A Randomized, Phase II Study Comparing Trastuzumab and Vinorelbine in Combination With Avelumab or Avelumab and Utomilumab (41BB/CD137 Agonist), in Patients With HER2-positive Metastatic Breast Cancer Who Have Progressed on Prior Trastuzumab and Pertuzumab
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Adrienne G. Waks

A RANDOMIZED, PHASE II STUDY COMPARING TRASTUZUMAB AND 
VINORELBINE IN COMBINATION WITH AVELUMAB OR AVELUMAB AND 
UTOMILUMAB (41BB/CD137 AGONIST), IN PATIENTS WITH HER2-POSITIVE 
METASTATIC BREAST CANCER WHO HAVE PROGRESSED ON PRIOR 
TRASTUZUMAB AND PERTUZUMAB: 
The "AVIATOR” Study
TBCRC Protocol Number
TBCRC045 
DF/HCC Protocol #:
17-455
Coordinating Center
Dana-Farber Cancer Institute
*Principal Investigator
Adrienne Gropper Waks, MD
Dana-Farber Cancer Institute
450 Brookline Ave., Boston, MA 02215 
Phone:  617-632-3800
Fax:  617-623-1930
Email: awaks@partners.org 
Correlative Science Chair
Sherene Loi, M.D., Ph.D.
Peter MacCallum Cancer Centre
305 Grattan St, Melbourne, Victoria, Austrailia
Email: sherene.loi@petermac.org 
Statistician
Meredith Regan, Sc.D.
Dana-Farber Cancer Institute
Email: mregan@jimmy.harvard.edu 
Project Manager
Michelle DeMeo
Dana-Farber Cancer Institute
ctopm@dfci.harvard.edu  
Supporters
Johns Hopkins University on behalf of the Translational Breast 
Cancer Research Consortium (TBCRC)
Breast Cancer Research Foundation (BCRF) Investigator Initiated 
Drug Research Program
Agent(s) 
Avelumab, Utomilumab, supplied by Pfizer
Trastuzumab, Vinorelbine, commercially supplied
IND Number: 136460
IND Sponsor:  Adrienne Gropper Waks, MD
Protocol Type/Version #/ Version Dates: Protocol/ Version 6/ January 27, 2022

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TABLE OF CONTENTS
TABLE OF CONTENTS .............................................................................................................................................2
1.
OBJECTIVES AND ENDPOINTS ....................................................................................................................6
1.1
STUDY DESIGN...............................................................................................................................................6
1.2
PRIMARY OBJECTIVES....................................................................................................................................6
1.3
SECONDARY OBJECTIVES...............................................................................................................................7
1.4
EXPLORATORY OBJECTIVES...........................................................................................................................7
1.5
CORRELATIVE OBJECTIVES............................................................................................................................7
1.6
ENDPOINTS.....................................................................................................................................................8
2.
BACKGROUND ..................................................................................................................................................8
2.1
HER2-POSITIVE BREAST CANCER.................................................................................................................8
2.2
STUDY AGENT(S) ...........................................................................................................................................9
2.3
RATIONALE..................................................................................................................................................16
2.4
CORRELATIVE SCIENCE BACKGROUND........................................................................................................22
3.
PARTICIPANT SELECTION..........................................................................................................................24
3.1
INCLUSION CRITERIA ...................................................................................................................................24
3.2
EXCLUSION CRITERIA ..................................................................................................................................26
3.3
INCLUSION OF UNDERREPRESENTED POPULATIONS.....................................................................................27
4.
REGISTRATION AND RANDOMIZATION PROCEDURES....................................................................27
4.1
REGISTRATION PROCESS FOR DF/HCC INSTITUTIONS.................................................................................27
4.2
GENERAL GUIDELINES FOR OTHER INVESTIGATIVE SITES...........................................................................28
4.3
REGISTRATION PROCESS FOR OTHER INVESTIGATIVE SITES........................................................................28
5.
STUDY CALENDARS ......................................................................................................................................29
5.1
REQUIRED DATA: ARMS A, B, AND C..........................................................................................................30
5.2
REQUIRED DATA: CROSSOVER.....................................................................................................................32
6.
TREATMENT PLAN........................................................................................................................................34
6.1
PRE-TREATMENT CRITERIA .........................................................................................................................34
6.2
REGIMEN DESCRIPTIONS..............................................................................................................................35
6.3
AGENT ADMINISTRATION ............................................................................................................................39
6.4
DOSE LIMITING TOXICITY (DLT) ................................................................................................................42
6.5
CONCOMITANT TREATMENT AND SUPPORTIVE CARE GUIDELINES .............................................................43
6.6
DURATION OF THERAPY...............................................................................................................................44
6.7
ISOLATED CNS PROGRESSION......................................................................................................................44
6.8
CRITERIA FOR TAKING A PARTICIPANT OFF TREATMENT............................................................................45
6.9
CRITERIA FOR CROSSOVER THERAPY ..........................................................................................................45
6.10
DURATION OF FOLLOW-UP ..........................................................................................................................46
6.11
CRITERIA FOR TAKING A PARTICIPANT OFF STUDY.....................................................................................46
7.
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS.....................................46
7.1
ANTICIPATED TOXICITIES ............................................................................................................................47
7.2
DOSE MODIFICATION GUIDELINES...............................................................................................................50
8.
DRUG FORMULATION/STORAGE/SUPPLY.............................................................................................62
8.1
TRASTUZUMAB OR BIOSIMILAR ...................................................................................................................62
8.2
VINORELBINE...............................................................................................................................................65
8.3
UTOMILUMAB (PF-05082566) (FOR REFERENCE ONLY – UTOMILUMAB IS NO LONGER BEING USED IN THIS 
PROTOCOL) ...............................................................................................................................................................68
8.4
AVELUMAB ..................................................................................................................................................70

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9.
CORRELATIVE/SPECIAL STUDIES ...........................................................................................................72
9.1
CORRELATIVE STUDIES BACKGROUND........................................................................................................72
9.2
SPECIMEN SUBMISSION REQUIREMENTS......................................................................................................72
9.3
TRANSLATIONAL RESEARCH BLOOD ...........................................................................................................73
9.4
RESEARCH TUMOR BIOPSIES........................................................................................................................74
9.5
ARCHIVAL TISSUE COLLECTION ..................................................................................................................75
9.6
TRANSLATIONAL RESEARCH PLANNED ANALYSES .....................................................................................76
9.7
GENETIC TESTING........................................................................................................................................78
9.8
ADDITIONAL INFORMATION.........................................................................................................................78
10.
SPECIMEN BANKING ....................................................................................................................................79
11.
MEASUREMENT OF EFFECT ......................................................................................................................79
11.1
DEFINITIONS ................................................................................................................................................79
11.2
GUIDELINES FOR EVALUATION OF DISEASE.................................................................................................81
11.3
LESION DOCUMENTATION............................................................................................................................84
11.4
RESPONSE CRITERIA ....................................................................................................................................85
12.
ADVERSE EVENT REPORTING REQUIREMENTS.................................................................................90
12.1
ADVERSE EVENT CHARACTERISTICS ...........................................................................................................90
12.2
ADVERSE EVENT CHARACTERISTICS ...........................................................................................................91
12.3
EXPEDITED ADVERSE EVENT REPORTING....................................................................................................92
12.4
EXPEDITED REPORTING TO THE FOOD AND DRUG ADMINISTRATION (FDA)...............................................95
12.5
EXPEDITED REPORTING TO HOSPITAL RISK MANAGEMENT ........................................................................95
12.6
ROUTINE ADVERSE EVENT REPORTING .......................................................................................................95
12.7
IND SAFETY REPORTS.................................................................................................................................95
13.
DATA REPORTING / REGULATORY REQUIREMENTS .......................................................................95
13.1
DATA REPORTING ........................................................................................................................................95
13.2
DATA AND SAFETY MONITORING BOARD....................................................................................................96
13.3
SUPPLEMENTAL MONITORING OF SAFETY ...................................................................................................96
13.4
MULTI-CENTER GUIDELINES .......................................................................................................................97
13.5
COLLABORATIVE RESEARCH AND FUTURE USE OF DATA AND BIOSPECIMENS ...........................................98
13.6
REORTING TO THE NCI ................................................................................................................................98
14.
PUBLICATION PLAN......................................................................................................................................99
14.1
PUBLICATION ...............................................................................................................................................99
15.
STATISTICAL CONSIDERATIONS .............................................................................................................99
15.1
STUDY DESIGN/ ENDPOINTS ........................................................................................................................99
15.2
SAMPLE SIZE/ ACCRUAL RATE ....................................................................................................................99
15.3
MODIFICATION OF STUDY DESIGN DUE TO AD HOC FUTILITY ANALYSIS.....................................................100
15.4
STRATIFICATION FACTORS.........................................................................................................................100
15.5
ANALYSIS OF PRIMARY ENDPOINT ............................................................................................................100
15.6
ANALYSIS OF SECONDARY EFFICACY ENDPOINTS.....................................................................................101
15.7
ANALYSIS OF SAFETY AND TOLERABILITY ................................................................................................101
15.8
EXPLORATORY AND BIOMARKER OBJECTIVES ..........................................................................................101
15.9
REPORTING AND EXCLUSIONS ...................................................................................................................103
15.10
INTERIM ANALYSIS FOR INEFFICACY, ARM C VS B.....................................................................................103
16.
REFERENCES.................................................................................................................................................104
APPENDICES...........................................................................................................................................................110
APPENDIX A:  ECOG PERFORMANCE STATUS SCALE.........................................................................................111

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APPENDIX B:  STRONG CYP3A INDUCERS/INHIBITORS AND INFORMATION ON POSSIBLE DRUG INTERACTIONS
112
APPENDIX C:  DATA SAFETY MONITORING PLAN ...............................................................................................113

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Revised SCHEMA
N=100
 
  
*Arm C was permanently discontinued in February 2021.
Eligibility:

HER2+ Metastatic 
Breast Cancer   

Progression on 
prior trastuzumab 
& pertuzumab

Prior tx with TDM1
R
A
N
D
O
M
I
Z
A
T
I
O
N
CR, PR, SD
Continue 
treatment
Arm B - PD or 
toxicity 
requiring 
discontinuation
Off-Treatment. 
30-day safety 
follow-up after 
last dose
A: Trastuzumab D1 , 
D15 and Vinorelbine 
D1, D8, D15
B: Trastuzumab D1, 
D15, Vinorelbine  
D1, D8, D15 with 
Avelumab D1, D15
Arm A-PD: 
Crossover to 
Trastuzumab, 
Avelumab
Continue 
treatment
1:2
Stratification Factors
1. Lines of Prior Metastatic Therapy ( <3 vs. 3+)
2. Hormone Receptor Status (ER+ vs. ER-)
3. Presence of Liver Metastases (yes or no)
Research 
biopsy 
Cycle 3 
Research 
biopsy 
Optional 
Research 
biopsy 

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1.
OBJECTIVES AND ENDPOINTS 
1.1
Study Design
This is a randomized phase II study designed to evaluate the safety and efficacy of trastuzumab 
and vinorelbine alone, in combination with an anti-PD-L1 monoclonal antibody (avelumab) or in 
combination with both avelumab and an anti 41BB/CD137 agonist mAb (utomilumab) in patients 
with advanced HER2+ breast cancer that has progressed on prior trastuzumab, pertuzumab and 
TDM-1 therapy. 
At least 100 eligible patients will be randomized 1:2:2 to receive trastuzumab/vinorelbine (Arm 
A: approximately 20 patients), trastuzumab/vinorelbine plus avelumab (Arm B: approximately 40 
patients), or trastuzumab/vinorelbine plus avelumab plus utomilumab (Arm C: approximately 40 
patients).
Because of an interim futility analysis in January 2021 that met the criteria for utomilumab 
inefficacy, Arm C has been closed to further enrollment and the crossover arm will now be  
trastuzumab and avelumab (Sponsor Amendment 4/Protocol Version 5).  Going forward, all 
newly enrolled patients will be randomized 1:2 to receive trastuzumab/vinorelbine (Arm A: 
approximately 20 patients) or trastuzumab/vinorelbine plus avelumab (Arm B: approximately 40 
patients).  
Arm A (n=20)  
o
trastuzumab 4mg/kg IV D1, D15  
o
vinorelbine 25mg/m2 IV D1, D8, D15
o
NOTE:  Crossover option to trastuzumab and avelumab upon progression.
Arm B (n=40)
o
trastuzumab 4mg/kg IV D1, D15  
o
vinorelbine 25mg/m2 IV D1, D8, D15
o
avelumab 10mg/kg IV D1, D15
Arm C (n=40) (Closed with protocol version 5/Sponsor Amendment 4)
o
trastuzumab 4mg/kg IV D1, D15 
o
vinorelbine 25mg/m2 IV D1, D8, D15 
o
avelumab 10mg/kg IV D1, D15
o
utomilumab 100mg IV D1
Patients will be stratified by lines of prior metastatic therapy (< 3 vs. 3+), ER status (positive vs 
negative) and presence of liver metastases (yes vs no).  
 
1.2
Primary Objectives

To determine whether the addition of avelumab to the combination of trastuzumab and 
vinorelbine will improve progression-free survival (PFS) compared to the trastuzumab 

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and vinorelbine combination alone in patients with advanced HER2-positive breast 
cancer. 

To determine whether the addition of utomilumab to the combination of avelumab, 
trastuzumab, and vinorelbine will improve progression-free survival (PFS) compared to 
the avelumab, trastuzumab, and vinorelbine combination alone in patients with advanced 
HER2-positive breast cancer.
1.3
Secondary Objectives
The secondary objectives of the study are to evaluate efficacy of the no immunotherapy arm 
(Arm A), single immunotherapy (Arm B) and doublet immunotherapy (Arm C) using the 
following endpoints:

Objective response (ORR), defined as Complete Response or Partial Response by RECIST 
1.1

Duration of response (DOR)

Overall survival, defined as time from randomization to death from any cause

Preliminary assessment of the clinical activity, as measured by ORR and PFS, of the cross-
over regimen of trastuzumab, avelumab and utomilumab in patients who progress on 
vinorelbine/trastuzumab

Safety and tolerability using NCI-CTCAE version 5.0. In particular, emphasis will be on 
cardiac, hepatic and pulmonary events (nature, severity and timing of these adverse events)
1.4
Exploratory Objectives
The exploratory objectives in this study are to determine efficacy of the combinations using the 
following endpoints:

PFS measures according to PD-L1 immunohistochemistry (IHC) status

PFS measures according to tumor infiltrating lymphocytes (TILs) level (baseline absolute 
levels and change) 

PFS measures as defined by immune modified RECIST

ORR by PD-L1 IHC status and various categories

Estimate two-year overall survival rate according to treatment arm
1.5
Correlative Objectives 

To assess if baseline PD-L1 IHC expression is associated with responders and if this differs 
by treatment arm

 To assess if baseline TIL (as determined on H&E slides) levels are associated with 
responders and if this differs by treatment arm

To assess if baseline “activated” immune status (defined by high TILs/ high PD-L1 
expression, mRNA enrichment of interferon signaling) is associated with responders and 
if this differs by treatment arm

To assess the above (1.3.6-1.3.8) by ER status

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
To determine if mutational profiles of material from baseline tumor biopsies are associated 
with efficacy and if this differs by treatment arm

To determine if baseline levels or change in IHC or gene expression levels of immune 
biomarkers are associated with efficacy and if this differs by treatment arm

To determine if clonality and diversity derived from sequencing of the T cell receptor 
(TCR) in tumor and blood are associated with efficacy 

To track mutations in plasma to understand biomarkers of responders and non-responders

To determine if levels of T cell phenotypes (activated effector T cells in blood) are 
associated with efficacy

To determine if any biomarkers are associated with safety signals
1.6
Endpoints
1.6.1
Primary Endpoint

Progression-Free Survival (PFS): Both median PFS and 12 month PFS will be 
estimated from the PFS distribution.
1.6.2
Secondary Endpoints

Objective Response (ORR: Complete Response or Partial Response)

Duration of Response (DOR)

Overall Survival (OS)

ORR and PFS in the crossover arm

Safety and Tolerability (by NCI CTCAE Version 5.0)
2.
BACKGROUND
2.1
HER2-Positive Breast Cancer 
Breast cancer is the most common cancer, other than skin cancer, in women and is one of 
the leading causes of cancer deaths among women in the United States. The introduction of 
trastuzumab into the treatment of HER2- overexpressing breast cancer has significantly 
changed the natural history of this disease, especially in the adjuvant setting. Trastuzumab 
treatment in the adjuvant setting in combination with chemotherapy has now resulted in 
high cure rates 16-18. However, the prevalence of metastatic breast cancer is still significant 
and is not currently considered curable. For the HER2-positive disease subtype, studies 
now suggest that at least 50-70% of patients with a new diagnosis of metastatic disease are 
presenting de novo 19,20.  Hence even as adjuvant cure rates are increasing, the number of 
patients being diagnosed with de novo advanced HER2-positive disease is static or even 
increasing. Therefore, this group of patients still remains in high need of efficacious 
therapies that can improve survival.
The current standard first line treatment for advanced HER2-positive disease is 
combination trastuzumab, pertuzumab and docetaxel 20. This combination significantly 
improved both progression free and overall survival compared with trastuzumab and 
docetaxel alone. Trastuzumab emtansine (T-DM1) has subsequently shown superiority in 

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the 2nd and later settings after failure of trastuzumab, or trastuzumab and lapatinib 21,22. 
There is no standard in the 3rd line setting and after, so therapy beyond this point remains 
suboptimal. While treatment in the advanced setting is thought to be palliative, an increase 
in survival is still an important objective for these patients, highlighting the need for new 
and effective therapies in this group of patients.
Increasing preclinical and correlative clinical data suggest that HER2-positive breast 
cancer is immunogenic 23,24. These data suggest that successful treatment of HER2-positive 
breast cancer with anti-HER2 therapies relies on intact and functional host anti-tumor 
immunity. Thus, we believe that HER2-positive breast cancer is potentially highly 
amenable to immunotherapeutic approaches. Relatively high rates of TILs in this subtype, 
and the observation that TIL levels correlate with prognosis and higher responses to anti-
HER2 therapy, as well as knowledge that one of the main mechanisms of action of 
trastuzumab is ADCC and generation of adaptive immunity, together all support immune 
evasion as a critical requirement for tumor progression in HER2-positive cancers.
Due to the competitive therapy landscape in HER2-positive breast cancer, there are not 
many studies evaluating immunotherapy in this breast cancer subtype.  However, the 
preclinical and correlative data suggest that HER2-positive disease may be the most 
amenable subtype to immune modulation due to partially effective reinstatement of 
immunosurveillance by trastuzumab, the presence of a strong tumor antigen (HER2) as 
well as a higher mutational load 23.
At present, the advanced setting remains the optimal setting to evaluate new approaches 
given the high cure rates of many early-stage HER2-positive patients. Nearly all patients 
with advanced disease will suffer disease progression and die from their disease. Hence, 
there is a still a critical need to develop more efficacious therapies that may prolong 
survival in this subgroup. In addition, successful approaches in the advanced setting may 
also lead to more tailored approaches and de-escalation of chemotherapy in the early-stage 
setting.
2.2
Study Agent(s)
2.2.1
Avelumab
Avelumab is a fully human anti-PD-L1 mAb of the IgG1 isotype that is FDA approved 
for the treatment of patients with metastatic Merkel cell carcinoma (MCC) or metastatic 
previously treated urothelial carcinoma. It is also currently being investigated in 
combination with other immunotherapies in patients with locally advanced or metastatic 
solid tumors. 
Avelumab selectively binds to PD-L1 and competitively blocks its interaction with PD-1. 
Compared with anti-PD-1 antibodies that target T-cells, avelumab targets tumor cells, 
and is therefore expected to have fewer side effects, including a lower risk of 
autoimmune-related toxicity, as blockade of PD-L1 leaves the PD-L2/PD-1 pathway 
intact to promote peripheral self-tolerance.

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Avelumab has 2 main mechanisms of action for exerting its anti-tumor effects:  

PD-L1 on tumor cells can interact with PD-1 or B7-1 on activated T cells. These 
interactions have been shown to significantly inhibit T cell activities. Therefore, blocking 
PD-L1 interaction with PD-1 or B7-1 by anti-PD-L1 can release T cells from 
immunosuppression, and lead to elimination of tumor cells by T cells. 

Tumor cells may express high levels of PD-L1 on their surface compared with normal 
tissues. As a fully human IgG1 MoAb, avelumab has antibody-dependent cellular 
cytotoxicity (ADCC) potential. Upon binding to PD-L1 on tumor cells and binding with 
their Fcpart to Fc-gamma receptors on leukocytes, avelumab can trigger tumor-directed 
ADCC. 
A dose of 10 mg/kg of avelumab, intravenous (IV) once every 2 weeks is the FDA 
approved adult dosing of avelumab and is the dose used in the ongoing Phase III trials 
based on the preliminary pharmacokinetic(PK),target occupancy, and preliminary clinical 
safety data collected in the clinical trials. 
Avelumab plasma levels leading to full programmed death ligand 1 (PD-L1) receptor target 
occupancy (TO) on PBMCs resulted in tumor growth inhibition in a murine disease model. 
Therefore, full TO on PBMCs can be considered a PD marker for the ability of avelumab 
to act on its target and to show clinical activity.
Preliminary PK data from EMR 100070-001 show that the concentration at the end of dose 
interval (Cmin) increased more than proportionally to dose between 1 to 10 mg/kg, but 
proportionally for doses above 10 mg/kg. Consistently the t1/2 also increased with the dose. 
However, the average value was 102 and 120 hours for 10 mg/kg and 20 mg/kg, 
respectively, with no significant difference between these two dose groups. This PK 
characteristic suggests that target mediated drug disposition is involved in the clearance of 
avelumab and a high PD-L1 TO is likely achieved at the trough concentration for doses of 
10mg/kg and 20mg/kg. 
The in vitro target occupancy data further support that a high TO is likely achieved at 10 
mg/kg and above. 
Target occupancy was measured ex vivo by flow cytometry on peripheral blood CD3+ T 
cells from patients (n=9) treated with avelumab. After the first dose of the initial dose-
escalation portion of Trial EMR 100070-001, the observed mean target occupancy reached 
a plateau of about 90% on Day 15 pre-dose for dose levels of 3 mg/kg and above. 
In addition, in vitro target occupancy was measured using flow cytometry on peripheral 
blood CD3+ T cells from 8 healthy volunteers after spiking avelumab over a concentration 
range of 0.003 to 10 μg/mL. A 50% target occupancy was observed at a drug concentration 
(standard deviation [StD]) of 0.122 (0.042) μg/mL, and a concentration of 1 µg/mL 
avelumab was required for > 95% target occupancy. Based on these data and the trough 
serum levels observed in EMR 100070-001, target occupancy was projected to reach or 

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exceed > 95% throughout the entire dosing interval for 10/13 subjects at 3 mg/kg, and for 
all (15/15) subjects at 10 mg/kg group from dose escalation group in EMR1000700-001. 
Based on the ex-vivo peripheral blood CD3+ T cell and in vitro target occupancy results, 
the dose of 10 mg/kg every 2weeks is expected to achieve target saturation during the entire 
dosing interval in the majority of patients. 
As of the safety cutoff date of 05 November 2015, 1353 subjects have received at least 1 
dose of avelumab at doses ranging from 1.0 to 20 mg/kg in the Phase I Trial EMR 100070-
001, of which 1315 have received the proposed dose of 10mg/kg (15 in the dose escalation 
part of the study and 1300 subjects in the pooled expansion cohort). 
In the dose escalation portion of the Phase I study, there was no evidence of differences in 
the safety profile across all administered dose levels from 1 mg/kg to 20 mg/kg. The MTD 
was not reached. Ongoing review of the safety data by the Safety Monitoring Committee 
(SMC) suggests an acceptable safety profile of avelumab administered at the 10 mg/kg 
every 2 weeks dose and schedule. Treatment-related treatment-emergent adverse events 
(TEAEs) were observed in 813 (62.5%) subjects in the pooled expansion cohort. The most 
frequently observed treatment related TEAEs (incidence > 5%) were fatigue (212 subjects, 
16.3%), infusion-related reaction (209 subjects, 16.1%), nausea (108 subjects, 8.3%), chills 
(102 subjects, 7.8%), diarrhea (79 subjects, 6.1%), and pyrexia (72 subjects, 5.5%).Grade 
≥ 3 treatment-related TEAEs were observed in 124 subjects (9.5%) in the pooled expansion 
cohort. The most frequently reported Grade ≥ 3 treatment related TEAEs were gamma-
glutamyl transferase increased (GGT) and infusion-related reaction (each occurred in 9 
subjects; 0.7%). Infusion-related reactions including drug hypersensitivity reactions and 
immune-mediated adverse reactions have been identified as expected adverse drug 
reactions of avelumab. The safety profile of avelumab is consistent with findings reported 
for other anti-PD-1 or anti-PD-L1 antibodies.
In conclusion, preliminary data from EMR 100070-001 showed that avelumab at doses up 
to 20mg/kg Iv every 2 weeks was well tolerated, and the dose of 10 mg/kg Iv every 2 weeks 
was considered to have an acceptable safety profile for further investigation in clinical 
studies.
 
Avelumab is currently in clinical development across Phases I, II, and III. These include: 

EMR 100070-001: A Phase I, open-label, multiple ascending dose trial to investigate 
the safety, tolerability, pharmacokinetics, biological and clinical activity of avelumab 
in subjects with metastatic or locally advanced solid tumors and expansion to selected 
indications 

EMR 100070-002: A Phase I trial to investigate the tolerability, safety, 
pharmacokinetics, biological and clinical activity of avelumab in Japanese subjects 
with metastatic or locally advanced solid tumors, with expansion part in Asian 
subjects with gastric cancer 

EMR 100070-004: A Phase III open-label, multicenter trial of avelumab versus 
docetaxel in subjects with non-small cell lung cancer that has progressed after a 
platinum-containing doublet 

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EMR 100070-001 is a Phase I, open-label, multiple ascending dose trial to investigate the 
safety, tolerability, PK, biological and clinical activity of avelumab in subjects with 
metastatic or locally advanced solid tumors and expansion to selected indications. This 
trial consists of 2 parts. In the dose escalation part, sequential cohorts of subjects were 
enrolled at progressively higher dose levels (ranging from 1.0, 3.0, 10.0, and 20.0 mg/kg 
once every 2 weeks) with a 3 + 3 algorithm design for determination of the maximum 
tolerated dose (MTD) of avelumab; in the treatment expansion phase, subjects in 
different tumor cohorts are being treated with 10 mg/kg of avelumab once every 2 weeks 
until, confirmed progression, unacceptable toxicity, or any reason for withdrawal occurs. 
More than 1500subjects have been enrolled in the EMR100070-001 trial. The 3 + 3 dose 
escalation algorithm to determine the MTD is complete and a dose of 10 mg/kg once 
every 2 weeks was determined for the tumor expansion cohorts on the basis of safety, 
PK, and PD observations. The treatment expansion part of the trial consists of 16tumor 
treatment cohorts. As of 05 November 2015 (data cutoff for a pre-planned safety data 
review by the study Safety Monitoring Committee [SMC]), 53 subjects in the dose 
escalation part had received avelumab (4, 13, 15, and 21 subjects had received 1.0, 3.0, 
10.0, and 20.0mg/kg of avelumab, respectively) and 1300 subjects in the pooled 
expansion part had received 10 mg/kg avelumab and were followed up for at least 
4weeks.
The safety summary summarizes data from 1300 subjects treated in the pooled treatment 
expansion cohort from the ongoing Phase I Trial EMR100070-001 (as of 05 November 
2015). The pooled data included subjects treated in all tumor expansion cohorts, 
including non-small cell lung cancer (NSCLC), metastatic gastric cancer, breast cancer, 
colorectal cancer, castrate-resistant prostate cancer, adrenocortical carcinoma, melanoma, 
mesothelioma, urothelial carcinoma, ovarian cancer, renal cell carcinoma, and squamous 
cell cancer of the head and neck. Safety data are also summarized for 52 subjects in the 
ongoing Phase I Trial EMR 100070-002 and for 88 subjects in the ongoing Phase II Trial 
EMR100070-003 (as of 17December 2015). For TrialEMR100070-004, an overview of 
the serious adverse events (SAEs) is provided.
Most of the observed adverse events (AEs) were either in line with those expected in 
subjects with advanced solid tumors or with class effects of monoclonal antibody (mAb) 
blocking the PD-1/PD-L1 axis. Infusion-related reactions including drug hypersensitivity 
reactions and immune-mediated adverse reactions (immune-related pneumonitis, 
immune-related colitis, immune-related hepatitis, immune-related endocrinopathies 
(thyroid disorders, adrenal insufficiency, new onset type I diabetes mellitus, pituitary 
disorders), immune-related nephritis and renal dysfunction and other immune-related 
AEs (myositis, myocarditis, Guillain-Barré syndrome, uveitis). Guidelines for the 
management of immune-mediated adverse reactions and infusion-related reactions are 
implemented in all ongoing clinical studies with avelumab.
The clinical efficacy information summarized in the Investigator’s Brochure includes 
data from the following expansion cohorts of the ongoing Phase I Trial EMR100070-001, 
NSCLC (second line and first line cohorts), ovarian cancer, GC/GEJ, UC, mesothelioma, 

