain 
(19.2%), constipation (19.2%), dyspnea (19.2%), headache (17.3%), alanine aminotransferase 
increase (15.4%), chills (15.4%), cough (15.4%), diarrhea (15.4%), pyrexia (15.4%),  vomiting 
(15.4%), back pain (13.5%), blood bilirubin increase (11.5%), and insomnia (11.5%). 
A total of 30 (57.7%) patients out of 52 experienced treatment-related AEs.  The most frequent 
treatment-related AE experienced by ≥10% of patients was fatigue (25.0%).  Most 
treatment-related events reported were Grade 2 or below.  There was 1 Grade 3 treatment-related 
event of gamma-glutamyltransferase increased reported.  There did not appear to be a 
dose-dependent increase in any treatment-related AEs.  No dose-limiting toxicities (DLTs) were 
observed. 
The only treatment-related Serious Adverse Event (SAE) reported to date was Grade 2 
congestive heart failure (CHF) in an HCC patient receiving the 0.1 mg/kg dose.  This patient had 
a prior history of anthracycline exposure.  There were no treatment-related deaths in the FIP 
study.  
8.1.4.5 
Efficacy 
 
There have been 4 confirmed PRs; 1 PR was reported in a melanoma patient treated at 0.1 mg/kg 
dose level, and three PRs were reported in patients treated at 0.3 mg/kg dose level. A total of 
57% of patients, of the 49 evaluable patients treated experienced a best overall response of SD. 
 
8.1.4.6 
Ordering 
 
PF-04518600 will be supplied by Pfizer.  No patients or third-party payers will be charged.  Use 
the Drug Supply Request Form provided to order PF-04518600.  For all inquiries regarding PF-
04518600 supplies, please contact: 
Donna Stocker 
100 Rt. 206 North 
SOM-PPK3-020323 
Peapack, NJ 07977 


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Phone 908-901-7356 
 
PF-04518600 drug product, 10 mg/mL injection is presented as a sterile solution for IV 
administration, compounded in histidine buffer with excipients at pH 5.5. Each vial contains 108 
mg of PF-04518600 in 10.8 mL of aqueous buffered solution, with a nominal volume of 10 mL, 
is sealed with a coated stopper and an overseal, and labeled according to local regulatory 
requirements. The vial is intended for single use only. The drug product should be stored 
refrigerated (2-8ºC) and protected from light. 
 
8.1.4.7 
Preparing and Dispensing  
 
Detailed information on the preparation of PF-04518600 will be provided in the IP Manual.  
Investigational product should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, practitioner, 
pharmacist, or medical assistant) as allowed by local, state, and institutional guidance.  Only 
qualified personnel who are familiar with procedures that minimize undue exposure to them and 
to the environment should undertake the preparation, handling, and safe disposal of biologic 
agents. 
The dose amount required to prepare the PF-04518600 infusion solution will be based on the 
patient’s weight in kilograms (kgs).  All patients should be weighed within 3 days prior to dosing 
for every cycle to ensure they did not experience either a weight loss or gain >10% from the 
weight used for the last dose calculation.  For weight change less than 10% the decision to 
recalculate the PF-04518600 dose can be in accordance with institutional practice.  If the patient 
experienced either a weight loss or gain >10% compared to the weight used for the last dose 
calculation, the amount of study drug must be recalculated. 
PF-04518600 must not be used for any purpose other than for the trial.  The administration of 
trial drug to patients who have not been enrolled into the trial is prohibited.  Vials are for single 
use only.  Any unused portion of the solution must be discarded in a biohazard waste disposal 
container with final disposal according to accepted local and national standards of incineration. 
8.1.4.8 
Administration 
 
PF-04518600 will be administered per the IP Manual as an IV infusion over 60 minutes on an 
outpatient basis.  On days whereby both PF-04518600 and utomilumab are to be administered on 
the same day, PF-04518600 will be administered after, but no sooner than 30 minutes after 
completion of the utomilumab infusion in absence of infusion reaction.  On days whereby both 
PF-04518600 and avelumab are to be administered on the same day, avelumab will be 
administered after, but no sooner than 30 minutes after completion of the PF-04518600 infusion 
in absence of infusion reaction.   
 
Site staff should make every effort to target the timing of PF-04518600 infusion to be as close to 
1 hour as possible.  However, given the variability of infusion pumps from site to site, time 
windows of minus 10 minutes and plus 20 minutes is permitted (ie, infusion time is 
50-80 minutes).  The exact duration of infusion should be recorded in both source documents and 
CRFs. 


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62 
 
8.1.5 PF-04518600 and Utomilumab Combination Therapy 
 
PF-04518600 is currently being tested in a phase 1 clinical trial in combination with utomilumab 
in selected locally advanced or metastatic carcinoma.  Forty-two patients (23 male and 
19 females, mean ages of 58.6 years) were treated with PF-04518600 across 5 dose levels of 
PF-04518600 (0.1, 0.3, 1 or 3 mg/kg) in combination with 20 or 100 mg of utomilumab. 
The most frequent all-causality TEAEs that occurred in ≥10% of patients include: decreased 
appetite (23.8%), nausea (21.4%), fatigue (19.0%), anemia (16.7%), pyrexia (16.7%), abdominal 
pain (14.3%), constipation (14.3%), diarrhea (14.3%), and pain (11.9%). 
A total of 15 (32.1%) patients out of 42 experienced treatment-related TEAEs.  The most 
frequent treatment-related TEAE experienced in ≥5% of patients include fatigue (9.5%) and 
nausea (7.1%).  All treatment-related events reported were Grade 1 or 2, with the exception of a 
Grade 3 amylase and a Grade 4 lipase elevation in a single subject receiving 0.3 mg/kg PF-
04518600 and 100 mg utomilumab. No DLTs have been reported. 
The only treatment-related SAE, which occurred on 19June2017, was a Grade 3 infusion 
reaction attributed to PF-04518600 but not utomilumab in a 67-year-old patient with bladder 
cancer who was receiving 1 mg/kg PF-04518600 and 100 mg utomilumab. 
8.1.6 IP Storage 
 
The Investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparators and/or marketed products, are stored in a 
secured area with controlled access under required storage conditions and in accordance with 
applicable regulatory requirements. 
 
Investigational product should be stored in its original container and in accordance with the 
label.  See the IP Manual, package insert, or equivalent for storage conditions of the product 
once reconstituted and/or diluted. 
 
Storage conditions stated in the SRSD (eg, investigator’s brochure [IB], core data sheet [CDS], 
United States package insert [USPI], summary of product characteristics [SPC], or local product 
document [LPD]) will be superseded by the storage conditions stated in the labeling. 
 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.   
 
Even for continuous monitoring systems, a log or site procedure that ensures active daily 
evaluation for excursions should be available.  The intent is to ensure that the minimum and 
maximum temperature is checked each business day to confirm that no excursion occurred since 
the last evaluation and to provide the site with the capability to store or view the 
minimum/maximum temperature for all non-working days upon return to normal operations.  


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The operation of the temperature monitoring device and storage unit (for example, refrigerator), 
as applicable, should be regularly inspected to ensure it is maintained in working order.  
 
Any excursions from the product label storage conditions should be reported to the Overall 
Principal Investigator upon discovery.  The site should actively pursue options for returning the 
product to the storage conditions as described in the labeling, as soon as possible.  Deviations 
from the storage requirements, including any actions taken, must be documented and reported to 
Pfizer.  Once an excursion is identified, the investigational product must be quarantined and not 
used until Pfizer provides documentation of permission to use the investigational product.  It will 
not be considered a protocol deviation if Pfizer approves the use of the investigational product 
after the temperature excursion.  Use of the investigational product prior to Pfizer approval will 
be considered a protocol deviation.  
 
Receipt of materials, door opening and closing, and other routine handling operations where the 
product(s) are briefly out of the temperature range described in the labeling are not considered 
excursions.  Specific details regarding information the site should report for each excursion will 
be provided to the site.  
 
Site staff will instruct patients on the proper storage requirements for take home investigational 
products.  
 
8.1.7 IP Accountability 
 
The investigative site must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. For all drugs from a commercial supply, 
sites should keep records per their institutional policies.  
 
8.1.8 IP Destruction 
 
The Principal Investigator or designee will provide guidance on the destruction of unused 
investigational product (eg, at the site).  If destruction is authorized to take place at the 
Investigator site, the Investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions provided 
by Pfizer, and all destruction must be adequately documented. 
8.2 
Other Agent(s) 
 
8.2.1 Rituximab 
 
Single agent monoclonal antibodies are an attractive treatment option given excellent tolerability. 
Rituximab is approved as a single agent in relapsed or refractory FL and in combination with 
chemotherapy for first line therapy of FL.51   
 
Rituximab is a genetically engineered, chimeric, murine/human monoclonal antibody directed 
against the CD20 antigen found on the surface of normal and malignant pre-B and mature B 
cells. The antibody is an IgG1 κ immunoglobulin containing murine light and heavy-chain 


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variable region sequences and human constant region sequences. Rituximab is composed of two 
heavy chains of 451 amino acids and two light chains of 213 amino acids (based on cDNA 
analysis) and has an approximate molecular mass of 145 kD. Rituximab has a binding affinity for 
the CD20 antigen of ~8.0 nM.  Several mechanisms of action have been proposed in various 
models including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated 
cytoxicity (ADCC), induction of apoptosis, and a “vaccinal” effect.52  It is likely that rituximab 
works through a combination of these mechanisms. 
 
The objective response rate for rituximab monotherapy in relapsed low-grade B-cell lymphoma 
is approximately 24-36% with complete response rates of approximately 7%.53  Several 
mechanisms for rituximab resistance have been proposed including variable CD20 expression by 
lymphoma subtype, variability in complement activation, and polymorphisms in Fc receptors.54-
56  Novel agents that overcome these resistance mechanisms might offer similar complete 
response rates to combined chemotherapy and immunotherapy with improved tolerability. 
 
Rituximab monotherapy has been evaluated in the upfront therapy as well.  When given as 4 
weekly infusions to patients who would otherwise have undergone observation, the objective 
response rate was 72% and the median time to progression was 2.2 years.51  The addition of 
maintenance rituximab, given once every 8 weeks for 4 treatments, to patients with at least stable 
disease following induction therapy with rituximab monotherapy is associated with an 
improvement in event free survival (24 versus 13 months, <0.001).57  
 
8.2.2 Ordering 
 
Rituximab and rituximab biosimilars are commercially available from various manufacturers.  
All supplies will be provided locally by the trial site, subsidiary or designee, depending on local 
country operational or regulatory requirements.  Detailed information regarding rituximab 
formulation can be found in the Package Insert (PI) or Summary of Product Characteristics 
(SPC). 
 
8.2.3 Preparing and Dispensing 
 
Refer to specific preparation and dispensing instructions provided in the Package Insert. 
 
8.2.4 Administration 
 
Rituximab is administered in this study at the dose of 375 mg/m2 weekly for four treatments 
starting on Day -6.  On days when rituximab is to be given with other intravenous agents, it will 
be given last, at a minimum of 30 minutes (but up to 28 hours) after the last infusion has 
completed.   
 
Rituximab should not be administered as an IV push or bolus.  Premedication with 
acetaminophen and an antihistamine should be administered 30 minutes before each IV infusion.  
 
Premedication with acetaminophen and an antihistamine is mandatory.  If rituximab is 
administered more than 4 hours after premedication for avelumab, then the premedication must 


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be repeated.  The line should be flushed, according to local practice, between infusions. 
 
Infusions will follow institutional guidelines. 
 
The infusion should be interrupted or slowed for infusion reactions.  Upon improvement of 
symptoms, continue the infusion at one-half the previous rate.  Medical management should be 
instituted (glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as 
needed.  Depending on the severity of the infusion reaction and the required interventions, 
temporarily or permanently discontinue rituximab. 
 
If the infusion cannot be completed within 1 day, the patient is allowed to receive the remainder 
of the infusion the following day as long as the dose is administered within 2 consecutive days.  
This will only be allowed if the reason for dose interruption does not include a Grade ≥3 toxicity 
attributed to rituximab.  Any patient requiring two dose interruptions, each of which prevent 
administration of the full rituximab dose within 24 hours will be withdrawn from the study. 
 
 
9. BIOMARKER STUDIES 
 
The biomarkers for the trial include measurements from tumor tissues and analyses of blood 
samples to explore molecular, cellular, and soluble markers that may be relevant to the 
mechanism of action of the drug(s) or response/resistance to the drug(s).  We will also collect 
stool samples to explore the relationship between the microbiome and immune response. 
Peripheral blood samples will be collected before treatment on C1D-6 (for all cohorts except 
cohort A2a, dose level 0), C1D1, C1D2, C1D8, C1D15, C1D16, on day 1 of C2-6, and the end of 
treatment visit, and every 6 months from 6-24 months following the end of treatment.  Analyses 
may include flow cytometry and CyTOF for immune cell subsets and their cell surface markers 
(including PD1, 4-1BB, and OX-40) as well as intracellular markers of immune cell activation; 
Luminex technology for measurement of soluble receptors and cytokines; and/or tumor free 
DNA sequencing and TCR sequencing for minimal residual disease (at baseline, at the end of 
treatment, and at 6 months +/- 2weeks from the end of treatment) and T cell repertoire studies, 
respectively. 
Fresh tumor biopsies will be collected during screening, between C1D22 and C2D1, and at the 
time of progression.  An archival sample within 90 days and without intervening treatment is 
acceptable as the pre-treatment biopsy assuming that the following provisions are met: 1.) 
Priority: tumor containing formalin-fixed, paraffin-embedded (FFPE) tissue block; 2). Priority: if 
the tumor containing FFPE tissue block cannot be provided in total, sections from this block 
should be provided that are freshly cut and mounted on positively-charged glass slides 
(SuperFrost Plus are recommended).  Preferably, 25 slides should be provided; if not possible, a 
minimum of 15 slides is required. 
These may be obtained by excisional or core needle biopsy.  Biopsies may be analyzed for tumor 
and microenvironmental expression of checkpoint markers and for immune architecture by a 
combination of immunohistochemistry and multiparameter spectral imaging.  Ideally, 4-6 core 
needle biopsies will be collected.  Baseline patient samples from all sites will be used from the 


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following studies (in order of priority): 1) immunohistochemistry and multiparameter spectral 
imaging; 2) whole exome sequencing and RNAseq; 3) sequencing for clonotype determination 
(for minimal residual disease analysis) and TCR repertoire analysis; 4) banked biospecimens for 
future research pertaining to the drugs and/or disease being studied on this study.  On treatment 
patient samples from sites will be analyzed, in the following order of priority, by: 1) 
immunohistochemistry and multiparameter spectral imaging; 2) RNAseq; 3) sequencing for TCR 
repertoire analysis.  In addition, freshly obtained baseline and on-treatment samples from Dana-
Farber Cancer Institute (DFCI) will be used for single-cell RNA sequencing testing. DFCI 
specimens will be allocated for this testing after 1) immunohistochemistry/multiparameter 
spectral imaging and prior to 2) whole exome sequencing/RNAseq.      
Tissue processing: The cancer tissues should be fixed in 10% neutral buffered formalin, paraffin 
embedded, and routinely processed for histological evaluation.  Formalin substitutes are not 
suitable as fixatives.  Sample and tissue repository: Biomarker samples may be stored beyond the 
end of the trial and utilized at a later time jointly with samples from other studies in order to 
investigate actions of the investigational drug(s) or aspects of the disease under study.   
Banked biospecimens will be handled in a manner that protects each subject’s privacy and 
confidentiality.  Banked biospecimens will be assigned the subject’s study identification code 
(ID) at the site.  The data generated from these banked biospecimens will also be indexed by this 
ID.  Biospecimens will be kept until destruction in facilities with access limited to authorized 
personnel, and biospecimen-derived data will be stored on password-protected computer 
systems.  The key between the subject’s ID and the subject’s direct personally identifying 
information (eg, name, address) will be held at the study site.  Biospecimens will be used only 
for the purposes described in the protocol and informed consent document; any other uses 
require additional ethical approval.  Unless a time limitation is required by local regulations or 
ethical requirements, biospecimens will be stored for many years (no time limit) to allow for 
research in the future, including research conducted during the lengthy drug-development 
process and also postmarketing research.  Subjects may withdraw their consent for the use of 
their banked biospecimens at any time by making a request to the investigator; in this case, any 
remaining biospecimens will be destroyed, but data already generated from the biospecimens 
will continue to be available to protect the integrity of existing analyses.  Unless prohibited by 
local regulations or ethics committee decision, a 4-mL blood genomic banked biospecimen Prep 
D1 (dipotassium edetic acid [ethylenediaminetetraacetic acid] [K2EDTA] whole-blood collection 
optimized for DNA analysis) will be collected at the time specified in the Study Calendar section 
of the protocol to be retained for potential pharmacogenomic/genomic/biomarker analyses 
related to drug response and disease/condition under study.  For example, putative safety 
biomarkers, drug-metabolizing enzyme genes, drug-transport protein genes, or genes thought to 
be related to the mechanism of drug action may be examined.  The primary purpose is to 
examine DNA; however, the biospecimen may also be used to study other molecules (eg, RNA, 
proteins, and metabolites).  
Stool samples will be collected at screening, during cycle 1, and at the end of treatment, for 
analysis of gut microbial composition in fecal samples using 16S ribosomal RNA gene 
sequencing or equivalent phylogenetic method. 
 


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Details of time points and sampling are provided in the Study Calendar.  Reference the 
laboratory manual for specimen collection, processing, and shipment instructions. 
In order to complete all the assessments on tumor materials and blood and fecal samples, the 
Principal investigator will provide instructions and necessary supplies to the site, including 
shipping materials and prepaid mailers.  The panel of biomarkers might be adjusted based on 
results from ongoing research related to anti-PD-1/PD-L1 therapies and/or safety; therefore, each 
patient will also be asked whether any remaining tumor tissue and/or blood-derived samples can 
be stored at a central repository (until such time as these samples cannot support any further 
analysis) and can be used for future exploratory research on the drug(s) and / or disease-related 
aspects.  Biomarker analyses may be conducted after the conclusion of this study and may be 
based on samples derived from multiple studies. 
 
10. STUDY CALENDAR 
 
All patients must sign an informed consent document prior to undergoing any study-specific 
procedures; informed consent must be obtained within 28 days to start of protocol therapy. 
Baseline evaluations are to be conducted within 4 weeks prior to the start of protocol therapy.  
Recent scans may be used but must be done < 6 weeks prior to the start of therapy.  In the event 
that the participant’s condition is deteriorating, laboratory evaluations should be repeated within 
48 hours prior to initiation of the next cycle of therapy. 
All assessments must be performed prior to administration of any study medication.  All study 
assessments and medications should be administered within + 2 days of the protocol-specified 
date, unless otherwise noted. 


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Study Calendar Cohorts A1a (all dose levels), A1b and B1 
 
 
Cycle 1 
Cycles 
2-6 
EOT8 
Follow-
up 
Study Assessment 
Baseline 
Week 
-1 
Week 1 
Week 
2 
Week 3 
Week 
4 
 
 
Week 4 
from last 
treatment 
Every 
3 
months 
+/- 2 
weeks) 
Study Days 
-28 to -1 
-6 
1 
2 
8 
15 
16 
22 
1 
15 
 
 
Visit window +/- days 
0 
0 
2 
N/A 
2 
2 
N/A 
2 
2 
2 
N3 
14 
Study Drug 
Utomilumab 
 
 
 
x 
 
 
 
 
x 
 
 
 
Avelumab 
 
 
 
 
 
 
x 
 
x 
x 
 
 
Rituximab (or 
rituximab 
biosimilar) 
 
x 
x 
 
x 
x 
 
 
 
 
 
 
Medical History, Medication 
Review, Physical Exam, 
Weight 
x 
x 
x 
 
x 
x 
 
 
x 
x 
x 
x 
Toxicity Assessment 
x 
x 
x 
 
x 
x 
 
 
x 
x 
x 
x 
ECOG Performance Status 
(Appendix A) 
x 
 
x 
 
 
 
 
 
x 
 
x 
x 
CBC, Differential, and 
Blood chemistries1 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
TSH, creatinine kinase, 
lipase, triglycerides, urine 
dipstick for blood and 
protein 
x 
 
x 
 
 
 
 
 
x 
 
x 
 
Hepatitis B and C testing2 
x 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing 
x 
x 
 
x 
 
x 
 
 
x 
 
 
 
Tumor restaging3 
x3 
 
 
 
 
 