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and adrenocortical carcinoma. In addition, efficacy results for 20 subjects in the gastric 
cancer expansion cohort of the ongoing Phase I Trial EMR 100070-002 and 88 subjects 
in Part A of the ongoing Phase 1 Trial EMR 100070-003 in mMCC are summarized. 
The NSCLC expansion cohort in the ongoing Phase I Trial EMR100070-001 had a cutoff 
date of 15 January 2015, 6 months after start of avelumab treatment of the last subject in 
this expansion cohort (a total of 184 treated subjects). The objective response rate (ORR) 
based on confirmed and unconfirmed responses for subjects treated in the NSCLC 
expansion cohort was 14.1% (26 of 184 NSCLC subjects). Progression free survival 
(PFS) and overall survival (OS) were all evaluated for all NSCLC subjects treated in the 
expansion phase. As of 15 January 2015, the median PFS and OS for the NSCLC 
treatment expansion cohort were 11.6 weeks and 8.4 months, respectively.
The clinical activity of avelumab was also evaluated by subjects’ tumor PD-L1 
expression status in the NSCLC expansion cohort. An objective response was observed in 
20 of 122 subjects (16.4%) who were PD-L1 positive (defined as having at least 1% PD-
L1 positive tumor cells) compared with 2 of 20 subjects (10.0%) who were considered 
PD-L1 negative (defined as having less than 1% PD-L1 positive tumor cells). A longer 
median PFS (12.0vs 5.9 weeks) and OS (8.9 vs 4.6months) were both observed in PD-L1 
positive compared with PD-L1 negative subjects.
The ovarian cancer expansion cohort had a data cutoff of 13 February 2015, 
approximately 13 weeks after the start of avelumab treatment on the last subject who was 
included in this pre-planned interim analysis on this expansion cohort. The ORR based on 
confirmed and unconfirmed responses for subjects treated in the ovarian cancer 
expansion cohort was 10.7% (8 of 75 subjects). The median PFS for the ovarian cancer 
expansion cohort was 11.4 weeks (95%confidence interval (CI): 6.3 to 12.0weeks).
The preliminary efficacy data for the ongoing Phase I Trial EMR 100070-002 are based 
on a data cutoff of 11 March 2015. As of the data cutoff, 3 of 20 subjects responded to 
trial treatment (all responses were partial responses [PRs] and all responses were 
confirmed responses), and the best overall response (BOR) was 15.0% (95%CI: 3.2%to 
37.9%). The median PFS of this group was 11.9 weeks (95% CI: 6.0 to 12.3weeks).
The results of a Phase I cohort expansion trial in patients with metastatic breast cancer 
were presented at the 2015 San Antonio Breast Cancer meeting (Dirix et al, SABCS 
2015).  In this trial, 168 patients with metastatic breast cancer with up to 3 prior lines of 
therapy in the metastatic setting were treated with avelumab 10 mg/kg every 2 weeks 
until disease progression. Overall, treatment was well tolerated, with the primary grade 
>3 clinically significant toxicities including autoimmune hepatitis (3 patients, 1.8%), 
GGT increase (3 patients, 1.8%) and fatigue (3 patients, 1.8%). Eight patients (4.8%) 
experienced grade 1/2 hypothyroidism, and one patient each experienced grade 3 
pneumonitis, or grade 4 thrombocytopenia. The overall response rate in this unselected 
population was 4.8% (95% CI 2.1, 9.2) with one complete and 7 partial responses. An 
additional 23.2% of patients had stable disease. The median time to response was 11.4 
weeks (range, 5.7-17.7 weeks), the median duration of response was 28.7 weeks (95% 

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CI: 6.1, ne), and responses were ongoing in 5/8 patients at time of the analysis. Tumor 
shrinkage of ≥30% was observed in 16 patients (9.5%), including 2 patients with 
progressive disease by RECIST who had partial responses by modified Immune RECIST 
Criteria (irRC). Responses were seen in all molecular subtypes. PD-L1 status in 136 
evaluable patients did not appear to correlate with response, although small numbers and 
varying cut-offs make this data difficult to interpret. 
For additional details, refer to the Avelumab Investigator’s Brochure.
2.2.2
Utomilumab 
Utomilumab is a novel full humanized IgG2 mAb agonist of 4-1BB (CD137, TNFRSF9)
 A membrane spanning glycoprotein of the Tumor Necrosis Factor (TNF) receptor 
superfamily, 4-1BB was first identified as 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, eosinophils and activated B cells 4. 4-1BB expression has also been 
demonstrated on tumor vasculature 5,6. 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 4. 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. The 
addition of 4-1BB agonists to in vitro cultures of B lymphoma cells with rituximab and 
NK cells resulted in increased lymphoma killing 7. 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 8. 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 9-11.
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 
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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.
Numerous studies of murine and human T cells indicate that 4-1BB promotes enhanced 
cellular proliferation, survival, and cytokine production 12. 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 13. 4-1BB agonists also inhibit 
autoimmune reactions in a variety of autoimmunity models 14. 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.
2.2.2.1
Preclinical and clinical development of Utomilumab
Utomilumab (PF-05082566), an intravenous (IV) fully human IgG2 monoclonal antibody 
(mAb), binds to the extracellular domain of human 4-1BB with high affinity and 
specificity and is capable of 4-1BB agonism. Treatment with Utomilumab as a single 
agent results in tumor cell line growth inhibition in xenogeneic tumor models. In 
addition, 4-1BB agonist mAbs demonstrate significant combinatorial efficacy with 
antibody-dependent cell-mediated cytotoxicity (ADCC) 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.
It is thought that tumor expression of PD-L1 can limit the ability of cytotoxic T cells to 
directly kill the tumor cells. Therefore, even if a 4-1BB agonist is used to stimulate 
cytotoxic T cells, capable of recognizing such tumors, PD-L1 expressed on the tumor 
cells may down-modulate the activity of these stimulated T cells. A 4-1BB agonist 
antibody resistant mouse MC38 colon cancer tumor model that expresses PD-L1 was 
used to provide evidence for improved anti-tumor activity using the combination of a 4-
1BB agonist antibody with PD-1 antagonist antibody compared with either single agent. 
In immunocompetent mouse models of colon carcinoma (MC38), melanoma (B16F10) 
and triple negative breast cancer (AT3-ova), statistically significant anti-tumor activity 
versus the vehicle control is observed in the cohort of mice that received a combination 
of a PD-1 antagonist antibody with a 4-1BB agonist antibody, but not with either 
antibody administered as a single agent (see IB for further information). Consistent with 
the proposed mechanism for the combination, significant increases in CD8+ effector 
memory cells and tumor responsive IFN-gamma producing cells were found in the 
spleens of mice treated with the combination (data not shown). In addition, preliminary 
toxicology data in mice suggest that the toxicity of an anti-4-1BB agonist is not increased 
by addition of an anti-PD-1 antagonist (data not shown).
As of October 2015 (see IB), utomilumab has been administered as a single agent to 47 
patients with advanced cancerat dose levels between 0.006 and 10.0 mg/kg, in 40 patients 
at dose levels between 0.03 and 10.0 mg in combination with rituximab and in 23 patients 

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at dose levels between 0.45mg/kg and 5.0 mg/kg in combination with pembrolizumab for 
a total of 110 patients treated.
The ongoing first in-patient clinical Study B1641001 is a Phase 1, open–label, dose-
escalation study to evaluate the safety and tolerability, in one study arm, of PF- 05082566 
given as a single agent in subjects with solid tumors or relapsed or refractory B-cell 
lymphoma, and in another study arm, of Utomilumab given in combination with 
rituximab in patients with relapsed or refractory CD20 positive Non-Hodgkin’s 
Lymphoma (NHL). Key study parameters assessed included pharmacokinetics of PF-
05082566, pharmacodynamic markers of activity, and preliminary anti-tumor activity. 
No dose limiting toxicities have thus far been seen. The most frequently occurring 
treatment related AEs were pyrexia (10.6%) which was generally mild, followed by 
fatigue (8.5%). One case of grade 3 thrombocytopenia was observed which lasted less 
than 7 days and was not considered a serious adverse event.
For additional details, refer to the Utomilumab Investigator’s Brochure.
2.2.3
Trastuzumab and Biosimilars
Refer to the Full Prescribing Information for trastuzumab or biosimilars for complete 
safety information: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ in addition to 
information provided in Sections 7 and 8 of the protocol.
2.2.4
Vinorelbine 
Refer to the Full Prescribing Information for trastuzumab for complete safety 
information: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ in addition to 
information provided in Sections 7 and 8 of the protocol.
2.3
Rationale
2.3.1
Rationale for combination administration of avelumab and utomilumab
As noted above, the combination of a 4-1BB agonist antibody with a PD-1 antagonist 
antibody shows significant inhibition of tumor growth in preclinical models of colon 
carcinoma, melanoma model and triple negative breast cancer compared with either agent 
alone. In addition, the combination of a 4-1BB agonist antibody with an anti-HER2 agent 
also shows synergy in preclinical models of HER2-positive disease 15. Patients previously 
progressing on anti-PD-1 therapy have responded to utomilumab monotherapy 
suggesting a viable alternative mechanism of relief of T cell exhaustion. The core 
hypothesis to be evaluated in this study is that a 4-1BB agonist antibody will synergize 
with anti PD-L1 to activate cytolytic T cells and synergize with trastuzumab to increase 
ADCC. Hence the combination of avelumab and Utomilumab is a rational combination to 
evaluate in HER2-positive disease.

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The benefit-risk relationship has been carefully considered in the planning of this study.
Avelumab demonstrated clinical activity in patients with advanced solid tumors as well 
as breast cancers. The clinical safety data available to date, with single-agent avelumab in 
patients with advanced solid tumors, suggest an acceptable safety profile of the 
compound. Most of the observed events were either in line with those expected in 
patients with advanced solid tumors or with similar class effects of monoclonal 
antibodies blocking the PD-1/PD-L1 axis. Infusion-related reactions including 
hypersensitivity and immune related (ir) AEs/autoimmune disorders have been identified 
as important risks for avelumab. Respective risk mitigation measures have been 
implemented in all ongoing clinical studies with avelumab, including this clinical trial 
protocol. These include guidelines for treatment interruption and discontinuation in case 
of irAEs, as well as mandatory pretreatment with a histamine H1 receptor (H1) blocker 
and acetaminophen.
The anti-4-1BB mAb, utomilumab, has also demonstrated clinical activity as 
monotherapy in patients with advanced solid tumors and in combination with rituximab 
in patients with NHL in an ongoing Phase 1 study. The clinical safety profile of 
Utomilumab supports its use as both a single agent and in combination with other 
monoclonal antibodies. Fatigue and skin rashes represent the most common utomilumab 
related AEs, although they have been generally mild to moderate in intensity. While 
clinically significant irAEs have not been observed with PF-05082566, risk mitigation 
measures have been implemented in ongoing clinical studies with PF-05082566, 
including this clinical trial protocol. These include guidelines for treatment interruption 
and discontinuation in case of treatment related irAEs. Based on the nonclinical and 
Phase 1 data available to date for both avelumab and PF-05082566, the conduct of this 
trial is considered justifiable using the dose and frequency of administration of avelumab 
and the dose and frequency of administration of utomilumab as specified in this clinical 
trial protocol. Of note, the highest utomilumab dose to be administered in this study is 
considerably lower than the highest dose tested as a single agent and in combination with 
rituximab, where no severe treatment related toxicities were observed. In addition, 
toxicity data from the ongoing phase Ib study of avelumab and utomilumab will provide 
additional information regarding the safety of this combination and these data will inform 
this protocol as warranted. Lastly, this study shall be discontinued in the event of any 
new findings that indicate a relevant deterioration of the risk-benefit relationship that 
would render continuation of the trial unjustifiable.
Thus, the projected benefit/risk of avelumab given in combination with Utomilumab is 
anticipated to be favorable for investigation in this population of patients. 
2.3.2
Rationale for combination with chemotherapy and dual immunotherapeutic approaches
Anti-HER2 therapies, in particular trastuzumab and T-DM1, have been shown to require 
and also induce anti-tumor immunity which likely contributes to an effective clinical 
response. In preclinical studies, the combination of trastuzumab or T-DM1 with 
checkpoint blockade have enhanced tumor regressions in immunocompetent mouse 
models 15,25,26. Given the strong positive prognostic associations of inducing an immune 

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response as evidenced by tumor immune cell infiltration, we hypothesize that therapies 
that can induce or enhance an immune response could be beneficial in improving survival 
of advanced HER2-positive disease.
Certain chemotherapy agents given weekly or metronomically (i.e., paclitaxel, 
vinorelbine) have always synergized well with anti-HER2 therapy and this mechanism of 
action may be through enhancement of immune responses through apoptosis, 
inflammation and presentation of MHC I/II 27. Hence the rationale to combine with 
chemotherapy in HER2-positive breast cancer is compelling.
Trials with trastuzumab in combination with an anti-PD-1 antibody in advanced HER2-
positive patients are currently ongoing (NCT02129556).  To date, early efficacy data 
suggest that whilst there are some patients who respond very well to PD-1 blockade as 
monotherapy with durable responses, these represent a minority of patients. This could be 
due to lower levels of pre-existing immunity (as evidenced by lower levels of TILs) in 
the advanced setting. Hence it is plausible that combination immunotherapy approaches 
(i.e. with chemotherapy or targeting other checkpoints) will be needed to reinstate 
immunosurveillance in most patients in the advanced setting in order to improve survival. 
Early data in other solid tumor types support that combination immunotherapies look 
promising. Combination CTLA-4 and PD-1 blockade in both melanoma and non-small 
cell lung cancer (NSCLC) have shown higher objective response rates as well as longer 
progression free survival. These responses seem independent of baseline PD-L1 levels if 
one considers PD-L1 as a surrogate for a pre-existing immune response (T effector/IFN-
gamma type signature)28. Melanoma and NSCLC are considered more “immunogenic” 
than breast cancer, with almost 10-fold higher mutational loads. In preclinical models 
combination checkpoint blockade increases T effector cell infiltration, reduces T-
regulatory cells and increases IFN-gamma production.
Our preliminary data analyzing the composition of TILs in breast cancer suggest that 
CD137/4-1BB is involved in the generation of an effective T cell anti-tumor response. 
Furthermore, we and others have shown the importance of adaptive immunity in 
trastuzumab response as well as synergism of checkpoint modulation (4-1BB /PD-1) with 
anti-HER2 therapy in preclinical immunocompetent mice models. 4-1BB  has also been 
shown to be upregulated on NK cells post trastuzumab treatment-- hence strategies that 
can enhance ADCC may also increase response rates in an immunosuppressive 
microenvironment. Together the data suggests that the anti-tumor immune response could 
be enhanced by combination T cell agonist (4-1BB) and checkpoint blockade (PD-L1) 
together with anti-HER2 therapy. This combination may also have less toxicity than dual 
checkpoint (CTLA-4 and PD-1/L1) blockade as preclinical models suggest that 4-1BB  
may play a role in reducing autoimmunity side effects of checkpoint blockade. Pre-
clinical data also supports a role for 4-1BB  agonists in protecting T cells from 
detrimental actions of agents such as chemotherapy and MEK inhibition (personal 
communication  S Loi).

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In view of the low mutational burden of breast cancer relative to other immunogenic 
tumor types, the lower frequency of PD-L1 protein expression and TILs observed in 
advanced breast cancer to date, we propose that the combination of a 4-1BB agonist with 
PD-L1 blockade could be a suitable treatment strategy in advanced HER2 breast cancer 
as a means to enhance T cell infiltration and activity.  This may be most relevant to 
HER2-positive patients who are ER-positive vs. negative as the former have lower levels 
of immune infiltrate. Patients who progress post pertuzumab and T-DM1 based regimens 
still have poor survival and are hence a population requiring novel and efficacious 
therapies to be developed. If efficacy is observed with the strategy of combination 
checkpoint blockade, then this approach can be applied to earlier line and/or stage 
settings, particularly in patients who lack TILs, given that TILs are strongly associated 
with improved survival in both early and late stage settings.
This study will provide proof of concept data for two important clinical and translational 
questions. First, whether PD-1/L1 blockade (single immunotherapy) can improve the 
efficacy of a standard-of-care chemotherapy/trastuzumab combination in PD-L1-
unselected patients. Second, can dual immunotherapy further enhance efficacy compared 
to single immunotherapy regimen in the same patient population. Lastly, the study’s 
biomarker work may allow us to begin to determine which patients particularly need the 
combination regimens. 
2.3.3
Rationale for using a vinorelbine/trastuzumab backbone
Vinorelbine is a microtubule inhibitor, similar to the taxanes. These agents interfere with 
mitosis and as such promote polyploidization. Such stress in chromosomal content has 
been linked to an endoreticulum stress response that favors calreticulin exposure and 
hence facilitates the recognition and elimination of malignant cells by the immune 
system.  In non-small cell lung cancer, treatment with vinorelbine has been shown to 
increase the levels of cytoxic T cells over T regs. Both vinorelbine and the taxanes have 
demonstrated strong synergistic clinical activity with trastuzumab 1. This synergy can be 
hypothesized to be due in part to promotion of immune effects in combination with 
trastuzumab. In randomized studies, the combination of vinorelbine and trastuzumab has 
shown comparable or potentially superior efficacy compared to taxane and trastuzumab, 
typically with lower rates of severe toxicity 2,29,30. Vinorelbine, unlike taxanes, does not 
require the use of prophylactic steroids, which may be an advantage in the setting of 
immunotherapy. Vinorelbine also is not typically used in the early disease setting, 
therefore most patients with advanced disease are vinorelbine naïve. For these reasons, 
the combination of vinorelbine and trastuzumab offers a convincing alternative to taxane-
based regimens in combination with immunotherapy in the advanced HER2 setting and 
as a non-immunotherapy standard of care control arm in this study.
 
2.3.4
Rationale for trial design
This trial is a comparative proof-of-concept phase II study to determine if 1) avelumab 
adds to the standard of care combination of trastuzumab and vinorelbine and 2) if 
utomilumab adds to avelumab in combination with trastuzumab and vinorelbine. It is 
noted that both avelumab and Utomilumab are investigational agents with no proven 

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benefit in HER2-positive breast cancer. Because the population that will be enrolled in 
this study may be heterogenous, it is challenging to accurately predict the PFS of the 
trastuzumab and vinorelbine control arm. Thus, it is possible that the study may be 
slightly underpowered to detect a benefit of avelumab when added to trastuzumab and 
vinorelbine. However, we will soon have the results of ongoing phase III studies 
evaluating the addition of PD-1/PD-L1 blockade to standard chemotherapy/trastuzumab 
to provide more definitive data on the benefit of PD-1/PD-L1 blockade in this context. In 
addition, we will also have the correlative work described below which will help 
determine who benefits from the addition of immunotherapy. Given the current limited 
efficacy data in advanced breast cancer with PD-1/PD-L1 blockade, the move in other 
solid tumor types towards combination approaches, and the low immunogenicity of 
advanced breast cancer in general, our hypothesis is that this forward-looking study 
design evaluating both a single immunotherapy and a combination immunotherapy 
regimen is warranted.
2.3.5
Rationale for allowing cross-over for patients randomized to the control arm
As noted above, at this time there is no proven benefit to either Utomilumab or avelumab 
in HER2+ breast cancer, therefore there is not an ethical responsibility to provide 
crossover in this study. However, patients enrolling on this study are likely interested in 
immunotherapy approaches to treating their cancer. Thus, for those patients who are 
randomized to the no-immunotherapy control arm, providing an option to receive an 
immunotherapy regimen at the time of progression is appropriate. As overall survival is 
not a primary endpoint of this study, allowing cross-over will not significantly 
compromise the study’s ability to assess its objectives. Importantly, this crossover will 
provide an opportunity to obtain a preliminary assessment of the clinical activity of the 
trastuzumab, Avelumab and Utomilumab regimen in the absence of chemotherapy. 
2.3.6
Safety of the proposed two investigational study arms
The safety evaluation of utomilumab is ongoing and is reported in the current 
Invenstigator Brochure (October 2017).  Study B9991004 is a Phase 1b/2, open label, 
multi center, multiple dose, safety, efficacy, PK/PD study of immune modulators in 
combination with avelumab (PD-L1 blocking mAb) in adult patients with locally 
advanced or metastatic solid tumors. Utomilumab is the first agent to be evaluated in 
combination with avelumab in this study and is designated as Combination A. 
Combination A consists of three lead-in cohorts patients with advanced NSCLC 
randomly assigned to a utomilumab flat dose cohort of 20 mg, 100 mg, or 500 mg, 
administered concurrently with avelumab at 10 mg/kg on Day 1 of each 4-week cycle 
(avelumab is administered every 2 weeks within a 4-week cycle). Cohorts found to be 
safe and well tolerated are then to be expanded in the Phase 2 stage in patients with 
advanced NSCLC. Upon activation of the Phase 2 portion of Combination A, cohorts of 
patients with advanced melanoma, squamous cell carcinoma of the head and neck, and 
triple negative breast cancer will be treated with 100 mg utomilumab plus avelumab. In 
Phase 2, bothsafety and efficacy objectives will be assessed.

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The combination of an anti-PD-1 inhibitor (pembrolizumab) with trastuzumab is also 
being evaluated in an ongoing phase 2 study with more than 60 patients enrolled thus far 
(NCT02129556). Again, no unexpected safety signals have been observed; the main drug 
related toxicity was fatigue.
PD-1/PD-L1 blockade in combination with various cytotoxic agents is currently being 
evaluated in large studies. The toxicity profile of these agents as monotherapy is now 
well established. In particular, there appears to be no cardiac toxicity which is 
particularly relevant when considering combinations with trastuzumab. Pfizer reports that 
avelumab is in phase III studies in ovarian cancer with combination with carboplatin/ 
paclitaxel and with pegylated liposomal doxorubicin (JAVELIN Ovarian 200: 
NCT02580058).  Again, there has been no unexpected toxicity seen. Therefore, the 
combination of avelumab with the chemotherapy proposed seems feasible.
Vinorelbine has been extensively evaluated in combination with trastuzumab in phase 3 
studies. In these studies, the main drug related toxicity was hematological, with 
predominantly grade 2 leucopenia. 
Overall, we do not expect significant safety issues with the triplet and quadruple 
combination. However careful safety monitoring is incorporated into this study to address 
concerns that these combinations have not been evaluated together yet.
2.3.7
Rationale for allowing patients to continue treatment beyond initial progression per 
RECIST 1.1
Conventional response criteria may not be the most suitable to assess activity of 
immunotherapeutic agents. There are numerous documented responses of patients who 
progress by RECIST 1.1 criteria who then demonstrate durable anti-tumor activity. In 
many trials of checkpoint blockade there are patients who demonstrate tumor shrinkage 
even after an initial increase in tumor burden. This may be due to increase in immune 
infiltrates. The most commonly observed pattern was the appearance of new lesions such 
as FDG avid lymph nodes in the context of decreased overall tumor burden at the first or 
second tumor assessment. The potential for pseudo-progression or delayed anti-tumor 
immunity with combination chemotherapy, trastuzumab, and immunotherapy is 
unknown. 
2.3.8
Rationale for revised study design discontinuing enrollment to utomilumab-containing 
regimens
In October 2020, the study team was informed that Pfizer had discontinued development 
of utomilumab. This decision was based on a perceived lack of efficacy observed in a study 
of utomilumab and avelumab in a mixed population of solid cancers that did not include 
HER2-positive breast cancer. There were no concerns about the safety of the combination. 
To address this new information, in consultation with the study’s Data Safety Monitoring 
Board, in January 2021 an interim futility analysis for utomilumab benefit was performed 
on available efficacy data from the AVIATOR study.  Results from this analysis indicated 

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the accumulating data were inconsistent with the targeted benefit hazard ratio of 0.60.  
Based 
on 
this 
analysis, 
new 
enrollment 
to 
Arm 
C 
of 
this 
study 
(vinorelbine/trastuzumab/avelumab/utomilumab) has been permanently discontinued. 
Utomilumab has also been removed from the crossover regimen for all new patients 
starting that portion of the study.
Importantly, the AVIATOR trial has a co-primary objective to determine whether the 
PD-L1 inhibitor avelumab adds benefit to vinorelbine and trastuzumab. This important 
question remains unanswered in HER2+ breast cancer.  Thus, there is still strong 
rationale to complete enrollment to Arms A (vinorelbine/trastuzumab) and B 
(vinorelbine/trastuzumab/avelumab) of AVIATOR. Notably this comparison was not part 
of the interim analysis. 
Of note, at the time of Sponsor Amendment 4, there were no longer any active patients 
receiving utomilumab.
2.4
Correlative Science Background
Our preliminary data analyzing the composition of TILs in breast cancer suggest that 
CD137/4-1BB is involved in the generation of an effective T cell anti-tumor response 
(Figure below showing strong correlations with 4-1BB and TILs [by hematoxylin and 
eosin staining (H&E)31] and expression of other immune markers  in the TCGA breast 
cohort 32. Furthermore, we and others have shown the importance of adaptive immunity in 
trastuzumab response as well as synergism of checkpoint modulation (4-1BB /PD-1) with 
anti-HER2 therapy in preclinical immunocompetent mice models15,33.  4-1BB  also has 
been shown to be upregulated on NK cells post trastuzumab treatment-- hence strategies 
that can enhance ADCC may also increase response rates in an immunosuppressive 
microenvironment33. Together the data suggests that the anti-tumor immune response 
could be enhanced by combination T cell agonist (4-1BB) and checkpoint blockade (PD-
L1) together with anti-HER2 therapy. This combination may also have less toxicity than 
dual checkpoint (CTLA-4 and PD-1/L1) blockade.
We hypothesize that the presence of a pre-
existing immune response (i.e. using PD-L1 or 
TILs as a proxy for a T-effector/IFN-gamma 
signature) will bode for higher responses to 
avelumab alone, but the lack of one may mean 
that the addition of utomilumab may be 
required. The other main hypothesis is that the 
combination will be more effective in all 
patients (i.e. with or without a pre-existing 
immune response).
Hence, the main objectives of the correlative 
elements of this study will be to determine 

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which patients need the combination of utomilumab and avelumab as opposed to avelumab 
alone, as well as to identify early biomarkers of responders.
2.4.1
Rationale for biomarker evaluations
TILs as measured in a semi-quantitative fashion on routine H&E slides are strongly 
associated with prognosis in both primary and advanced HER2 positive disease in the 
setting of anti-HER2 therapy and chemotherapy 31,34. Immune gene signatures have also 
been strongly associated with both pCR and survival in both early and advanced disease 
35-37.  PD-L1 protein expression both on tumor cells and on TILs are associated with 
increased responses to checkpoint blockade 38. This study will evaluate the potential 
39prognostic and predictive effect of TILs and PD-L1 expression for treatment of HER2-
positive breast cancer treated with combination trastuzumab, vinorelbine and 
immunotherapy. Activating PIK3CA mutations in HER2-positive disease has been shown 
to be associated with resistance to HER2-targeted therapies in prior trials. In the 
CLEOPATRA study, PIK3CA mutations were shown to be associated with a worse 
outcome, although the treatment benefit remained the same 39. PIK3CA and other somatic 
mutations will be measured in the baseline tumor samples to determine associations with 
prognosis and relationship with immune infiltrates.
Studies have shown that chemotherapy and anti-HER2 therapies can cause increases in 
TILs in human breast cancer and these TILs are largely tumor effector T cells in murine 
models 15,25,40. As such, an important exploratory effect of this study is to test how the 
doublet immunotherapy vs the avelumab alone and the control regimen can change the 
expression levels of TILs, T effector cells (infiltration of CD8+ T cells for example) and 
other immune biomarkers in the tumor and peripheral blood that suggest initiation and 
ongoing anti-tumor immune activation.  Baseline pre-treatment and on-treatment tumor 
and blood samples will be collected to assist in these assessments. 
2.4.2
Rationale for collection of archival and metastatic tumor specimens
For a comparative proof-of-concept phase II study, correlative investigations into tumor 
biology will be of high importance. The most recent tumor block will be used for 
evaluation of baseline HER2, TILS by H&E, and PD-L1 status. This is preferably a 
recently obtained sample as we know that the immune infiltrate changes over time and 
quantities are prognostic in the advanced setting 41. In addition to these biomarkers other 
exploratory biomarkers will be evaluated in tumor specimens which may help us 
understand the value of adding utomilumab to avelumab by assessing tumor immune 
activation markers, genomics and other resistance mechanisms. These analyses may 
involve large panels of genes at both the RNA (gene expression) and DNA (targeted 
exome/genome sequencing) level. Serial HER2 levels, TILs and PD-L1 status may also 
be evaluated to understand changes in HER2 heterogeneity and immune status over time 
and on therapy.

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2.4.3
Rationale for collection of mandatory on-treatment biopsy 
The collection of serial biopsies from patients undergoing study treatment will contribute 
to the biological understanding of how the study treatments work and differences 
between the control arm, avelumab and the combination with utomilumab. Such biopsies 
may lead to the identification of novel biomarkers and/or signatures which may identify 
responders and those who require avelumab or the combination. Often changes in 
biomarkers (i.e. comparison to baseline) can be highly informative and as such, a biopsy 
from the patient prior to Cycle 3 day 1 will be performed (if feasible). TILs, CD8+ T 
cells, PD-L1, HER2 status, and other relevant biomarkers, will be evaluated on these 
paired samples. Increase in TILs has been reported to be significantly associated with 
pCR and disease free survival in the early stage setting (Loibl et al, submitted- data from 
NeoPhoebe study NCT1816594] 42).
 
2.4.4
Rationale for collection of biopsy at time of progression.
If clinically feasible, patients will be asked to undergo an optional tumor biopsy at time 
of evidence of radiographic or RECIST disease progression. Analyses of biological 
material will include biomarkers (DNA and RNA) as well as changes in expression of 
biomarkers related to immunity. This knowledge will help us understand molecular 
changes related to resistance.  Comprehensive examination of specimens on progression 
may help us understand important pathways. Such information will also be combined 
with data from other similar studies, thus increasing the power to identify important 
resistance mechanisms and new drug targets.
2.4.5
Rationale for collection of serial blood specimens
Plasma of cancer patients contains cell-free tumor DNA that carries information on tumor 
mutations and tumor burden. This information may be useful as a non-invasive way of 
monitoring advanced disease using cancer genetic alterations (mutations, rearrangements) 
that are specific to the individual’s tumor43. This information may allow us to track and 
monitor tumor dynamics during the disease course as well emergence of new clones (i.e., 
resistance mechanisms). Individual mutations may be assessed using technologies such as 
digital PCR or next generation deep sequencing. Plasma samples will be collected at the 
same times as planned restaging imaging.
3.
 PARTICIPANT SELECTION
3.1
Inclusion Criteria
3.1.1
Age ≥18 years or older
3.1.2
Histologically confirmed breast cancer that is metastatic or unresectable loco-regionally 
advanced 
3.1.3
Histologically confirmed HER-2 positive breast cancer by ASCO CAP 2013 guidelines.  
NOTE: Central confirmation of HER-2 status is not required:

IHC 3+ based on circumferential membrane staining that is complete, intense 

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-AND/OR-

FISH positive based on one of the three following criteria: 
o
Single-probe average HER2 copy number ≥6.0 signals/cell; OR
o
Dual-probe HER2/CEP17 ratio ≥2.0 OR
o
Dual-probe HER2/CEP17 ratio <2.0 with an average HER2 copy number≥6.0 
signals/cell
3.1.4
Measurable disease per RECIST v1.1 (see Section 11)
3.1.5
Participants must have previous treatment with ado-trastuzumab emtansine (Kadcyla, T-
DM1) in any setting.  
3.1.6
Participants must have previously received trastuzumab and pertuzumab in the metastatic 
setting or recurred ≤12 months after a neoadjuvant/adjuvant regimen containing 
trastuzumab and pertuzumab.It is not mandatory to have a trastuzumab and/or 
pertuzumab containing regimen as the most recent treatment.
3.1.7
Participants must have progressed on their most recent line of therapy. Progression must 
have been demonstrated by radiological or clinical assessment.
3.1.8
Left ventricular ejection fraction (LVEF) ≥50%, as determined by MUGA or 
echocardiogram
3.1.9
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
3.1.10 Participants must have normal organ and marrow function as defined below:

Absolute neutrophil count ≥ 1250/µL

Platelet count ≥ 100,000/µL 

Hemoglobin ≥ 9 g/dL

Serum total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN). In the case of 
known Gilbert’s syndrome, a higher serum total bilirubin (< 2 × ULN) is allowed.