 
 
x3 
 
x3 
x3 
Peripheral blood collection 
for biomarker studies4 
 
x 
x 
x 
x 
x 
x 
 
x4 
 
x4 
x4 


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69 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 
Cycles 
2-6 
EOT8 
Follow-
up 
Study Assessment 
Baseline 
Week 
-1 
Week 1 
Week 
2 
Week 3 
Week 
4 
 
 
Week 4 
from last 
treatment 
Every 
3 
months 
+/- 2 
weeks) 
Study Days 
-28 to -1 
-6 
1 
2 
8 
15 
16 
22 
1 
15 
 
 
Visit window +/- days 
0 
0 
2 
N/A 
2 
2 
N/A 
2 
2 
2 
N3 
14 
Bone marrow biopsy5 
 
 
 
 
 
 
 
 
 
 
x5 
 
Tumor biopsies for 
biomarker studies 
x 
 
 
 
 
 
 
x6 
 
 
 
 
Stool studies for 
biomarker/microbiome 
studies7 
x 
 
 
 
 
 
 
x 
 
 
x 
 
TTE or MUGA scan 
x 
 
 
 
 
 
 
 
 
 
 
 
1 See Sections 10.1 and 10.2. All tests will be required at screening and tumor lysis labs (CMP, uric acid, LDH, phosphorus) will be 
repeated at each study visit in cycle 1.  Patients do need to meet laboratory eligibility criteria on C1D-6. 
2 Consisting at a minimum of hepatitis C antibody, hepatitis B surface antigen and hepatitis B core antibody. 
3 See Sections 10.1, 10.2, and 10.3. 
4 One pretreatment peripheral blood sample(s) will be collected for correlative studies (Section 9) before rituximab on C1D-6, and then 
before treatment on C1D1, C1D2, C1D8, C1D15, C1D16 and on day 1 of cycles 2-6, at the end of treatment visit and at every other 
follow-up visit beginning 6 months (+/- 2 weeks) from the end of treatment and then every 6 months (+/- 2 weeks) until 24 months from 
the end of treatment. 
5 A bone marrow biopsy done will be required at the end of treatment if a PET/CT scan shows a complete metabolic response to confirm a 
complete response.  
6 On treatment tumor biopsy will be done between C1D22 and C2D1.  A tumor biopsy will also be done at the time of disease progression. 
7 Stool studies will be collected during Screening, between C1D22 and C2D1, and at the completion of therapy by patient at home using 
kit provided by the research staff. 
8EOT = end of treatment, to take place 4-6 weeks from the last dose of study treatment. 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
70 
Study Calendar Cohort A2a, Dose Level 0 
 
 
 
 
Cycle 1 
Cycles 
2-6 
EOT10 
Follow-
up 
Study Assessment 
Baseline 
Week 1 
Week 
2 
Week 3 
Week 
4 
 
 
Week 4 
from last 
treatment 
Every 
3 
months 
+/- 2 
weeks) 
Study Days 
-28 to -1 
1 
2 
8 
15 
16 
22 
1 
15 
 
 
Visit window +/- days 
0 
2 
N/A 
2 
2 
N/A 
2 
2 
2 
N3 
14 
Study Drug 
PF-04518600 
 
x 
 
 
x 
 
 
x 
x 
 
 
Medical History, 
Medication Review, 
Physical Exam, Weight 
x 
x 
 
x 
x 
 
 
x 
x 
x 
x 
Toxicity Assessment 
x 
x 
 
x 
x 
 
 
x 
x 
x 
x 
ECOG Performance 
Status (Appendix A) 
x 
x 
 
 
 
 
 
x 
 
x 
x 
CBC, Differential, and 
Blood chemistries1 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
TSH, creatinine kinase, 
lipase, triglycerides, 
urine dipstick for blood 
and protein 
x 
x 
 
 
 
 
 
x 
 
x 
 
Troponin, NTproBNP 
x 
 
 
 
 
 
 
x11 
 
 
 
Hepatitis B and C 
testing2 
x 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing 
x 
 
 
 
x 
 
 
x 
 
 
 
Tumor restaging3 
x3 
 
 
 
 
 
 
x3 
 
x3 
x3 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
71 
 
 
 
Cycle 1 
Cycles 2-
6 
EOT10 
Follow-
up 
Study Assessment 
Baseline 
Week 1 
Week 
2 
Week 3 
Week 
4 
 
 
Week 4 
from last 
treatme
nt 
Every 3 
months 
+/- 2 
weeks) 
Study Days 
-28 to -1 
1 
2 
8 
15 
16 
22 
1 
15 
 
 
Visit window +/- days 
0 
2 
N/A 
2 
2 
N/A 
2 
2 
2 
N3 
14 
Peripheral blood 
collection for biomarker 
studies4 
x 
x 
x 
x 
x 
x 
 
x4 
 
x4 
x4 
Bone marrow biopsy5 
 
 
 
 
 
 
 
 
 
x5 
 
Tumor biopsies for 
biomarker studies 
x 
 
 
 
 
 
x6 
 
 
 
 
Stool studies for 
biomarker/microbiome 
studies7 
x 
 
 
 
 
 
x 
 
 
x 
 
EKG8 
x8 
x8 
 
 
x8 
 
 
x8 
x8 
x8 
 
TTE or MUGA scan9 
x 
 
 
 
 
 
 
x9 
 
 
 
1 See Sections 10.1 and 10.2. All tests will be required at screening and tumor lysis labs (CMP, uric acid, LDH, phosphorus) will be 
repeated at each study visit in cycle 1.  Patients do need to meet laboratory eligibility criteria on C1D-6 
2Consisting at a minimum of hepatitis C antibody, hepatitis B surface antigen and hepatitis B core antibody. 
3 See Sections 10.1, 10.2, and 10.3.  Note, patients with SD or PD at midtreatment CT scans restaging after cycle 3 will have the 
option to stay on study and received 4 weekly infusions of rituximab 375mg/m2 during cycle 4 (days 1, 8, 15, and 22) while 
continuing PF-04518600 at the same dose and schedule. 
4 One pretreatment peripheral blood sample(s) will be collected for correlative studies (Section 9) before treatment on C1D1, and 
then before treatment C1D2, C1D8, C1D15, C1D16 and on day 1 of cycles 2-6, at the end of treatment visit and at every other 
follow-up visit beginning 6 months (+/- 2 weeks) from the end of treatment and then every 6 months (+/- 2 weeks) until 24 months 
from the end of treatment. 
5 A bone marrow biopsy done will be required at the end of treatment if a PET/CT scan shows a complete metabolic response to 
confirm a complete response.  
6 On treatment tumor biopsy will be done between C1D22 and C2D1.  A tumor biopsy will also be done at the time of disease 
progression. 
7 Stool studies will be collected during Screening, between C1D22 and C2D1, and at the completion of therapy by patient at home 
using kit provided by the research staff. 
8 EKGs (single EKG at screening and then triplicate EKGs for all subsequent EKGs) will be performed for patients in cohorts A2, 
A3, and B2 at screening, on each day of administration of PF-04518600 and at the EOT visit. 
9 TTE/MUGA will be performed at screening and every 3 months on treatment and when clinically indicated. 
10 EOT = end of treatment, to take place 4-6 weeks from the last dose of study treatment. 
11For patients with a previous history of anthracycline treatment and who are at high risk of cardiac failure (ie those that have New 
York Heart Association Class I heart failure), troponin I (troponin T is allowed if the assay utilized can be verified to have cardiac 
specificity) and N-terminal of the prohormone brain natriuretic peptide (Nt-proBNP) levels will be evaluated at baseline in screening 
and every other cycle starting with cycle 2 and when clinically indicated.  Any elevation in troponin or Nt-proBNP should be 
discussed with the study principal investigator prior to enrollment or treatment. 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
72 
 
Study Calendar Cohort A2a Dose Level 1 
 
 
 
 
 
Cycle 1 
Cycles 
2-6 
EOT10 
Follow-
up 
Study Assessment 
Baseline 
Week 
-1 
Week 1 
Week 
2 
Week 3 
Week 
4 
 
 
Week 4 
from last 
treatment 
Every 
3 
months 
+/- 2 
weeks) 
Study Days 
-28 to -1 
-6 
1 
2 
8 
15 
16 
22 
1 
15 
 
 
Visit window +/- days 
0 
0 
2 
N/A 
2 
2 
N/A 
2 
2 
2 
N3 
14 
Study Drug 
PF-04518600 
 
 
 
x 
 
 
x 
 
x 
x 
 
 
Rituximab (or 
rituximab 
biosimiar 
 
x 
x 
 
x 
x 
 
 
 
 
 
 
Medical History, Medication 
Review, Physical Exam, 
Weight 
x 
x 
x 
 
x 
x 
 
 
x 
x 
x 
x 
Toxicity Assessment 
x 
x 
x 
 
x 
x 
 
 
x 
x 
x 
x 
ECOG Performance Status 
(Appendix A) 
x 
 
x 
 
 
 
 
 
x 
 
x 
x 
CBC, Differential, and Blood 
chemistries1 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
TSH, creatinine kinase, 
lipase, triglycerides, urine 
dipstick for blood and protein 
x 
 
x 
 
 
 
 
 
x 
 
x 
 
Troponin, NTproBNP 
x 
 
 
 
 
 
 
 
x11 
 
 
 
Hepatitis B and C testing2 
x 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
Tumor restaging3 
x3 
 
 
 
 
 
 
 
x3 
 
x3 
x3 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
73 
 
 
 
 
 
Cycle 1 
Cycles 
2-6 
EOT10 
Follow-
up 
Study Assessment 
Baseline 
Week 
-1 
Week 1 
Week 
2 
Week 3 
Week 
4 
 
 
Week 4 
from last 
treatment 
Every 
3 
months 
+/- 2 
weeks) 
Study Days 
-28 to -1 
-6 
1 
2 
8 
15 
16 
22 
1 
15 
 
 
Visit window +/- days 
0 
0 
2 
N/A 
2 
2 
N/A 
2 
2 
2 
N3 
14 
Peripheral blood collection 
for biomarker studies4 
 
x 
x 
x 
x 
x 
x 
 
x4 
 
x4 
x4 
Bone marrow biopsy5 
 
 
 
 
 
 
 
 
 
 
x5 
 
Tumor biopsies for 
biomarker studies 
x 
 
 
 
 
 
 
x6 
 
 
 