AST ≤ 2.5 × ULN or ≤ 5 × ULN if patient has liver metastases

ALT ≤ 2.5 × ULN  or ≤ 5 × ULN if patient has liver metastases

Creatinine ≤ 1.5 ×institutional ULN or creatinine clearance > 60 mL/min/1.73 m2 

Urinary protein:creatinine (UPC) ratio < 1.0 
3.1.11 International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 × ULN unless 
patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulant.
3.1.12 Willingness and availability to submit FFPE tissue for research purposes. This can be 
from archival tissue from unresectable loco-regional or metastatic disease obtained ≤1 
year prior to enrollment or new tissue material from a recently obtained surgical or 
diagnostic biopsy. Tissue obtained for the biopsy must not have been previously 
irradiated. If a patient does not have any available archival tissue  ≤1 year old and the 
treating investigator does not feel that it would be safe to perform a fresh biopsy, the 
requirement for a fresh biopsy may be waived after discussion with the Protocol Chair.
3.1.13 If female of childbearing potential, must have a negative pregnancy test within 7 days of 
registration. Childbearing potential is defined as: those who have not been surgically 

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sterilized and/or have had a menstrual period in the past 12 months or who have been on 
ovarian suppression in the past year. 
3.1.14 Participants of childbearing potential (males and females as defined above) must be 
willing to use effective contraception during treatment and up to 7 months after stop of 
trial treatment.  Acceptable methods of contraception are intrauterine devices, bilateral 
tubal occlusion, vasectomized, or total abstinence. Oral, injectable, or implant hormonal 
contraceptives are not allowed.
3.1.15 Ability to understand and the willingness to sign a written informed consent document.
3.2
Exclusion Criteria
3.2.1
Prior therapy with vinorelbine in any setting 
3.2.2
Prior therapy with any anti-PD-1, anti-PD-L1, L2, anti-4-1BB (CD137), or anti-CTLA4 
therapy 
3.2.3
Known Human Immunodeficiency Virus (HIV) positive (testing not required)
3.2.4
 Active or chronic Hepatitis B or C (testing not required)  
3.2.5
History of interstitial lung disease
3.2.6
Active central nervous system metastases, as indicated by clinical symptoms, cerebral 
edema, and/or progressive growth (patients with history of CNS metastases or spinal cord 
compression are eligible if they are clinically stable for at least 4 weeks before first dose 
of investigational product and do not require high-dose steroid treatment)
3.2.7
History of clinically significant or uncontrolled cardiac disease, including congestive 
heart failure (New York Heart Association functional classification > 3), angina, 
myocardial infarction or ventricular arrhythmia
3.2.8
Previous severe hypersensitivity reaction to treatment with another monoclonal antibody
3.2.9
Active infection requiring systemic therapy
3.2.10 Chronic systemic therapy with immunosuppressive agents including corticosteroids
3.2.11 Active autoimmune disease or a documented history of autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents. Patients with 
vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients 
that require intermittent use of bronchodilators or local steroid injections would not be 
excluded from the trial. Patients with hypothyroidism stable on hormone replacement or 
Sjögren’s syndrome will not be excluded from the trial.
3.2.12 Concurrent disease or condition that would make the patient inappropriate for trial 
participation or any serious medical disorder that would interfere with the patient’s safety 
in the opinion of the treating investigator.
3.2.13 No current uncontrolled hypertension (≥180/110), unstable diabetes mellitus, dyspnea at 
rest, or chronic therapy with oxygen.
3.2.14 Chemotherapy, radiotherapy, and/or biological cancer therapy (excluding trastuzumab) 

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within 3 weeks prior to the planned treatment start date 
3.2.15 Unresolved or unstable adverse events from prior therapy, except alopecia (has not 
recovered to CTCAE v.5 ≤grade 1 or baseline).
3.2.16 Pregnant women or women who are lactating/breastfeeding due to the teratogenic 
potential of the study drugs
3.2.17 Participants receiving any medications or substances that are strong inhibitors or inducers 
of CYP3A are ineligible. A list of medications and substances known or with the 
potential to interact with the CYP3A isoenzymes is provided in Appendix B. Because the 
lists of these agents are constantly changing, it is important to regularly consult a 
frequently-updated list such as the Physicians’ Desk Reference. As part of the 
enrollment/informed consent procedures, the participant will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the participant is considering a new over-the-counter medicine or herbal product.  
3.2.18 Live vaccines within 30 days prior to the first dose of trial therapy and during trial 
treatment. 
3.3
Inclusion of Underrepresented Populations
Both men and women of all  races and ethnic groups are eligible for this trial. 
4.
REGISTRATION AND RANDOMIZATION PROCEDURES
Eligible participants will be registered in the Clinical Trials Management System (CTMS) 
OnCore at Dana-Farber Cancer Institute (DFCI). Registrations must occur prior to the initiation 
of protocol therapy. Any participant not registered to the protocol before protocol therapy 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 must begin protocol therapy within 2 weeks (14 calendar 
days). Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator/Protocol Chair.
4.1
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.  
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Randomization can only occur during ODQ business hours (8:30am - 5pm Eastern Time, 
Monday through Friday excluding holidays).

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An email confirmation of the registration and randomization will be sent to the Overall PI, study 
coordinator(s) from the Lead Site, treating investigator and registering person immediately 
following the registration and/or randomization.
4.2
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 or call the Project Manager to verify slot availability.  
The required forms in Section 4.3 should be emailed or faxed to the Project Manager. 
Following registration, participants should begin protocol therapy within 2 weeks (14 calendar 
days days). Issues that would cause treatment delays should be discussed with the Overall 
PI/Protocol Chair.  If a participant does not receive protocol therapy following registration, the 
participant’s registration on the study must be canceled.  The Project Manager should be notified 
of cancellations as soon as possible.
4.3
Registration Process for Other Investigative Sites
To register a participant, the following documents should be completed by the research nurse or 
data manager and emailed to the Project Manager at CTOPM@dfci.harvard.edu or faxed to 617-
632-5152:

Clinic visit note documenting history and physical exam

Copy of required laboratory tests including: Hematology (CBC with differential), 
comprehensive metabolic panel (sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose total bilirubin, calcium, total protein, albumin, AST, ALT, and 
alkaline phosphatase), pregnancy testing (if necessary), T3, T4, TSH, Urinalysis, UPC 
ratio, LDH, Coagulation profile

Pathology report and documentation of ER/PR status and HER2 status

Tumor assessments by CT, PET, or MRI

Bone Scan (If applicable)

ECHO or MUGA report

Signed participant consent form

HIPAA authorization form (if separate from the informed consent document)

Completed DF/HCC Eligibility Checklist with stratification 
 
To complete the registration process, the Project Manager will

follow the DF/HCC Standard Operating Procedure for Human Subject Research Titled 
Subject Protocol Registration (SOP #: REGIST-101) and register the participant on the 
protocol

call or email the research nurse or data manager at the participating site with the 
participant study number, and to confirm registration

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NOTE: Registration can only be conducted during the business hours of 8:00 AM and 5:00 
PM Eastern Time Monday through Friday. Same day treatment registrations will only be 
accepted with prior notice and discussion with the DF/HCC Project Manager. 
5.
STUDY CALENDARS
Scans must be done within 30 days prior to planned start of protocol therapy. Exams and 
MUGAs or echocardiograms are to be done within 30 days prior to registration. Baseline bone 
scan is not required, but should be performed if clinically indicated. 
All assessments must be performed prior to administration of any study agent unless otherwise 
specified. The following windows apply:  

Screening assessments performed ≤ 96 hours prior to Day 1 of Cycle 1 do not have to 
be repeated for Day 1 of Cycle 1. 

Day 1 study assessments for Cycle 2 and beyond must be performed within +/- 3 days of 
the protocol-specified date.  

Day 8 and Day 15 study assessments for all cycles must be performed within -1/+3 days 
of the scheduled day (e.g., Day 8 visit must occur between Day 7 and Day 11). A 
minimum of 6 days between D1, D8, and D15 of vinorelbine administration is required.
Restaging scans for tumor evaluation should continue on schedule if treatment is held or 
delayed. 
In the event that the patient’s condition is deteriorating, laboratory evaluations should be 
repeated as soon as possible prior to initiation of the next cycle of therapy. Subjects withdrawn 
from study with responsive or stable disease will be followed approximately every 9-12 weeks 
from the date of last assessment until progression. 

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5.1
Required Data: Arms A, B, and C
Table 1.
Screening
All Cycles
30-Day 
Follow- Upj
Long Term 
Follow-Up
D1
D8
D15
<30 days of 
registration, unless 
otherwise noted
+/- 3 days
+3/- 1 day(s) 
+3/- 1 day(s)
30-37 days after
last dose
Annually after 
PD
Medical History/Demographics
X
Physical Exam (full at screening, limited at 
subsequent cycle D1), ECOG PS
X
X
X
Vital signs, weight, height 
(height at baseline only)
X
X
X
X
X
Hematology (CBC with diff)
X
X
X
X
X
Serum Chemistry a
X
X
X
X
X
Pregnancy Test (serum or urine)b
X
X
Total T3 and T4, TSH and Urinalysis c
X
X
(odd cycles)
X
Urine Creatinine and Urine Protein
X
LDH
X
X
Coagulation (INR and PTT) a 
X
Tumor Assessmentsd
X
X
Xe
MUGA or Echocardiogramf
X
X
Research Biopsyg
X
Xg
Xg
Research Bloodh
X
Xi
Xi
X
Archival Tissue
X
Adverse Event Assessment
X
X
X
Overall Survival
Xk
a.
Serum chemistry includes measurement of sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total bilirubin, calcium, total 
protein, albumin, AST, ALT, and alkaline phosphatase. INR and aPTT at screening only, then as clinically indicated.

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b.
For women of childbearing potential only. A negative pregnancy test (urine or serum β- HCG) is required prior to registration and must be 
repeated, if necessary, within the 7 days prior to planned treatment start. All positive urine pregnancy tests must be confirmed by a serum β-HCG 
test.
c.
T3, T4, TSH and Urinalysis are required at Screening, prior to dosing on C3D1, and then on Day 1 of every odd cycle (e.g. C5D1, C7D1, etc.)
d.
Clinical and radiological tumor assessments will be performed by CT, PET or MRI scan at baseline (within 30 days) and then every 2 cycles 
(i.e., within -7 days prior to Cycles 3, 5, 7, and 9) until completion of Cycle 10;  and then every 3 cycles (i.e., within -7 days prior to cycles 11, 
14, 17, etc.) until disease progression. Responses of CR or PR should be confirmed with a second assessment no earlier than 4 weeks, but no 
later than the next scheduled scan, per protocol. Bone scan will be performed if clinically indicated. Results must be reviewed by RECIST for 
each scan prior to dosing at next cycle. Scans must be assessed by RECIST and irRECIST criteria
e.
During follow-up of patients who went off study for reasons other than PD, tumor assessments should continue every 9 to 12 weeks from the date 
of the last assessment until progressive disease is documented
f.
Cardiac evaluation (ECHO or MUGA) will be done at screening (within 30 days of registration) and then every 12 weeks (within -14 days i.e. 
prior to Cycles 4, 7, etc.) 
g.
Research biopsy at screening is mandatory if archival tissue is not available; biopsy is preferred. Cycle 3 Day 1 biopsy is mandatory. Time of 
progression biopsy is optional.  If feasible, progression biopsy should be of same site as Cycle 3 Day 1 biopsy. Cycle 3 biopsy should occur 
prior to administration of treatment on Cycle 3 Day 1 (up to 7 days prior). If possible, this biopsy should be of same site as screening biopsy. 
Biopsies from bone or bone marrow are not acceptable. 
h.
See Section 9 for detailed research blood sampling schedule 
i.
Cycle 1 only. See Section 9
j.
Extended safety follow-up is required for Arms B and C (90 days). The extended follow-up may be performed by phone call 
k.
Survival status should be collected annually, either by review of the medical record or by phone call

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5.2
Required Data: Crossover
 Table 2.
All Cycles
30-Day 
Follow- Uph
Long Term 
Follow-Upi
Day 1
Day 15
Pre-Crossover 
+/- 3 day(s)
 
+3/- 1 day(s)
30-37 days after
last dose
Medical History/Demographics
X
Physical Exam, ECOG PS
X
X
X
Vital signs, weight, height 
(height at baseline only)
X
X
X
Hematology (CBC with diff)
X
X
X
X
Serum Chemistry a
X
X
X
X
Total T3 and T4, TSH and Urinalysisb
X
X
X
LDH
X
X
Coagulation (INR and PTT) a 
X
Tumor Assessmentsc
X
X
Xd
MUGA or Echocardiograme
X
X
Research Biopsyf
X
Research Bloodg
X
X
X
Adverse Event Assessment
X
X
X
Overall Survivalh
X
a.
Serum chemistry includes measurement of sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total bilirubin, calcium, total 
protein, albumin, AST, ALT, and alkaline phosphatase. INR and aPTT at screening only, then as clinically indicated.
b.
T3, T4, TSH and Urinalysis are required at Screening, prior to dosing on C3D1, and then approximately every 8 weeks on Day 1 of every odd 
cycle  (e.g. C5D1, C7D1, etc.)
c.
Clinical and radiological tumor assessments will be performed by CT, PET or MRI scan at baseline (within 30 days) and repeated every 2 cycles 
(i.e., within 7 days prior to Cycles 3, 5, 7, and 9) until completion of Cycle 10; and then every 3 cycles (i.e., within 7 days prior to cycles 11, 14, 
17, etc.) until disease progression. Responses of CR or PR should be confirmed with a second assessment no earlier than 4 weeks, but no later than 
the next scheduled scan, per protocol. Bone scan will be performed if clinically indicated. Results by RECIST must be reviewed for each scan 
prior to dosing at next cycle. Scans must be assessed by RECIST and irRECIST criteria

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d.
During follow-up of patients who went off treatment for reasons other than PD, tumor assessments should continue every 9 to 12 weeks from the date 
of the last assessment until progressive disease is documented
e.
Cardiac evaluation (ECHO or MUGA) will be done pre-crossover treatment and then every 12 weeks (within -14 days, i.e. prior to Cycles 4, 7, 
etc.) 
f.
Time of progression biopsy is optional.  If feasible, progression biopsy should be of same site as Baseline and/or Cycle 3 Day 1 biopsy. See 
Section 9.
g.
ctDNA and PBMCs will be collected according to the Crossover Research Specimen Table in Section 9 
h.
Extended safety follow-up is required for the crossover arm (90 days). The extended follow-up may be performed by phone call 
i.
Survival status should be collected annually, either by review of the medical record or by phone call

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6.
TREATMENT PLAN
Treatment cycles are defined as 28 days.  Treatment will be administered on an outpatient basis 
unless patient is hospitalized for other reasons.  Patients will be randomized to one of the following 
treatment regimens: Arm A or B. Patients initially assigned to Arm A (control arm), may cross 
over to the combination of trastuzumab and avelumab (Cross-over arm) at the time of progression. 
Reported adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications are described in Section 7.2.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the participant's 
malignancy. Biosimilars may be used for trastuzumab on any arm on this study. 
Randomization will be 1:2 ratio to:  

Arm A (n=20): trastuzumab + vinorelbine

Arm B (n=40): trastuzumab + vinorelbine + avelumab
Cross-Over: Participants initially randomized to Arm A may cross over to a combination of 
trastuzumab and avelumab at the time of disease progression. 
Patients will be stratified by  lines of prior metastatic therapy (< 3 vs. 3+),  ER status (positive vs 
negative) and presence of liver metastases (yes vs no). 
6.1
Pre-Treatment Criteria 
For C1D1 labs:
Patients must have adequate organ function before initiating treatment on day 1:

absolute neutrophil count
≥1,250/mcL

platelets
≥100,000/mcL

hemoglobin
> 9 g/dl

total bilirubin
≤ 1.5 x institutional upper limit of normal

AST(SGOT)/ALT(SGPT)
≤2.5 × institutional upper limit of normal (or ≤ 5 x ULN 
(for subjects with documented liver metastases)

Serum or plasma creatinine
≤ 1.5 x institutional upper limit of normal (ULN) OR
creatinine clearance  ≥ 60 mL/min/1.73 m2 for 
participants with creatinine levels above institutional
             ULN

Negative pregnancy test (in appropriate patients)
Day 1 of Subsequent Cycles +/- 3 days):

absolute neutrophil count
≥1,250/mcL(if 750-1249/ mcL, can proceed with the 
next cycle at a reduced dose of vinorelbine (see 
Section 7.2.2)

In the event of a grade 4 decrease in absolute neutrophil count without fever, CBC 
should be assessed at least weekly until resolution to determine the length of the 

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event. This bloodwork may be done at a local lab to the participant as long as the 
results are reviewed by a study staff member qualified to assess toxicity. 

platelets
≥100,000/mcL (if 50,000-99,000/ mcL, can proceed 
with the next cycle at a reduced dose of vinorelbine 
(see Section 7.2.2)

hemoglobin
> 9 g/dl

total bilirubin
≤ 1.5 x institutional upper limit of normal

AST(SGOT)/ALT(SGPT)
≤2.5 × institutional upper limit of normal or AST and 
 
ALT levels ≤ 5 x ULN (for subjects with documented 
metastatic disease to the liver)

creatinine
≤ 1.5 x institutional upper limit of normal (ULN)
6.2
Regimen Descriptions
6.2.1
Arm A Regimen Description
 Table 3.
Agent
Premedications
Dose
Route
Schedule
Cycle Length
Trastuzumab 
or Biosimilar
No routine premedication 
required.  May be given at the 
investigator’s discretion.
4 mg/kg*
IV per 
institutional 
guidelines
D1, D15  
Vinorelbine
Optional:
prochlorperazine 
(Compazine) 10 mg PO/IV 
and/or
lorazepam (Ativan) 1 mg 
PO/IV or
other anti-emetics as per local 
institutional standard of care.
25mg/m2
IV over 6-10 
minutes or 
per 
institutional 
guidelines
D1, D8, D15
28 days 
(4 weeks)
*if > 6 weeks from last trastuzumab dose, patients will receive loading dose of 6 mg/kg of trastuzumab on 
C1D1 and then 4 mg/kg for subsequent doses
Order of administration of study agents will be as written above.
Treatment visits should occur within +/- 3 days for Day 1 of the cycle and +3/-1 for Day 8 or Day 15days of 
the scheduled day (e.g., Day 8 visit must occur between Day 7 and Day 11). A minimum of 6 days between 
D1, D8, and D15 of vinorelbine administration is required.
Day 8 of vinorelbine therapy for may be administered at a non-participating institution and should be 
administered per protocol or per institutional standards.  

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6.2.2
Arm B Regimen Description 
Table 4.
Agent
Premedications
Dose
Route
Schedule
Cycle 
Length
Trastuzumab 
or Biosimilar
No routine premedication 
required.  May be given at the 
investigator’s discretion.
4 mg/kg*
IV 
institutional 
guidelines**
D1, D15  
Vinorelbine
Optional:
prochlorperazine (Compazine) 
10 mg PO/IV and/or
lorazepam (Ativan) 1 mg 
PO/IV or
other anti-emetics as per local 
institutional standard of care.
25 mg/m2
IV over 6-10 
minutes or 
per 
institutional 
guidelines
D1, D8, 
D15
Avelumab
Premedicate with 
antihistamine and 
acetaminophen, or per local 
guidelines 30-60 minutes prior 
to the first 4 
infusions.Premedication 
should be administered for 
subsequent avelumab doses 
based upon clinical judgment 
and presence/ severity of prior 
infusion reactions. This 
regimen may be modified 
based on local treatment 
standards and guidelines as 
appropriate; however, the 
prophylactic use  of systemic 
corticosteroids is not 
permitted.
10 mg/kg
IV over 60 
minutes 
(a +20/-10 
minutes 
window is 
permissible 
i.e. infusion 
time is 50-80 
minutes)
D1, D15  
28 days 
(4 weeks)
*if > 6 weeks from last trastuzumab dose, patients will receive loading dose of 6 mg/kg of trastuzumab on 
C1D1 and then 4 mg/kg for subsequent doses
Order of administration of study agents will be as written above (i.e. standard of care agents prior to 
investigational agents).
Treatment visits should occur within +/- 3 days for Day 1 of the cycle and +3/-1 for Day 8 or Day 15 (e.g., 
Day 8 visit must occur between Day 7 and Day 11). A minimum of 6 days between D1, D8, and D15 of 
vinorelbine administration is required.
Day 8 of vinorelbine therapy for may be administered at a non-participating institution and should be 
administered per protocol or per institutional standards.

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6.2.3
Arm C Regimen Description (CLOSED TO NEW ENROLLMENT)
Table 5.
Agent
Premedications
Dose
Route
Schedule
Cycle 
Length
Trastuzumab 
or Biosimilar
No routine premedication 
required.  May be given at 
the investigator’s discretion.
4 mg/kg*
IV per 
institutional 
guidelines**
D1, D15  
Vinorelbine
Optional:
prochlorperazine 
(Compazine) 10 mg PO/IV 
and/or
lorazepam (Ativan) 1 mg 
PO/IV or
other anti-emetics as per 
local institutional standard 
of care.
25 mg/m2
IV over 6-10 
minutes or per 
institutional 
guidelines
D1, D8, 
D15
Utomilumab 
No routine premedication 
required.  May be given at 
the investigator’s discretion.
100 mg
IV over 60 
minutes
(a +15/-5 
minutes 
window is 
permissible 
i.e. infusion 
time is 55-75 
minutes)
D1  
Avelumab
Premedicate with 
antihistamine and 
acetaminophen, or per local 
guidelines  30-60 minutes 
prior to the first 4 infusions. 
Premedication should be 
administered for subsequent 
avelumab doses based upon 
clinical judgment and 
presence/ severity of prior 
infusion reactions. This 
regimen may be modified 
based on local treatment 
standards and guidelines as 
appropriate; however, the 
10 mg/kg
IV over 60 
minutes
(a +20/-10 
minutes 
window is 
permissible 
i.e. infusion 
time is 50-80 
minutes)
D1, D15  
28 days
(4 weeks)

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prophylactic use  of 
systemic corticosteroids is 
not permitted.
*if > 6 weeks from last trastuzumab dose, patients will receive loading dose of 6 mg/kg of trastuzumab 
on C1D1 and then 4 mg/kg for subsequent doses
Order of administration of study agents will be as written above (i.e. standard of care agents prior to 
investigational agents).
Treatment visits should occur within +/- 3 days for Day 1 of the cycle and +3/-1 for Day 8 or Day 15 
(e.g., Day 8 visit must occur between Day 7 and Day 11). A minimum of 6 days between D1, D8, and 
D15 of vinorelbine administration is required.
Day 8 of vinorelbine therapy for may be administered at a non-participating institution and should be 
administered per protocol or per institutional standards.  
6.2.4
Cross-over Arm Regimen Description 
Table 6.
Agent
Premedications
Dose
Route
Schedule
Cycle 
Length
Trastuzumab 
or Biosimilar
No routine premedication 
required.  May be given 
at the investigator’s 
discretion.
4 mg/kg
(6 mg 
loading 
dose, if 
needed*)
IV per 
institutional 
guidelines**
D1, D15  
Avelumab
Premedicate with 
antihistamine and 
acetaminophen, or per 
local guidelines prior to 
the first 4 infusions. 
Premedication should be 
administered for 
subsequent avelumab 
doses based upon clinical 
judgment and presence/ 
severity of prior infusion 
reactions. This regimen 
may be modified based 
on local treatment 
standards and guidelines 
as appropriate; however, 
the prophylactic use  of 
systemic corticosteroids 
is not permitted.
10 mg/kg
IV over 60 
minutes (a 
+20/-10 
minutes 
window is 
permissible 
i.e. infusion 
time is 50-80 
minutes)
D1, D15  
28 days 
(4 weeks)

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*if > 6 weeks 
from last 
trastuzumab 
dose, patients 
will receive 
loading dose 
of 6 mg/kg of 
trastuzumab 
on C1D1 and 
then 4 mg/kg 
for subsequent 
doses
Order of 
administration 
of study 
agents will be 
as written 
above (i.e. 
standard of 
care agents 
prior to 
investigational 
agents).
Treatment 
visits should 
occur within 
+/- 3 days for 
Day 1 of the 
cycle and +3/-
1 for Day 8 or 
Day 15 (e.g., 
Day 15 visit 
must occur 
between Day 
14 and Day 
18).
6.3
Agent Administration

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6.3.1
Trastuzumab and Biosimilars 
Trastuzumab (or biosimilar) will be administered in clinic at 4 mg/kg on Day 1 and 15 of each 
28-day cycle (+/- 3days).  If the patient is > 6 weeks from last trastuzumab dose, patients will 
receive loading dose of 6 mg/kg of trastuzumab on C1D1 and then 4 mg/kg for subsequent 
doses. The total dose of trastuzumab will be calculated according to the institution’s standard 
administration guidelines.  Trastuzumab dose reductions are not allowed.
All infusions of trastuzumab (or biosimilar) may be administered according to institutional 
guidelines.Since all participants on this study have previously tolerated trastuzumab prior to 
study entry, the preferred first infusion time for participants is over approximately 30-60 minutes 
followed by a 30-minute post-infusion observation period, or according to institutional 
guidelines. 
Infusion Associated Symptoms (IAR):  If a significant infusion reaction occurs, the infusion 
should be interrupted and appropriate medical therapies should be administered (see below). 
Permanent discontinuation should be considered in participants with severe IAR. This clinical 
assessment should be based on the severity of the preceding reaction and response to 
administered treatment for the adverse reaction.
If participants develop an IAR, participants should be treated according to the following 
guidelines, or according to institutional guidelines, at discretion of the study physician:
Stop infusion and notify physician.
Assess vital signs.
Administer acetaminophen 650 mg PO.
Consider administration of: Meperidine 50 mg IM, Diphenhydramine 50 mg IV, 
Ranitidine 50 mg IV or cimetidine 300 mg IV, Dexamethasone 10 mg IV or famotidine 20 
mg IV.
If vital signs are stable, resume trastuzumab infusion.
Participants tend not to develop infusion syndromes with subsequent cycles. No standard 
premedication is required for future treatments if participants have developed an infusion 
syndrome. Participants may be given acetaminophen prior to treatments.
Serious reactions have been treated with supportive therapy such as oxygen, beta-agonists, 
corticosteroids and withdrawal of study agent as indicated.
6.3.2
Vinorelbine 
6.3.2.1
Pretreatment Antiemetic Medication 
Recommended optional antiemetic pretreatments include the following:

prochlorperazine (Compazine) 10 mg PO/IV and/or

lorazepam (Ativan) 1 mg PO/IV

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
Other anti-emetics may be used as per local institutional standard of care.
6.3.2.2
Dosing
The dose for weekly treatments with vinorelbine is 25 mg/m2 IV infusion. Vinorelbine doses 
may be adjusted for expected side effects (see Section 7.2).  There must be a minimum of 6 days 
between doses of vinorelbine.
6.3.2.3
Administration
Vinorelbine is given after trastuzumab when both treatments are given in the same day.  
Vinorelbine is a vesicant, and must be infused through a free-flowing IV infusion.  It is 
administered as an IV infusion over 6 to 10 minutes preferred or per institutional guidelines.  
After administration, the vein is flushed with 125 mL of NS IV solution. Leakage into 
surrounding tissue during intravenous administration of vinorelbine may cause considerable 
irritation, local tissue necrosis, and/or thrombophlebitis. If extravasation occurs, the injection 
should be discontinued immediately, and any remaining portion of the dose should then be 
introduced into another vein. Skin reactions may occur with accidental exposure. The use of 
gloves is recommended. If the solution of vinorelbine contacts the skin or mucosa, immediately 
wash the skin or mucosa thoroughly with soap and water.
Vinorelbine should not be mixed or diluted with other drugs. 
No hydration required. This is no observation period for Vinorelbine.
After Cycle 1, day 8 of vinorelbine therapy may be administered at a non-participating 
institution. Vinorelbine should be administered per protocol or per institutional standards.  
6.3.3
Utomilumab (for reference only – Utomilumab has been removed from this study)
Utomilumab will be administered in clinic at a dose of 100 mg (fixed dose) on Day 1 of each 28-
day cycle (+3/- 1 days).  Utomilumab is administered as a 1-hour IV infusion (a +15/-5 minutes 
window is permissible i.e. infusion time is 55-75 minutes), diluted with 0.9% saline solution.
 
No routine premedication is required, but may be given at the investigator’s discretion.
There is no observation period for Utomilumab. 
6.3.4
Avelumab
Avelumab will be administered as 10 mg/kg body weight IV on Day 1 (+/- 3 days)and 15 (+3/-1 
day) of each 28-day cycle every 2 weeks. Avelumab is administered as a 1-hour IV infusion (a 
+20/-10 minutes window is permissible i.e. infusion time is 50-80 minutes), diluted with 0.9% 
saline solution; alternatively, a 0.45% saline solution can be used if needed.  
6.3.4.1
Premedication

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In order to mitigate infusion-related reactions, a premedication with an antihistamine and with 
acetaminophen 30 to 60 minutes prior to the first 4 infusions of avelumab is mandatory (for 
example, 25-50 mg oral diphenhydramine and 500-650 mg oral acetaminophen).  Premedication 
should be administered for subsequent avelumab doses based upon clinical judgment and 
presence/severity of prior infusion reactions. This regimen may be modified based on local 
treatment standards and guidelines as appropriate; however the prophylactic use of systemic 
corticosteroids is not permitted.   
6.3.4.2
Setting
Avelumab should be administered in a setting that allows for immediate 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.
6.3.4.3
Observation period
Following avelumab infusions, patients must be observed for 30 minutes post-infusion for 
potential infusion-related reactions. Documentation of observation time is not required.
6.4
Dose Limiting Toxicity (DLT) 
Once 6 patients assigned to each investigational treatment group (Arms B, C) have received at 
least one cycle of assigned treatment, a safety review will be conducted before additional 
patients are enrolled. Based on the monitoring criteria, if ≥4 of 6 patients (or before 6, if 3/3, 
≥3/4, ≥4/5 patients) experience DLT within the first cycle of treatment, then the treatment 
regimen will be modified or discontinued. The review will include a per-patient listing of all 
reported AEs to date, including actions required for dosing, to more fully review the nature, 
frequency, severity and timing of the events. This information combined with fewer DLTs may 
also result in modification of a treatment regimen.    
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as suspected to be trial treatment related (possible, probable or definite) and unrelated to 
disease or disease progression that occurs within the first cycle of treatment. Toxicities and lab 
values will be categorized and graded according to CTCAE v5.0.
1. Any grade ≥ 3 non-hematologic, non-hepatic adverse event with the following 
exceptions:

Grade 3 nausea that resolves in ≤ 3 days, 

Grade 3 fatigue that resolves to ≤ grade 2 in ≤ 3 days,

Grade 3 fever (>40C for ≤ 24 hrs), 

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
Grade 3 adverse event of tumor flare, 

Grade 3/4 lab values that are not considered clinically significant, 

Grade 3 rash that resolves to ≤ grade 2 in ≤ 7 days with therapy equivalent to 
prednisolone 10 mg/day or less,

Grade 3 arthralgia that can be managed with supportive care that resolves to ≤ grade 2 
within 7 days,

Grade 3 autoimmune thyroiditis or other endocrine abnormality that can be managed 
by endocrine replacement without systemic steroids (not including replacement 
steroids for adrenal insufficiency.
2. Grade ≥ 4 neutropenia (ANC < 500uL) lasting > 7 days. In the event of a grade 4 
decrease in absolute neutrophil count without fever, CBC should be assessed at least 
weekly until resolution to determine the length of the event. This bloodwork may be done 
at a local lab to the participant as long as the results are reviewed by a study staff member 
qualified to assess toxicity. 
3. Grade ≥ 3 febrile neutropenia.
4. Grade ≥ 4 anemia.
5. Grade ≥ 4 thrombocytopenia or grade 3 with clinically significant bleeding.
6. Grade ≥ 3 or more elevation of serum hepatic transaminase (ALT or AST) lasting > 7 
days. With patients with grade 1 elevations due to disease at baseline only grade ≥ 3 
elevation that is ≥ 3 x baseline lasting >7 days will be considered a DLT.
7. ALT/AST >3 x upper limit of normal (ULN) AND total bilirubin > 2 x ULN
8. LVEF drop < 45% and/or symptomatic heart failure.
9. Grade ≥ 3 pneumonitis.
6.5
Concomitant Treatment and Supportive Care Guidelines
Chronic immunosuppressive therapies should be avoided, including systemic corticosteroids.  
Steroids given for physiological replacement, as anti-emetics or inhaled as well as short course 
of oral/topical steroids given for allergic reactions or asthma flares are allowed. If steroids are 
given at any time on trial, this should be recorded on the applicable page in the case report forms. 
Supportive care medications are allowed at any time on trial.  Specifically, the following agents 
are permitted:

Antiemetics

Antidiarrheal therapy

Antiallergic measures such as corticosteroids and antihistamines

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
Bone modifying agents: Subjects being treated with bisphosphonates or denosumab when 
they enter the study may continue the medication as long as the dose is stable. Subjects 
may also initiate bisphosphonate or denosumab therapy while on protocol therapy if it is 
thought to be medically necessary.
The use of concurrent investigational or other antitumor therapies is not permitted. Concurrent 
palliative radiotherapy is not allowed on trial.
Because there is a potential for interaction of vinorelbine with other concomitantly administered 
drugs through the cytochrome P450 system in the CYP3A subfamily, strong CYP3A 
inhibitors/inducers are not allowed on study.  These agents include inhibitors such amprenavir, 
atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, 
fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, 
voriconazole, and grapefruit, grapefruit juice or any product containing grapefruit. CYP3A 
inducers include carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, 
rifabutin, rifampin, rifapentin, and St. John’s wort.  This medication list may also be found in 
Appendix B.
Concomitant use of moderate CYP3A inducers and CYP3A substrates is allowable on study, 
however precaution should be exercised for use of any concomitant medication.
The use of herbal medicine is not recommended during protocol treatment.
Participants of childbearing potential (defined by:  those who have not been surgically sterilized 
and/or have had a menstrual period in the past calendar year) must be willing to use effective 
contraception during treatment and up to 7 months after stop of trial treatment.  Acceptable 
methods of contraception are intrauterine devices, bilateral tubal occlusion, vasectomized, or 
total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed.
6.6
Duration of Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue 
until one of criteria in Section 6.8 applies.
6.7
Isolated CNS progression
Patients who have demonstrated control of their extra-cranial disease (defined for this purpose as 
objective response or SD maintained for at least 2 cycles) from study therapy, but who have 
developed isolated brain metastases that are felt to be treatable with radiation will be allowed to 
receive radiation therapy and then continue their assigned study therapy until they either 
experience systemic progression of their disease and/or further progression in the brain.  Patients 
should have their study therapy held until radiation is completed. Patients can recommence study 
therapy once clinically stable as deemed by the investigator.

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6.8
Criteria for Taking a Participant Off Treatment
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 
until one of the following criteria applies:

Disease progression (except isolated CNS progression – see Section 6.7)

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the study 
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 electronic case report form (eCRF). Alternative care options will be discussed 
with the participant.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify Dr. Adrienne Gropper Waks at 617-632-3800.
All patients who initiate protocol treatment will be included in the overall evaluation of response 
(intent-to-treat analysis). All reasons for discontinuation of therapy should be documented 
clearly in the medical record. 
If a subject discontinues or withdraws from the study, every attempt will be made to get a 
tissue/tumor biopsy and study bloods if the subject is able and willing to do so.
6.9
Criteria for Crossover Therapy 
If treatment is permanently discontinued due to disease progression (i.e. not due to toxicity) in a 
participant randomized to Arm A, the participant will be offered the option to crossover to 
receive trastuzumab and avelumab  until documented disease progression per RECIST 1.1 
criteria or unacceptable toxicity. 
Screening does not need to be repeated, however, patients must meet the following criteria to treat 
Day 1 of Crossover Therapy, and eligibility must be confirmed by the treating investigator:

ECOG performance status
0-2 

Absolute neutrophil count
≥ 1,000/mcL

Platelets
≥ 75,000/mcL

Total bilirubin
≤ 1.5 × institutional upper limit of normal (ULN) 
(or ≤ 2.0 x ULN in patients with documented Gilbert’s 
Syndrome)

AST(SGOT)/ALT(SGPT)
≤ 2.5 × institutional ULN or ≤ 5 × institutional ULN for

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 participants with documented liver metastases

Negative pregnancy test within 7 days of planned treatment start

LVEF 
> 50% by MUGA or echocardiogram 

No ongoing unresolved, unstable, or serious adverse events from prior administration 
of protocol therapy
For DF/HCC Institutions: Documents to support the above criteria should be reviewed and 
signed by the treating investigator. The Crossover portion of the DF/HCC Eligibility Checklist 
will be completed by a Screening Staff member and confirmed by an Enrollment Monitor, per 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101). Provided the patient meets criteria, ODQ will process the 
request and enroll the participant on the Crossover arm. Once enrolled, the patient may begin 
Crossover therapy. 
For Other Investigative Sites: Documents to support the above criteria should be reviewed and 
signed by the treating investigator/screening staff and faxed or emailed to the Project Manager at 
617-632-5152 or ctopm@dfci.harvard.edu for review. The DF/HCC Project Manager confirm 
eligibility and submit the cross-over registration request to ODQ. The DF/HCC Project Manager 
will contact the participating site via email with a confirmation that registration to the Crossover 
arm has occurred and the participant may begin Crossover Therapy.
NOTE: Registration can only be conducted during the business hours of 8:00 AM and 5:00 
PM Eastern Time Monday through Friday.
6.10 Duration of Follow-Up 
For participants who went off treatment for reasons other than Progressive Disease, tumor 
assessments should continue every 9 to 12 weeks from the date of the last assessment until 
progressive disease is documented.
Participants will be followed annually until death, withdrawal of consent, or lost to follow-up.  
6.11 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 

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the electronic case report form (eCRF).
7.
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made using the following sections and tables. The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A 

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copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, antidiarrheals, etc.).
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study, and until the final study visit.  Participants continuing to 
experience toxicity at the off-protocol-therapy visit may be contacted for additional assessments 
until the toxicity has resolved or is deemed irreversible.
In the event of significant treatment-related toxicity, dosing may be interrupted or delayed and/or 
reduced as described below. If treatment is held for toxicity, restaging scans should stay on 
schedule according to the required data table.  In the event of multiple toxicities, dose 
modification should be based on the worst toxicity observed.  Patients are to be instructed to 
notify Investigators at the first occurrence of any adverse sign or symptom.
7.1
Anticipated Toxicities
7.1.1
Anticipated Toxicities for Trastuzumab (or biosimilar)
The following information is from the package insert for trastuzumab (Herceptin®; Genentech, 
Inc.). This is a list of those adverse events most likely to occur to this study; please refer to the 
trastuzumab package insert for the comprehensive list of adverse events that have occurred with 
trastuzumab administration. The side effect profile for trastuzumab biosimilars is the same as 
trastuzumab. 
Cardiac Failure/Dysfunction:  Signs and symptoms of cardiac dysfunction, such as dyspnea, 
increased cough, paroxysmal nocturnal dyspnea, peripheral edema, S3 gallop, or reduced 
ejection fraction, have been observed in participants treated with trastuzumab. Congestive heart 
failure associated with trastuzumab therapy may be severe and has been associated with 
disabling cardiac failure, death, and mural thrombosis leading to stroke. The probability of 
cardiac dysfunction was highest in participants who received trastuzumab concurrently with 
anthracyclines. The data suggest that advanced age may increase the probability of cardiac 
dysfunction. Subjects entering this study will undergo a baseline cardiac assessment including 
history, physical exam and an echocardiogram or MUGA scan.
Anemia and Leukopenia:  An increased incidence of anemia and leukopenia was observed in the 
treatment group receiving trastuzumab and chemotherapy, especially in the trastuzumab and 
adriamycin/cytoxan subgroup, compared with the treatment group receiving chemotherapy 
alone. The majority of these cytopenic events were mild or moderate in intensity, reversible, 
and none resulted in discontinuation of therapy with trastuzumab. Hematologic toxicity is 
infrequent following the administration of trastuzumab as a single agent, with an incidence of 

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Grade III toxicities for WBC, platelets, hemoglobin all <1%. No Grade IV toxicities were 
observed.
Diarrhea:  Of participants treated with trastuzumab as a single agent, 25% experienced 
diarrhea. An increased incidence of diarrhea, primarily mild to moderate in severity, was 
observed in participants receiving trastuzumab in combination with chemotherapy.
Infection:  An increased incidence of infections, primarily mild upper respiratory infections of 
minor clinical significance or catheter infections was observed in participants receiving 
trastuzumab in combination with chemotherapy.
Infusion Reactions:  During the first infusion with trastuzumab, a symptom complex most 
commonly consisting of chills and/or fever was observed in about 40% of participants in 
clinical trials. The symptoms were usually mild to moderate in severity and were treated with 
acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of 
trastuzumab infusion). Trastuzumab discontinuation was infrequent. Other signs and/or 
symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, 
dizziness, dyspnea, hypotension, rash and asthenia. The symptoms occurred infrequently with 
subsequent trastuzumab infusions.
7.1.2
Anticipated Toxicities for Vinorelbine
The following information is from the insert for vinorelbine (Navelbine®) by GlaxoSmithKline, 
Inc. This is a list of those adverse events most likely to occur in this study, please refer to the 
vinorelbine package insert for a comprehensive list of adverse events that have occurred with 
vinorelbine administration.
Hematologic: Granulocytopenia was the major dose-limiting toxicity with vinorelbine. Dose 
adjustments are required for hematologic toxicity and hepatic insufficiency. Granulocytopenia 
was generally reversible and not cumulative over time. Granulocyte nadirs occurred 7 to 10 days 
after the dose, with granulocyte recovery usually within the following 7 to 14 days. 
Granulocytopenia resulted in hospitalizations for fever and/or sepsis in 8% of patients. Septic 
deaths occurred in approximately 1% of patients. 
Neurologic: Loss of deep tendon reflexes occurred in less than 5% of patients. The development 
of severe peripheral neuropathy was infrequent (1%) and generally reversible.
Skin: Like other anticancer vinca alkaloids, vinorelbine is a moderate vesicant. Injection site 
reactions, including erythema, pain at injection site, and vein discoloration, occurred in 
approximately one third of patients; 5% were severe. Chemical phlebitis along the vein proximal 
to the site of injection was reported in 10% of patients.
Gastrointestinal: Prophylactic administration of antiemetics was not routine in patients treated 
with single-agent vinorelbine, but was used when given in combination.
Hepatic: Transient elevations of liver enzymes were reported without clinical symptoms.

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Cardiovascular: Chest pain was reported in 5% of patients. Most reports of chest pain were in 
patients who had either a history of cardiovascular disease or tumor within the chest. There have 
been rare reports of myocardial infarction.
Pulmonary: Shortness of breath was reported in 3% of patients; it was severe in 2%.  Interstitial 
pulmonary changes were documented.
Other: Fatigue occurred in 27% of patients. It was usually mild or moderate but tended to 
increase with cumulative dosing. Other toxicities that have been reported in less than 5% of 
patients include jaw pain, myalgia, arthralgia, and rash. Hemorrhagic cystitis and the syndrome 
of inappropriate ADH secretion were each reported in <1% of patients. The incidence of Grade 3 
and/or 4 nausea and vomiting, alopecia, and renal toxicity were reported more frequently in the 
cisplatin-containing combinations compared to single-agent vinorelbine. Severe local reactions 
occurred in 2% of patients treated with combinations containing vinorelbine. 
7.1.3
Anticipated Toxicities for Utomilumab (for reference only, utomilumab therapy has been 
removed from this protocol)
There is limited toxicity available for utomilumab monotherapy. In a phase 1 study of 
Utomilumab monotherapy, the most commonly reported Treatment-Emergent Adverse Events 
(TEAE) (all grades) that were considered treatment-related were in the System Organ Class of 
general disorders and administration site conditions (18.6%), and gastrointestinal disorders 
(12.8%). The most frequently observed treatment-related TEAE (≥10% of patients; all grades) 
was fatigue (11.6%). Treatment-related TEAEs were mostly Grade 1 or Grade 2 with only three 
Grade 3 AEs reported (fatigue, alanine aminotransferase elevation (ALT), and hyponatremia). 
The reported Grade 3 fatigue was of limited duration approximately 20 days and seen at the 
highest dose tested of 10 mg/kg of utomilumab. Of note, after the data cut-off date causality of 
the Grade 3 ALT elevation was re-assessed as not related to utomilumab by the Investigator. No 
Grade 4 treatment-related AEs were observed. 
Two immune-related AEs (irAEs) potentially related to use of utomilumab have been observed 
(G2 pneumonitis, G2 enterocolitis). In both cases the events were observed in the setting of 
immediate prior treatment with immune checkpoint inhibitors (anti-PD-1 mAb; nivolumab) 
utomilumab administration is considered possibly related to these irAEs.
7.1.4
Anticipated Toxicities for Avelumab
For regulatory reporting requirements during clinical development, the following AEs will be 
considered as expected and meet the threshold of causal association (based on comprehensive 
medical evaluation considering the mechanism of action and temporal relationship after 
excluding other possible etiologies).
The following side effects have been observed among 1738 patients treated with avelumab 
according to the results from studies EMR100070-001 in various solid tumors (N=1650) and 

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EMR100070-003 Part A in Merkel cell carcinoma (N=88) where avelumab was administered 
intravenously (IV) as single agent at a dose of 10 mg/kg every 2 weeks (Q2W) 
Three types of risks are associated with avelumab: general signs and symptoms, reactions that 
occur during or following the infusion, and immune-mediated side effects:

General signs and symptoms including fatigue, nausea, diarrhea, constipation, 
anorexia, weight loss, vomiting, anemia, abdominal pain, cough, shortness of breath, 
edema of the feet and legs, back pain, joint pain

Infusion related symptoms including hypersensitivity reactions which may include 
chills, shaking, fever, back pain, belly pain, shortness of breath or wheezing, decrease 
in blood pressure or hives. 

Immune-mediated adverse reactions including immune-mediated colitis, pneumonitis, 
immune-mediated thyroid disorders including hyperthyroidism, hypothyroidism, 
thyroiditis and autoimmune thyroiditis; immune-mediated skin reactions including 
rash, pruritis, redness, blisters, pemphigoid or peeling; other immune-mediated 
reactions including myocarditis, hepatitis, pneumonitis, adrenal insufficiency, 
diabetes, uveitis, myosistis, pancreatitis and Guillain-Barre syndrome. 
7.2
Dose Modification Guidelines
Patients will be assessed for toxicity prior to each dose. Patients will be instructed to notify their
physician immediately for any and all toxicities. CTCAE v 5.0 must be used to grade the
severity of AEs. Assessment of causality (chronology, confounding factors, concomitant
medications, medical history, diagnostic tests, and previous experience with the study treatment)
should be conducted by the investigator prior to dose modification and/or delay whenever
possible.
As a general approach, it is suggested that all AEs be managed with supportive care when
possible at the earliest signs of toxicity. If supportive care is ineffective, a dose delay or dose
reduction may be considered to avoid worsening toxicity. Dosing will occur only if the clinical
assessment and laboratory test values are acceptable.
In the event that any of the individual study drug(s) in a regimen is delayed because of toxicity,
the administration of other agent(s) may be continued.
General guidelines on dose delays for study treatment-related toxicity, other than those specified
below are as follows:

If significant treatment–related toxicities have not recovered to Grade 1 or baseline grade, the 
next scheduled dose of the causative study agent(s) may be delayed for up to 28 days from 
the last scheduled dose. “Significant” and “related” will be based on the judgment of the 
investigator. For example, alopecia, even if considered related, would most likely not be 
considered significant. Fatigue may or may not be considered either related or significant.

After a treatment delay, study therapy should be resumed as soon as possible and within 28 
days from the last schedule dose. 

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7.2.1
Special Considerations

For toxicities, which are considered by the treating investigator unlikely to develop 
into serious or life–threatening events (e.g. alopecia, altered taste etc.), treatment may 
be continued at the same dose without reduction or interruption.

The treating investigator may reduce a subject’s dose for a toxicity of any 
grade/duration where s/he believes it to be in the best interest of the subject.

Any consideration to modification of the above dose modification guidelines should 
be discussed with the Principal Investigator for approval or disapproval in advance.
7.2.2
Vinorelbine Toxicity Management 
Vinorelbine is a commonly used standard of care in this patient population and therefore 
management of its toxicity can be per local institutional guidelines. Alternatively, guidelines 
below can be utilized.  In the event that a patient’s vinorelbine dose is held, the patient will still 
proceed with other study therapy unless otherwise specified in the protocol. If vinorelbine 
treatment is delayed more than 4 weeks, vinorelbine will be permanently discontinued.
Hematologic Toxicity. Prior to weekly therapy, patients should be assessed for hematologic 
toxicity.  Vinorelbine therapy will be adjusted based on local institutional standards or the 
following parameters in Table 7.  
Table 7. Dose Adjustment of Vinorelbine for Hematologic Toxicity
(Dose Adjusted for Either ANC or Platelet Count Parameters)
Absolute 
Neutrophil Count 
(ANC)
Platelet Count
Dose 
Adjustment
Vinorelbine 
Dose
>1250/ mcL
≥100,000/ mcL
No change 
25 mg/m2
750-1250/ mcL
50,000-99,000/ mcL
Decrease 40%*
15 mg/m2
< 750 / mcL
< 50,000/ mcL
Dose skipped for 
that week
Delay > 4 weeks
Delay > 4 weeks
Off protocol
*Note: dose adjustment applies to that dose only.  Patients can be dosed at full dose (25 mg/m2) 
in subsequent weeks if hematologic toxicity resolves.
In the event of a grade 4 decrease in absolute neutrophil count without fever, CBC should be 
assessed at least weekly until resolution to determine the length of the event. This bloodwork 
may be done at a local lab to the participant as long as the results are reviewed by a study staff 
member qualified to assess toxicity. 
Filgrastim (Neupogen®) is to be considered under the following circumstances:

Treatment delay of  2 weeks due to of ANC < 750 / mcL in patients who have 
received at least 2 weeks of vinorelbine therapy.

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
Patients who previously experienced febrile neutropenia. 

Filgrastim (Neupogen®) should be administered 24 hrs after the end of chemotherapy 
at the discretion of the treating investigator. In the event the patient receives 
Trastuzumab alone, Neupogen® may be given on the same day.
Neurologic Toxicity:  Patients who develop grade 2 neurologic toxicity should be treated 
at a dose of 15 mg/m2/week until the toxicity resolves to grade 1 or less. Vinorelbine will 
be held in patients who develop grade 3 neurologic toxicity until the toxicity resolves to 
grade 1 or less. Treatment for symptomatic neuropathy is allowed at the discretion of the 
treating physician.   If vinorelbine treatment is delayed more than 4 weeks, vinorelbine 
will be permanently discontinued.
Hepatic Toxicity:  Patients who develop bilirubin levels 2 mg/dl to 3 mg/dl should 
receive a 50% dose reduction in vinorelbine dose (to 12.5 mg/m2).  Patients who develop 
bilirubin > 3 mg/dl should have vinorelbine held.  
Gastrointestinal Toxicity:  Patients who develop grade 3 GI toxicity should have 
vinorelbine therapy held until toxicity has resolved to  grade 1. Treatment for 
symptomatic nausea, constipation or diarrhea is allowed at the discretion of the treating 
physician. If treatment is held more than 4 weeks (28 days), vinorelbine should be 
discontinued. Patients can be dose reduced to 40% at the discretion of the treating 
investigator.
Other Toxicity:  Patients who develop drug related grade 3 non-hematological toxicity 
should have vinorelbine therapy delayed until toxicity has resolved to  grade 1. If the 
toxicity fails to resolve with a 4-week treatment delay, vinorelbine will be permanently 
discontinued.  Patients with grade 4 non-hematological toxicity attributed to vinorelbine 
will discontinue treatment unless exception is given by the Principal Investigator.  Prior 
to retreatment, toxicity must resolve to  grade 1.  Patients can be dose reduced to 40% at 
the discretion of treating investigator.
7.2.3
Trastuzumab (or biosimilar) Toxicity Management
Cardiac toxicity: Left ventricular ejection fraction (LVEF) will be determined at baseline 
prior to study entry, and every 12 weeks on study.  LVEF assessments will be 
determined by echocardiogram or MUGA scan.  Among patients with asymptomatic 
cardiotoxicity, the algorithm in Table 8 for antibody (trastuzumab, avelumab, and 
utomilumab) dosing will be followed. As there is a theoretical risk that the 
immunotherapy agents (avelumab, and utomilumab) can contribute to trastuzumab 
mediated cardiotoxicity, all antibodies will be held.
Table 8. Algorithm for continuation or withdrawal of antibody therapy in asymptomatic 
patients based on serial measurements of left ventricular ejection fraction (LVEF) 

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Asymptomatic decrease in LVEF from Baseline
Relationship of LVEF to 
Radiology Facility’s LLN
Decrease of < 10 
Percentage Points
Decrease of 10 to 
15 Percentage 
Points
Decrease of 
 16 Percentage 
Points
Within normal limits
Continue antibody
Continue antibody
Continue 
antibodya
1-5 percentage points below LLN
Continue antibody 
Hold antibodya,b
Hold 
antibodya,b
 6 percentage points below LLN
Continue antibodya 
Hold antibodya,b
Hold 
antibodya,b
LLN, lower limit of normal; LVEF, left ventricular ejection fraction; MUGA, multiple gated acquisition scan 
Source: Modified from  Cardiac management during adjuvant trastuzumab therapy 44
aRepeat MUGA/ECHO after 4 weeks (one cycle)
bAfter two consecutive holds permanently discontinue antibody
Any clinically significant cardiac adverse event should be treated according to current medical 
practice with the help of a cardiologist as needed.
Patients will stop receiving antibody for the following reasons:

Grade ≥3 cardiac toxicity (symptomatic congestive heart failure).

Ejection fraction less than 40%.
7.2.4
Avelumab and Utomilumab Toxicity Management (discussion of utomilumab is for 
reference only – it is no longer being used in this protocol)
There are no dose reductions for avelumab or utomilumab.
Because both avelumab and utomilumab can cause similar irAEs, it may be difficult to identify 
the causative agent for such an AE. Thus, in general, both agents should be adjusted 
concordantly for AE’s as noted below. The exception to this rule is that infusion related reactions 
are not typically seen with utomilumab and therefore unless strong evidence is present to suggest 
that an infusion related reactions is caused by utomilumab, only avelumab should be modified.
In the event that the participant holds or discontinues avelumab and utomilumab, therapy with 
other study medications may continue.  
7.2.4.1
Management of Severe Hypersensitivity Related to Avelumab
In order to mitigate infusion-related reactions, premedication with an antihistamine and 
with acetaminophen is mandatory prior to each dose of avelumab. Management of 
infusion-related reactions should follow guidelines set forth in Table 9.
Table 9: Treatment Modification for Symptoms of Infusion-Related Reactions 
NCI-CTCAE Grade
Treatment Modification for Avelumab

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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  24 
hours
Stop 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 must be withdrawn immediately from 
avelumab treatment and must not receive any 
further avelumab treatment
•
Once the avelumab infusion rate has been decreased by 50% or interrupted due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions. If a 
subject experiences a Grade 3 or 4 infusion-related reaction at any time, the subject 
must discontinue avelumab. 
 