 
Stool studies for 
biomarker/microbiome 
studies7 
x 
 
 
 
 
 
 
x 
 
 
x 
 
EKG8 
x8 
 
 
x8 
 
 
x8 
 
x8 
x8 
x8 
 
TTE or MUGA scan9 
x 
 
 
 
 
 
 
 
x9 
 
 
 
1 See Sections 10.1 and 10.2. All tests will be required at screening and tumor lysis labs (CMP, uric acid, LDH, phosphorus) will be repeated 
at each study visit in cycle 1.  Patients do need to meet laboratory eligibility criteria on C1D-6 
2Consisting at a minimum of hepatitis C antibody, hepatitis B surface antigen and hepatitis B core antibody. 
3 See Sections 10.1, 10.2, and 10.3. 
4 One pretreatment peripheral blood sample(s) will be collected for correlative studies (Section 9) before rituximab on C1D-6, and then before 
treatment on C1D1, C1D2, C1D8, C1D15, C1D16 and on day 1 of cycles 2-6, at the end of treatment visit and at every other follow-up visit 
beginning 6 months (+/- 2 weeks) from the end of treatment and then every 6 months (+/- 2 weeks) until 24 months from the end of treatment. 
5 A bone marrow biopsy done will be required at the end of treatment if a PET/CT scan shows a complete metabolic response to confirm a 
complete response.  
6 On treatment tumor biopsy will be done between C1D22 and C2D1.  A tumor biopsy will also be done at the time of disease progression. 
7 Stool studies will be collected during Screening, between C1D22 and C2D1, and at the completion of therapy by patient at home using kit 
provided by the research staff. 
8 EKGs (single EKG at screening and then triplicate EKGs for all subsequent EKGs) will be performed for patients in cohorts A2, A3, and B2 
at screening, on each day of administration of PF-04518600 and at the EOT visit. 
9 TTE/MUGA will be performed at screening and every 3 months on treatment and when clinically indicated. 
10 EOT = end of treatment, to take place 4-6 weeks from the last dose of study treatment. 
11For patients with a previous history of anthracycline treatment and who are at high risk of cardiac failure (ie those that have New York Heart 
Association Class I heart failure), troponin I (troponin T is allowed if the assay utilized can be verified to have cardiac specificity) and N-
terminal of the prohormone brain natriuretic peptide (Nt-proBNP) levels will be evaluated at baseline in screening and every other cycle 
starting with cycle 2 and when clinically indicated.  Any elevation in troponin or Nt-proBNP should be discussed with the study principal 
investigator prior to enrollment or treatment. 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
74 
Study Calendar Cohorts A2a dose level 2, A2b, and B2 
 
 
 
 
 
Cycle 1 
Cycles 
2-6 
EOT10 
Follow-
up 
Study Assessment 
Baseline 
Week 
-1 
Week 1 
Week 
2 
Week 3 
Week 
4 
 
 
Week 4 
from last 
treatment 
Every 
3 
months 
+/- 2 
weeks) 
Study Days 
-28 to -1 
-6 
1 
2 
8 
1
5 
16 
22 
1 
15 
 
 
Visit window +/- days 
0 
0 
2 
N/A 
2 
2 
N/A 
2 
2 
2 
N3 
14 
Study Drug 
Utomilumab 
 
 
 
x 
 
 
 
 
x 
 
 
 
PF-04518600 
 
 
 
 
 
 
x 
 
x 
x 
 
 
Rituximab (or 
rituximab 
biosimilar) 
 
x 
x 
 
x 
x 
 
 
 
 
 
 
Medical History, Medication 
Review, Physical Exam, Weight 
x 
x 
x 
 
x 
x 
 
 
x 
x 
x 
x 
Toxicity Assessment 
x 
x 
x 
 
x 
x 
 
 
x 
x 
x 
x 
ECOG Performance Status 
(Appendix A) 
x 
 
x 
 
 
 
 
 
x 
 
x 
x 
CBC, Differential, and Blood 
chemistries1 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
TSH, creatinine kinase, lipase, 
triglycerides, urine dipstick for 
blood and protein 
x 
 
x 
 
 
 
 
 
x 
 
x 
 
Troponin, NTproBNP 
x 
 
 
 
 
 
 
 
x11 
 
 
 
Hepatitis B and C testing2 
x 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
Tumor restaging3 
x3 
 
 
 
 
 
 
 
x3 
 
x3 
x3 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
75 
 
 
 
Cycle 1 
Cycles 
2-6 
EOT10 
Follow-
up 
Study Assessment 
Baseline 
Week 
-1 
Week 1 
Week 
2 
Week 3 
Week 
4 
 
 
Week 4 
from last 
treatment 
Every 
3 
months 
+/- 2 
weeks) 
Study Days 
-28 to -1 
-6 
1 
2 
8 
15 
16 
22 
1 
15 
 
 
Visit window +/- days 
0 
0 
2 
N/A 
2 
2 
N/A 
2 
2 
2 
N3 
14 
Peripheral blood collection 
for biomarker studies4 
 
x 
x 
x 
x 
x 
x 
 
x4 
 
x4 
x4 
Bone marrow biopsy5 
 
 
 
 
 
 
 
 
 
 
x5 
 
Tumor biopsies for 
biomarker studies 
x 
 
 
 
 
 
 
x6 
 
 
 
 
Stool studies for 
biomarker/microbiome 
studies7 
x 
 
 
 
 
 
 
x 
 
 
x 
 
EKG8 
x8 
 
 
 
 
 
x8 
 
x8 
x8 
x8 
 
TTE or MUGA scan9 
x 
 
 
 
 
 
 
 
x9 
 
 
 
1 See Sections 10.1 and 10.2. All tests will be required at screening and tumor lysis labs (CMP, uric acid, LDH, phosphorus) will be repeated 
at each study visit in cycle 1.  Patients do need to meet laboratory eligibility criteria on C1D-6 
2Consisting at a minimum of hepatitis C antibody, hepatitis B surface antigen and hepatitis B core antibody. 
3 See Sections 10.1, 10.2, and 10.3. 
4 One pretreatment peripheral blood sample(s) will be collected for correlative studies (Section 9) before rituximab on C1D-6, and then 
before treatment on C1D1, C1D2, C1D8, C1D15, C1D16 and on day 1 of cycles 2-6, at the end of treatment visit and at every other follow-
up visit beginning 6 months (+/- 2 weeks) from the end of treatment and then every 6 months (+/- 2 weeks) until 24 months from the end of 
treatment. 
5 A bone marrow biopsy done will be required at the end of treatment if a PET/CT scan shows a complete metabolic response to confirm a 
complete response.  
6 On treatment tumor biopsy will be done between C1D22 and C2D1.  A tumor biopsy will also be done at the time of disease progression. 
7 Stool studies will be collected during Screening, between C1D22 and C2D1, and at the completion of therapy by patient at home using kit 
provided by the research staff. 
8 EKGs (single EKG at screening and then triplicate EKGs for all subsequent EKGs) will be performed for patients in cohorts A2, A3, and 
B2 at screening, on each day of administration of PF-04518600 and at the EOT visit. 
9 TTE/MUGA will be performed at screening and every 3 months on treatment and when clinically indicated. 
10 EOT = end of treatment, to take place 4-6 weeks from the last dose of study treatment. 
11For patients with a previous history of anthracycline treatment and who are at high risk of cardiac failure (ie those that have New York 
Heart Association Class I heart failure), troponin I (troponin T is allowed if the assay utilized can be verified to have cardiac specificity) and 
N-terminal of the prohormone brain natriuretic peptide (Nt-proBNP) levels will be evaluated at baseline in screening and every other cycle 
starting with cycle 2 and when clinically indicated.  Any elevation in troponin or Nt-proBNP should be discussed with the study principal 
investigator prior to enrollment or treatment. 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
76 
Study Calendar Cohorts A3a, all dose levels, and A3b  
 
 
Cycle 1 
Cycles 
2-6 
EOT10 
Follow-
up 
Study Assessment 
Baseline 
Week 
-1 
Week 1 
Week 
2 
Week 3 
Week 
4 
 
 
Week 4 
from last 
treatment 
Every 
3 
months 
+/- 2 
weeks) 
Study Days 
-28 to -1 
-6 
1 
2 
8 
1
5 
16 
22 
1 
15 
 
 
Visit window +/- days 
0 
0 
2 
N/A 
2 
2 
N/A 
2 
2 
2 
N3 
14 
Study Drug 
Avelumab 
 
 
 
 
 
 
x 
 
x 
x 
 
 
PF-04518600 
 
 
 
x 
 
x 
 
 
x 
x 
 
 
Rituximab (or 
rituximab 
biosimilar) 
 
x 
x 
 
x 
x 
 
 
 
 
 
 
Medical History, 
Medication Review, 
Physical Exam, Weight 
x 
x 
x 
 
x 
x 
 
 
x 
x 
x 
x 
Toxicity Assessment 
x 
x 
x 
 
x 
x 
 
 
x 
x 
x 
x 
ECOG Performance Status 
(Appendix A) 
x 
 
x 
 
 
 
 
 
x 
 
x 
x 
CBC, Differential, and 
Blood chemistries1 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
TSH, creatinine kinase, 
lipase, triglycerides, urine 
dipstick for blood and 
protein 
x 
 
x 
 
 
 
 
 
x 
 
x 
 
Troponin, NTproBNP 
x 
 
 
 
 
 
 
 
x11 
 
 
 
Hepatitis B and C testing2 
x 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
Tumor restaging3 
x3 
 
 
 
 
 
 
 
x3 
 
x3 
x3 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
77 
 
 
 
Cycle 1 
Cycles 
2-6 
EOT10 
Follow-
up 
Study Assessment 
Baseline 
Week 
-1 
Week 1 
Week 
2 
Week 3 
Week 
4 
 
 
Week 4 
from last 
treatment 
Every 
3 
months 
+/- 2 
weeks) 
Study Days 
-28 to -1 
-6 
1 
2 
8 
1
5 
16 
22 
1 
15 
 
 
Visit window +/- days 
0 
0 
2 
N/A 
2 
2 
N/A 
2 
2 
2 
N3 
14 
Peripheral blood collection 
for biomarker studies4 
 
x 
x 
x 
x 
x 
x 
 
x4 
 
 
x4 
Bone marrow biopsy5 
 
 
 
 
 
 
 
 
 
 
x5 
 
Tumor biopsies for 
biomarker studies 
x 
 
 
 
 
 
 
x6 
 
 
 
 
Stool studies for 
biomarker/microbiome 
studies7 
x 
 
 
 
 
 
 
x 
 
 
x 
 
EKG8 
x8 
 
 
x8 
 
x8 
 
 
x8 
x8 
x8 
 
TTE or MUGA scan9 
x 
 
 
 
 
 
 
 
x9 
 
 
 
1See Sections 10.1 and 10.2. All tests will be required at screening and tumor lysis labs (CMP, uric acid, LDH, phosphorus) will be 
repeated at each study visit in cycle 1.  Patients do need to meet laboratory eligibility criteria on C1D-6.  . 
2 Consisting at a minimum of hepatitis C antibody, hepatitis B surface antigen and hepatitis B core antibody. 
3 See Sections 10.1, 10.2, and 10.3. 
4 One pretreatment peripheral blood sample(s) will be collected for correlative studies (Section 9) before rituximab on C1D-6, and then 
before treatment on C1D1, C1D2, C1D8, C1D15, C1D16 and on day 1 of cycles 2-6, at the end of treatment visit and at every other 
follow-up visit beginning 6 months (+/- 2 weeks) from the end of treatment and then every 6 months (+/- 2 weeks) until 24 months from 
the end of treatment. 
5 A bone marrow biopsy done will be required at the end of treatment if a PET/CT scan shows a complete metabolic response to confirm a 
complete response.  
6 On treatment tumor biopsy will be done between C1D22 and C2D1.  A tumor biopsy will also be done at the time of disease progression. 
7Stool studies will be collected during Screening, between C1D22 and C2D1, and at the completion of therapy by patient at home using 
kit provided by the research staff. 
8 EKGs (single EKG at screening and then triplicate EKGs for all subsequent EKGs) will be performed for patients in cohorts A2, A3, and 
B2 at screening, on each day of administration of PF-04518600 and at the EOT visit. 
9TTE/MUGA will be performed in all patients at screening and every 3 months on treatment and when clinically indicated. 
10 EOT = end of treatment, to take place 4-6 weeks from the last dose of study treatment. 
11For patients with a previous history of anthracycline treatment and who are at high risk of cardiac failure (ie those that have New York 
Heart Association Class I heart failure), troponin I (troponin T is allowed if the assay utilized can be verified to have cardiac specificity) 
and N-terminal of the prohormone brain natriuretic peptide (Nt-proBNP) levels will be evaluated at baseline in screening and every other 
cycle starting with cycle 2 and when clinically indicated.  Any elevation in troponin or Nt-proBNP should be discussed with the study 
principal investigator prior to enrollment or treatment. 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
78 
10.1 
Required Data for Study Screening 
The following must be obtained within 28 days prior to the 1st day of treatment: 
• Medical history, medication review, physical exam, height and weight, ECOG 
performance status (see Appendix A) 
• CBC with differential, blood chemistries including complete metabolic panel, 
phosphorus, magnesium, uric acid, LDH, TSH, creatinine kinase, lipase, triglycerides.  
Urine studies to include a urine dipstick for blood and protein and if positive (2+ or 
greater for protein) a microscopic urinalysis and 24 hour urine collection (for protein).    
o For patients assigned to cohorts A2, A3, and B2 with a previous history of 
anthracycline treatment and who are at high risk of cardiac failure (ie those that 
have New York Heart Association Class I heart failure), troponin I (troponin T is 
allowed if the assay utilized can be verified to have cardiac specificity) and N-
terminal of the prohormone brain natriuretic peptide (Nt-proBNP) levels will be 
evaluated at baseline in screening and every other cycle starting with cycle 2 and 
when clinically indicated.  Any elevation in troponin or Nt-proBNP should be 
discussed with the study principal investigator prior to enrollment or treatment. 
• Serum or urine β-HCG for females of childbearing potential 
• Tumor restaging (within 6 weeks).  This will consist of PET and CT scans (including 
neck, chest, abdomen/pelvis), which can be a combined study.  MRIs may be used for 
patients in whom CT imaging is contraindicated.  
• Tumor biopsy for biomarker studies (Section 9). An archival sample within 90 days and 
without intervening treatment is acceptable as the pre-treatment biopsy assuming that at 
least 15 unstained slides are available for evaluation.   
• Stool sample for microbiome biomarker studies (Section 9) 
• 12-Lead Electrocardiogram (EKG).  A single 12-lead EKG will be done at screening in 
patients in cohorts A2, A3, and B2.   
• Echocardiogram (TTE) or multigated acquisition (MUGA) scan: TTE or MUGA scan 
should be performed at screening for patients.  All patients with an EF<50% must be 
discussed with the principal investigator prior to enrollment. 
10.2 
Required Data During Study 
The following must be obtained during the study: 
• Medical history, medication review, physical exam, and weight, ECOG performance 
status (see Appendix A) 
• Toxicity assessment 
• CBC with differential, blood chemistries including complete metabolic panel, 
phosphorus, magnesium, uric acid, LDH. These are required at each planned study visit 
during cycle 1 (C1D-6, C1D1, C1D2, C1D8, C1D15, C1D16) and on day 1 and day 15 of 
cycles 2-6.  Patients do need to meet laboratory eligibility criteria on C1D-6. 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
79 
• TSH, creatinine kinase, lipase, and triglycerides, as well as urine studies to include a 
urine dipstick for blood and protein and if positive a microscopic urinalysis and 24 hour 
urine collection (for protein) will be checked on day 1 of each cycle 1-6.    
o For patients assigned to cohorts A2, A3, and B2 with a previous history of 
anthracycline treatment and who are at high risk of cardiac failure (ie those that 
have New York Heart Association Class I heart failure), troponin I (troponin T is 
allowed if the assay utilized can be verified to have cardiac specificity) and N-
terminal of the prohormone brain natriuretic peptide (Nt-proBNP) levels will be 
evaluated at every other cycle starting with cycle 2 and when clinically indicated.  
Any elevation in troponin or Nt-proBNP should be discussed with the study 
principal investigator prior to treatment. 
• Pregnancy test at screening, C1D-6 (except for cohort A2a dose level 0), C1D2 (only for 
cohorts A1a, A1b, and B1), C1D15, and C2-6D1. 
• Peripheral blood sample for biomarker studies before treatment on C1D-6 (for all cohorts 
except cohort A2a, dose level 0), C1D1, C1D2, C1D8, C1D15, C1D16, and on day 1 of 
C2-6 (Section 9).  
• Tumor biopsy between C1D22 and C2D1. 
• Tumor restaging: CT scans with PO and IV contrast of the chest, abdomen and pelvis (+/- 
neck if involved at screening baseline) between C3D22 and C4D1.  MRIs may be used 
for patients in whom CT scans are contraindicated. 
o Patients enrolled in cohort A2a, dose level 0, who have SD or PD on this scan 
have the option to remain on study and receive 4 weekly doses of rituximab 
during cycle 4 (days 1, 8, 15, and 22) while remaining the same dose and schedule 
of PF-04518600. 
• Stool sample for biomarker studies between C1D22 and C2D1 using a home kit 
• EKGs: Triplicate 12-lead EKGs will be done in cycle 1 in patients in cohorts A2, A3, and 
B2 on days when PF-04518600 is administered prior to administration. Triplicate 12-lead 
EKGs will be done on day 1 and 15 of cycles 2-6 in cohorts A2, A3, and B2 prior to 
therapy on those days.  If the mean QTcF is prolonged (>501msec) immediate correction 
for reversible causes should be performed.  If the QTc reverts to <501msec, and in the 
judgment of the investigator(s) and principal investigator is determined to be due to 
cause(s) other than investigational product, treatment may be continued with regular 
EKG monitoring.  If in that timeframe the QTcF intervals rise above 501msec the 
investigational product will be held until the QTcF interval decreases to < 480msec.  
Patients will then restart the investigational product.  If the QTcF has not decreased to 
480msec of less after 2 weeks, or if at any time a patient has a QTcF interval >515msec 
or becomes symptomatic, the patient will be removed from the study.  Additional 
triplicate EKGs should be performed as clinically indicated (ie at the time of any cardiac 
or neurologic AE) 
• Echocardiogram (TTE) or multigated acquisition (MUGA) scan: TTE or MUGA scan 
should be performed every 3 months while on therapy for patients in cohorts A2, A3, and 


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
80 
B2. All patients with an EF<50%, or a decrease from baseline EF of >10%, must be 
discussed with the principal investigator prior to treatment. 
10.3 
Required at End of Treatment (4-6 weeks from last study treatment) 
 
The following must be obtained at post-treatment visit (4-6 weeks from the last day of 
treatment).  
• Medical history, medication review, physical exam, height and weight, ECOG 
performance status (see Appendix A) 
 
• Toxicity assessment 
 
• CBC with differential, blood chemistries including complete metabolic panel, 
phosphorus, magnesium, uric acid, LDH, TSH, creatinine kinase, lipase, triglycerides.  
Urine studies to include a urine dipstick for blood and protein and if positive (2+ or 
greater for protein) a microscopic urinalysis and 24 hour urine collection (for protein).    
o For patients assigned to cohorts A2, A3 and B2 with a previous history of 
anthracycline treatment and who are at high risk of cardiac failure (ie those that 
have New York Heart Association Class I heart failure), troponin I (troponin T is 
allowed if the assay utilized can be verified to have cardiac specificity) and N-
terminal of the prohormone brain natriuretic peptide (Nt-proBNP) levels will be 
evaluated at the end of treatment visit 
 
• Peripheral blood sample for biomarker studies 
 
• Tumor restaging, which will consist of PET and CT scans, which may be a combined 
study; in the event of a complete response by imaging, a bone marrow biopsy will be 
necessary to confirm a complete response.  MRIs may be used for patients in whom CT 
scans are contraindicated. Restaging will occur 4-6 weeks after the last dose of study 
therapy, then at 6, 12, and 18 months from the end of treatment (+/-2 weeks).  CT scans 
(neck if involved at baseline, chest, abdomen, pelvis) may be done in place of PET scans 
for surveillance at the above timepoints following a complete response.  For all complete 
responses by imaging, a bone marrow biopsy will be necessary as part of their restaging 
to confirm complete remission.   
 