7.2.4.2
Severe Hypersensitivity Reactions 
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. Subjects should be instructed to report any delayed reactions to the investigator 
immediately.
Symptoms:

Impaired airway

Decreased oxygen saturation (< 92%)

Confusion

Lethargy

Hypotension

Pale/clammy skin

Cyanosis
Management:

Epinephrine injection and dexamethasone infusion

Subject should be placed on monitor immediately

Alert intensive care unit for possible transfer if required
7.2.4.3
Management of Immune-Related Adverse Events (irAEs)

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Since inhibition of PD-L1 or agonism of 4-1BB stimulates the immune system, irAEs may occur. 
Treatment of irAEs is dependent upon severity (NCI-CTCAE grade) and in general consist of:

Grade 1 to 2: treat symptomatically or with moderate dose steroids, more frequent 
monitoring

Grade 1 to 2 (persistent): manage similar to high grade AE (Grade 3 to 4)

Grade 3 to 4: treat with high dose corticosteroids
7.2.4.4
Management of Tumor Lysis Syndrome
Since avelumab and utomilumab can induce ADCC, there is a theoretical risk of tumor lysis 
syndrome. Should this occur, subjects should be treated as per local guidelines and the 
management algorithm described in Howard et al 2011.
7.2.4.5
Avelumab and Utomilumab Dose modification/delays
Treatment of immune related Adverse Events (irAEs) should follow guidelines set forth in the 
following Tables (per Investigator’s Brochure):
Table 10. Management of Avelumab and Utomilumab Related Immune-Mediated Adverse Events 
(discussion of utomilumab is for reference only – it is no longer being used in this protocol)
Gastrointestinal irAEs
Severity of Diarrhea / Colitis
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Diarrhea: < 4 stools/day over 
Baseline
Colitis: asymptomatic 
Continue avelumab and 
utomilumab therapy
Symptomatic treatment (for 
example, loperamide)
Close monitoring for worsening 
symptoms
Educate subject to report 
worsening immediately
If worsens:
Treat as Grade 2 or 3/4 
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 
Hold avelumab and utomilumab 
therapy
Symptomatic treatment
If improves to Grade 1: 
Resume avelumab and utomilumab 
therapy
If persists > 5 to 7 days or recur:
Treat as Grade 3 to 4

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Grade 3 to 4
Diarrhea (Grade 3): ≥ 7 stools 
per day over Baseline; 
incontinence; IV fluids ≥ 24 
hrs.; interfering with ADL
Colitis (Grade 3):  severe 
abdominal pain, medical 
intervention indicated, 
peritoneal signs
Grade 4:  life-threatening, 
perforation
Hold avelumab and utomilumab 
for Grade 3. 
Permanently discontinue 
avelumab and utomilumab for 
grade 4 or recurrent grade 3.
1.0 to 2.0 mg/kg/day 
methylprednisolone 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 avelumab and utomilumab 
therapy following steroids taper for 
initial Grade 3
If worsens or persists > 3 to 5 days, 
or recurs after improvement:
Add infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab 
should not be used in cases of 
perforation or sepsis 
Dermatological irAEs
Grade of Rash
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1 to 2 
Covering ≤ 30% body surface 
area 
Continue avelumab and 
utomilumab therapy 
Symptomatic therapy (for 
example, antihistamines, topical 
steroids) 
If persists > 1 to 2 weeks or recurs: 
Withhold Avelumab and 
utomilumab therapy 
Consider skin biopsy 
Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent. Once improving, taper 
steroids over at least 1 month, 
consider prophylactic antibiotics 
for opportunistic infections, and 
resume avelumab therapy 
following steroids taper
If worsens: 
Treat as Grade 3 to 4 
Grade 3 to 4
Grade 3: Covering > 30% body 
surface area; 
Grade 4: life threatening 
consequences 
Hold avelumab and utomilumab 
for grade 3
Permanently discontinue 
avelumab and utomilumab for 
grade 4 or recurrent grade 3
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections
If improves to Grade < 1: 
Taper steroids over at least 1 
month; resume Avelumab and 
utomilumab therapy following 
steroids taper (for initial grade 3)

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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. 
hold avelumab and utomilumab 
therapy
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 appropriate per 
cardiology consult.*
Consider myocardial biopsy if 
recommended per cardiology 
consult.
If symptoms improve and immune-
mediated etiology is ruled out, re-
start avelumab and utomilumab 
therapy.
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 
avelumab and utomilumab.
Guideline based supportive 
treatment as appropriate per 
cardiology consult.*
Methylprednisolone 1-2 
mg/kg/day 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. AHA guidelines

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Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only 
Consider holding avelumab 
therapy and utomilumab 
Monitor for symptoms every 2 to 
3 days 
Consider Pulmonary and 
Infectious Disease consults 
Re-image at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4 
Grade 2
Mild to moderate new 
symptoms 
Delay avelumab and utomilumab 
therapy
Pulmonary and Infectious Disease 
consults
Monitor symptoms daily, consider 
hospitalization 
1.0 to 2.0 mg/kg/day methyl-
prednisolone IV or oral equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Consider bronchoscopy, lung 
biopsy 
Re-image every 1 to 3 days 
If improves: 
When symptoms return to < Grade 
1, taper steroids over at least 1 
month and then resume avelumab 
and utomilumab therapy following 
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 
avelumab and utomilumab therapy
Hospitalize 
Pulmonary and Infectious Disease 
consults
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
If improves to < Grade 1: 
Taper steroids over at least1 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 v5)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT > ULN 
to 3.0 x ULN and / or total 
bilirubin > ULN to 1.5 x ULN 
Continue avelumab and 
utomilumab therapy
Continue liver function monitoring 
If worsens: 
Treat as Grade 2 or 3 to 4 

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Grade 2*
AST or ALT > 3.0 to ≤ 5 x 
ULN and / or total bilirubin > 
1.5 to ≤ 3 x ULN
Hold avelumab and utomilumab 
therapy 
Increase frequency of monitoring 
to every 3 days 
If returns to < Grade 1: 
Resume routine monitoring, 
resume avelumab and utomilumab 
therapy
If elevations persist > 5 to 7 days 
or worsen: 
Treat as Grade 3 to 4.
*AST or ALT> 3.0 to ≤ 5 x 
ULN in patients with 
documented liver mets and 
baseline AST or ALT> 3.0 to ≤ 
5 x ULN
Continue study therapy - no 
modification required
Grade 3 to 4*
AST or ALT > 5 x ULN and / 
or total bilirubin > 3 x ULN 
Permanently discontinue 
avelumab and utomilumab therapy 
Increase frequency of monitoring 
to every 1 to 2 days 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
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 < 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 
*AST or ALT > 5.0 to ≤ 8 x 
ULN in cases with documented 
liver mets and baseline AST or 
ALT> 3.0 to ≤ 5 x ULN
Hold avelumab and utomilumab 
therapy 
Increase frequency of monitoring 
to every 3 days 
If returns to < Grade 2: 
Resume routine monitoring, 
resume avelumab and utomilumab 
therapy
Renal irAEs
Grade of Creatinine Increase
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 
1.5 x ULN
Continue avelumab and 
utomilumab therapy
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
Hold avelumab and utomilumab 
therapy
If returns to Grade ≤1:
Taper steroids over at least 1 
month, and resume avelumab and 

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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
utomilumab therapy following 
steroids taper.
If worsens:
Treat as Grade 4.
Grade 4
Creatinine increased > 6 x 
ULN
Permanently discontinue 
avelumab and utomilumab therapy
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.
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2
endocrinopathies
(hypothyroidism,
hyperthyroidism, adrenal
insufficiency, type I diabetes
mellitus)
Continue avelumab and 
utomilumab therapy
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.
Grade 3 or Grade 4
endocrinopathies
(hypothyroidism,
hyperthyroidism, adrenal
insufficiency, type I diabetes
mellitus)
Hold avelumab and utomilumab 
therapy
Consider hospitalization
Endocrinology consult
Start thyroid hormone 
replacement
therapy (for hypothyroidism),
anti-thyroid treatment (for
Resume avelumab and utomilumab 
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

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hyperthyroidism), corticosteroids 
(for adrenal insufficiency) or 
insulin (for type I diabetes 
mellitus) as appropriate.
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis) 
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 avelumab if mild
symptoms with normal MRI.
Repeat the MRI in 1 month Hold 
avelumab 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 avelumab and utomilumab 
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.
 

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The following table (Table 11) should be used for guidance on management of all other adverse 
drug reactions to avelumab or utomilumab not specified in Table 10. 
Table 11. Adverse Drug Reactions requiring Avelumab and Utomilumab
discontinuation or modification
Any avelumab or utomilumab-related Grade 4 ADRs require treatment discontinuation with 
avelumab and utomilumab except for single laboratory values out of normal range that are unlikely 
related to study treatment as assessed by the Investigator, do not have any clinical correlate, and 
resolve within 7 days with adequate medical management.
Any avelumab or utomilumab related Grade 3 ADRs require treatment discontinuation with 
avelumab and utomilumab except for any of the following: 
Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management
Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves to 
Grade ≤ 1 
Single laboratory values out of normal range (excluding Grade ≥ 3 liver function test increase) that 
are unlikely related to study treatment according to the Investigator, do not have any clinical 
correlate, and resolve to Grade ≤ 1 within 7 days with adequate medical management
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor
Any avelumab or utomilumab-related Grade 2 ADR should be managed as follows:
If a Grade 2 ADR resolves to Grade ≤ 1 by the last day of the current cycle, treatment may 
continue.
If a Grade 2 ADR does not resolve to Grade ≤ 1 by the last day of the current cycle, infusions 
should not be given on the following cycle.  If at the end of the following cycle the event has not 
resolved to Grade 1, the subject should permanently discontinue treatment with avelumab and 
utomilumab (except for hormone insufficiencies, that can be managed by replacement therapy; for 
these hormone insufficiencies, up to 2 subsequent doses may be omitted).
Upon the second occurrence of the same Grade 2 ADR (except for hormone insufficiencies that 
can be managed by replacement therapy) in the same subject, treatment with avelumab and 
utomilumab must be permanently discontinued.
8.
DRUG FORMULATION/STORAGE/SUPPLY
8.1
Trastuzumab or Biosimilar
8.1.1
Description, form, and preparation 
This study will use trastuzumab from commercial supply. Trastuzumab is a sterile, white to pale 
yellow, preservative free lyophilized powder for intravenous (IV) administration, supplied as a 
150 mg vial. Each single-dose vial of trastuzumab delivers 150 mg trastuzumab, 136.2 mg α,α-
trehalose dihydrate, 3.4 mg L-histidine HCl monohydrate, 2.2 mg L-histidine, and 0.6 mg 
polysorbate 20.

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Use appropriate aseptic technique. Reconstitute each 150 mg vial of single-dose Trastuzumab with 
7.4 mL of sterile water for injection (SWFI) to yield a solution containing 21mg/mL trastuzumab 
that delivers 7.15 mL (150 mg trastuzumab), at a pH of approximately 6.
Use of other reconstitution diluents should be avoided. Determine the dose of trastuzumab needed, 
based on a loading dose of 8 mg trastuzumab/kg body weight for q3wk dosing schedules or a 
maintenance dose of 6 mg/kg trastuzumab/kg body weight for q3w dosing schedules. Calculate 
the correct dose using 21 mg/mL trastuzumab solution. Withdraw this amount from the vial and 
add it to an infusion bag containing 250 mL of 0.9% sodium chloride, USP. DEXTROSE (5%) 
SOLUTION SHOULD NOT BE USED. Gently invert the bag to mix the solution. The 
reconstituted preparation results in a colorless to pale yellow transparent solution. Parenteral drug 
products should be inspected visually for particulates and discoloration prior to administration.
 
Trastuzumab should not be mixed or diluted with other drugs. Trastuzumab should not be 
filtered during administration. 
If a trastuzumab biosimilar is used, please refer to the manufacturer’s prescribing information/ 
package insert for information about dosage and administration. 
8.1.2
Storage Conditions
Vials of trastuzumab are stable at 2ºC–8ºC (36ºF–46ºF) prior to reconstitution. Do not use 
beyond the expiration date stamped on the vial. Use the Herceptin solution immediately 
following reconstitution with SWFI, as the 150 mg vial contains no preservative. If not used 
immediately, store the reconstituted Herceptin solution for up to 24 hours at 2ºC-8ºC; discard 
any unused Herceptin after 24 hours.  DO NOT FREEZE.
The solution of trastuzumab for infusion diluted in polyvinylchloride or polyethylene bags 
containing 0.9% sodium chloride for injection, USP, may be stored at 2ºC–8ºC (36ºF–46ºF) for 
up to 24 hours prior to use. Diluted trastuzumab has been shown to be stable for up to 24 hours at 
room temperature 15ºC–25ºC; however, since diluted trastuzumab contains no effective 
preservative the reconstituted and diluted solution should be stored refrigerated (2ºC–8ºC).
If a trastuzumab biosimilar is used, please refer to the manufacturer’s prescribing information/ 
package insert for information about storage conditions. 
8.1.3
Compatibility
No incompatibilities between trastuzumab and polyvinylchloride, polyolefin or polypropylene 
bags have been observed. Dextrose 5% solution should not be used since it causes aggregation of 
the protein. Trastuzumab should not be mixed or diluted with other drugs.
If a trastuzumab biosimilar is used, please refer to the manufacturer’s prescribing 
information/package insert for information about drug compatibility.

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8.1.4
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.
If a trastuzumab biosimilar is used, please refer to the manufacturer’s prescribing 
information/package insert for information about handling of the agent.  
8.1.5
Availability
Trastuzumab is a commercially available agent. The cost of trastuzumab will be charged to the 
patient and/or his/her insurance company since its use is considered standard of care for 
metastatic, HER2-positive breast cancer. 
A biosimilar for trastuzumab may be used on this study according to the standard of care at the 
participating institution and/or the insurance company of the participant. 
 
8.1.6
Administration 
Trastuzumab (or biosimilar) will be administered in clinic at 4 mg/kg on Day 1 (+/- 3 days) and 
15 (+3/-1 days) of each 28-day cycle.If the patient is > 6 weeks from last trastuzumab dose, 
patients will receive loading dose of 6 mg/kg of trastuzumab on C1D1 and then 4 mg/kg for 
subsequent doses. The total dose of trastuzumab will be calculated according to the institution’s 
standard administration guidelines.  Trastuzumab dose reductions are not allowed.
All infusions of trastuzumab (or biosimilar) may be administered according to institutional 
guidelines. Since all participants on this study have previously tolerated trastuzumab prior to 
study entry, the preferred first infusion time for participants is over approximately 30-60 minutes 
followed by a 30-minute post-infusion observation period, or according to institutional 
guidelines. 
. 
If a biosimilar for trastuzumab is used, the administration of the agent should be according to the 
participating site’s institutional policy/standard of care. 
8.1.7
Ordering
Trastuzumab is a commercially available agent and therefore ordering should be performed as 
standard policy in the investigational site. 
If a biosimilar for trastuzumab is used, the agent should be ordered according to the participating 
site’s institutional policy/standard of care. 

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8.1.8
Drug Supplies and Accountability
Trastuzumab is a commercially available agent and therefore accountability should be performed 
as standard policy in the investigational site.
If a biosimilar for trastuzumab is used, accountability of the agent should be according to the 
participating site’s institutional policy/standard of care. 
8.2
Vinorelbine 
8.2.1
Description
Vinorelbine tartrate (NSC-608210) is a semi-synthetic vinca alkaloid with antitumor activity.  
The aqueous solubility is >1000 mg/mL in distilled water. The pH of vinorelbine tartrate 
injection is 3.3 to 3.8.
Chemical Name:
3',4'-Didehydro-4'-deoxy-8'- norvincaleukoblastine L-(+)-tartrate 
(1:2)(salt)
Molecular Formula:
C45H54N408•2C4H606
Chemical Structure:
Molecular weight:
1079.12
Mechanism of clearance: 
The mean plasma clearance ranges from 0.97 to 1.26 L/h per kg. 
Vinorelbine undergoes substantial hepatic elimination in humans, 
with large amounts recovered in feces after intravenous 
administration to humans.
Mean terminal half-life:
The terminal phase half-life averages 27.7 to 43.6 hours
Volume of distribution:
Steady-state volume of distribution (Vss) values range from 25.4 to 
40.1 L/kg.

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Drug Interactions:
Acute pulmonary reactions have been reported with vinorelbine and 
other anticancer vinca alkaloids used in conjunction with mitomycin. 
Although the pharmacokinetics of vinorelbine are not influenced by 
the concurrent administration of cisplatin, the incidence of 
granulocytopenia with vinorelbine used in combination with cisplatin 
is significantly higher than with single-agent vinorelbine. Patients who 
receive vinorelbine and paclitaxel, either concomitantly or 
sequentially, should be monitored for signs and symptoms of 
neuropathy. Administration of vinorelbine to patients with prior or 
concomitant radiation therapy may result in radiosensitizing effects.
Caution should be exercised in patients concurrently taking drugs 
known to inhibit drug metabolism by hepatic cytochrome P450
isoenzymes in the CYP3A subfamily (Appendix B), or in patients with 
hepatic dysfunction. Concurrent administration of vinorelbine tartrate 
with an inhibitor of this metabolic pathway may cause an earlier onset 
and/or an increased severity of side effects.
8.2.2
Form
Please refer to vinorelbine package insert for additional details. Vinorelbine Injection USP is for 
intravenous administration. Each vial contains vinorelbine tartrate equivalent to 10 mg (1 mL 
vial) or 50 mg (5 mL vial) vinorelbine in water for injection. Vinorelbine Injection USP is a 
clear, colorless to pale yellow solution.  No preservatives or other additives are present. The 
aqueous solution is sterile and nonpyrogenic. Vinorelbine tartrate is a white to yellow or light 
brown amorphous powder.  
8.2.3
Storage and Stability
Vinorelbine Injection USP is available in single-use, clear glass vials with elastomeric stoppers 
and royal blue caps, individually packaged
in a carton in the following vial sizes: 10 mg/1 mL Single-Dose Vial or 50 mg/5 mL Single-Dose 
Vial.
Unopened vials of vinorelbine are stable until the date indicated on the package when stored 
under refrigeration at 2° to 8°C (36° to 46°F) and protected from light in the carton. Unopened 
vials of vinorelbine are stable at temperatures up to 25°C (77°F) for up to 72 hours. This product 
should not be frozen.
Parenteral drug products should be visually inspected for particulate matter and discoloration 
prior to administration whenever solution and container permit. If particulate matter is seen, 
vinorelbine should not be administered.
 

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8.2.4
Compatibility
Vinorelbine should not be mixed or diluted with other drugs.  Vinorelbine should be given 
after the trastuzumab infusion. 
8.2.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
Skin reactions may occur with accidental exposure. The use of gloves is recommended. If the 
solution of vinorelbine contacts the skin or mucosa, immediately wash the skin or mucosa 
thoroughly with soap and water.
8.2.6
Availability
Vinorelbine is commercially available.  
8.2.7
Preparation
Vinorelbine Tartrate Injection must be diluted in either a syringe or IV bag using one of the 
recommended solutions. Diluted vinorelbine may be used for up to 24 hours under normal room 
light when stored in polypropylene syringes or polyvinyl chloride bags at 5° to 30°C (41° to 
86°F).
Syringe: The calculated dose of vinorelbine should be diluted to a concentration between 1.5 and 
3.0 mg/mL, or per institutional standards. The following solutions may be used for dilution:

5% Dextrose Injection

0.9% Sodium Chloride Injection
IV Bag: The calculated dose of vinorelbine should be diluted to a concentration between 0.5 and 
2 mg/mL, or per institutional standards. The following solutions may be used for dilution:

5% Dextrose Injection

0.9% Sodium Chloride Injection

0.45% Sodium Chloride Injection

5% Dextrose and 0.45% Sodium Chloride Injection

Ringer's Injection

Lactated Ringer's Injection
8.2.8
Administration
See Section 6.2.1

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8.2.9
Ordering
Vinorelbine is commercially available and therefore ordering should be performed as standard 
policy in the investigational site.
8.2.10 Accountability
Vinorelbine is a commercially available agent and therefore accountability should be performed 
as standard policy in the investigational site.
8.2.11 Destruction and Return
Unused supplies of vinorelbine will be destroyed as per the site chemotherapy waste policy. 
Destruction will be documented per institutional standard operating procedure.
8.3
Utomilumab (PF-05082566) (for reference only – utomilumab is no longer being used 
in this protocol)
8.3.1
Pharmaceutical Properties
Utomilumab is a recombinant IgG2 fully human monoclonal antibody that is an agonist of 4-
1BB. 
Utomilumab is provided as a 10 mg/mL sterile solution for injection, in an aqueous histidine 
buffered solution at pH 5.5. The drug product is supplied in 20 mL Type 1 clear glass vial sealed 
with a coated serum stopper and aluminum seal (nominal fill volume of 5.0 mL). 
8.3.2
Instructions for Storage
The following supplies must be stored at 2 to 8 °C or 36 to 46 °F.

Utomilumab 10 mg/mL (100 mg/vial) Solution for Injection

Do not shake.

Protect from light until ready to use.
Utomilumab solution for Injection must be allowed to reach room temperature for 15 minutes 
prior to use in dose preparation. Unused vials containing utomilumab should not be left at room 
temperature for more than 4 hours. Discard any vials that are left at room temperature for more 
than 4 hours.
Minimize exposure of utomilumab 10 mg/mL (100 mg/vial) solution for injection vials and 
dosing solutions to room light during storage. Avoid direct sunlight and ultraviolet light 
exposure. From a microbiological point of view the prepared products should be used within 8 
hours starting from the start of dose preparation. If the prepared utomilumab is left at room 
temperature for more than 8 hours, contact Pfizer.

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The final IP must be administered within 8 hours of preparation if stored at room temperature 15 
to 25 °C, 59 to 77 °F. The total in-use stability is a period of not more than 24 hours at 2-8 °C or 
36-46 °F with no more than 8 of those hours at room temperature.
Prepared utomilumab solutions that are refrigerated must be allowed to reach room temperature 
prior to administration. Make sure the prepared dosing solution in its container is not cold to the 
touch.
No other drugs should be added to the solution for infusion containing utomilumab.
8.3.3
Preparation and Administration

Final infusion concentrations must be between 0.2 mg/mL to 9 mg/mL.

Dose preparation must be performed using sterile handling techniques in compliance 
with local, state, and national laws/regulations.

Inspect parenteral drug products visually for particulate matter and discoloration prior 
to administration, whenever the solution and container permit. If particles or 
discoloration are observed, do not use the vial(s) and notify Pfizer.

The final IP must be administered within 24 hours with a maximum of 8 hours at 20 
to 25 °C (68 to 77 °F) and the remainder at 2 to 8 °C (36 to 46 °F). If storage of the 
diluted dosing solution exceeds 8 hours at room temperature or 24 hours total do not 
use and contact Pfizer

The final IP must be administered within 8 hours of preparation if stored at room 
temperature 15 to 25 °C, 59 to 77 °F. The total in-use stability is a period of not more 
than 24 hours at 2-8 °C or 36-46 °F with no more than 8 of those hours at room 
temperature.

Minimize exposure of vials and dosing solutions to light (e.g. room light, UV light 
and sunlight)

Prepared solutions that are refrigerated must be allowed to reach room temperature, 
prior to administration. Make sure the prepared study solution is not cold to the touch.

Each vial is for single-use only. Each vial is for use in a single patient, for a single 
dose.
8.3.4
Compatibility
No known compatibility issues exist for co-administration of utomilumab with any of the 
other agents
8.3.5
Availability
Utomilumab is an investigational agent and will be supplied free-of-charge from Pfizer.

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8.3.6
Drug Accountability
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the agent (investigational or free of charge) using the 
NCI Drug Accountability Record or another comparable drug accountability form. 
8.3.7
Destruction and Return
All opened (i.e. aluminum overseal broken) vials (full, partially used, and empty) may be 
destroyed at the site by the appropriate site personnel local environmental requirements and 
institutional policies. Discarded volumes of IP solutions must be disposed of as pharmaceutical 
waste according to local site procedures. Destruction must be adequately documented.
8.4
Avelumab
8.4.1
Pharmaceutical Properties
The active pharmaceutical ingredient in avelumab drug product is a fully human antibody of the 
IgG1 isotype that specifically targets and blocks the ligand (PD-L1) for PD-1.
Avelumab drug product is a sterile, clear, and colorless concentrate for solution for infusion 
presented at the concentration of 20 mg/mL in European Pharmacopeia (Ph. Eur.) and United 
States Pharmacopeia (USP) type I glass vials closed with a rubber stopper and sealed with an 
aluminum Flip Off crimp seal closure.
8.4.2
Description of the Formulations
Each single-use vial contains 200 mg of avelumab as a preservative-free acetate-buffered 
solution (pH 5.2) containing Mannitol, and Polysorbate 20 (Tween 20). 
8.4.3
Instructions for Storage
Avelumab drug product must be stored at 2°C to 8°C until use. The storage condition is based on 
data from ongoing long term stability studies with avelumab. Avelumab drug product stored at 
room (23 °C to 27 °C) or higher temperatures for extended periods of time might be subject to 
degradation. Avelumab drug product must not be frozen. Rough shaking of the solution must be 
avoided. For administration in clinical trials, avelumab drug product must be diluted with 0.9% 
saline solution (sodium chloride injection) supplied in an infusion bag. The immediate 
administration of the prepared solution for dosing kept at room temperature is preferred.  In case 
the aseptically prepared dosing solution cannot be administered immediately after preparation, the 
acceptable holding time is: not more than 24 hours under refrigerated conditions (2-8°C, 36-46°F) 
with no more than 8 of those hours at room temperature (15-25°C, 59-77°F), including infusion 
time.
No other drugs should be added to the solution for infusion containing avelumab.

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8.4.4
Handling of the Dosage Forms
For administration in clinical trials, avelumab drug product must be diluted with 0.9% saline 
solution (sodium chloride injection) supplied in an infusion bag; alternatively, a 0.45% saline 
solution can be used if needed. 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 IP 
Manual. 
To prepare the dilutions, subsequent preparation steps must be accomplished by adequate trained 
personnel under a laminar flow box using aseptic techniques:
Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to room 
temperature for a minimum of 30 minutes. Use a disposable syringe equipped with a needle of 
suitable size to remove a volume of sodium chloride solution to be replaced by avelumab from 
the infusion bag and discard the removed solution. Use a new disposable syringe equipped with a 
needle of suitable size to inject a volume of avelumab drug product identical to the discarded 
volume of sodium chloride solution into the infusion bag. Gently invert the mixture 10 times. 
Infusion bags must not be shaken, in order to avoid foaming or excessive shearing of the protein 
solution. The preparation must be carefully inspected as it should result in a homogeneous 
looking clear solution, free of visible particles.
8.4.5
Compatibility
No known compatibility issues exist for co-administration of avelumab with any of the other 
agents.
8.4.6
Availability
Avelumab is an investigational agent and will be supplied free-of-charge from Pfizer.
8.4.7
Preparation and Administraiton
Only clinical site personnel who are appropriately trained on the procedures may perform the 
preparation and administration step specified in the IP Manual. Clinical site personnel involved 
in these procedures must comply with all applicable regulations and standards. The preparation 
and administration of all sterile products must be performed using aseptic technique. Utilize local 
site procedures as appropriate.
Avelumab) infusion solutions must be prepared in 0.9% Sodium Chloride (Normal Saline) and 
the final concentration of MSB0010718C (avelumab) in the infusion solutions must be between 
0.016 mg/mL to 8 mg/mL. Total volume of final prepared solution must be 250 mL. 
Investigational drug products must be inspected visually for particulate matter and discoloration 
(i.e. change in color) prior to administration, whenever the solution and container permit. If 
particulates or discoloration are observed, do not use the vial(s) and notify the Principal 
Investigator or designee. Do not shake or freeze the vial(s). The final IP must be administered 
within 24 hours of preparation stored at room temperature 15 to 25 °C, 59 to 77 °F. Dose 
preparation must be performed using sterile handling techniques in compliance with local, state, 

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and national laws/regulations. Avelumab MUST be administered with a low protein binding 0.2 
micron PES filter. Each vial is for single-use only. Each vial is for use in a single patient, for a 
single dose. Avelumab is administered over 1 hour (-10/+20 minutes). 
8.4.8
Ordering 
Qualified personnel at participating sites will order the drug directly from Pfizer.  
8.4.9
Accountability
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the agent (investigational or free of charge) using the 
NCI Drug Accountability Record or another comparable drug accountability form. 
8.4.10 Destruction and Return
All opened (i.e. aluminum overseal broken) vials (full, partially used, and empty) may be 
destroyed at the site by the appropriate site personnel local environmental requirements and 
institutional policies. Discarded volumes of IP solutions must be disposed of as pharmaceutical 
waste according to local site procedures. Destruction must be adequately documented. 
9.
CORRELATIVE/SPECIAL STUDIES 
9.1
Correlative Studies Background 
This trial is exploring combination immunotherapy as a new therapeutic area for advanced HER2-
positive breast cancer. A comprehensive collection of biological materials is requested in order to 
be able to understand the molecular and immune landscape of these the patients enrolled on this 
study. The goals of the translational research will be to determine mechanisms and biomarkers for 
avelumab efficacy and resistance, and where the combination of avelumab and utomilumab may 
further aid in enhancing immune activation and improving outcomes in HER2-positive breast 
cancer patients.
9.2
Specimen Submission Requirements 
The following specimens are to be submitted to the indicated lab. Instructions for collection, 
processing, labeling, and shipment are included within the Study Manual. 
Collection Time Point
Specimen Type
Baseline 
(Pre-
Treatment) 
C3D1
C7D1
Progression/ 
EOT f
Crossover 
C3D1 
Crossover 
C7D1
Shipping 
Condition
Ship to
Paraffin block 
(or 20 unstained 
slides) a
X
Ambient 
temperature
DFCI 
AVIATOR 
study team

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1 H&E stained 
slide
X
Ambient 
temperature
DFCI 
AVIATOR 
study team
ctDNA 
(two 10 mL 
Streck tubes) b
X
X
X
X
X
X
Processed 
for plasma, 
frozen and 
batch 
shipped 
DF/HCC 
Core Blood 
and Tissue 
Bank
PBMCs (two  
CPT tubes) c
X
X
X
X
X
X
Processed 
for PBMCs, 
frozen and 
batch 
shipped
DF/HCC 
BTIL 
Germline DNA
 (one 10 mL 
purple top 
EDTA tube)d
X
Processed 
for whole 
blood, 
frozen and 
batch 
shipped
DF/HCC 
Core Blood 
and Tissue 
Bank
Research Biopsy 
(Fresh and 
frozen
 tumor tissue) e
X
X
X
Frozen in 
OCT & 
formalin-
fixed 
paraffin-
embedded 
block(s)
DF/HCC 
Core Blood 
and Tissue 
Bank
a.
If baseline biopsy is performed, archival tissue can be collected at any time point throughout the study.
b.
2 Streck tubes will be collected for ctDNA at baseline(C1D1), Cycle 3 Day 1, and Cycle 7 Day 1 PRIOR to 
dosing. These samples are processed locally, frozen, and batch shipped to DFCI. 
c.
PBMCs collected at Cycle 1: Days 1,8 and 15 PRIOR to dosing. Participants who cross-over will not have the 
C1D8 sample collected. These samples are processed locally, frozen, and batch shipped to DFCI.
d.
Sample for germline DNA should be collected at C1D1. If missed, this sample can be drawn at any time during 
treatment  
e.
Baseline and Cycle 3 biopsies are mandatory. Off-Treatment research biopsy at time of progression or EOT is 
optional, but strongly encouraged. Biopsy prior to start of cross-over therapy and at time of progression/EOT on 
cross-over arm are both optional, but encouraged. There is no Cycle 3 biopsy on the crossover arm.
f.
All time of progression/EOT samples must be collected prior to treatment on the cross-over arm. These samples 
are collected again at time of progression/EOT on the crossover arm. 
9.3
Translational Research Blood 
9.3.1
ctDNA (Streck Tubes) Blood Collection 
Blood will be collected for ctDNA analysis via 2 10 mL Streck tubes prior to dosing at Cycle 1 
Day 1, Cycle 3 Day 1, Cycle 7 Day 1 and at time of disease progression or treatment 
discontinuation, whichever comes first. 
For participants who cross-over, 2 10 mL Streck tubes will also be collected during cross-over 
prior to dosing at Cycle 3 Day 1, Cycle 7 Day 1 and at time of disease progression or treatment 
discontinuation, whichever comes first.

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Streck tubes will be processed for plasma at the local site where the sample was collected.  
Plasma is stored in cryovials at −80°C until shipment. Frozen plasma cryovials will be batch 
shipped on dry ice to DFCI. 
Collection tubes for research blood samples will be in the research sample collection kit provided 
by Core Prognostex. Please see the Study Manual for detailed instructions for collection, 
processing, labeling and shipping of ctDNA samples.
9.3.2
Peripheral Blood Mononuclear cells (PBMCs) Blood Collection
Blood will be collected for PBMC analysis via two CPT tubes prior to dosing at Cycle 1 Day 1, 
Cycle 1 Day 8, Cycle 1 Day 15, Cycle 3 Day 1, Cycle 7 Day 1 and at time of disease progression 
or treatment discontinuation, whichever comes first. 
For participants who cross-over, two CPT tubes will also be collected during cross-over prior to 
dosing at Cycle 3 Day 1, Cycle 7 Day 1 and at time of disease progression or study 
discontinuation visit, whichever comes first.
CPT tubes will be processed for at the local site where the sample was collected.  Processed 
samples are stored in cryovials at −80°C until shipment. Frozen cryovials will be batch shipped 
on dry ice to DFCI. 
Collection tubes for research blood samples will be in the research sample collection kit provided 
by Core Prognostex. Please see the Study Manual for detailed instructions for collection, 
processing, labeling and shipping of PBMC samples.
9.3.3
Germline DNA Blood Collection 
One 10 mL Lavender top [EDTA] tube of whole blood will be collected at Cycle 1 Day 1 for 
extraction of germline DNA. If it is missed, the sample may be drawn at any time during 
treatment. 
Whole blood (un-spun) from the EDTA tubes will be aliquoted into cryovials at the local site 
where the sample was collected.  Processed samples are stored in cryovials at −80°C until 
shipment. Frozen cryovials will be batch shipped on dry ice to DFCI.
Collection tubes for research blood samples will be in the research sample collection kit provided 
by Core Prognostex. Please see the Study Manual for detailed instructions for collection, 
processing, labeling and shipping of PBMC samples.
9.4
Research Tumor Biopsies 
Tumor Biopsy will be performed at the following time-points:

Mandatory Baseline (Pre-Treatment): to be performed up to 2 weeks prior to starting 
treatment. 

Mandatory Cycle 3: to be performed prior to starting Cycle 3 treatment. 

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
Optional Off-Treatment/Disease Progression: to be performed when disease progression 
has been determined or treatment discontinuation (whichever comes first). If a participant 
will crossover, the off-treatment biopsy should be performed prior to initiation of 
crossover therapy. An additional Off-Treament biopsy is desired, but optional at time of 
disease progression/treatment discontinuation on the Cross-over arm. 
Eligible patients should have lesions suitable for serial biopsies. If a mandatory biopsy is unsafe 
or not feasible, permission must be granted by the overall study PI, Dr. Adrienne Gropper Waks, 
to decline the mandatory biopsies. 
At baseline (pre-treatment), in lieu of the mandatory baseline biopsy, previously collected tumor 
tissue from a metastaic or loco-regional lesion obtained < 1 year prior to enrollment may be 
submitted. Availability of tissue from a metastatic biopsy/surgery must be comfirmed prior to 
enrollment if this will be submitted instead of the baseline biopsy. 
or new tissue material from a recently obtained surgical or diagnostic biopsy.
A goal of six (6) core biopsy samples will be obtained:

Three cores should be frozen in OCT, each core frozen in a separate cassette.

Two additional core biopsies should be placed in a 10% neutral buffered formalin tube. 
These cores must be paraffin embedded with the local pathology department prior to 
shipment to DFCI. 
Collection tubes for research biopsy samples will be in the research sample collection kit 
provided by Core Prognostex. Please see the Study Manual for detailed instructions for 
collection, processing, labeling and shipping of research biopsy samples. 
9.5
Archival Tissue Collection 
The following archival tissue specimens are required for gene profiling: 

1 paraffin block (or 20 unstained charged slides 4-5μm thick) 

1 H&E slide 
Archival tissue will be collected for all participants. If a metastatic sample collected within 1 
year is submitted in lieu of the baseline biopsy sample, the archival tissue sample should be 
submitted from a primary breast cancer surgery/biopsy. If primary tissue is unavailable, a 
metastatic sample may be submitted. Archival tissue sample is shipped ambient in conventional 
paraffin block or slide shipper to the DFCI study team with the Specimen Requisition form 
found in the Study Manual. The Study Manual contains additional information on labeling and 
shipment of archival tissue to DFCI. Paraffin blocks will be returned after completion of 
correlative research. Unstained slides will not be returned. 
Archival tissue blocks/slides are shipped to the following address: 
Dana-Farber Cancer Institute
Breast Oncology 
Attn: 17-455 AVIATOR study team

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450 Brookline Avenue, Dana-157
Boston, MA 02215
9.6
Translational Research Planned Analyses 
9.6.1
Biomarkers of PD-1/PD-L1
Quantification of PD-L1 and PD-1 expression will be done by a CLIA-certified IHC test in a 
central lab. This marker will be performed in the primary tumor and unresectable loco-regional 
or metastatic biopsies pre-treatment and at time of trial treatment discontinuation.
9.6.2
Multiparametric IHC 
Spatial association of PD-1+ TILs and PD-L1+ cells (tumor and myeloid cells) suggests 
“induction” of PD-L1. Interferon-gamma production by antigen-specific PD-1+ CD8+ T cells is 
hypothesized to drive local intratumoral upregulation of PD-L1 on adjacent tumor and myeloid 
cells, leading to a “stalled Cytotoxic T Lymphocyte (CTL)” response which may be predictive of 
response to checkpoint blockade therapy.  We will also evaluate NK cells for markers of 
activation (CD11). By assessing both required elements, (i.e., PD-L1 expressing cells and PD-1+ 
T cells) an IHC assay may be a better predictor of response than PD-L1 expression alone.
9.6.3
Characterization of HER2 and tumor infiltrating lymphocytes (TILs)
The BWH Pathology Department will determine the HER2 status for submitted biopsies 
retrospectively. Five 5 µm sections (FFPE) will be sent to the certified lab for PD-L1 determination 
by IHC. HER2 status will be quantified by copy number and FISH ratio.
Tumor infiltrating lymphocytes (TILs) will be quantified on H&E slides using a pre-defined 
method.
Quantification of tumor infiltrating lymphocytes will be performed independently by an 
experienced pathologist. The percentage infiltration in the adjacent stromal areas as previously 
described will be recorded 31. This assessment will be performed in the primary tumor and 
metastatic biopsies pre-treatment and at time of trial treatment discontinuation.
Agreement between assessments by local and central pathologists will be analyzed.
Objective responses will be assessed as a function of TILs adjusted for other clinicopathological 
factors, the hypothesis being that high levels of TILs will be associated with a higher rate of 
objective responses in this trial.
9.6.4
Characterization of circulating tumor DNA (ctDNA)
Plasma of cancer patients contains cell-free tumor DNA that carries information on tumor 
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advanced disease using cancer genetic alterations (mutations, rearrangements) that are specific to 
the individual’s tumor. This information may allow us to track and monitor tumor dynamics during 
the disease course as well emergence of new clones (i.e., resistance mechanisms). Individual 
mutations may be assessed using technologies such as digital PCR, or next generation sequencing.
9.6.5
Characterization of peripherial blood Mononuclear cells (PBMCs)
We expect to see evidence of immune activation in peripheral blood subsets and will determine 
this with multiparameter FACs for T cells, T reg, NK cells and MDSC subsets. We will also 
examine immune suppression molecules (i.e. PD-1, TIM3) as well as activation molecules 
(OX40, CD137) on PB T cell subsets. NK cells will be CD3-, CD56+, CD16+ with markers of 
activation such as CD25, CD11 and CD54.
9.6.6
Sequencing of tumor biopsies (DNA and RNA)
FFPE biopsies will be retained for deep sequencing using next generation technologies at the 
completion of the trial. Nucleic acids will be extracted according to standard protocols. Sequencing 
will be performed using the Illumina Hi-Seq, though the technology is improving at a rapid rate.
The aim of the sequencing is to understand the molecular landscape (mutations, rearrangements 
and copy number changes) associated with HER2-positive, PD-L1 expressing and or high TIL 
tumors, as well as response or resistance to the trial therapy. Specific mutational patterns may be 
associated with increasing PD-L1 expression or lack of TILs (i.e., chromosomal instability, certain 
somatic mutations) which could imply a means by which the tumor escapes and subverts host 
immunity. This may be amenable to targeting with another compound. Similarly, tumors may 
upregulate specific pathways in order to avoid immune destruction after the PD-1 pathway has 
been inhibited. The presence of intra-tumoral heterogeneity will be investigated for in tumor 
biopsies and if this correlates with tumor responses. New data are emerging that suggest we can 
define certain tumor types as being ‘hypermutated.’ There is a potential that this hypermutated 
state may correlate with response to avelumab therapy, and/or that the converse, ‘hypomutated’ 
state may require the combination.
Paired metastatic lesions will be compared for the changes that occur during progression and 
resistance to trastuzumab/vinorelbine, or the combination with Avelumab or 
avelumab/utomilumab. These data will be also compared with the primary tumor. 
If enough RNA is able to be extracted from baseline and serial biopsies, gene expression of these 
tumors will be evaluated using a genome-wide, deep sequencing technology (RNA-seq). Specific 
markers of immune response (T-effector/IFNgamma signature, immunosuppression etc) can be 
then assessed for changes during the treatment course. For example, the expression of T regs 
(FOXP3) as well as IDO1, an immunosuppressive soluble factor may be increased at 
progression. Gene signatures that are published in the literature representing various aspects of 
immunity could also be assessed for their change during treatment.
Whole blood will be collected at baseline prior to treatment. It will be used to confirm the somatic 
nature of any interesting mutations found. This will not be used for analysis of germline 
abnormalities. DNA and RNA will be analyzed to attempt to define a gene set critical for clinical 

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response to either avelumab alone or the combination. The hypothesis to be tested is that avelumab 
alone responders will exhibit a “stalled Cytotoxic T Lymphocyte (CTL)” response within the 
tumor reflected in the physical proximity between PD-1 and PD-L1 expression and the presence 
of an aborted (e.g. weak but discernible) interferon-gamma transcriptional program will be 
detectable by profiling analyses. Significant alterations identified with these technologies can also 
be evaluated using ctDNA.
9.6.7
Further exploratory biomarkers
Other immune biomarkers will be performed using IHC evaluation, minimally to include PD-1 
and PD-L1 IHC, as well as Nanostring-based gene expression analysis. 
9.6.8
Not yet specified translational research
Translational research proposals not outlined in this protocol will be assessed by a trial-specific 
research committee for merit and feasibility. Biomarkers that are published in the future and 
considered to be of relevance can then also be assessed in the context of this trial.
For example, an anti-HER2 adaptive response could be assessed and monitored in plasma 
samples should a suitable antibody be found.
9.7
Genetic Testing
Participants will be given information as part of the informed consent process that samples will 
be used for research tests that will include genetic studies and testing.  The intent is not to give 
participants (or his/her medical providers) the results of any testing done for research purposes; 
however, incidental germline (heritable) mutations may be identified of which a participant may 
or may not already be aware.  In the case that an incidental genetic finding is identified, the 
Protocol Chair of this project will be notified.  The possible decisions for handling incidental 
findings may include notification of the participant (and provider); recommendation for genetic 
counseling, which may or may not include genetic testing (e.g., if the finding was not done in a 
CLIA certified laboratory); or, neither.  In general, a member of the participant’s treating team 
will be given the information to help with notification.  In all cases, the current policy of the 
Dana Farber Cancer Institute and local/participating site IRB, as applicable, will be followed and 
any additional approvals that may be required prior to participant notification will be secured in 
advance.
9.8
Additional Information
Submission of data for Genome Wide Association Studies (GWAS) is not currently planned; 
however, subjects will be asked for permission in the informed consent process. A revision to the 
protocol and/or any regulatory approvals will be secured prior to any GWAS submission or 
inclusions in the future, if applicable.

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10. SPECIMEN BANKING
The Protocol Chair and collaborators have approval by the TBCRC to use all research bio-
specimens collected during the conduct of this trial to address the research questions described in 
the protocol document.  All future use of residual or repository specimens collected in this trial 
for purposes not prospectively defined will require review and approval by the TBCRC 
according to its established policies, whether the specimens are stored in a central site or at a 
local institution in a virtual repository.
Secondary use of biospecimens for new endpoints must be submitted to the TBCRC Central 
Office for possible review by the TBCRC Correlative Science Review Committee.
11. MEASUREMENT OF EFFECT
For the purposes of this study, patients should be re-evaluated for response per the study 
calendar. In the case of documented response (CR or PR), confirmation scan is required no  
earlier than 4 weeks, but no later than the next scheduled scan. Response and progression will be 
evaluated in this study using the international criteria proposed by the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1). Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the 
case of malignant lymph nodes are used in the RECIST criteria.
Avelumab, like other immunotherapeutic agents, may produce antitumor effects by
potentiating endogenous cancer-specific immune responses. The response patterns seen with 
such an approach may extend beyond the typical time course of image responses seen with 
cytotoxic agents, and can manifest as a clinical response after an initial increase in tumor burden 
or even the appearance of new lesions.
For any subject who shows first radiologic evidence of progressive disease (PD) by RECIST 1.1 
and is deemed clinically stable, it is at the discretion of the investigator to continue treating the 
subject until progression is confirmed at the next scheduled restaging. These cases should be 
discussed with the Principal Investigator.

If progression is not confirmed on the subsequent scan, the subject should continue to 
receive treatment if the treating investigator feels that the participant is clinically stable, 
demonstrates improved condition, or is clearly continuing to benefit from the treatment.  
In this case, radiographic scans should continue to be performed according to the study 
calendar (i.e., every 8 weeks for the first 10 cycles; and, then every 12 weeks). 

If radiologic progression is confirmed on the subsequent scan, then the subject should be 
discontinued from all study treatment.  
In all participants, the date of progression for the primary endpoint will be documented as the 
first date progression was observed. 
11.1 Definitions 

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11.1.1 Evaluable for toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with 
Avelumab OR the combination of Avelumab and Utomilumab.
11.1.2 Evaluable for best overall objective response  
Only those patients have received at least one cycle of therapy will be considered 
evaluable for best overall response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.)
11.1.3 Disease Parameters
Measurable Disease:

A non-nodal lesion is considered measurable if its longest diameter can be accurately 
measured as 20 mm with chest x-ray, or as ≥10 mm with CT scan, CT component of 
a PET/CT, or MRI. 

A superficial non-nodal lesion is measurable if its longest diameter is ≥10 mm in 
diameter as assessed using calipers (e.g. skin nodules) or imaging. In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size of 
the lesion, is recommended.

A malignant lymph node is considered measurable if its short axis is >15 mm when 
assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 
mm).  At baseline and in follow-up, only the short axis will be measured and followed.
NOTE: Tumor lesions in a previously irradiated area are only considered measurable 
disease in the event that there is evidence of post-radiation progression.
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.
Non-Measurable Disease:
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm 
or pathological lymph nodes with ≥10 to <15 mm, are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable.
NOTE: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. “Cystic lesions” thought to represent cystic 

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metastases can be considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are present in the same 
subject, these are preferred for selection as target lesions. In addition, lymph nodes that 
have a short axis <10 mm are considered non-pathological (i.e., normal) and should not 
be recorded or followed.
Target Lesions:  
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
Non-Target Lesions:
All other lesions (or sites of disease) including any measurable lesions over and above the 
5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in 
rare cases unequivocal progression of each should be noted throughout follow up. 
11.2 Guidelines for Evaluation of Disease
11.2.1 Measurement Methods 

All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers.

The same method of assessment and the same technique must be used to characterize 
each identified and reported lesion at baseline and during follow-up. 

Imaging-based evaluation is preferred to evaluation by clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam.
11.2.2 Modalities for Measurable Disease 

Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. CT is preferred; MRI is also acceptable in certain 
situations (e.g., for body scans).

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Diagnostic quality CT is expected (with oral and IV contrast); any deviations from this 
must be approved by the Protocol Chair/designee in advance. (See note below regarding 
contrast allergy).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible.
NOTE: If prior to enrollment it is known a subject is not able to undergo CT scans with 
IV contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast 
CT or MRI (with or without IV contrast) should be used to evaluate the subject at 
baseline and follow-up should be guided by the anatomic location(s) of the disease. For 
subjects who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) should be 
performed should also be based on the anatomic location of the disease and should be 
optimized to allow for comparison to the prior studies if possible. Each case should be 
discussed with the radiologist and Protocol Chair/designee to determine if substitution of 
these other approaches is possible and, if not, the subject may be considered not 
evaluable from that point forward. 

Chest X-ray: Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung. However, CT scans are 
preferable.

Clinical Lesions: For superficial non-nodal lesions, physical examination is 
acceptable, but imaging is preferable, if both can be done. Clinical lesions will only 
be considered measurable when they are superficial (e.g., skin nodules and palpable 
lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using calipers (e.g., skin 
nodules). In the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.

Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised. If there is concern 

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about radiation exposure at CT, MRI may be used instead of CT in selected instances.

PET-CT: If the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the 
CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over 
time with approval from the Protocol Chair/designee. 

FDG-PET: FDG-PET scanning is allowed to complement CT scanning in assessment 
of progressive disease [PD] and particularly possible 'new' disease. A ‘positive’ FDG-
PET scanned lesion is defined as one which is FDG avid with an update greater than 
twice that of the surrounding tissue on the attenuation corrected image; otherwise, an 
FDG-PET scanned lesion is considered ‘negative.’ New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm: 
o
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
o
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
o
FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication. However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity.
NOTE: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image.
11.2.3 Additional Considerations

Tumor markers alone cannot be used to assess response. If markers are initially above 
the upper normal limit, they must normalize for a subject to be considered in 
complete clinical response. 

The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease.

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
Cytologic and histologic techniques can be used to differentiate between PR and CR 
in rare cases (e.g., residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain).
11.3 Lesion Documentation
11.3.1 Target Lesions

Measurable lesions: up to a maximum of 5 lesions, representative of all involved 
organs, should be identified as “Target Lesions” and recorded and measured at 
baseline. These lesions can be non-nodal or nodal (as defined), where no more than 2 
lesions are from the same organ and no more than 2 malignant nodal lesions are 
selected. 
NOTE: If fewer than 5 target lesions and target lymph nodes are identified (as there 
often will be), there is no reason to perform additional studies beyond those specified 
in the protocol to discover new lesions. 

Target lesions and target lymph nodes should be selected on the basis of their size, be 
representative of all involved sites of disease, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion (or malignant lymph node) does not lend itself to 
reproducible measurements in which circumstance the next largest lesion (or 
malignant lymph node) which can be measured reproducibly should be selected. 

Baseline Sum of Diameters (BSD): A sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes will be calculated 
and reported as the baseline sum of dimensions (BSD). The BSD will be used as 
reference to further characterize any objective tumor response in the measurable 
dimension of the disease. 

Post-Baseline Sum of the Diameters (PBSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will be 
calculated and reported as the post-baseline sum of dimensions (PBSD). If the 
radiologist is able to provide an actual measure for the target lesion (or target lymph 
node), that should be recorded, even if it is below 0.5 cm. If the target lesion (or 
target lymph node) is believed to be present and is faintly seen but too small to 
measure, a default value of 0.5 cm should be assigned. If it is the opinion of the 
radiologist that the target lesion or target lymph node has likely disappeared, the 
measurement should be recorded as 0 cm.

The minimum sum of the diameters (MSD) is the minimum of the BSD and the 
PBSD.
11.3.2 Non-Target Lesions & Non-Target Lymph Nodes
Non-measurable sites of disease including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions or non-target lymph nodes and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 

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throughout follow-up. 
11.4 Response Criteria
11.4.1 Overview
All target lesions, as well as non-target lesions must be measured on re-evaluation at evaluation 
time points. Specifically, a change in objective status to either a PR or CR cannot be done without 
re-measuring target lesions and target lymph nodes. 
If CR or PR occurs at tumor evaluation timepoint within the first 10 cycles, a confirmation scan 
will occur no earlier than 4 weeks, but no later than the next scheduled scan, per protocol; future 
tumor evaluations then occur/resume at protocol-defined intervals from the date of response 
confirmation. 
NOTE: Non-target lesions and non-target lymph nodes should be evaluated at each assessment, 
especially in the case of first response or confirmation of response. In selected circumstances, 
certain non-target organs may be evaluated less frequently. For example, bone scans may need to 
be repeated only when complete response is identified in target disease or when progression in 
bone is suspected.
11.4.2 Evaluation of Target Lesions

Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm.

Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.

Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. (NOTE: 
The appearance of one or more new lesions is also considered progression.)

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
11.4.3 Evaluation of Non-Target Lesions & Non-target Lymph Nodes

Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm 
short axis).
NOTE: If tumor markers are initially above the upper normal limit, they must 
normalize for a subject to be considered in complete clinical response.

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
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits.

Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase.
NOTE: To achieve “unequivocal progression” on the basis of non-target disease 
there must be an overall level of substantial worsening in non-target disease such that, 
even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the 
size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of CR, PR or SD of target disease is 
therefore expected to be rare. In order for a PD to be assigned on the basis of non-
target lesions, the increase in the extent of the disease must be substantial even in 
cases where there is no measurable disease at baseline. If there is unequivocal 
progression of non-target lesion(s), then at least one of the non-target lesions must be 
assigned a status of “Worsened.” Where possible, similar rules to those described 
above for target lesions for assigning PD following a CR for the non-target lesion 
response in the presence of non-target lesions nodal lesions should be applied.
11.4.4 Symptomatic Deterioration
Subjects with global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time, and not either related to study treatment or 
other medical conditions, should be reported as PD due to “symptomatic deterioration.” Every 
effort should be made to document the objective progression even after discontinuation of 
treatment due to symptomatic deterioration. A subject is classified as having PD due to 
“symptomatic deterioration” if any of the following occur that are not either related to study 
treatment or other medical conditions:
o
Weight loss >10% of body weight
o
Worsening of tumor-related symptoms
o
Decline in performance status of >1 level on ECOG scale
11.4.5 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The subject's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
For subjects with measurable disease at baseline:
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required
CR
CR
No
CR
4-8 wks Confirmation

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CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
4-8 wks Confirmation
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
confirmation not required
PD
Any
Yes or No
PD
Any
PD**
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 for further details on what is evidence of a new lesion.
**      In exceptional circumstances, unequivocal progression in non-target lesions may be
            accepted as disease progression.
For subjects with Non-Measurable/evaluable Disease Only at Baseline:
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/Non-PD**
No
Non-CR/Non-PD
UNK/Not All Evaluated*
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status.
11.4.6 Progression-Free Survival
Progression-free survival (PFS) is defined as the time from randomization until the date of 
objective disease progression or death (by any cause in the absence of progression). In the 
absence of an event, PFS is censored at last disease assessment; the statistical analysis plan will 
provide details of censoring rules and sensitivity analyses for the rules.  
11.4.7 Objective Response
Confirmed best overall response of CR or PR on two consecutive measurements. 
11.4.8 Response Review
There is no independent or central review of the radiology assessments planned for this trial. It is 
the responsibility of each Principal Investigator to ensure that tumor assessments are reported per 

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the RECIST 1.1 criteria outlined above. The Protocol Chair (or designee) may choose to review 
select cases.
11.4.9 Confirmatory Measurement/Duration of Response
Confirmation of Response:   
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed no less than 4 weeks, but no later than 
the next scheduled scan, per protocol.  
Duration of Response:  
The duration of response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease 
is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented.
The duration of SD is measured from randomization until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements. 
Overall Survival:
Overall survival is defined as the time from randomization to death from any cause, or is 
censored at date last known alive.
11.4.10
 Other Response Parameters – irRECIST
Definition of Tumor Response Using Immune-Related Response Criteria (irRECIST):
The sum of the product of the longest diameter of lesions (SPD) at tumor assessment 
using the immune-related response criteria (irRECIST) for progressive disease 
incorporate the contribution of new measurable lesions.  Each net Percentage Change in 
Tumor Burden per assessment using irRC criteria accounts for the size and growth 
kinetics of both old and new lesions as they appear.
Impact of New Lesions on irRECIST:
New lesions in and of themselves do not qualify as progressive disease.  However, their 
contribution to total tumor burden is included in the SPD which in turn feeds into the 
irRECIST criteria for tumor response.  Therefore, new non-measurable lesions will not 
discontinue any subject from the study.
Definition of Target Lesions Response Using irRECIST:

irRECIST Complete Response (irRECIST CR): Complete disappearance of all 
target lesions.  This category encompasses exactly the same subjects as “CR” by the 
mWHO criteria.

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
irRECIST Partial Response (irRECIST PR): Decrease, relative to baseline, or 
50% or greater in the sum of the products of the two largest perpendicular diameters 
of all target and all new measurable target lesions (i.e., Percentage Change in Tumor 
Burden).  Note: the appearance of new measurable lesions is factored into the overall 
tumor burden, but does not automatically qualify as progressive disease until the SBD 
increases by >25% when compared to SPD at nadir.

irRECIST Stable Disease (irRECIST SD): Does not meet criteria for irRECIST RC 
or irPR, in the absence of progressive disease.

irRECIST Progressive Disease (irRECIST PD): At least 25% increase Percentage 
Change in Tumor Burden (i.e. taking SPD of all target lesions and any new lesions) 
when compared to SPD at nadir.
Definition of Non-Target Lesions Response Using irRECIST:

irRECIST Complete Response (irRECIST CR): Complete disappearance of all 
non-target lesions.  This category encompasses exactly the same subjects as “CR” by 
the mWHO criteria.

irRECIST Partial Response (irRECIST PR) or irRECIST Stable Disease 
(irRECIST SD): Non-target lesion(s) are not considered in the definition of PR; 
these terms do not apply.

irRECIST Progressive Disease (irRECIST PD): Increases in number or size of 
non-target lesion(s) does not constitute progressive disease unless/until the 
Percentage Change in Tumor Burden increases by 25% (i.e. the SPD at nadir of the 
target lesions increases by the required amount).
Definition of Overall Response Using irRECIST:
Overall response using irRECIST will be based on these criteria:

Immune-Related Complete Response (irRECIST CR): Complete disappearance of 
all tumor lesions (target an non-target) together with no new 
measurable/unmeasurable lesions for at least 4 weeks from the date of documentation 
of complete response.

Immune-Related Partial Response (irRECIST PR): The sum of the products of the 
two largest perpendicular diameters of all target lesions is measured and captured as 
the SPD baseline.  At each subsequent tumor assessment, the SPD of the two largest 
perpendicular diameters of all target lesions and of new measurable lesions are added 
together to provide the Immune Response Sum of Product Diameters (irRECIST 
SPD).  A decrease, relative to baseline, of the irRECIST SPD compared to the 
previously SPD baseline  of 50% or greater is considered an irRECIST PR.

Immune-Related Stable Disease (irRECIST SD): irRECIST SD is defined as the 
failure to meet criteria for immune complete response or immune partial response, in 
the absence of progressive disease

Immune-Related Progressive Disease (irRECIST PD): It is recommended in 
difficult cases to confirm PD by serial imaging.  Any of the following will constitute 
PD:
o
At least 25% increase in the SPD of all target lesions over nadir SPD calculated 

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for the target lesions.
o
At least 25% increase in the SPD of all target lesions and new measurable lesions 
(irRECIST SPD) over the baseline SPD calculated for the target lesions. Criteria 
for determining overall response by irRECIST are summarized as follows:
Immune-Related Best Overall Response Using  irRECIST (irRECIST BOR):
irRECIST BOR is the best confirmed overall response over the study as a whole, 
recorded between the date of first dose until the last tumor assessment before subsequent 
therapy (except for local palliative radiotherapy for painful bone lesions) for the 
individual subject in the study.  For the assessment of irBOR, all available assessments 
per subject are considered.
irRECIST CR or irRECIST PR determinations included in the irRECIST BOR 
assessment must be confirmed by a second (confirmatory) evaluation meeting the criteria 
for response and performed no less than 4 weeks after the criteria for response are first 
met.
12. ADVERSE EVENT REPORTING REQUIREMENTS
12.1 Adverse Event Characteristics
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 will 
determine whether the event requires expedited reporting in addition to routine reporting.

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This study will use the descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events v5 (CTCAEv.5) that is available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
12.2 Adverse Event Characteristics

CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version  5.0.  A copy of the CTCAE version  5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

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 Investigator Brochure or included in the informed consent 
document as a potential risk.
Unexpected adverse events are those not listed in the 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 if the P.I. or I.B. only referred to elevated hepatic 
enzymes or hepatitis.
12.2.1 Serious adverse event (SAE)
A serious adverse event is an undesirable sign, symptom, or medical condition which:

is fatal; 

is life-threatening;

requires or prolongs inpatient hospitalization for ≥24 hours;

results in persistent or significant disability/incapacity to conduct normal life 
functions;

constitutes a congenital anomaly or birth defect; or

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
jeopardizes the participant and requires medical or surgical intervention to prevent 
one of the outcomes listed above;

Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.
Events not considered to be serious adverse events are hospitalizations for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures

elective or pre-planned treatment for a pre-existing condition that did not worsen, or 
that is required per protocol

emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission

respite care

death due to disease progression unless attributable to the study drug(s)

a hospitalization due to an expected adverse event (e.g., hospitalization due to 
expected febrile neutropenia).
12.3 Expedited 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 SAE 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. 
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.
12.3.1 DF/HCC Expedited Reporting Guidelines
The following adverse events must be reported to the DFCI IRB according to the expedited 
reporting guidelines:

CTCAE Grade 2 and Grade 3 Events – that are Unexpected and there is a Reasonable 
Possibility that the Adverse Event is related to the study Intervention.

CTCAE Grade 4 Events – Report all events that are Unexpected. Events that are 
Expected and listed within the protocol and/or current consent form do not need to be 
reported to the DFCI IRB. Please note, an event that presents at a higher severity than 
what is currently listed within the protocol and/or current consent as expected would be 
considered unexpected and reportable. 

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
ALL CTCAE Grade 5 Events.
Investigative sites within DF/HCC will report SAEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy. For all events that meet the 
expedited reporting criteria, a full written adverse event report must be submitted to the DFCI 
IRB within 10 working days from notification of the event.
Other investigative sites will report SAEs to their respective IRB according to their local IRB’s 
policies and procedures for reporting adverse events. A copy of the submitted institutional AE 
form will be forwarded to the Coordinating Center. 
The Coordinating Center will submit AE reports from outside institutions to the DFCI IRB 
according to DFCI IRB policies and procedures in reporting adverse events.
12.3.2 Participating Sites Reporting Requirement of SAEs to Pfizer
Participating sites will report related SAEs to Pfizer within 1 business day of first awareness of 
the event using the Pfizer or MedWatch SAE Reporting Form.  Follow-up information will be 
provided to Pfizer as reasonably requested.  A copy of these reports should also be sent to the 
lead site at the time of reporting.
Via fax: Pfizer U.S. Clinical Trial Department; Fax 1‐866‐997‐8322 or
Via email: USA.AEReporting@pfizer.com
A copy of the Pfizer or MedWatch SAE Reporting Form and the email correspondence or fax 
confirmation sheet must be kept within the Trial Master File at the study site.
Follow up events should be reported in the same manner as above, stating that this is a follow-up 
to the previously reported SAE and providing the follow-up number if appropriate. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, and whether the subject continued 
or withdrew from study participation.
12.3.3 Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (e.g., because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product. An example of environmental exposure 
would be a case involving direct contact with a Pfizer product in a pregnant woman (e.g., 
a nurse reports that she is pregnant and has been exposed to chemotherapeutic products).