• Stool sample for biomarker testing 
• EKG: Triplicate 12-lead EKGs will be done in patients in cohorts A2, A3, and B2 at the 
end of treatment visit.   
• Echocardiogram (TTE) or multigated acquisition (MUGA) scan: TTE or MUGA scan 
should be performed at the end of treatment visit (if not performed within the preceding 3 
months) for patients in cohorts A2, A3, and B2 
 
 
 


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10.4 
Required during Follow-Up (every 3 months +/- 2 weeks from the end of treatment) 
 
• Medical history, medication review, physical exam, height and weight, ECOG 
performance status (see Appendix A) 
• Toxicity assessment 
• CBC with differential, blood chemistries including complete metabolic panel, 
phosphorus, magnesium, uric acid, and LDH.  
• Peripheral blood sample for biomarker studies at every other follow-up visit starting at 6 
months (+/- 2 weeks) from the end of treatment until 24 months (+/- 2 weeks) from the 
end of treatment. 
• Tumor restaging, which will consist of PET and CT scans, which can be a combined 
study, at month 6, 12, and 18 months from the end of therapy; in the event of a complete 
response by imaging, a bone marrow biopsy will be necessary to confirm a complete 
response.  Also in the event of a complete response, PET scans need not be repeated and 
patients may be followed with CT scans of the chest, abdomen and pelvis (+/- neck if the 
neck was previously involved) with PO and IV contrast alone.  MRIs may be used for 
patients in whom CT scans are contraindicated. 
• Tumor biopsy at the time of progression 
• After 2 years of follow up, patients will be followed only for relapse and survival with 
follow up in person or by phone call with the patient or the local physician every 6 
months. 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Disease Response Assessments  
 
18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET) imaging will be used 
in conjunction with Computerized Tomography (CT) imaging to confirm a disease assessment of 
CR at the end of treatment.  The screening 18F-FDG PET-CT imaging will be used to determine 
evaluable index lesions for each patient.  For 18F-FDG PET-CT, tumor background ratios and 
development of new sites of abnormality will be recorded. 
Results of the 18F-FDG PET studies will be scored according to methods developed by the 
American College of Radiology Imaging Network.  All centers participating in the study will use 
the same 18F-FDG PET methodologies and measures, to the extent possible, and one center will 
be designated as the central lab to be used for final interpretation of 18F-FDG PET data. 
Anti-cancer activity will be assessed at baseline, during treatment as specified in the Study 
Calendar, whenever disease progression is suspected (eg, symptomatic deterioration), at the time 
of withdrawal from treatment (if not performed in the previous 6 weeks) or at the end of 
treatment (4-6 weeks from the last dose of study therapy) and at follow-up visits 6, 12, and 18 
months (+/- 2weeks) from the end of therapy or until disease progression. 


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If imaging is used in disease assessment, the same imaging technique (CT) used to characterize 
each identified and reported lesion at baseline will be employed in post-baseline disease 
assessments. 
Assessment of response will be made using the Lugano 2014 criteria and LyRIC (Appendix D).   
All patients’ files and radiologic images and pathology samples must be available for source 
verification and for potential peer review. 
For all patients who achieve a complete response (CR) by imaging, a bone marrow biopsy is 
necessary to confirm a complete remission. 
11.1.1 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started, or death due to any 
cause. Participants without events reported are censored at the last disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that progressive disease is 
objectively documented, or death due to any cause. Participants without events reported are 
censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
11.1.2 Progression-Free and Overall Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from randomization (or 
registration) to progression, or censored at date of last disease evaluation for those without 
progression reported. 
 
11.1.3 Response Review 
 
For purposes of data analysis and reporting, responses on this trial will be centrally assessed 
through the Tumor Imaging Metrics Core at DF/HCC. 
 


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83 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data 
for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites are responsible for submitting data and/or data forms to the Office of Data 
Quality (ODQ) in accordance with DF/HCC policies. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research.  
Information that raises any questions about participant safety will be addressed with the Overall 
PI and study team. 
 
The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews. Information to be provided to the committee may include: up-
to-date participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths occurring 
within 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of 
all deaths while being treated and during active follow-up; any response information; audit 
results, and a summary provided by the study team. Other information (e.g. scans, laboratory 
values) will be provided upon request.  
12.3 
Multi-Center Guidelines 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix C. 
• The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required. 
 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 


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84 
 
• Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
This is an open-label, phase 1b clinical trial of immunotherapy in combination with rituximab in 
patients with both relapsed/refractory or previously untreated follicular lymphoma.   
 
13.1 
Study Design/Endpoints 
 
Primary endpoints: 
• Determine the RP2D of these immunotherapy combinations for further testing 
• Complete response rate using 2014 Lugano criteria 
 
Secondary endpoints: 
• Efficacy as measured by the objective, complete and partial response, stable disease and 
progressive disease rates by 2014 Lugano and LyRIC criteria, rate of MRD negativity at 
6 and 12 months, 2-year progression free survival (by 2014 Lugano and LyRIC), overall 
survival and time to next treatment response duration 
• Safety categorized by the rate of: 
o Grade 3 and higher toxicities, both regardless of attribution, and at least 
possibly attributed to the study treatment 
o Grade 2 or higher toxicity at least probably related to study treatment. 
o Adverse events leading to discontinuation due to toxicity.   
 
Correlative or exploratory endpoints (when possible):  
• Correlation between overall and complete response rates and MRD negativity and 
histologic grade (1-2 versus 3A) and FLIPI 
• Calculation of the m7-FLIPI and correlation with overall and complete response rate and 
MRD negativity 
• Comparisons of the tumor microenvironment composition and gene expression pre- and 
on-treatment 
• Comparisons of the composition of the circulating immune environment, including the T 
cell repertoire, in the peripheral blood pre- and on-treatment   
• Exploration of genetic markers of tumor response or resistance to therapy through whole 
exome sequencing 
• Correlation between fecal microbiome and response or resistance to therapy 
 
All exploratory or correlative endpoints will be analyzed descriptively. 
 


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85 
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
13.2.1 Determining RP2D 
 
The Dose Escalation phase of this study follows a 3+3 design with 2 or 3 dose levels for each 
cohort to determine the RP2D for each drug combination being tested.  The RP2D will be 
defined as the highest dose level for which there are no more than 1/6 DLTs observed. 
 
The following table shows the probability of escalation under various true DLT rates.  With this 
design there is 91% probability of dose escalation if the true rate of DLT is 10% and 8% 
probability of escalation if the true DLT rate is 60%. 
 
True Rate of DLT 
Probability of escalation 
10% 
0.91 
20% 
0.71 
30% 
0.49 
40% 
0.31 
50% 
0.17 
60% 
0.08 
 
Dose Expansion 
Once the RP2D is established for a given cohort/drug combination in the relapsed/refractory 
setting (part A), an additional 9 or 12 eligible patients will be treated at the RP2D, for a total of 
15 patients treated at that dose level. Whether it is 9 or 12 is dependent on whether 6 or 3 
patients were treated at that dose level to determine the RP2D, respectively.  With 15 patients, 
the 90% confidence interval for DLT will be no wider than +/- 23%. 
 
A combination will be judged promising in terms of efficacy in part A (relapsed/refractory 
setting) if in addition to being tolerable 3 or more patients out of 15 obtain a CR (based on a null 
hypothesis of CRR 5% and alternative hypothesis of CRR 30% with 87% power and a 4% one 
sided type I error). 
 
True but unknown CR 
rate 
0.05 
0.1 
0.15 
0.2 
0.25 
0.3 
Prob of observing ≥ 3 
CRs 
0.04 
0.18 
0.40 
0.60 
0.76 
0.87 
 
In the relapsed/refractory setting (part A), a particular combination (A1b, A2b, A3b) will be 
judged tolerably safe if 3 or fewer patients out of 15 experience a DLT (based on a null 
hypothesis for DLT rate of 40% and an alternative hypothesis of 10% with 94% power and a 9% 
one-sided type I error).   
 
 
 


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86 
True but 
unknown prob. of 
excessive toxicity 
0.05 
0.1 
0.15 
0.2 
0.25 
0.3 
0.35 
 
0.4 
Prob of observing 
≤3  
pts with excessive 
tox 
0.99 
0.94 
0.82 
0.65 
0.46 
0.30 
0.15 
 
 
0.09 
 
If a cohort in part A meets these efficacy and toxicity endpoints, it will open in cohort B in 
previously untreated FL patients.  These cohorts will treat up to 15 patients each.  A combination 
will be judged promising in terms of efficacy in part B (previously untreated setting) if in 
addition to being tolerable based on above criteria) if 6 or more patients out of 15 obtain a CR 
(based on a null hypothesis of CRR 20% and alternative hypothesis of CRR 50% with 85% 
power and a 6% one sided type I error). 
 
True but unknown CR rate 
0.2 
0.25 
0.3 
0.35 
0.4 
0.5 
Prob of observing ≥ 6 CRs 
0.06 
0.15 
0.28 
0.44 
0.60 
0.85 
 
In the upfront setting (part B), a particular combination (B1, B2) will be judged safe if 2 or 
fewer patients out of 15 experience excessive toxicity as defined above (based on a null 
hypothesis for excessive toxicity rate of 35% and an alternative hypothesis of 10% with 82% 
power and a 6% one-sided type I error). 
 
True but unknown prob. 
 of excessive toxicity 
0.05 
0.1 
0.15 
0.2 
0.25 
0.3 
0.35 
Prob of observing ≤2  
pts with excessive tox 
0.96 
0.82 
0.60 
0.40 
0.24 
0.13 
0.06 
 
Based on historical rates, anticipated accrual will be 24 months.  The anticipated time to primary 
endpoint is 30 months, and to study completion 48 months. 
 
13.3 
Reporting and Exclusions 
 
The primary analysis will be performed on all evaluable patients. 
 
13.4 
Disclosures and Confidentiality  
 
The investigator requests strict confidentiality from his/her staff and the IRB.  Study documents 
provided by Pfizer (protocols, investigators’ brochures, case report forms, and other material) 
will be stored appropriately to ensure their confidentiality.  The information provided by Pfizer 
to the investigator may not be disclosed to others without direct written authorization from 
Pfizer, except to the extent necessary to obtain informed consent from patients who wish to 
participate in the trial. 
 


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14. PUBLICATION PLAN 
 
The results of this study will be submitted for presentation at national meetings and for 
publication in appropriate journals within 24 months of the completion of the study.  The first 
analysis and submission will be conducted when all patients have reached the End of Study visit 
(or been taken off study). 
 
 
 
 


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lymphocytic leukemia. Blood. 2004;103(4):1472-1474. 
56. 
Maloney DG, Smith B, Rose A. Rituximab: mechanism of action and resistance. 
Semin Oncol. 2002;29(1 Suppl 2):2-9. 
57. 
Martinelli G, Schmitz SF, Utiger U, et al. Long-term follow-up of patients with 
follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 
35/98. J Clin Oncol. 2010;28(29):4480-4484. 
 
 
 
 


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


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APPENDIX B 
CAIRO-BISHOP CLINICAL TUMOR LYSIS SYNDROME 
DEFINITION AND GRADING 
 
Complication 0 
1 
2 
3 
4 
5 
Creatinine 
< 1.5xULN 
1.5xULN 
>1.5-
3.0xULN 
>3.0-
6.0xULN 
>6.0xULN 
Death 
Cardiac 
arrhythmia 
None 
Intervention 
not indicated 
Nonurgent 
medical 
intervention 
indicated 
Symptomati
c and 
incompletely 
controlled 
medically or 
controlled 
with device 
Life-
threatening 
(eg 
arrhythmia 
associated 
with CHF, 
hypotension, 
syncope, 
shock) 
Death 
Seizure 
None 
---- 
One brief, 
generalized 
seizure well 
controlled 
by 
anticonvulsa
nt or 
infrequent 
focal motor 
seizures not 
interfering 
with ADLs 
Seizure in 
which 
consciousne
ss is altered; 
poorly 
controlled 
seizure 
disorder; 
with 
breakthroug
h 
generalized 
seizures 
despite 
medical 
intervention 
Seizure of 
any kind 
which are 
prolonged, 
repetitive, or 
difficult to 
control (eg 
status 
eplipecticus, 
intractable 
epilepsy) 
Death 
Note: Tumor lysis syndrome is defined by laboratory tumor lysis syndrome (uric acid > 476µmol/L or 8mg/dL or a 
25% increase from baseline; potassium > 6.0mmol/L or 6mg/L or a 25% increase from baseline; phosphorus > 
1.45mmol/L or a 25% increase from baseline; calcium < 1.75mmol/L or a 25% decrease from baseline) and at least one 
clinical complication. 
Increases in creatinine and seizures are considered a clinical complication if they are not deemed attributable to the 
therapeutic agent 
 
 
 
 


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APPENDIX C 
DF/HCC MULTI-CENTER DATA AND SAFETY MONITORING 
PLAN 
 
1. INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC 
DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research protocol. The 
DF/HCC DSMP serves as a reference for any sites external to DF/HCC that are participating in a 
DF/HCC clinical trial.  
1.1 
Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability 
Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures.        
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside institutions 
are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC investigator is the 
sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial 
Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-
Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess 
Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham and Women’s Hospital 
(BWH) responsible for the coordination, development, submission, and approval of a protocol as 
well as its subsequent amendments per the DFCI IRB and applicable regulatory guidelines (CTEP, 
Food and Drug Administration (FDA), Office of Biotechnology Activities (OBA) etc.).  The Lead 
Institution is typically the home of the DF/HCC Sponsor. The Lead Institution also typically serves 
as the Coordinating Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol who takes 
responsibility for initiation, management and conduct of the protocol at all research locations. In 
applicable protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory 
agencies (i.e. the FDA). The DF/HCC Sponsor has ultimate authority over the protocol and is 
responsible for the conduct of the study at DF/HCC and all Participating Institutions. In most cases 
the DF/HCC Sponsor is the same person as the DF/HCC Overall Principal Investigator; however, 
both roles can be filled by two different people.  
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC consortium 
that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator.  The 
Participating Institution acknowledges the DF/HCC Sponsor as having the ultimate authority and 
responsibility for the overall conduct of the study.    
 
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research 
Organization (CRO), etc) that provides administrative support to the DF/HCC Sponsor in order 


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that he/she may fulfill the responsibilities outlined in the protocol document and DSMP, and as 
specified in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines). In general, the 
Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol.  
 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring high-
quality standards are used for data collection and the ongoing management of clinical trials, 
auditing, and data and safety monitoring. ODQ also coordinates quality assurance efforts related 
to multi-center clinical research. 
 
DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within DF/HCC 
responsible for providing a comprehensive data management platform for managing clinical trial 
data. 
 
 
2. GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the 
Participating Institutions are expected to adhere to the following general responsibilities:  
2.1 DF/HCC Sponsor 
 
The DF/HCC Sponsor, Caron Jacobson, MD, will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
• Oversee the coordination, development, submission, and approval of the protocol as well 
as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.   
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives adequate 
protocol training (and/or a Site Initiation Visit prior to enrolling participants) and 
throughout trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language understandable 
to all applicable site personnel when English is not the primary language.  
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable (i.e. 
FDA) reporting requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Act as the single liaison with the FDA (investigator-held IND trials) as applicable. 
• Ensure compliance with all requirements as set forth in the Code of Federal Regulations, 
applicable DF/HCC requirements, HIPAA requirements, and the approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by anyone other 
than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments prior to 
extending the protocol to that site. 


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• Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements.  
2.2 Coordinating Center  
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development.  
• Maintain FDA correspondence, as applicable. 
• Review registration materials for eligibility and register participants from Participating 
Institutions in the DF/HCC clinical trial management system (CTMS). 
• Distribute protocol and informed consent document updates to Participating Institutions as 
needed. 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the DF/HCC 
Sponsor for timely review and submission to the DFCI IRB, as necessary.  
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the DFCI 
IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide Participating Institutions with information regarding DF/HCC requirements that 
they will be expected to comply with. 
 
• Carry out plan to monitor Participating Institutions either by on-site or remote monitoring.  
• Maintain Regulatory documents of all Participating Institutions which includes but is not 
limited to the following: local IRB approvals/notifications from all Participating 
Institutions, confirmation of Federalwide Assurances (FWAs) for all sites,  all SAE 
submissions, Screening Logs for all sites, IRB approved consents for all sites 
• Conduct regular communications with all Participating Institutions (conference calls, 
emails, etc) and maintain documentation all relevant communications. 
2.3 Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations and 
DF/HCC requirements, the protocol and HIPAA requirements.  
 
The general responsibilities for each Participating Institution may include but are not limited to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents as 
requested. 
• Participate in protocol training prior to enrolling participants and throughout the trial as 
required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research related 
activities.  


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• Submit Serious Adverse Event (SAE) reports to local IRB per institutional requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements. Submit 
protocol deviations and violations to local IRB per institutional requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated drugs per 
federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at the 
conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring queries or 
audit findings. 
 
 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
The following section will clarify DF/HCC Requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol.  
3.1 
Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any subsequent 
amended protocols to all Participating Institutions.    
 
3.2 
Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institution’s responsibility to notify its IRB 
of these revisions. 
 
• Non-life-threatening revisions: Participating Institutions will receive written notification 
of protocol revisions regarding non-life-threatening events from the Coordinating Center. 
Non-life-threatening protocol revisions must be IRB approved and implemented within 90 
days from receipt of the notification. 
• Revisions for life-threatening causes: Participating Institutions will receive immediate 
notification from the Coordinating Center concerning protocol revisions required to protect 
lives with follow-up by fax, mail, e-mail, etc.  Life-threatening protocol revisions will be 
implemented immediately followed by IRB request for approval. 
• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately.  In addition, the Coordinating Center, 
will update the Participating Institutions on an ongoing basis about protocol accrual data 
so that they will be aware of imminent protocol closures. 
 
 
 


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3.3 
Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for Participating Institutions. The Participating Institution consent form must follow the 
consent template as closely as possible and should adhere to specifications outlined in the DF/HCC 
Guidance Document on Model Consent Language for PI-Initiated Multi-Center Protocols.  This 
document will be provided separately to each Participating Institution upon request. 
 
Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior to 
submission to their local IRB. The approved consent form must also be submitted to the 
Coordinating Center after approval by the local IRB for all consent versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician members 
of the study team who will be obtaining consent and signing the consent form for therapeutic 
protocols. Participating institutions must follow the DF/HCC requirement that only attending 
physicians obtain informed consent and re-consent for all interventional drug, biologic, or device 
research, only attending physicians may obtain initial informed consent and any re-consent that 
requires a full revised consent form.     
 
3.4 
IRB Documentation 
 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB.  
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB.  
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
 
3.5 
IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to continue 
research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received from 
the Participating Institution on or before the anniversary of the previous approval date.   
 
3.6 
Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information known as 
the Health Insurance Portability and Accountability Act (HIPPA). Any information, related to the 
physical or mental health of an individual is called Protected Health Information (PHI). HIPAA 
outlines how and under what circumstances PHI can be used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the course of a 
study, the study participant must sign an authorization statement.  This authorization statement 
may or may not be separate from the informed consent document.  The Coordinating Center, with 


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the approval from the DFCI IRB will provide a consent template, with information regarding 
authorization for the disclosure of protected health information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its trials. 
However, because of the nature of these trials, certain protected health information must be 
collected. DF/HCC has chosen to use authorizations, signed by the participant in the trial, rather 
than limited data sets with data use agreements. 
 
3.6.1  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should be 
de-identified. It is recommended that the assigned protocol case number (as described below) be 
used for all participant specific documents. Participant initials may be included or retained for 
cross verification of identification.  
 
3.7 
DF/HCC Multi-Center Protocol Registration Policy 
 
3.7.1  Participant Registration and Randomization  
To register a participant, the following documents should be completed by the Participating 
Institution and e-mailed to Samantha_Pazienza@dfci.harvard.edu the Coordinating Center  
• Copy of required laboratory tests including: see section 10.1 
• Signed informed consent document 
• HIPAA authorization form (if separate from the informed consent document) 
• Completed Eligibility Checklist  
 
The Coordinating Center will review the submitted documents in order to verify eligibility and 
consent. To complete the registration process, the Coordinating Center will: 
• Register the participant on the study with the DF/HCC Clinical Trial Management System 
(CTMS). 
• Upon receiving confirmation of registration, the Coordinating Center will inform the 
Participating Institution and provide the study specific participant case number, and, if 
applicable, assigned treatment and/or dose level.  
 
Treatment or other protocol-specific interventions may not begin without confirmation 
from the Coordinating Center that the participant has been registered.  
 