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
A male has been exposed (e.g., because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed during 
his partner’s pregnancy.
If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on a Serious Adverse Event (SAE) Form and 
Exposure in Utero (EIU) Supplemental Form, regardless of whether an SAE has occurred. In 
addition, the investigator must submit information regarding environmental exposure to a 
Pfizer product in a pregnant woman (e.g., a patient reports that she is pregnant and has been 
exposed to a cytotoxic product by inhalation or spillage) using the EIU Form. This must be 
done irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure. The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion or until pregnancy termination) and notify Pfizer of the outcome as a follow up to 
the initial EIU Form. In the case of a live birth, the structural integrity of the neonate can be 
assessed at the time of birth. In the event of a termination, the reason(s) for termination 
should be specified and, if clinically possible, the structural integrity of the terminated fetus 
should be assessed by gross visual inspection (unless pre-procedure test findings are 
conclusive for a congenital anomaly and the findings are reported).  
If the outcome of the pregnancy meets the criteria for an SAE (i.e., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows:  

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
serious adverse events when the investigator assesses the infant death as related or 
possibly related to exposure to the investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator. Further follow-up of birth outcomes will be handled on a case-by-case basis (e.g., 
follow-up on preterm infants to identify developmental delays). In the case of paternal exposure, 
the investigator will provide the study patient with the Pregnant Partner Release of Information 
Form to deliver to his partner. The Investigator must document in the source documents that the 
patient was given the Pregnant Partner Release of Information Form to provide to his partner.

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12.3.4 Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person (whether a 
healthcare professional or otherwise) gets in unplanned direct contact with the product, which 
may or may not lead to the occurrence of an adverse event. 
An occupational exposure is reported to the drug safety unit within 24 hours of the Investigator’s 
awareness, using the SAE Report form, regardless of whether there is an associated AE/SAE. 
Since the information does not pertain to a subject enrolled in the study, the information is not 
reported on a Case Report Form (eCRF); however, a copy of the completed SAE Report form is 
maintained in the investigator site file.
12.4 Expedited 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.
12.5 Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 
12.6 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. Abnormal laboratory results deemed to be not-clinically significant 
(NCS) by a treating investigator do not need to be entered as an adverse event in the 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.
12.7 IND Safety Reports 
Pfizer will provide to the Overall PI IND safety reports from external studies that involve the 
study drug(s) per their guidelines.  Based on the sponsor-investigator’s review, applicable 
changes will be made to the protocol and informed consent document (if required).  
13. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 12.0 
13.1 Data Reporting

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13.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data 
for this study.
13.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms in accordance with DF/HCC SOPs.
13.2 Data and Safety Monitoring Board
The Dana-Farber/Harvard Cancer Center (DF/HCC) Data and Safety Monitoring Board (DSMB) 
will review and monitor study progress, toxicity, safety and other data from this study. The board 
is chaired by a medical oncologist from outside of DF/HCC and has external and internal 
representation. Information that raises any questions about participant safety or protocol 
performance will be addressed by the Overall PI, statistician and study team. Should any major 
concerns arise, the DSMB will offer recommendations regarding whether or not to suspend the 
study.
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual; 
treatment regimen information; adverse events and serious adverse events reported by category; 
summary of any deaths on study; audit results; and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request. 
13.3 Supplemental Monitoring of Safety 
The safety plan has been developed considering the risk measures for each investigational agent 
as well as the potential overlapping toxicities. While the safety profile of trastuzumab and 
vinorelbine is generally well understood given its approval for treatment of HER2-positive 
advanced disease, avelumab and Utomilumab are currently in clinical development and human 
experience is limited with the entire safety profile of both agents not known at this time. Please 
refer to the latest versions of the avelumab and Utomilumab IBs for a complete summary of 
safety information. The safety considerations are based on results from nonclinical and ongoing 
clinical studies and published data on similar molecules. 
Several measures will be taken to ensure the safety of patients participating in this study. 
Eligibility criteria have been designed to exclude patients at higher risk for toxicities from study 
participation. Guidelines for managing adverse events, including criteria for dosage modification 
and treatment interruption or discontinuation, are provided. 
Safety monitoring reported to the DSMB will be supplemented by 1) a formal, prespecified 
safety monitoring guidance for pausing study accrual to more fully evaluate safety in case of 
unexpectedly high dose-limiting toxicities; 2) a pause of study accrual after the first 6 patients in 

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each investigational treatment group (Arms B, C) to more fully review safety, regardless of the 
number of dose-limiting toxicities observed.  
13.3.1 Monitoring of dose-limiting toxicity (DLT)
Please reference section 6.4 for more information regarding the definition of DLTs.
Throughout enrollment, DLTs (defined below) of each investigational treatment group separately 
(Arms B, C) will be summarized with pre-specified criteria based on sequential boundaries to 
pause enrollment to more fully review safety if excessive numbers of DLTs are observed. The 
criteria are such that the probability of pausing is at most 0.05 if the true DLT rate is equal to 
15%, and the probabilities of pausing will be 0.66 or 0.95 if the true DLT rate is equal to 30% or 
40% 45.
Separately by treatment, the cumulative number of patients (X) experiencing DLT will be 
compared with the number of safety-evaluable patients (N), i.e., in the safety population (defined 
in Section 15.8), at that time, and an associated cutoff of safety-evaluable patients (Nx). If the 
number of patients N is greater than Nx then enrollment will continue; if the number of patients 
N is less than or equal to Nx then enrollment will pause in order to more fully review the nature, 
frequency, severity and timing of the events. The Table gives the criteria for pausing enrollment 
to more fully evaluate safety.
   Criteria for pausing enrollment because of DLTs to more fully review safety, for sample size       
up to 40 patients, with probability of pausing of 0.05 when the true toxicity rate is 15%. 
Number of patients 
for whom DLT is 
reported
X
1
2
3
4
5
6
7
8
9
10
11
12
Pause enrollment if 
safety-evaluable 
patients N is ≤Nx
Nx
-
-
≤4
≤7
≤10
≤14
≤18
≤23
≤27
≤31
≤36
≤40
Continue enrollment 
if safety-evaluable 
patients N is ≥ Nx
Nx
≥1
≥2
≥5
≥8
≥11
≥15
≥19
≥24
≥28
≥32
≥37
-
13.3.2 Assessment of first 6 patients per investigational treatment group
Once 6 patients assigned to each investigational treatment group (Arms B, C) have 
received at least one cycle of assigned treatment, a safety review will be conducted before 
additional patients are enrolled. Based on the monitoring criteria, if ≥4 of 6 patients (or 
before 6, if 3/3, ≥3/4, ≥4/5 patients) experience DLT within the first cycle of treatment, 
then the treatment regimen will be modified or discontinued. The review will include a 
per-patient listing of all reported AEs to date, including actions required for dosing, to 
more fully review the nature, frequency, severity and timing of the events. This 
information combined with fewer DLTs may also result in modification of a treatment 
regimen.    
13.4 Multi-Center Guidelines

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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.

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.
13.5 Collaborative Research and Future Use of Data and Biospecimens
Tissue, blood, bodily fluids, and other materials derived from these will be collected in this study 
to analyze genes, DNA, RNA, proteins and cells for the study’s correlative endpoints and potential 
future research, utilizing new types of biomarker testing as it becomes available. 
These samples and any data generated as a part of these clinical trials may be used for future 
research studies and may be provided to collaborating investigators both within and outside of the 
DF/HCC for either correlative endpoints or secondary use. Samples and data may be shared with 
outside non-profit academic investigators, as well as with for-profit pharmaceutical investigators 
or commercial entities, with whom we collaborate. When samples or data are sent to collaborators 
and when any research is performed on them, all information will be identified with a code, and 
will not contain any PHI, such as name, birthday, or MRNs. 
In order to allow the greatest amount of research to be performed on the specimens and 
information generated as a part of this trial, researchers in this study may share results of genetic 
sequencing with other scientists. De-identified specimen or genetic data may be placed into one 
of more publicly-accessible scientific databases, such as the National Institutes of Health’s 
Database for Genotypes and Phenotypes (dbGaP). The results from the correlative research on 
this study will be shared with these public databases. Through such databases, researchers from 
anywhere will have access to de-identified samples or data for future research. More detailed 
information, beyond the public database, may only be accessed by scientists at other research 
centers who have received special permission to review de-identified data.
13.6 Reorting to the NCI
As a provision of funding from the NCI under the Dana-Farber Cancer Institute Breast Cancer 
SPORE, the NCI will be notified should there be any temporary or permanent suspension of the 
trial. This notification will be inclusive of any actions taken by the FDA, institutional IRB, 
institutional PI, or commercial sponsor. Additionally, any major changes in the scope or aims of 
the study that would affect the objectives of the funding grant will be communicated to the NCI.

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14. PUBLICATION PLAN
14.1 Publication
It is understood that any manuscript or releases resulting from the collaborative research must be 
approved by the Protocol Chair and will be circulated to applicable participating 
sites/investigators prior to submission for publication or presentation.  
Additionally, any publication of study data and results must conform to the publications policy 
as stated the Translational Breast Cancer Research Consortium’s (TBCRC) “Policies and 
Procedures”.
15. STATISTICAL CONSIDERATIONS
15.1 Study Design/ Endpoints
This is a proof-of-concept, randomized, three-arm, phase II open-label study to evaluate the 
efficacy and safety of trastuzumab/vinorelbine alone, or in combination with avelumab OR 
avelumab and utomilumab (doublet immunotherapy) in patients with HER2-positive, locally 
advanced of metastatic breast cancer who have received prior trastuzumab and pertuzumab. 
The primary endpoint is progression-free survival (PFS; defined in Section 11.4.6). Secondary 
efficacy endpoints include objective response and duration of response, and overall survival 
(defined in Section 12).
The study will include additional monitoring of safety (see Section 13.3), implementing a 
continuous monitoring for toxicity using Pocock-type boundary.   
15.2 Sample Size/ Accrual Rate
One hundred (100) patients will be enrolled and randomized in a 1:2:2 ratio. An enrollment 
period of 30 months (3.3 patients per month) is anticipated.
The TH3RESA study (Krop et al. 2014) included patients with progressive HER2-positive 
advanced breast cancer who had received two or more HER2-directed regimens in the advanced 
setting, including trastuzumab and lapatinib, and previous taxane therapy in any setting. In that 
study, the median investigator-assessed PFS for patients randomized to T-DM1 was 6.2 months 
(95% CI 5.59-6.87) and was 3.3 months (95% CI 2.89-4.14) in the physician’s choice control 
group. Patients entering this study will be more heavily pre-treated with pertuzumab as standard 
first-line therapy, so achieving a similar PFS as for T-DM1 is a reasonable goal of therapy. 
Studies evaluating vinorelbine with trastuzumab in 2nd line and beyond patients have shown a 
PFS of around 5 months, without prior pertuzumab treatment [LUX1, BOLERO-3], hence 
today’s advanced HER2-population are likely to have a much shorter PFS in the 2nd line setting 
and beyond.

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One primary objective is to determine whether the addition of Utomilumab to the combination of 
avelumab and trastuzumab/vinorelbine will improve PFS compared to the avelumab, 
trastuzumab/vinorelbine combination alone (Arm C vs Arm B). With 80 patients randomized to 
the investigational treatments, (40 per group) there is 80% power for a log-rank test to detect a 
difference in median PFS of 6.67 months with avelumab and Utomilumab vs. 4 months with 
avelumab (HR=0.60) with one-sided α=0.10, assuming analysis with a total of 70 PFS events. 
A second primary objective is to determine whether the addition of avelumab to the combination 
of trastuzumab/vinorelbine will improve PFS compared to the trastuzumab/ vinorelbine 
combination alone (Arm B vs Arm A). With 60 patients randomized (40 Arm B; 20 Arm A) 
there is 88% power for a log-rank test to detect a difference in median PFS of 4 months with 
avelumab/ trastuzumab/vinorelbine vs. 2.0 months with trastuzumab/vinorelbine (HR=0.50) with 
one-sided α=0.10, assuming analysis with a total of 57 PFS events; power is 65% if median PFS 
is 2.5 months with trastuzumab/vinorelbine (HR=0.625).  
The calculations assumed 30 months of uniform accrual and 6 months’ additional follow-up after 
the last patient enrolled and no dropout (i.e., no withdrawn consent or loss to follow-up prior to a 
PFS event). No interim efficacy analysis is planned. As a proof-of-concept phase II trial, two 
one-sided α=0.10 level tests will be conducted without α-level adjustment.   
15.3 Modification of study design due to ad hoc futility analysis
As noted in Section 2.3.8, Pfizer’s discontinuation of utomilumab led to an ad hoc futility 
analysis of the comparison of Arm C vs Arm B on 2 February 2021, in consultation with the 
DSMB.  This interim analysis met the criteria for utomilumab inefficacy (see below).  Based on 
this result, further randomization to Arm C is discontinued and the trial will continue with 
randomization to Arms A and B only, maintaining the 1:2 randomization. At the time of this 
change in design, a total of 87 patients had been enrolled,  (ARM A: 17, ARM B: 36,ARM C: 
34). To account for missed C3D1 tissue biopsies in approximately 40 patients (predominately 
due to inaccessible tissue), this study will continue to enroll to the original goal of 100 patients in 
order to provide a small number of additional biopsy samples in Arms A and B to facilitate the 
planned correlative analyses. 
15.4 Stratification Factors
Randomization will be stratified, as described in Section 6. Details for incorporating 
stratification factors in the analyses will be described in the statistical analysis plan.
15.5 Analysis of Primary Endpoint
For the primary and secondary efficacy endpoints, the analysis population is intention-to-treat of 
all randomized patients who initiate treatment. 
The hazard ratio for PFS will be estimated using a stratified Cox proportional hazard model. 
Consistent with the design (1-sided α=0.10), a two-sided 80% CI will be reported, and may be 

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accompanied by a two-sided 90% CI. The distributions of PFS according to treatment 
assignment will be compared using a stratified logrank test (one-sided α=0.10) and will be 
estimated by Kaplan-Meier method, with reporting of median PFS and 12-month PFS with two-
sided 90% CIs. 
Sensitivity analyses for the censoring rules, considering for example new anti-cancer treatment 
initiated before PD or missed disease assessments, will be described in the statistical analysis 
plan.
15.6 Analysis of Secondary Efficacy Endpoints
The objective response rate will be reported as N (%) with two-sided 90% CIs, according to 
treatment assignment. Among patients having objective response, the distribution of duration of 
response will be estimated by Kaplan-Meier method, according to treatment assignment. 
The distribution of overall survival will be estimated by Kaplan-Meier method, including 
estimation of 2-year OS with two-sided 90% CIs, according to treatment assignment. 
These endpoints, as well as PFS, will also be summarized for the subset of patients randomized 
to Arm A who crossover to receive the combination of trastuzumab, Avelumab and Utomilumab 
after progression on vinorelbine/trastuzumab. The endpoints will be defined from the time that 
crossover treatment begins.   
15.7 Analysis of Safety and Tolerability
The safety population is randomized patients who initiate treatment as defined in Section 15.8, to 
be summarized according to treatment received. Safety and tolerability will be assessed based on 
adverse events reported according to NCI-CTCAE version 4.0. Of particular emphasis for safety 
reporting are cardiac, hepatic and pulmonary events. Details of the safety monitoring plan are 
described in Sections 13.3.1 and 13.3.3.
For each patient within the safety analysis population, recorded AE data over time will 
summarized as maximum grade observed of each AE. All reported AEs will be tabulated by 
maximum grade, according to treatment, as N and percentage of patients. For AEs, including 
cardiac, hepatic and pulmonary events, more detailed summaries of timing of onset, duration and 
severity (grade) over time may be reported, for example by swimmers plot. 
As well, clinical laboratory results during and following administration of study therapy will be 
summarized over time according to treatment, specifically hemoglobin, absolute neutrophil count 
and platelet count to assess anemia, neutropenia and thrombocytopenia.
15.8 Exploratory and Biomarker Objectives 
15.8.1 Overview of Analyses
PFS measures as defined by immune modified RECIST will be analyzed similarly as for the 
primary analysis of PFS.

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Considering the number of biomarker and exploratory analyses, the emphasis will be on 
descriptive and graphical summaries of data, and the interpretation based on the cumulative 
evidence of the analyses rather than on any one analysis in isolation. 
Analyses investigating pre-treatment markers (e.g., tumor PD-L1 and TILs) with efficacy 
endpoints (PFS and objective response) will use modeling (Cox or logistic, respectively) to 
investigate the association overall, as well as the interaction with treatment assignment, by 
reporting of HRs/ORs (and two-sided 90% CI). Test of marker-by-treatment interaction will be 
performed but emphasis will be on the HR (and CI) estimates of treatment effect according to 
marker status. As for the primary objective, the key treatment comparisons continue to be Arms 
B vs C and Arms B vs A. The PFS distributions and summary measures will be estimated using 
the Kaplan-Meier method as described for the primary analysis. 
It is also of interest to understand immune status (defined by PD-L1 expression, TILs and other 
markers by mRNA and IHC), ER status and HER2 measures (copy number, FISH ratio, mRNA 
levels) prior to treatment in relation to efficacy, and interactions of these markers would be 
investigated with the same approach, as feasible in consideration of subgroup sizes.
Tissue samples will be collected at multiple timepoints. The association of change in TILs after 2 
cycles of treatment with PFS will be assessed using a conditional landmark approach, redefining 
PFS from start of C3D1. Its association with response assessment after 2 cycles of treatment will 
also be investigated. Other markers measured in the samples following 2 cycles of therapy 
samples would be similarly analyzed. Analyses incorporating the tissue biopsy at progression 
would be descriptive and graphical, for example with spider plots to show marker levels at 
baseline, after 2 cycles and at the actual timepoint of progression. Serial plasma samples are also 
collected and markers would be analyzed in the same framework.
Markers in relation with safety signals would be explored with the same approaches as for 
efficacy endpoints; the safety endpoints could be defined as binary or time-to-event.
15.8.2 Sample Size Considerations
For the association of pre-treatment biomarkers with PFS among the 3 treatment groups 
combined, assuming 80% success rate with any biomarker, the analysis population would be 
expected to be about 80 patients and 65-70 PFS events. This sample size would provide 80% 
power (two-sided α=0.10) to detect HR=0.55 if marker-positive prevalence is 50% and HR=0.50 
if marker-positive prevalence is 25%.  
For the association of pre-treatment baseline biomarkers with OR among the treatment groups 
combined, assuming 80% success rate with any biomarker, the analysis population would be 
expected to be about 80 patients and 16-20 objective responses if the ORR is 20-25% across all 3 
treatment groups. This sample size would provide 75-80% power (one-sided α=0.10) to detect 
odds ratios of at least 3.7 (approx. 30-40% vs 10-15% ORR) if marker-positive prevalence is 
50% and odds ratio of at least 3.9 (approx. 40-45% vs 13-18% ORR) if marker-positive 
prevalence is 25%.  

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For the association of 2-cycle biomarker change with PFS status after 2 cycles among the 
treatment groups combined, the detectable odds ratio would be similar, as the 2-month 
progression rate would be expected to be about 24% in the treatment groups combined, under the 
same assumption that 80% of patients have successfully established change in marker status 
from pre-treatment to post 2 cycles of treatment. 
15.9 Reporting and Exclusions
The primary and secondary efficacy analysis population will be defined according to an 
intention-to-treat approach, of all randomized patients, and reported according to CONSORT 
guidelines.
The safety analysis population is all patients who initiate avelumab +/-  utomilumab treatment; 
any toxicity among a patient who receives trastuzumab and/or vinorelbine after randomization 
but without avelumab +/- utomilumab will be described separately. 
15.10 Interim analysis for inefficacy, Arm C vs B
An ad hoc interim analysis was added, in consultation with the DSMB. Based on the linear 
inefficacy boundary (LIB20) approach46, a single interim analysis for inefficacy for the primary 
objective (arm C vs B) was conducted to ensure some signal of benefit of the addition of 
utomilumab. With the design one-sided α=0.10 and power 80%, the LIB20 would suggest 
interim analysis after 60% events, at which point an estimated HR>1 would imply that the 2-
sided 90% CI for log HR would exclude the design alternative of 0.60. At the analysis, the 
observed information fraction was 53% events and the critical value was HR>1.02 indicating 
inefficacy.   

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16. REFERENCES
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for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical 
outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance 
algorithm. J Clin Oncol 21:2889-95, 2003
2. Burstein HJ, Keshaviah A, Baron AD, et al: Trastuzumab plus vinorelbine or taxane 
chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and 
vinorelbine or taxane study. Cancer 110:965-72, 2007
3. Dirix LY, Takacs I, Nikolinakos P, et al: Avelumab (MSB0010718C), an anti-PD-L1 
antibody, in patients with locally advanced or metastatic breast cancer: a phase Ib JAVELIN 
Solid Tumor trial (S1-04), San Antonio Breast Cancer Conference. December 8-12, 2015 San 
Antonio, TX, 2015
4. Zhang X, Voskens CJ, Sallin M, et al: CD137 promotes proliferation and survival of human 
B cells. J Immunol 184:787-95, 2010
5. Broll K, Richter G, Pauly S, et al: CD137 expression in tumor vessel walls. High correlation 
with malignant tumors. Am J Clin Pathol 115:543-9, 2001
6. Seaman S, Stevens J, Yang MY, et al: Genes that distinguish physiological and pathological 
angiogenesis. Cancer Cell 11:539-54, 2007
7. Kohrt HE, Houot R, Goldstein MJ, et al: CD137 stimulation enhances the antilymphoma 
activity of anti-CD20 antibodies. Blood 117:2423-32, 2011
8. Chan FK: Three is better than one: pre-ligand receptor assembly in the regulation of TNF 
receptor signaling. Cytokine 37:101-7, 2007
9. Furtner M, Straub RH, Kruger S, et al: Levels of soluble CD137 are enhanced in sera of 
leukemia and lymphoma patients and are strongly associated with chronic lymphocytic 
leukemia. Leukemia 19:883-5, 2005
10. Hentschel N, Krusch M, Kiener PA, et al: Serum levels of sCD137 (4-1BB) ligand are 
prognostic factors for progression in acute myeloid leukemia but not in non-Hodgkin's 
lymphoma. Eur J Haematol 77:91-101, 2006
11. Michel J, Langstein J, Hofstadter F, et al: A soluble form of CD137 (ILA/4-1BB), a member 
of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of 
patients with rheumatoid arthritis. Eur J Immunol 28:290-5, 1998
12. Croft M: The role of TNF superfamily members in T-cell function and diseases. Nat Rev 
Immunol 9:271-85, 2009
13. Lynch DH: The promise of 4-1BB (CD137)-mediated immunomodulation and the 
immunotherapy of cancer. Immunol Rev 222:277-86, 2008
14. Vinay DS, Cha K, Kwon BS: Dual immunoregulatory pathways of 4-1BB signaling. J Mol 
Med (Berl) 84:726-36, 2006
15. Stagg J, Loi S, Divisekera U, et al: Anti-ErbB-2 mAb therapy requires type I and II 
interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc Natl Acad Sci U 
S A 108:7142-7, 2011
16. Chan A, Delaloge S, Holmes FA, et al: Neratinib after trastuzumab-based adjuvant therapy in 
patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-
blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2016
17. Piccart-Gebhart M, Holmes E, Baselga J, et al: Adjuvant Lapatinib and Trastuzumab for 
Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Results From the 

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Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization 
Trial. J Clin Oncol 34:1034-42, 2016
18. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab for node-
negative, HER2-positive breast cancer. N Engl J Med 372:134-41, 2015
19. Ellis P, Barrios CH, Eiermann W, et al: Phase III, randomized study of trastuzumab 
emtansine ± pertuzumab vs trastuzumab + taxane for first-line treatment of HER2-positive 
MBC: Primary results from the MARIANNE study, American Society of Clinical Oncology 
(ASCO). Chicago, IL, 2015
20. Swain SM, Baselga J, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-
positive metastatic breast cancer. N Engl J Med 372:724-34, 2015
21. Krop IE, Kim SB, Gonzalez-Martin A, et al: Trastuzumab emtansine versus treatment of 
physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a 
randomised, open-label, phase 3 trial. Lancet Oncol 15:689-99, 2014
22. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced 
breast cancer. N Engl J Med 367:1783-91, 2012
23. Luen S, Virassamy B, Savas P, et al: The genomic landscape of breast cancer and its 
interaction with host immunity. Breast, 2016
24. Savas P, Salgado R, Denkert C, et al: Clinical relevance of host immunity in breast cancer: 
from TILs to the clinic. Nat Rev Clin Oncol 13:228-41, 2016
25. Muller P, Kreuzaler M, Khan T, et al: Trastuzumab emtansine (T-DM1) renders HER2+ 
breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Transl Med 7:315ra188, 
2015
26. Park S, Jiang Z, Mortenson ED, et al: The therapeutic effect of anti-HER2/neu antibody 
depends on both innate and adaptive immunity. Cancer Cell 18:160-70, 2010
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breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res 7:3025-30, 2001
28. Rizvi NA, Mazieres J, Planchard D, et al: Activity and safety of nivolumab, an anti-PD-1 
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locally advanced human epidermal growth factor receptor 2-positive breast cancer: the 
HERNATA study. J Clin Oncol 29:264-71, 2011
30. Burstein HJ, Kuter I, Campos SM, et al: Clinical activity of trastuzumab and vinorelbine in 
women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 19:2722-30, 2001
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(TILs) in breast cancer: recommendations by an International TILs Working Group 2014. 
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34. Loi S, Michiels S, Salgado R, et al: Tumor infiltrating lymphocytes are prognostic in triple 
negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results 
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35. Bianchini G, Pusztai L, Pienkowski T, et al: Immune modulation of pathologic complete 
response after neoadjuvant HER2-directed therapies in the NeoSphere trial. Ann Oncol 
26:2429-36, 2015
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predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28:105-13, 
2010
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to neoadjuvant chemotherapy with or without carboplatin in HER2-positive and triple-
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of print], 2014
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39. Baselga J, Cortes J, Im SA, et al: Biomarker analyses in CLEOPATRA: a phase III, placebo-
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line metastatic breast cancer. J Clin Oncol 32:3753-61, 2014
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Depends on Both Innate and Adaptive Immunity. Cancer cell 18:160-170, 2010
41. Luen S, Salgado R, Fox S, et al: Tumor infiltrating lymphcytes in advanced HER2-positive 
breast cancer treated with pertuzumab and trastuzumab: a retrospective analysis of the 
CLEOPATRA study. Lancet Oncol Epub on line December 7th 2016, 2016
42. Dieci MV, Criscitiello C, Goubar A, et al: Prognostic value of tumor-infiltrating lymphocytes 
on residual disease after primary chemotherapy for triple-negative breast cancer: a 
retrospective multicenter study. Ann Oncol 25:611-8, 2014
43. Murtaza M, Dawson SJ, Tsui DW, et al: Non-invasive analysis of acquired resistance to 
cancer therapy by sequencing of plasma DNA. Nature 497:108-12, 2013
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therapy: recommendations of the Canadian Trastuzumab Working Group. Curr Oncol 15:24-
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oncology. Biometrics 61:540-545, 2005
46. 1. Burstein HJ, Harris LN, Marcom PK, et al: Trastuzumab and vinorelbine as first-line 
therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with 
clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac 
surveillance algorithm. J Clin Oncol 21:2889-95, 2003
2. Burstein HJ, Keshaviah A, Baron AD, et al: Trastuzumab plus vinorelbine or taxane 
chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and 
vinorelbine or taxane study. Cancer 110:965-72, 2007
3. Dirix LY, Takacs I, Nikolinakos P, et al: Avelumab (MSB0010718C), an anti-PD-L1 
antibody, in patients with locally advanced or metastatic breast cancer: a phase Ib JAVELIN 
Solid Tumor trial (S1-04), San Antonio Breast Cancer Conference. December 8-12, 2015 San 
Antonio, TX, 2015
4. Zhang X, Voskens CJ, Sallin M, et al: CD137 promotes proliferation and survival of human 
B cells. J Immunol 184:787-95, 2010
5. Broll K, Richter G, Pauly S, et al: CD137 expression in tumor vessel walls. High correlation 
with malignant tumors. Am J Clin Pathol 115:543-9, 2001

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6. Seaman S, Stevens J, Yang MY, et al: Genes that distinguish physiological and pathological 
angiogenesis. Cancer Cell 11:539-54, 2007
7. Kohrt HE, Houot R, Goldstein MJ, et al: CD137 stimulation enhances the antilymphoma 
activity of anti-CD20 antibodies. Blood 117:2423-32, 2011
8. Chan FK: Three is better than one: pre-ligand receptor assembly in the regulation of TNF 
receptor signaling. Cytokine 37:101-7, 2007
9. Furtner M, Straub RH, Kruger S, et al: Levels of soluble CD137 are enhanced in sera of 
leukemia and lymphoma patients and are strongly associated with chronic lymphocytic 
leukemia. Leukemia 19:883-5, 2005
10. Hentschel N, Krusch M, Kiener PA, et al: Serum levels of sCD137 (4-1BB) ligand are 
prognostic factors for progression in acute myeloid leukemia but not in non-Hodgkin's 
lymphoma. Eur J Haematol 77:91-101, 2006
11. Michel J, Langstein J, Hofstadter F, et al: A soluble form of CD137 (ILA/4-1BB), a member 
of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of 
patients with rheumatoid arthritis. Eur J Immunol 28:290-5, 1998
12. Croft M: The role of TNF superfamily members in T-cell function and diseases. Nat Rev 
Immunol 9:271-85, 2009
13. Lynch DH: The promise of 4-1BB (CD137)-mediated immunomodulation and the 
immunotherapy of cancer. Immunol Rev 222:277-86, 2008
14. Vinay DS, Cha K, Kwon BS: Dual immunoregulatory pathways of 4-1BB signaling. J Mol 
Med (Berl) 84:726-36, 2006
15. Stagg J, Loi S, Divisekera U, et al: Anti-ErbB-2 mAb therapy requires type I and II 
interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc Natl Acad Sci U 
S A 108:7142-7, 2011
16. Chan A, Delaloge S, Holmes FA, et al: Neratinib after trastuzumab-based adjuvant therapy in 
patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-
blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2016
17. Piccart-Gebhart M, Holmes E, Baselga J, et al: Adjuvant Lapatinib and Trastuzumab for 
Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Results From the 
Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization 
Trial. J Clin Oncol 34:1034-42, 2016
18. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab for node-
negative, HER2-positive breast cancer. N Engl J Med 372:134-41, 2015
19. Ellis P, Barrios CH, Eiermann W, et al: Phase III, randomized study of trastuzumab 
emtansine ± pertuzumab vs trastuzumab + taxane for first-line treatment of HER2-positive 
MBC: Primary results from the MARIANNE study, American Society of Clinical Oncology 
(ASCO). Chicago, IL, 2015
20. Swain SM, Baselga J, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-
positive metastatic breast cancer. N Engl J Med 372:724-34, 2015
21. Krop IE, Kim SB, Gonzalez-Martin A, et al: Trastuzumab emtansine versus treatment of 
physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a 
randomised, open-label, phase 3 trial. Lancet Oncol 15:689-99, 2014
22. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced 
breast cancer. N Engl J Med 367:1783-91, 2012
23. Luen S, Virassamy B, Savas P, et al: The genomic landscape of breast cancer and its 
interaction with host immunity. Breast, 2016