3.7.2 Initiation of Therapy 
 
Participants must be registered with the DF/HCC CTMS before the initiation of treatment or other 
protocol-specific interventions. Treatment and other protocol-specific interventions may not be 
initiated until the Participating Institution receives confirmation of the participant’s registration 
from the Coordinating Center. The DF/HCC Sponsor and DFCI IRB must be notified of any 
violations to this policy. 
 


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3.7.3 Eligibility Exceptions 
 
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will be 
permitted. All Participating Institutions are required to fully comply with this requirement. The 
process for requesting an eligibility exception is defined below. 
 
3.8 
DF/HCC Protocol Case Number 
 
At the time of registration, the following identifiers are required for all subjects: initials, date of 
birth, gender, race and ethnicity. Once eligibility has been established and the participant 
successfully registered, the participant is assigned a unique protocol case number.  Participating 
Institutions should submit all de-identified subsequent communication and documents to the 
Coordinating Center, using this case number to identify the subject.   
 
3.8.1 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to ensure 
that researchers do not initiate changes in approved research without IRB review and approval, 
except when necessary to eliminate apparent immediate hazards to the participant. DF/HCC 
requires all departures from the defined procedures set forth in the IRB approved protocol to be 
reported to the DF/HCC Sponsor, who in turn is responsible for reporting to the DFCI IRB. 
 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to 
describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy for 
reporting to their local IRB. 
 
3.8.2 Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
 
 
Protocol Violation: Any protocol departure that was not prospectively approved by the IRB prior 
to its initiation or implementation.  
 
 
3.8.3 Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the medical 
record and/or regulatory documents to describe all protocol exceptions, deviations and violations. 
The DF/HCC Sponsor will also be responsible for ensuring that all protocol violations/deviations 
are promptly reported per DFCI IRB guidelines.  
 


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Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. 
The Participating Institution must submit the deviation request to the Coordinating Center who 
will then submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation is 
submitted to the Participating Institution IRB, per institutional policy. A copy of the Participating 
Institution’s IRB report and determination will be forwarded to the Coordinating Center within 10 
business days after the original submission.  The deviation may not be implemented without all 
required approvals. 
 
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of violations.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for review. 
Subsequently, the Participating Institution’s IRB violation/deviation report will be submitted to 
the DFCI IRB for review per DFCI IRB reporting guidelines. 
 
3.9 
Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, rights and 
well-being of study participants. Recording and reporting of adverse events that occur during the 
course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated therapy will be 
evaluated for safety. The safety parameters include all laboratory tests and hematological 
abnormalities, physical examination findings, and spontaneous reports of adverse events reported 
by participants.  All toxicities encountered during the study will be evaluated according to the 
NCI criteria specified in the protocol. Life-threatening toxicities must be reported immediately to 
the DF/HCC Sponsor via the Coordinating Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.9.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed 
in protocol section 7.  
 
 
 
 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the Coordinating 
Center following the DFCI IRB Adverse Event Reporting Policy.  
 
The Coordinating Center will maintain documentation of all Participating Institution Adverse 
Event reports and be responsible for communicating to all participating investigators, any 
observations reportable under the DFCI IRB Reporting Requirements.  Participating Institutions 
will review and submit to their IRB according to their institutional policies and procedures 
 
3.9.2 Guidelines for Processing IND Safety Reports  
 


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The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety Reports 
are distributed to the Participating Institutions. Participating Institutions will review/submit to 
their IRB according to their institutional policies and procedures.  
3.10 
Data Management 
 
DF/HCC CTRIO develops case report forms (CRF/eCRFs), for use with the protocol.  These forms 
are designed to collect data for each study. DF/HCC CTRIO provides a web based training for all 
eCRF users. 
   
3.10.1 
Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. If study forms are 
received with missing or questionable data, the submitting institution will receive a written or 
electronic query from the DF/HCC Office of Data Quality, Coordinating Center, or designee.  
 
Responses to all queries should be completed and submitted within 14 calendar days.   
 
Responses may be returned on the written query or on an amended paper case report form, or in 
the case of electronic queries, within the electronic data capture (eDC) system. In the case of a 
written query for data submitted on a paper case report form, the query must be attached to the 
specific data being re-submitted in response.   
 
If study forms are not submitted on schedule, the Participating Institution will periodically receive 
a Missing Form Report from the Coordinating Center noting the missing forms.  
 
 
4. REQUISITIONING INVESTIGATIONAL DRUG 
 
 
The ordering of investigational agent is specified in the protocol section 8.  
 
Participating Institutions should order their own agent regardless of the supplier.  
 
If the agent is commercially available, check with the local Director of Pharmacy and/or the 
Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure that the 
agent can be ordered once the protocol is approved by the local IRB.  
 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the agent 
according to state and federal requirements. The local IRB should be kept informed of who will 
supply the agent so that any regulatory responsibilities can be met in a timely fashion.  
 
 
 
 
 


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5. MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires verification of protocol compliance and data 
accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides 
quality control oversight for the protocol. 
 
5.1 
Ongoing Monitoring of Protocol Compliance 
 
The Participating Institutions may be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institution may also be subject to on-site 
monitoring conducted by the Coordinating Center.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that Participating 
Institutions are complying with regulatory and protocol requirements, data quality, and participant 
safety. Monitoring practices may include but are not limited to source data verification, and review 
and analysis of eligibility requirements, informed consent procedures, adverse events and all 
associated documentation, review of study drug administration/treatment, regulatory files, 
protocol departures reporting, pharmacy records, response assessments, and data management.  
 
Participating institutions will be required to participate in regular Coordinating Center initiated 
teleconferences.  
 
Participating institutions will be required to participate in monitoring every 6 months. At this time, 
source documentation verification (SDV) will be conducted by having access to participants’ 
complete medical record and source documents. 
 
5.2 
Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The 
DF/HCC Sponsor may increase the monitoring activities at Participating Institutions that are 
unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations.  
 
5.3 
Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each participating institution. Accrual will be monitored for each participating 
institution by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual 
expectations may be subject to termination.   Minimum site accrual expectations have been set to 
3 subjects per year. 
 
 
6. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance and involves the systematic and independent 
examination of all trial related activities and documents.  Audits determine if evaluated activities 
were appropriately conducted and whether data was generated, recorded and analyzed, and 


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accurately reported per the protocol, applicable Standard Operating Procedures (SOPs), and the 
Code of Federal Regulations (CFR). 
 
6.1 
DF/HCC Internal Audits 
  
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). 
Typically, approximately 3-4 participants would be audited at the site over a 2-day period. If 
violations which impact participant safety or the integrity of the study are found, more participant 
records may be audited.  
 
6.2 
Audit Notifications 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all external 
audits or inspections (e.g., FDA, EMA, NCI) that involve this protocol. All institutions will 
forward a copy of final audit and/or re-audit reports and corrective action plans (if applicable) to 
the Coordinating Center, within 12 weeks after the audit date.  
 
6.3 
Audit Reports  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if applicable. 
The Coordinating Center, must forward any reports to the DF/HCC ODQ per DF/HCC policy for 
review by the DF/HCC Audit Committee. For unacceptable audits, the DF/HCC Audit Committee 
would forward the final audit report and corrective action plan to the DFCI IRB as applicable. 
 
6.4 
Participating Institution Performance 
 
The DF/HCC Sponsor and the DFCI IRB are charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of timely 
and accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be recommended for a six-month probation period. Such institutions must 
respond with a corrective action plan and must demonstrate during the probation period that 
deficiencies have been corrected, as evidenced by the improved performance measures. 
Participating Institutions that fail to demonstrate significant improvement will be considered by 
the DF/HCC Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI IRB 
may terminate a site’s participation if it is determined that a site is not fulfilling its responsibilities 
as described above. 
 
 
 


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APPENDIX D 
RESPONSE CRITERIA FOR LYMPHOMA: LUGANO 2014 AND LYRIC 
 
Criteria 
Complete Response (CR) 
Partial Response (PR) 
Stable Disease (SD) 
Progressive disease (PD) 
Lugano 
PET-CT, score 1, 2, or 3* with 
or without a residual mass on 
5PS†   
 
Or 
 
on CT, target nodes/nodal 
masses must regress to ≤ 1.5 cm 
in LDi, and no extralymphatic 
sites of disease 
 
PET-CT Score 4 or 5 
with reduced uptake 
compared with baseline 
and residual mass(es) of 
any size.   
 
Or 
 
On CT ≥ 50% decrease in 
SPD of up to 6 target 
measurable nodes and 
extranodal sites; no 
increase in non-measured 
lesions; spleen if enlarged 
must have regressed by 
>50% in length beyond 
normal 
Neither CR, PR, nor 
PD 
PET-CT score 4 or 5 with an increase in intensity of 
uptake from baseline and/or new FDG-avid foci 
consistent with lymphoma at interim or end-of-
treatment assessment.  
 
Or 
 
On CT, an individual node/lesion must be abnormal 
with: 
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the splenic length must 
increase by > 50% of the extent of its prior increase 
beyond baseline (eg, a 15-cm spleen must increase to > 
16 cm). If no prior splenomegaly, must increase by at 
least 2 cm from baseline 
New or recurrent splenomegaly. 
New or clear progression of preexisiting nonmeasured 
lesions.   
Regrowth of previously resolved lesions. 
A new node > 1.5 cm in any axis or a new extranodal 
site > 1.0 cm in any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and must be attributable 
to lymphoma 
Assessable disease of any size unequivocally 
attributable to lymphoma 
 
And/Or  
 
New or recurrent involvement of the bone marrow 
 
 


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Criteria 
Complete Response (CR) 
Partial Response (PR) 
Stable Disease (SD) 
Progressive Disease (PD) 
LYRIC 
Same as Lugano 
Same as Lugano 
Neither CR, PR, 
PD, nor IR 
As with Lugano with the following exceptions: 
Indeterminate response (IR) 
IR1: >50% increase in SPD in first 12 wks 
IR2: <50% increase in SPD with 
   a. New lesion(s), or 
   b. >50% increase in PPD of a lesion or set of lesions 
at any time during treatment 
IR(3): Increase in FDG uptake without a concomitant 
increase in lesion size meeting criteria for PD 
SPD – sum of the product of the diameters; PPD – product of the perpendicular diameters; LDi – longest diameter; SDi – short diameter; 5PS – 5-point scale; IR 
– immune response 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving PET 
where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment).


DF/HCC Protocol #: 18-311 
Protocol Version Date: 18 February 2021 
 
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