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24. Savas P, Salgado R, Denkert C, et al: Clinical relevance of host immunity in breast cancer: 
from TILs to the clinic. Nat Rev Clin Oncol 13:228-41, 2016
25. Muller P, Kreuzaler M, Khan T, et al: Trastuzumab emtansine (T-DM1) renders HER2+ 
breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Transl Med 7:315ra188, 
2015
26. Park S, Jiang Z, Mortenson ED, et al: The therapeutic effect of anti-HER2/neu antibody 
depends on both innate and adaptive immunity. Cancer Cell 18:160-70, 2010
27. Demaria S, Volm MD, Shapiro RL, et al: Development of tumor-infiltrating lymphocytes in 
breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res 7:3025-30, 2001
28. Rizvi NA, Mazieres J, Planchard D, et al: Activity and safety of nivolumab, an anti-PD-1 
immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell 
lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 16:257-65, 2015
29. Andersson M, Lidbrink E, Bjerre K, et al: Phase III randomized study comparing docetaxel 
plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or 
locally advanced human epidermal growth factor receptor 2-positive breast cancer: the 
HERNATA study. J Clin Oncol 29:264-71, 2011
30. Burstein HJ, Kuter I, Campos SM, et al: Clinical activity of trastuzumab and vinorelbine in 
women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 19:2722-30, 2001
31. Salgado R, Denkert C, Demaria S, et al: The evaluation of tumor-infiltrating lymphocytes 
(TILs) in breast cancer: recommendations by an International TILs Working Group 2014. 
Ann Oncol 26:259-71, 2015
32. TCGA: Comprehensive molecular portraits of human breast tumours. Nature 490:61-70, 
2012
33. Kohrt HE, Houot R, Weiskopf K, et al: Stimulation of natural killer cells with a CD137-
specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J 
Clin Invest 122:1066-75, 2012
34. Loi S, Michiels S, Salgado R, et al: Tumor infiltrating lymphocytes are prognostic in triple 
negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results 
from the FinHER trial. Ann Oncol 25:1544-50, 2014
35. Bianchini G, Pusztai L, Pienkowski T, et al: Immune modulation of pathologic complete 
response after neoadjuvant HER2-directed therapies in the NeoSphere trial. Ann Oncol 
26:2429-36, 2015
36. Denkert C, Loibl S, Noske A, et al: Tumor-associated lymphocytes as an independent 
predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28:105-13, 
2010
37. Denkert C, von Minckwitz G, Brase JC, et al: Tumor-infiltrating lymphocytes and response 
to neoadjuvant chemotherapy with or without carboplatin in HER2-positive and triple-
negative primary breast cancers. J Clin Oncol Dec 22. pii: JCO.2014.58.1967. [Epub ahead 
of print], 2014
38. Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously treated, 
PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised 
controlled trial. Lancet 387:1540-50, 2016
39. Baselga J, Cortes J, Im SA, et al: Biomarker analyses in CLEOPATRA: a phase III, placebo-
controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-
line metastatic breast cancer. J Clin Oncol 32:3753-61, 2014

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40. Park S, Jiang Z, Mortenson ED, et al: The Therapeutic Effect of Anti-HER2/neu Antibody 
Depends on Both Innate and Adaptive Immunity. Cancer cell 18:160-170, 2010
41. Luen S, Salgado R, Fox S, et al: Tumor infiltrating lymphcytes in advanced HER2-positive 
breast cancer treated with pertuzumab and trastuzumab: a retrospective analysis of the 
CLEOPATRA study. Lancet Oncol Epub on line December 7th 2016, 2016
42. Dieci MV, Criscitiello C, Goubar A, et al: Prognostic value of tumor-infiltrating lymphocytes 
on residual disease after primary chemotherapy for triple-negative breast cancer: a 
retrospective multicenter study. Ann Oncol 25:611-8, 2014
43. Murtaza M, Dawson SJ, Tsui DW, et al: Non-invasive analysis of acquired resistance to 
cancer therapy by sequencing of plasma DNA. Nature 497:108-12, 2013
44. Mackey JR, Clemons M, Cote MA, et al: Cardiac management during adjuvant trastuzumab 
therapy: recommendations of the Canadian Trastuzumab Working Group. Curr Oncol 15:24-
35, 2008
45. Ivano va A, Qaqish BF, Schell MJ: Continuous toxicity monitoring in phase II trials in 
oncology. Biometrics 61:540-545, 2005
46. Freidlin B, Korn EL, Gray R: A inefficacy interim monitoring rule for randomized clinical 
trials. Clin Trials 7:197-208, 2010

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Appendices 
Appendix A:
ECOG Performance Status Scale
Appendix B:
Strong CYP3A Inducers/Inhibitors and Information on Possible Drug Interactions   
Apprendix C:   DF/HCC Multi-Center Data Safety Monitoring Plan 

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APPENDIX A:  ECOG Performance Status Scale
Score
Definition
Karnofsky Equivalent
0
Asymptomatic
100
1
Symptomatic, fully ambulatory
80 – 90
2
Symptomatic, in bed less than 50% of day
60 – 70
3
Symptomatic, in bed more than 50% of day, 
but not bedridden
40 – 50
4
Bedridden
20 – 30

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APPENDIX B:  Strong CYP3A Inducers/Inhibitors and Information on Possible 
Drug Interactions
Medications that strongly inhibit CYP3A:
Amprenavir
Atazanavir
Boceprevir
Clarithromycin
Conivaptan
Delavirdine
Diltiazem
Erythromycin
Fosamprenavir
Indinavir
Itraconazole
Ketoconazole
Lopinavir
Mibefradil
Miconazole
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Verapamil
Voriconazole
Grapefruit, grapefruit juice, or any product containing grapefruit
Medications that strongly induce CYP3A:
Carbamazepine
Felbamate
Nevirapine
Phenobarbital
Phenytoin
Primidone
Rifabutin
Rifampin
Rifapentin
St. John’s wort

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APPENDIX C:  Data Safety Monitoring Plan 
DFCI Protocol #: 17-455
Dana-Farber/Harvard Cancer Center
Multi-Center Data and Safety Monitoring Plan

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TABLE OF CONTENTS
TABLE OF CONTENTS .............................................................................................................................................2
1.
OBJECTIVES AND ENDPOINTS ....................................................................................................................6
1.1
STUDY DESIGN...............................................................................................................................................6
1.2
PRIMARY OBJECTIVES....................................................................................................................................6
1.3
SECONDARY OBJECTIVES...............................................................................................................................7
1.4
EXPLORATORY OBJECTIVES...........................................................................................................................7
1.5
CORRELATIVE OBJECTIVES............................................................................................................................7
1.6
ENDPOINTS.....................................................................................................................................................8
1.6.1
Primary Endpoint..................................................................................................................8
1.6.2
Secondary Endpoints ............................................................................................................8
2.
BACKGROUND ..................................................................................................................................................8
2.1
HER2-POSITIVE BREAST CANCER.................................................................................................................8
2.2
STUDY AGENT(S) ...........................................................................................................................................9
2.2.1
Avelumab..............................................................................................................................9
2.2.2
Utomilumab........................................................................................................................14
2.2.3
Trastuzumab and Biosimilars..............................................................................................16
2.2.4
Vinorelbine .........................................................................................................................16
2.3
RATIONALE..................................................................................................................................................16
2.3.1
Rationale for combination administration of avelumab and utomilumab .........................16
2.3.2
Rationale for combination with chemotherapy and dual immunotherapeutic approaches
17
2.3.3
Rationale for using a vinorelbine/trastuzumab backbone..................................................19
2.3.4
Rationale for trial design.....................................................................................................19
2.3.5
Rationale for allowing cross-over for patients randomized to the control arm .................20
2.3.6
Safety of the proposed two investigational study arms .....................................................20
2.3.7
Rationale for allowing patients to continue treatment beyond initial progression per 
RECIST 1.1...........................................................................................................................................21
2.3.8
Rationale for revised study design discontinuing enrollment to utomilumab-containing 
regimens 21
2.4
CORRELATIVE SCIENCE BACKGROUND........................................................................................................22
2.4.1
Rationale for biomarker evaluations ..................................................................................23
2.4.2
Rationale for collection of archival and metastatic tumor specimens ...............................23
2.4.3
Rationale for collection of mandatory on-treatment biopsy..............................................24
2.4.4
Rationale for collection of biopsy at time of progression...................................................24
2.4.5
Rationale for collection of serial blood specimens.............................................................24
3.
PARTICIPANT SELECTION..........................................................................................................................24
3.1
INCLUSION CRITERIA ...................................................................................................................................24

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3.1.1
Age ≥18 years or older........................................................................................................24
3.1.2
Histologically confirmed breast cancer that is metastatic or unresectable loco-regionally 
advanced24
3.1.3
Histologically confirmed HER-2 positive breast cancer by ASCO CAP 2013 guidelines.  
NOTE: Central confirmation of HER-2 status is not required: ............................................................24
3.1.4
Measurable disease per RECIST v1.1 (see Section 11)........................................................25
3.1.5
Participants must have previous treatment with ado-trastuzumab emtansine (Kadcyla, T-
DM1) in any setting. ...........................................................................................................................25
3.1.6
Participants must have previously received trastuzumab and pertuzumab in the 
metastatic setting or recurred ≤12 months after a neoadjuvant/adjuvant regimen containing 
trastuzumab and pertuzumab.It is not mandatory to have a trastuzumab and/or pertuzumab 
containing regimen as the most recent treatment. ...........................................................................25
3.1.7
Participants must have progressed on their most recent line of therapy. Progression must 
have been demonstrated by radiological or clinical assessment. ......................................................25
3.1.8
Left ventricular ejection fraction (LVEF) ≥50%, as determined by MUGA or 
echocardiogram ..................................................................................................................................25
3.1.9
Eastern Cooperative Oncology Group (ECOG) performance status 0-1 .............................25
3.1.10
Participants must have normal organ and marrow function as defined below: ................25
3.1.11
International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 × ULN unless patient 
is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use 
of anticoagulant..................................................................................................................................25
3.1.12
Willingness and availability to submit FFPE tissue for research purposes. This can be from 
archival tissue from unresectable loco-regional or metastatic disease obtained ≤1 year prior to 
enrollment or new tissue material from a recently obtained surgical or diagnostic biopsy. Tissue 
obtained for the biopsy must not have been previously irradiated. If a patient does not have any 
available archival tissue  ≤1 year old and the treating investigator does not feel that it would be safe 
to perform a fresh biopsy, the requirement for a fresh biopsy may be waived after discussion with 
the Protocol Chair...............................................................................................................................25
3.1.13
If female of childbearing potential, must have a negative pregnancy test within 7 days of 
registration. Childbearing potential is defined as: those who have not been surgically sterilized 
and/or have had a menstrual period in the past 12 months or who have been on ovarian 
suppression in the past year...............................................................................................................25
3.1.14
Participants of childbearing potential (males and females as defined above) must be 
willing to use effective contraception during treatment and up to 7 months after stop of trial 
treatment.  Acceptable methods of contraception are intrauterine devices, bilateral tubal occlusion, 
vasectomized, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not 
allowed. 26
3.1.15
Ability to understand and the willingness to sign a written informed consent document.26
3.2
EXCLUSION CRITERIA ..................................................................................................................................26

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3.2.1
Prior therapy with vinorelbine in any setting .....................................................................26
3.2.2
Prior therapy with any anti-PD-1, anti-PD-L1, L2, anti-4-1BB (CD137), or anti-CTLA4 
therapy
26
3.2.3
Known Human Immunodeficiency Virus (HIV) positive (testing not required)...................26
3.2.4
Active or chronic Hepatitis B or C (testing not required)....................................................26
3.2.5
History of interstitial lung disease ......................................................................................26
3.2.6
Active central nervous system metastases, as indicated by clinical symptoms, cerebral 
edema, and/or progressive growth (patients with history of CNS metastases or spinal cord 
compression are eligible if they are clinically stable for at least 4 weeks before first dose of 
investigational product and do not require high-dose steroid treatment) ........................................26
3.2.7
History of clinically significant or uncontrolled cardiac disease, including congestive heart 
failure (New York Heart Association functional classification > 3), angina, myocardial infarction or 
ventricular arrhythmia........................................................................................................................26
3.2.8
Previous severe hypersensitivity reaction to treatment with another monoclonal antibody
26
3.2.9
Active infection requiring systemic therapy .......................................................................26
3.2.10
Chronic systemic therapy with immunosuppressive agents including corticosteroids ......26
3.2.11
Active autoimmune disease or a documented history of autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or 
resolved childhood asthma/atopy would be an exception to this rule. Patients that require 
intermittent use of bronchodilators or local steroid injections would not be excluded from the trial. 
Patients with hypothyroidism stable on hormone replacement or Sjögren’s syndrome will not be 
excluded from the trial. ......................................................................................................................26
3.2.12
Concurrent disease or condition that would make the patient inappropriate for trial 
participation or any serious medical disorder that would interfere with the patient’s safety in the 
opinion of the treating investigator....................................................................................................26
3.2.13
No current uncontrolled hypertension (≥180/110), unstable diabetes mellitus, dyspnea at 
rest, or chronic therapy with oxygen..................................................................................................26
3.2.14
Chemotherapy, radiotherapy, and/or biological cancer therapy (excluding trastuzumab) 
within 3 weeks prior to the planned treatment start date.................................................................26
3.2.15
Unresolved or unstable adverse events from prior therapy, except alopecia (has not 
recovered to CTCAE v.5 ≤grade 1 or baseline)....................................................................................27
3.2.16
Pregnant women or women who are lactating/breastfeeding due to the teratogenic 
potential of the study drugs.................................................................................................................27
3.2.17
Participants receiving any medications or substances that are strong inhibitors or 
inducers of CYP3A are ineligible. A list of medications and substances known or with the potential 
to interact with the CYP3A isoenzymes is provided in Appendix B. Because the lists of these agents 
are constantly changing, it is important to regularly consult a frequently-updated list such as the 

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Physicians’ Desk Reference. As part of the enrollment/informed consent procedures, the 
participant will be counseled on the risk of interactions with other agents, and what to do if new 
medications need to be prescribed or if the participant is considering a new over-the-counter 
medicine or herbal product................................................................................................................27
3.2.18
Live vaccines within 30 days prior to the first dose of trial therapy and during trial 
treatment. ..........................................................................................................................................27
3.3
INCLUSION OF UNDERREPRESENTED POPULATIONS.....................................................................................27
4.
REGISTRATION AND RANDOMIZATION PROCEDURES....................................................................27
4.1
REGISTRATION PROCESS FOR DF/HCC INSTITUTIONS.................................................................................27
4.2
GENERAL GUIDELINES FOR OTHER INVESTIGATIVE SITES...........................................................................28
4.3
REGISTRATION PROCESS FOR OTHER INVESTIGATIVE SITES........................................................................28
5.
STUDY CALENDARS ......................................................................................................................................29
5.1
REQUIRED DATA: ARMS A, B, AND C..........................................................................................................30
5.2
REQUIRED DATA: CROSSOVER.....................................................................................................................32
6.
TREATMENT PLAN........................................................................................................................................34
6.1
PRE-TREATMENT CRITERIA .........................................................................................................................34
6.2
REGIMEN DESCRIPTIONS..............................................................................................................................35
6.2.1
Arm A Regimen Description................................................................................................35
6.2.2
Arm B Regimen Description................................................................................................36
6.2.3
Arm C Regimen Description (CLOSED TO NEW ENROLLMENT) ..........................................37
6.2.4
Cross-over Arm Regimen Description.................................................................................38
6.3
AGENT ADMINISTRATION ............................................................................................................................39
6.3.1
Trastuzumab and Biosimilars..............................................................................................40
6.3.2
Vinorelbine .........................................................................................................................40
6.3.3
Utomilumab (for reference only – Utomilumab has been removed from this study)........41
6.3.4
Avelumab............................................................................................................................41
6.4
DOSE LIMITING TOXICITY (DLT) ................................................................................................................42
6.5
CONCOMITANT TREATMENT AND SUPPORTIVE CARE GUIDELINES .............................................................43
6.6
DURATION OF THERAPY...............................................................................................................................44
6.7
ISOLATED CNS PROGRESSION......................................................................................................................44
6.8
CRITERIA FOR TAKING A PARTICIPANT OFF TREATMENT............................................................................45
6.9
CRITERIA FOR CROSSOVER THERAPY ..........................................................................................................45
6.10
DURATION OF FOLLOW-UP ..........................................................................................................................46
6.11
CRITERIA FOR TAKING A PARTICIPANT OFF STUDY.....................................................................................46
7.
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS.....................................46
7.1
ANTICIPATED TOXICITIES ............................................................................................................................47
7.1.1
Anticipated Toxicities for Trastuzumab (or biosimilar).......................................................47
7.1.2
Anticipated Toxicities for Vinorelbine.................................................................................48
7.1.3
Anticipated Toxicities for Utomilumab (for reference only, utomilumab therapy has been 
removed from this protocol) ..............................................................................................................49
7.1.4
Anticipated Toxicities for Avelumab...................................................................................49

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7.2
DOSE MODIFICATION GUIDELINES...............................................................................................................50
7.2.1
Special Considerations........................................................................................................51
7.2.2
Vinorelbine Toxicity Management......................................................................................51
7.2.3
Trastuzumab (or biosimilar) Toxicity Management............................................................52
7.2.4
Avelumab and Utomilumab Toxicity Management (discussion of utomilumab is for 
reference only – it is no longer being used in this protocol) ..............................................................53
8.
DRUG FORMULATION/STORAGE/SUPPLY.............................................................................................62
8.1
TRASTUZUMAB OR BIOSIMILAR ...................................................................................................................62
8.1.1
Description, form, and preparation....................................................................................62
8.1.2
Storage Conditions..............................................................................................................63
8.1.3
Compatibility.......................................................................................................................63
8.1.4
Handling..............................................................................................................................64
8.1.5
Availability ..........................................................................................................................64
8.1.6
Administration....................................................................................................................64
8.1.7
Ordering..............................................................................................................................64
8.1.8
Drug Supplies and Accountability .......................................................................................65
8.2
VINORELBINE...............................................................................................................................................65
8.2.1
Description..........................................................................................................................65
8.2.2
Form....................................................................................................................................66
8.2.3
Storage and Stability...........................................................................................................66
8.2.4
Compatibility.......................................................................................................................67
8.2.5
Handling..............................................................................................................................67
8.2.6
Availability ..........................................................................................................................67
8.2.7
Preparation.........................................................................................................................67
8.2.8
Administration....................................................................................................................67
8.2.9
Ordering..............................................................................................................................68
8.2.10
Accountability.....................................................................................................................68
8.2.11
Destruction and Return ......................................................................................................68
8.3
UTOMILUMAB (PF-05082566) (FOR REFERENCE ONLY – UTOMILUMAB IS NO LONGER BEING USED IN THIS 
PROTOCOL) ...............................................................................................................................................................68
8.3.1
Pharmaceutical Properties..................................................................................................68
8.3.2
Instructions for Storage ......................................................................................................68
8.3.3
Preparation and Administration .........................................................................................69
8.3.4
Compatibility.......................................................................................................................69
8.3.5
Availability ..........................................................................................................................69

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8.3.6
Drug Accountability ............................................................................................................70
8.3.7
Destruction and Return ......................................................................................................70
8.4
AVELUMAB ..................................................................................................................................................70
8.4.1
Pharmaceutical Properties..................................................................................................70
8.4.2
Description of the Formulations.........................................................................................70
8.4.3
Instructions for Storage ......................................................................................................70
8.4.4
Handling of the Dosage Forms............................................................................................71
8.4.5
Compatibility.......................................................................................................................71
8.4.6
Availability ..........................................................................................................................71
8.4.7
Preparation and Administraiton .........................................................................................71
8.4.8
Ordering..............................................................................................................................72
8.4.9
Accountability.....................................................................................................................72
8.4.10
Destruction and Return ......................................................................................................72
9.
CORRELATIVE/SPECIAL STUDIES ...........................................................................................................72
9.1
CORRELATIVE STUDIES BACKGROUND........................................................................................................72
9.2
SPECIMEN SUBMISSION REQUIREMENTS......................................................................................................72
9.3
TRANSLATIONAL RESEARCH BLOOD ...........................................................................................................73
9.3.1
ctDNA (Streck Tubes) Blood Collection...............................................................................73
9.3.2
Peripheral Blood Mononuclear cells (PBMCs) Blood Collection.........................................74
9.3.3
Germline DNA Blood Collection..........................................................................................74
9.4
RESEARCH TUMOR BIOPSIES........................................................................................................................74
9.5
ARCHIVAL TISSUE COLLECTION ..................................................................................................................75
9.6
TRANSLATIONAL RESEARCH PLANNED ANALYSES .....................................................................................76
9.6.1
Biomarkers of PD-1/PD-L1..................................................................................................76
9.6.2
Multiparametric IHC ...........................................................................................................76
9.6.3
Characterization of HER2 and tumor infiltrating lymphocytes (TILs)..................................76
9.6.4
Characterization of circulating tumor DNA (ctDNA)...........................................................76
9.6.5
Characterization of peripherial blood Mononuclear cells (PBMCs)....................................77
9.6.6
Sequencing of tumor biopsies (DNA and RNA)...................................................................77
9.6.7
Further exploratory biomarkers .........................................................................................78
9.6.8
Not yet specified translational research.............................................................................78
9.7
GENETIC TESTING........................................................................................................................................78
9.8
ADDITIONAL INFORMATION.........................................................................................................................78
10.
SPECIMEN BANKING ....................................................................................................................................79
11.
MEASUREMENT OF EFFECT ......................................................................................................................79
11.1
DEFINITIONS ................................................................................................................................................79
11.1.1
Evaluable for toxicity ..........................................................................................................80

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11.1.2
Evaluable for best overall objective response ....................................................................80
11.1.3
Disease Parameters ............................................................................................................80
11.2
GUIDELINES FOR EVALUATION OF DISEASE.................................................................................................81
11.2.1
Measurement Methods......................................................................................................81
11.2.2
Modalities for Measurable Disease ....................................................................................81
11.2.3
Additional Considerations...................................................................................................83
11.3
LESION DOCUMENTATION............................................................................................................................84
11.3.1
Target Lesions.....................................................................................................................84
11.3.2
Non-Target Lesions & Non-Target Lymph Nodes ...............................................................84
11.4
RESPONSE CRITERIA ....................................................................................................................................85
11.4.1
Overview.............................................................................................................................85
11.4.2
Evaluation of Target Lesions...............................................................................................85
11.4.3
Evaluation of Non-Target Lesions & Non-target Lymph Nodes..........................................85
11.4.4
Symptomatic Deterioration ................................................................................................86
11.4.5
Evaluation of Best Overall Response ..................................................................................86
11.4.6
Progression-Free Survival ...................................................................................................87
11.4.7
Objective Response ............................................................................................................87
11.4.8
Response Review ................................................................................................................87
11.4.9
Confirmatory Measurement/Duration of Response...........................................................88
11.4.10
Other Response Parameters – irRECIST..........................................................................88
12.
ADVERSE EVENT REPORTING REQUIREMENTS.................................................................................90
12.1
ADVERSE EVENT CHARACTERISTICS ...........................................................................................................90
12.2
ADVERSE EVENT CHARACTERISTICS ...........................................................................................................91
12.2.1
Serious adverse event (SAE) ...............................................................................................91
12.3
EXPEDITED ADVERSE EVENT REPORTING....................................................................................................92
12.3.1
DF/HCC Expedited Reporting Guidelines............................................................................92
12.3.2
Participating Sites Reporting Requirement of SAEs to Pfizer..............................................93
12.3.3
Exposure During Pregnancy................................................................................................93
12.3.4
Occupational Exposure .......................................................................................................95
12.4
EXPEDITED REPORTING TO THE FOOD AND DRUG ADMINISTRATION (FDA)...............................................95
12.5
EXPEDITED REPORTING TO HOSPITAL RISK MANAGEMENT ........................................................................95
12.6
ROUTINE ADVERSE EVENT REPORTING .......................................................................................................95
12.7
IND SAFETY REPORTS.................................................................................................................................95
13.
DATA REPORTING / REGULATORY REQUIREMENTS .......................................................................95
13.1
DATA REPORTING ........................................................................................................................................95
13.1.1
Method ...............................................................................................................................96
13.1.2
Responsibility for Data Submission.....................................................................................96

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13.2
DATA AND SAFETY MONITORING BOARD....................................................................................................96
13.3
SUPPLEMENTAL MONITORING OF SAFETY ...................................................................................................96
13.3.1
Monitoring of dose-limiting toxicity (DLT)..........................................................................97
13.3.2
Assessment of first 6 patients per investigational treatment group ..................................97
13.4
MULTI-CENTER GUIDELINES .......................................................................................................................97
13.5
COLLABORATIVE RESEARCH AND FUTURE USE OF DATA AND BIOSPECIMENS ...........................................98
13.6
REORTING TO THE NCI ................................................................................................................................98
14.
PUBLICATION PLAN......................................................................................................................................99
14.1
PUBLICATION ...............................................................................................................................................99
15.
STATISTICAL CONSIDERATIONS .............................................................................................................99
15.1
STUDY DESIGN/ ENDPOINTS ........................................................................................................................99
15.2
SAMPLE SIZE/ ACCRUAL RATE ....................................................................................................................99
15.3
MODIFICATION OF STUDY DESIGN DUE TO AD HOC FUTILITY ANALYSIS.....................................................100
15.4
STRATIFICATION FACTORS.........................................................................................................................100
15.5
ANALYSIS OF PRIMARY ENDPOINT ............................................................................................................100
15.6
ANALYSIS OF SECONDARY EFFICACY ENDPOINTS.....................................................................................101
15.7
ANALYSIS OF SAFETY AND TOLERABILITY ................................................................................................101
15.8
EXPLORATORY AND BIOMARKER OBJECTIVES ..........................................................................................101
15.8.1
Overview of Analyses........................................................................................................101
15.8.2
Sample Size Considerations ..............................................................................................102
15.9
REPORTING AND EXCLUSIONS ...................................................................................................................103
15.10
INTERIM ANALYSIS FOR INEFFICACY, ARM C VS B.....................................................................................103
16.
REFERENCES.................................................................................................................................................104
APPENDICES...........................................................................................................................................................110
APPENDIX A:  ECOG PERFORMANCE STATUS SCALE.........................................................................................111
APPENDIX B:  STRONG CYP3A INDUCERS/INHIBITORS AND INFORMATION ON POSSIBLE DRUG INTERACTIONS
112
APPENDIX C:  DATA SAFETY MONITORING PLAN ...............................................................................................113

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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 (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. The DF/HCC Sponsor will serve as the single liaison with any regulatory 
agencies. 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. 
  

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Coordinating Center: The entity that provides administrative support to the DF/HCC 
Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 
document and DSMP, and as specified in applicable regulatory 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 Research Informatics Office (RIO): 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, Dr. Adrienne Gropper Waks 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 
FDA reporting requirements are met. 

Review data and maintain timely submission of data for study analysis. 

Act as the single liaison with the FDA, 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.

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
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.

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.

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
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. 

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 

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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.
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.  
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.

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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 the approval from the DFCI IRB and 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.
 3.7 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. 
3.8 DF/HCC Multi-Center Protocol Registration Policy
 Participant Registration and Randomization 
Please refer to Protocol Section 4 for participant registration information. Treatment 
cannot begin until site has received confirmation that participant has been registered with 
DF/HCC CTMS.  
Randomization can only occur during normal business hours, Monday through Friday from 
8:00 AM to 5:00 PM Eastern Standard Time.
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 

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number.  Participating Institutions should submit all de-identified subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject.  
 3.9 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.
3.10 Deviations, Violations, and Exceptions 
3.10.1 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.
 3.10.2 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. 
3.10.3 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.
 3.10.4 Reporting Procedures

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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. 
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. 
3.10.5 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.
3.10.6 Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol section 12.  
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Adverse Event Reporting Policy 

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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
3.10.7 Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions, if applicable. Participating 
Institutions will review/submit to their IRB according to their institutional policies and 
procedures.
3.10.8 Data Management
DF/HCC RIO develops case report forms (CRF/eCRFs), for use with the protocol.  These 
forms are designed to collect data for each study. DF/HCC RIO provides a web based 
training for all eCRF users.
  
3.10.9 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. 

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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 (i.e., NCI or a pharmaceutical company) so that any regulatory 
responsibilities can be met in a timely fashion. 
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. 
Additionally, a plan will be formulated to provide regular and ongoing communication to
Participating Institutions about study related information which will include participation
in regular Lead Institution initiated teleconferences. Teleconferences will occur every 2
weeks and will continue regularly until completion of accrual. Upon completion of
accrual, teleconferences will occur monthly until all patients complete protocol therapy.
Upon completion of protocol therapy, teleconferences will occur every 3 months until 
study completion. Additional communication may be distributed via “Newsletter” or email 
as deemed appropriate by DF/HCC Sponsor.
On-Site Monitoring: On-site monitoring will occur on an as-needed basis. Participating 
Institutions will be required to provide access to participants’ complete medical record and 
source documents for source documentation verification during the visit. In addition, 
Participating Institutions should provide access to regulatory documents, pharmacy records, 
local policies related to the conduct of research, and any other trial-related documentation 
maintained by the Participating Site. On-site monitoring visits can be substituted with remote 
(virtual) monitoring visits at the discretion of the Principal Investigator. 
Remote Monitoring: Remote monitoring will be performed on an as-needed basis by the 
Clinical Trial Monitor. Sites will be asked to provide source documentation via fax, email, 
or mail as specified by the Clinical Trial Monitor for virtual monitoring.

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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.
A minimum of 3 participants per site annually is recommended for Phase II trials. However, 
given the additional regulatory burden and cost of overseeing each site, a consideration of 5 
per site/annually should be a minimum target for each site.
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 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 

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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.